U.S. patent application number 14/924313 was filed with the patent office on 2016-02-18 for treatment of excess weight by neural downregulation in combination with compositions.
The applicant listed for this patent is EnteroMedics Inc.. Invention is credited to Dennis Dong-Won Kim, Mark B. Knudson.
Application Number | 20160045730 14/924313 |
Document ID | / |
Family ID | 40585754 |
Filed Date | 2016-02-18 |
United States Patent
Application |
20160045730 |
Kind Code |
A1 |
Kim; Dennis Dong-Won ; et
al. |
February 18, 2016 |
TREATMENT OF EXCESS WEIGHT BY NEURAL DOWNREGULATION IN COMBINATION
WITH COMPOSITIONS
Abstract
A method and system for designing a therapy or for treating a
condition associated with excess weight in a subject comprising
applying a neural conduction block to the vagus nerve at a blocking
site with the neural conduction block selected to at least
partially block nerve impulses on the vagus nerve at the blocking
site and administering a composition comprising an effective amount
of an agent that alters the energy balance of the subject.
Inventors: |
Kim; Dennis Dong-Won; (La
Jolla, CA) ; Knudson; Mark B.; (Shoreview,
MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EnteroMedics Inc. |
St. Paul |
MN |
US |
|
|
Family ID: |
40585754 |
Appl. No.: |
14/924313 |
Filed: |
October 27, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12370984 |
Feb 13, 2009 |
9186502 |
|
|
14924313 |
|
|
|
|
61028691 |
Feb 14, 2008 |
|
|
|
Current U.S.
Class: |
607/3 |
Current CPC
Class: |
A61N 1/36007 20130101;
A61M 2205/3515 20130101; A61N 1/36053 20130101; A61M 2210/105
20130101; A61M 5/14276 20130101; A61M 2205/3523 20130101; A61N
1/36114 20130101; A61M 2205/353 20130101; A61N 1/37223 20130101;
A61N 1/37264 20130101; A61M 2210/1053 20130101 |
International
Class: |
A61N 1/36 20060101
A61N001/36; A61M 5/142 20060101 A61M005/142; A61N 1/372 20060101
A61N001/372 |
Claims
1. A system for designing a therapy including a therapy signal and
an agent that alters the energy balance of a subject comprising: at
least one electrode configured to be implanted within a body of the
patient beneath a skin layer and placed at a vagus nerve, the
electrode also configured to apply therapy to the vagus nerve upon
application of a therapy signal to the electrode; an implantable
impulse generator for placement in the body of the patient beneath
the skin layer, the implantable impulse generator being configured
to generate the therapy signal and to transmit the therapy signal
to the electrode, the implantable impulse generator being coupled
to an implanted antenna; an external component configured to couple
to a first external antenna configured to be placed above the skin
layer and adapted to communicate with the implanted antenna across
the skin layer through radiofrequency communication, the external
component including a plurality of selectable operating modules,
each operating module being associated with a different set of
operations available for selection by a user; an external
programmer configured to communicatively couple to the external
component via a second port, the external programmer being
configured to provide therapy instructions comprising parameters
for each therapy cycle to the external component, wherein the
external component is configured to send the therapy instructions
to the implantable impulse generator via the external antenna and
the implanted antenna, and the parameters comprise a therapy signal
selected to downregulate activity on the vagus nerve with an on
time period and off time period, the off time period selected to
allow partial recovery of nerve function; and the external
programmer being configured to allow the user to select an agent
that alters energy balance in the patient based on the health
profile of the patient and the side effects of the agent.
2. The system of claim 1, wherein the implantable component is
configured to deliver a therapy cycle comprising an electrical
signal having a frequency of at least 300 Hz, an on time of at
least 30 seconds, and an off time that allows for partial recovery
of the nerve function.
3. The system of claim 1, wherein the external programmer is
configured to provide therapy instructions comprising parameters
for the therapy cycle to the external component, wherein the
parameters of the therapy cycle comprise an electrical signal with
a frequency of at least 300 Hz with an on time of at least 30
seconds and an off time that allows partial recovery of nerve
function.
4. The system of claim 1, wherein the implantable component is
configured to generate therapy signals for a treatment period.
5. The system of claim 4, wherein the treatment period is at least
1 hour.
6. The system of claim 5, wherein the external programmer is
configured to provide therapy instructions to the external
component comprising multiple therapy cycles in a treatment
period.
7. The system of claim 6, wherein the external program is
configured to provide therapy instructions to the external
component comprising at least 10 therapy cycles in a treatment
period.
8. The system of claim 1, wherein the external programmer includes
a personal computer.
9. The system of claim 1, wherein the external programmer is
configured to obtain patient data, wherein the patient data
comprises data obtained from the implantable component and patient
data concerning the health profile of the patient.
10. The system of claim 9, wherein the health profile comprises the
presence or absence of conditions selected from the group
consisting of diabetes, hypertension, cardiac condition, liver
disorder, a renal disorder and combinations thereof.
11. The system of claim 10, wherein the external programmer is
configured to obtain data about dosages and side effects of agents
that alter energy balance.
12. The system of claim 11, wherein the agents that alter energy
balance comprise agents that enhance the sensation of satiety,
agents that decrease appetite, agents that block the absorption of
fat or other nutrients, agents that inhibit enzymes that digest
fat, agents that are thermogenic, or combinations thereof.
13. The system of claim 12, wherein the agents are selected from
the group consisting of: ghrelin, ghrelin agonists, ghrelin
antagonists, leptin agonist, leptin antagonists, ciliary
neurotrophic factor (CNTF), CNTF analogues, amylin, and amylin
analogues.
14. The system of claim 13, wherein the agents are selected from
the group consisting of: sibutramine, fenfluramine, phentermine,
dexphenfluoramine, flouxetine, and bupropion.
15. The system of claim 13, wherein the agents are selected from
the group consisting of: sibutramine, leptin, leptin agonists,
leptin analogues, CNTF, and CNTF analogues.
16. The system of claim 13, wherein the agents are selected from
the group consisting of: GLP-1, PYY, CKK, and oxyntomodulin.
17. The system of claim 13, wherein the agents are selected from
the group consisting of: phentermine, fenfluramine,
dexfenfluramine, endocannabinoid receptor antagonists, ghrelin
antagonists, orexin antagonists, somatostatin receptor agonist,
GLP-1, PYY, and cholecystokinin agonists.
18. A method of selecting parameters for a therapy cycle for an
implantable device and of selecting an agent, wherein the therapy
cycle and the agent alter energy balance in a subject comprising:
a. selecting parameters of a therapy cycle to be applied to a vagus
nerve to provide weight loss to the subject, wherein the parameters
comprise an electrical signal having a frequency of 300 Hz or
greater, having an on time of at least 30 seconds, and having an
off time that allows partial recovery of the nerve; b.
communicating the selected parameters to the implantable device
using the system of claim 1 and delivering at least 10 therapy
cycles during a treatment period, and c. selecting an agent and a
dosage of agent that alters the energy balance of the subject based
on the health profile of the subject and the side effects of the
agent using an external programmer of the system of claim 1.
19. The method of claim 18, further comprising selecting the
parameters of the therapy cycle based on the body mass index of the
subject.
20. The method of claim 19, wherein the subject has a body mass
index of at least 25 or greater.
21. The method of claim 18, wherein the health profile of the
subject indicates the presence or absence of a condition selected
from the group consisting of hypertension, diabetes, cardiac
disease, liver disease, renal disease and combinations thereof.
22. The method of claim 18, wherein the side effects of the agent
are selected from the group consisting of cardiac arrhythmias,
cardiac valve disease, seizures, increased blood pressure,
depression, anxiety, diarrhea, increased fat in the stool and
combinations thereof.
23. The method of claim 18, wherein the agents that alter energy
balance comprise agents that enhance the sensation of satiety,
agents that decrease appetite, agents that block the absorption of
fat or other nutrients, agents that inhibit enzymes that digest
fat, agents that are thermogenic, and combinations thereof.
24. The method of claim 18, wherein communicating the selected
parameters using the system of claim 1 comprises communicating the
selected parameters from the external programmer to the external
component, and communicating the selected parameters from the
external component to the implantable device.
25. The method of claim 24, wherein the external programmer is
configured to obtain patient data, wherein the patient data
comprises data obtained from the implantable component and data
concerning the health profile of the patient.
26. The method of claim 18, wherein the external programmer is
configured to obtain data about dosages and side effects of agents
that alter energy balance.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional application of U.S. Ser.
No. 12/370,984, filed Feb. 13, 2009, which claims benefit of
Provisional Application No. 61/028,691, filed Feb. 14, 2008, which
application is incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention pertains to treating subjects having a
condition associated with excess weight comprising downregulating
neural activity on the vagus nerve and administering a composition
that alters the energy balance of the subject.
[0004] 2. Background
[0005] Obesity and other eating disorders are serious health
conditions that lead to increased morbidity and mortality. Over the
last decade, the prevalence of obesity has increased more than 80%,
representing an estimated 43 million adults in 2002. (Mokdad A H,
et al, The spread of the obesity epidemic in the United States,
1991-1998. JAMA 1999; (282):1519-22) In terms of mortality, an
estimated 280,000 to 325,000 adults in the United States die each
year from causes related to obesity. (Allison D B et al, Annual
deaths attributable to obesity in the United States. JAMA 1999;
282:1530-8) More importantly, excess weight has been positively
correlated with years of life lost. (Fontaine K R et al., Years of
life lost due to obesity. JAMA 2003; (289):187-93).
[0006] In addition to mortality, substantial morbidity is
associated with obesity. For example, in 2000, the total cost of
obesity in the United States was estimated to be $117 billion ($61
billion in direct medical costs, $56 billion in indirect costs).
(U.S. Department of Health and Human Services. The Surgeon
General's call to action to prevent and decrease overweight and
obesity. Rockville (Md.): U.S. Department of Health and Human
Services, Public Health Service, Office of the Surgeon General;
2001). An estimated 9.1% of annual medical spending in the United
States is attributed to overweight and obesity--a figure that
rivals medical costs attributable to cigarette smoking.
[0007] Treatments for overweight and/or obese patients include both
non pharmaceutical and pharmaceutical treatments. Non
pharmaceutical treatments include diet, exercise, nerve
stimulation, nerve block, and surgical treatments. Pharmaceutical
treatments include appetite suppressants, energy expenditure
modifying agents, antidepressants, and uptake of nutrient
inhibitors. Despite the existence of several treatments, the number
of people that are obese or have other eating disorders as well as
the costs associated with these conditions continue to rise.
[0008] A wide variety of disorders where the treatment includes
blocking neural impulses on the vagus nerve have been described.
Specific disorders treated include obesity and other eating
disorders. Such treatments are described in commonly assigned U.S.
Pat. No. 7,167,750 to Knudson et al. issued Jan. 23, 2007 and in
the following commonly assigned U.S. patent applications: US
2005/0131485 A1 published Jun. 16, 2005, US 2005/0038484 A1
published Feb. 17, 2005, US 2004/0172088 A1 published Sep. 2, 2004,
US 2004/0172085 A1 published Sep. 2, 2004, US 2004/0176812 A1
published Sep. 9, 2004 and US 2004/0172086 A1 published Sep. 2,
2004.
[0009] Since 1995, several agents have been available for treatment
of obesity and other eating disorders. However, in the case of
obesity, the amount of weight lost has been modest even with long
term treatment. In addition, several of the agents are known to
have serious side effects at the doses that are effective for
weight loss. For example, fenfluramine and dexfenfluramine were
withdrawn from the market due to a reported association between
administration of these drugs and valvular heart disease. Clinical
Guidelines of the Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults. NIH Publication No. 98-4083,
September 1998.
[0010] Thus, there remains a need to develop effective treatments
for conditions associated with excess weight.
SUMMARY
[0011] This disclosure is directed to systems and methods for
treating a condition associated with excess weight in a subject
comprising: applying an intermittent neural block to the vagus
nerve at a blocking site with said neural conduction block selected
to down-regulate afferent and/or efferent neural activity on the
nerve and with neural activity restoring upon discontinuance of
said block; and administering a composition to the subject
comprising an effective amount of an agent that alters the energy
balance of the subject. Conditions associated with excess weight in
a subject include such conditions as obesity, compulsive
overeating, bulimia. In some cases, the combination of treatments
may provide for a synergistic effect on weight loss and/or a
decrease in the amount of an agent that alters energy balance
required to be effective, thereby minimizing side effects. In some
cases, the methods can be applied to a subject who is overweight
and has not yet become obese.
[0012] Another aspect of the disclosure provides a system for
designing a therapy including a therapy signal and an agent that
alters the energy balance of a subject comprising: at least one
electrode configured to be implanted within a body of the patient
beneath a skin layer and placed at a vagus nerve, the electrode
also configured to apply therapy to the vagus nerve upon
application of a therapy signal to the electrode; an implantable
component for placement in the body of the patient beneath the skin
layer, the implantable component being configured to generate the
therapy signal and to transmit the therapy signal to the electrode,
the implantable component being coupled to an implanted antenna; an
external component configured to couple to a first external antenna
configured to be placed above the skin layer and adapted to
communicate with the implanted antenna across the skin layer
through radiofrequency communication, the external component
including a plurality of selectable operating modules, each
operating module being associated with a different set of
operations available for selection by a user; an external
programmer configured to communicatively couple to the external
component via a second port, the external programmer being
configured to provide therapy instructions comprising parameters
for each therapy cycle to the external component, wherein the
external component is configured to send the therapy instructions
to the implantable component via the external antenna and the
implanted antenna, and the parameters comprise a therapy signal
selected to downregulate activity on the vagus nerve with an on
time period and off time period, the off time period selected to
allow partial recovery of nerve function; and the external
programmer being configured to allow the user to select an agent
that alters energy balance in the patient based on the health
profile of the patient and the side effects of the agent.
[0013] Another aspect of the disclosure provides methods for
selecting a therapy cycle for an implantable device and for
selecting an agent that alters energy balance in a subject. In one
embodiment, the method comprises selecting parameters of a therapy
cycle to be applied to a vagus nerve to provide weight loss to the
subject, wherein the parameters comprise an electrical signal
having a frequency of 300 Hz or greater, having an on time of at
least 30 seconds, and having an off time that allows partial
recovery of the nerve; communicating the selected parameters to the
implantable device and delivering at least 10 therapy cycles during
a treatment period, and selecting an agent and a dosage of agent
that alters the energy balance of the subject based on the health
profile of the subject and the side effects of the agent using an
external programmer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a schematic illustration of an alimentary tract
(GI tract plus non-GI organs such as the pancreas and liver) and
its relation to vagal and enteric innervation;
[0015] FIG. 2 is the view of FIG. 1 showing the application of a
nerve conduction block electrode to the alimentary tract;
[0016] FIG. 3 is a schematic representation of an implantable
system configuration for a gastro-intestinal treatment involving
applying an electrical signal to a vagus nerve;
[0017] FIG. 4 is a schematic representation of a patient's stomach
shown partially in section and illustrating a representative
placement of anterior and posterior vagus nerves with respect to
the anatomy of the stomach and diaphragm;
[0018] FIG. 5 illustrates an impulse generator, leads and placement
of anterior and posterior electrodes on the vagus nerve;
[0019] FIG. 6 shows recovery of the vagal nerve after application
of blocking signal;
[0020] FIG. 7 is a side elevation schematic view of an external
coil in a desired alignment over an implanted coil;
[0021] FIG. 8 is the view of FIG. 7 illustrating misalignment of
the external and internal coils resulting from changes in patient
posture;
[0022] FIG. 9 is a scatter graph of patients treated with a vagal
down-regulation procedure and showing excess weight loss (EWL) over
time for each patient and showing a mean EWL;
[0023] FIG. 10 is a graph illustrating percent excess weight loss
over time experienced by patients grouped into visit
interval-defined quartiles based on frequency of occurrence of ON
times with durations less than 30 seconds;
[0024] FIG. 11 is a graph similar to that of FIG. 10 for patients
grouped into visit interval-defined quartiles based on frequency of
occurrence of ON times with durations between 30 and 180
seconds;
[0025] FIG. 12 is a graph similar to that of FIG. 10 for patients
grouped into visit interval-defined quartiles based on frequency of
occurrence of ON times with durations between 180 and 300
seconds;
[0026] FIG. 13 is a graph similar to that of FIG. 10 for patients
grouped into visit interval-defined quartiles based on frequency of
occurrence of ON times with durations between 30 and 120
seconds.
[0027] FIG. 14 is a graph similar to that of FIG. 10 for patients
grouped into visit interval-defined quartiles based on frequency of
occurrence of ON times with durations greater than or equal to 30
seconds;
[0028] FIG. 15 is a graph similar to that of FIG. 14 for patients
grouped into subject-defined quartiles based on frequency of
occurrence of ON times with durations greater than or equal to 30
seconds;
[0029] FIG. 16 is a graph illustrating efficacy as a function of
therapeutic ON times;
[0030] FIG. 17 is a table illustrating the results of FIG. 16;
[0031] FIG. 18 is a graph illustrating patient response to the
number of ON times experienced between follow-ups;
[0032] FIG. 19 shows graphs illustrating action potentials on a
nerve;
[0033] FIG. 20 is a graph illustrating recovery of a nerve
following a high frequency block; and
[0034] FIG. 21 is a graph illustrating a typical duty cycle.
DETAILED DESCRIPTION
[0035] The following commonly assigned patent and U.S. patent
applications are incorporated herein by reference: U.S. Pat. No.
7,167,750 to Knudson et al. issued Jan. 23, 2007; US 2005/0131485
A1 published Jun. 16, 2005, US 2005/0038484 A1 published Feb. 17,
2005, US 2004/0172088 A1 published Sep. 2, 2004, US 2004/0172085 A1
published Sep. 2, 2004, US 2004/0176812 A1 published Sep. 9, 2004
and US 2004/0172086 A1 published Sep. 2, 2004. Also incorporated
herein by reference is International patent application Publication
No. WO 2006/023498 A1 published Mar. 2, 2006.
[0036] A. Description of Vagal Innervation of the Alimentary
Tract
[0037] FIG. 1 is a schematic illustration of an alimentary tract
(GI tract plus non-GI organs such as the pancreas and gall bladder,
collectively labeled PG) and its relation to vagal and enteric
innervation. The lower esophageal sphincter (LES) acts as a gate to
pass food into the stomach S and, assuming adequate function of all
components, prevent reflux. The pylorus PV controls passage of
chyme from the stomach S into the intestines I (collectively shown
in the figures and including the large intestine or colon and the
small intestine including the duodenum, jejunum and ileum). The
biochemistry of the contents of the intestines I is influenced by
the pancreas P and gall bladder PG which discharge into the
duodenum. This discharge is illustrated by dotted arrow A.
[0038] The vagus nerve VN transmits signals to the stomach S,
pylorus PV, pancreas and gall bladder PG directly. Originating in
the brain, there is a common vagus nerve VN in the region of the
diaphragm (not shown). In the region of the diaphragm, the vagus VN
separates into anterior and posterior components with both acting
to innervate the GI tract. In FIGS. 1, and 2, the anterior and
posterior vagus nerves are not shown separately. Instead, the vagus
nerve VN is shown schematically to include both anterior and
posterior nerves. The vagus nerve VN contains both afferent and
efferent components sending signals to and away from, respectively,
its innervated organs.
[0039] In addition to influence from the vagus nerve VN, the GI and
alimentary tracts are greatly influenced by the enteric nervous
system ENS. The enteric nervous system ENS is an interconnected
network of nerves, receptors and actuators throughout the GI tract
and pancreas and gall bladder PG. There are many millions of nerve
endings of the enteric nervous system ENS in the tissues of the GI
organs. For ease of illustration, the enteric nervous system ENS is
illustrated as a line enveloping the organs innervated by the
enteric nervous system ENS. The vagus nerve VN innervates, at least
in part, the enteric nervous system ENS (schematically illustrated
by vagal trunk VN3 which represents many vagus-ENS innervation
throughout the gut). Also, receptors in the intestines I connect to
the enteric nervous system ENS. Arrow B in the figures illustrates
the influence of duodenal contents on the enteric nervous system
ENS as a feedback to the secretion function of the pancreas, liver
and gall bladder. Specifically, receptors in the intestine I
respond to the biochemistry of the intestine contents (which are
chemically modulated by the pancreao-biliary output of Arrow A).
This biochemistry includes pH and osmolality.
[0040] In FIGS. 1 and 2, vagal trunks VN1, VN2, VN4 and VN6
illustrate schematically the direct vagal innervation of the GI
organs of the LES, stomach S, pylorus PV and intestines I. Trunk
VN3 illustrates direct communication between the vagus VN and the
ENS. Trunk VN5 illustrates direct vagal innervation of the pancreas
and gall bladder. Enteric nerves ENS1-ENS4 represent the multitude
of enteric nerves in the stomach S, pylorus PV, pancreas and gall
bladder PG and intestines I.
[0041] While communicating with the vagus nerve VN, the enteric
nervous system ENS can act independently of the vagus and the
central nervous system. For example, in patients with a severed
vagus nerve (vagotomy--a historical procedure for treating ulcers),
the enteric nervous system can operate the gut. Most enteric nerve
cells are not directly innervated by the vagus. Gershon, "The
Second Brain", Harper Collins Publishers, Inc, New York, N.Y. p. 19
(1998).
[0042] B. Therapy Delivery Equipment
[0043] The disclosure provides systems for treating a condition
associated with excess weight comprising an impulse generator that
provides signals to modulate neural activity on the vagus
nerve.
[0044] In an embodiment, a system (schematically shown in FIG. 3)
for designing a therapy or for treating such conditions including
obesity or other eating disorders includes an impulse generator
104, an external mobile charger 101, and two electrical lead
assemblies 106, 106a, each comprising an electrode.
[0045] The impulse generator 104 is adapted for implantation within
a patient to be treated. The impulse generator 104 is implanted
just beneath a skin layer 103.
[0046] In some embodiments, the lead assemblies 106, 106a are
electrically connected to the circuitry of the impulse generator
104 by conductors 114, 114a. Industry standard connectors 122, 122a
are provided for connecting the lead assemblies 106, 106a to the
conductors 114, 114a. As a result, leads 116, 116a and the impulse
generator 104 may be separately implanted. Also, following
implantation, lead 116, 116a may be left in place while the
originally placed impulse generator 104 is replaced by a different
impulse generator.
[0047] The leads 106, 106a have distal electrodes 212, 212a which
are individually placed on the anterior and posterior vagal nerves
AVN, PVN, respectively, of a patient, for example, just below the
patient's diaphragm. It will be appreciated that the description of
two electrodes directly placed on a nerve is a description of a
preferred embodiment. Fewer or more electrodes can be placed on or
near fewer or more nerves. In some embodiments, the electrodes are
cuff electrodes.
[0048] In an embodiment, the external component comprises a mobile
charger 101 that includes circuitry for communicating with the
implanted impulse generator 104. In some embodiments, the
communication is a two-way radiofrequency (RF) signal path across
the skin 103 as indicated by arrows A. In embodiments, the external
component comprises a plurality of selectable operating modules,
each operating module being associated with a different set of
operations available for selection by a user.
[0049] Referring to FIG. 3, an external programmer such as a
computer (such as a personal computer) 100 can be connected to the
external mobile charger 101. With such a connection, a physician
can use the computer 100 to program therapies into the impulse
generator 104 as will be described. In embodiments, the external
programmer is configured to provide therapy instructions comprising
parameters for each therapy cycle to the external component, and
the parameters comprise a therapy signal selected to downregulate
activity on the vagus nerve with an on time period and off time
period, the off time period selected to allow partial recovery of
nerve function, and the external programmer is configured to allow
the user to select an agent that alters energy balance in the
patient based on the health profile of the patient and the side
effects of the agent.
[0050] In embodiments, the implantable component is configured to
deliver a therapy cycle comprising an electrical signal having a
frequency of at least 300 Hz, an on time of at least 30 seconds,
and an off time that allows for partial recovery of the nerve
function. The implantable component may be configured to generate
therapy signals for a treatment period. In some cases, the
treatment period is at least 8 hours. In some embodiments, the
frequency of the electrical signal ranges from 300 to 10,000 Hz,
about 500 to 8000 Hz, or about 1000 to about 5000 Hz. In some
embodiments, the frequency of the electrical signal is about 2500
to 5000 Hz. An on time for the signal of a therapy cycle can range
from 30 seconds to 3 minutes, 30 seconds to 2 minutes, or from 30
seconds to 1 minute. The on time can optionally include a ramp up
and a ramp down time of about 2 to 60 seconds. The off times of the
electrical signal in the therapy cycle are selected to allow at
least a partial recovery of nerve function. The off times can be
selected from 1 minute to about 20 minutes, 1 minute to 10 minutes,
or 1 minute to 5 minutes.
[0051] In other embodiments, the external programmer is configured
to provide therapy instructions comprising parameters for the
therapy cycle to the external component, wherein the parameters of
the therapy cycle comprise an electrical signal with a frequency of
at least 300 Hz with an on time of at least 30 seconds and an off
time that allows partial recovery of nerve function. The parameters
can vary as described above. The external programmer can be
configured to provide therapy instructions to the external
component comprising multiple therapy cycles in a treatment period.
In embodiments, a treatment period is from 1 hour to 24 hours, 1
hour to about 12 hours, 1 hour to 8 hours, or 1 hour to 4 hours. In
embodiments, the external programmer is configured to provide
therapy instructions that include multiple therapy cycles per
treatment period. In some embodiments, at least ten therapy cycles
are delivered per treatment period. In other embodiments, at least
10 to 600, 20 to 250, or 50 to 100 therapy cycles are delivered in
a treatment period.
[0052] In embodiments, the external programmer is configured to
obtain patient data, wherein the patient data comprises data
obtained from the implantable component and patient data concerning
the health profile of the patient. A health profile may include the
presence or absence of conditions in a subject selected from the
group consisting of diabetes, hypertension, cardiac condition,
liver disorder, a renal disorder and combinations thereof. A health
profile may also include age of the patient, the presence of other
implantable devices, and medications taken by the patient.
[0053] In some embodiments, the external programmer is configured
to obtain data about dosages and side effects of agents that alter
energy balance. The agents that alter energy balance comprise
agents that enhance the sensation of satiety, agents that decrease
appetite, agents that block the absorption of fat or other
nutrients, agents that inhibit enzymes that digest fat, agents that
are thermogenic, or combinations thereof. Examples of such agents
are described herein and include ghrelin, leptin, CNTF, amylin,
PYY,CKK, GLP-1 and analogues or antagonists thereof. Other agents
include sibutramine, fenfluramine, phenteramine, fluoxetine, and
bupropion. Side effects associated with a particular agent may
include cardiac arrhythmias, cardiac valve disease, seizures,
increased blood pressure, depression, anxiety, diarrhea, increased
fat in the stool and combinations thereof
[0054] The circuitry 170 of the external component mobile charger
101 can be connected to a first external antenna 102. The antenna
102 communicates with a similar antenna 105 implanted within the
patient and connected to the circuitry 150 of the impulse generator
104. The external component is configured to send the therapy
instructions to the implantable impulse generator via the external
antenna and the implanted antenna, Communication between the
external component mobile charger 101 and the impulse generator 104
includes transmission of pacing parameters and other signals as
will be described.
[0055] In embodiments, the selectable operating modules comprise:
an operating room module that is selectable when the external
component is coupled to the first external antenna, the operating
room module being associated with at least a testing operation to
test appropriate positioning of the implantable component within
the body; a therapy delivery module that is selectable when the
external component is coupled to a second external antenna, the
therapy delivery module being associated with therapy signal
generation; and a diagnostic module that is selectable when the
external component is coupled to an external programmer, the
programming module being configured to transfer a therapy schedule
from the external programmer to the implantable component.
[0056] Having been programmed by signals from the external
component mobile charger 101, the impulse generator 104 generates
blocking signals or downregulating signals to the leads 106, 106a.
As will be described, the external component mobile charger 101 may
have additional functions in that it may provide for periodic
recharging of batteries within the impulse generator 104, and also
allow record keeping and monitoring.
[0057] While an implantable (rechargeable) power source for the
impulse generator 104 is preferred, an alternative design could
utilize an external source of power, the power being transmitted to
an implanted module via the RF link (i.e., between coils 102, 105).
In this alternative configuration, while powered externally, the
source of the specific blocking signals could originate either in
the external power source unit, or in the implanted module.
[0058] Another embodiment of a system useful in treating a
condition associated with excess weight as described herein is
shown in FIG. 5.
[0059] With reference to FIG. 4, a stomach S is shown schematically
for the purpose of facilitating an understanding of applying a
vagal nerve modulating signal. In FIG. 4, the stomach S is shown
with a collapsed fundus F which is deflated due to fasting. In
practice, the fundus F can be reduced in size and volume (as shown
in FIG. 4) or expanded. The esophagus E passes through the
diaphragm D at an opening or hiatus H. In the region where the
esophagus E passes through the diaphragm D, trunks of the vagal
nerve (illustrated as the anterior vagus nerve AVN and posterior
vagus nerve PVN) are disposed on opposite sides of the esophagus E.
It will be appreciated that the precise location of the anterior
and posterior vagus nerves AVN, PVN relative to one another and to
the esophagus E are subject to a wide degree of variation within a
patient population. However, for most patients, the anterior and
posterior vagus nerves AVN, PVN are in close proximity to the
esophagus E at the hiatus H where the esophagus E passes through
the diaphragm D.
[0060] The anterior and posterior vagus nerves AVN, PVN divide into
a plurality of trunks that innervate the stomach directly and via
the enteric nervous system and may include portions of the nerves
which may proceed to other organs such as the pancreas, gallbladder
and intestines. Commonly, the anterior and posterior vagus nerves
AVN, PVN are still in close proximity to the esophagus E and
stomach (and not yet extensively branched out) at the region of the
junction of the esophagus E and stomach S.
[0061] In the region of the hiatus H, there is a transition from
esophageal tissue to gastric tissue. This region is referred to as
the Z-line (labeled "Z" in the Figures). Above the Z-line, the
tissue of the esophagus is thin and fragile. Below the Z-line, the
tissue of the esophagus E and stomach S are substantially thickened
and more vascular. Within a patient population, the Z-line is in
the general region of the lower esophageal sphincter. This location
may be slightly above, slightly below or at the location of the
hiatus H.
[0062] With reference to FIG. 5, electrodes 212, 212a are shown
placed near the esophagus E or proximal portion of the stomach
below the diaphragm D and on the anterior and posterior vagus
nerves AVN, PVN. In a preferred embodiment, the nerves AVN, PVN are
indirectly stimulated by passing electrical signals through the
tissue surrounding the nerves. In some embodiments, the electrodes
are bipolar pairs (ie. alternating anode and cathode electrodes).
In some embodiments, a plurality of electrodes may be placed
overlying the anterior and/or posterior vagus nerves AVN, PVN. As a
result, energizing the plurality of electrodes will result in
application of a signal to the anterior and posterior vagus nerves
AVN, PVN and/or their branches. In some therapeutic applications,
some of the electrodes may be connected to a blocking electrical
signal source (with a blocking frequency and other parameters as
described below). Of course, only a single array of electrodes
could be used with all electrodes connected to a blocking or a
downregulating signal.
[0063] The electrical connection of the electrodes to an impulse
generator may be as previously described by having a leads (eg.
106,106a) connecting the electrodes directly to an implantable
impulse generator (eg. 104). Alternatively, and as previously
described, electrodes may be connected to an implanted antenna for
receiving a signal to energize the electrodes.
[0064] Impulse Generator
[0065] The impulse generator generates electrical signals in the
form of electrical impulses according to a programmed regimen. In
embodiments, a blocking signal is applied as described herein.
[0066] The impulse generator utilizes a microprocessor and other
standard electrical and electronic components, and communicates
with an external programmer and/or monitor by asynchronous serial
communication for controlling or indicating states of the device.
Passwords, handshakes and parity checks are employed for data
integrity. The impulse generator also includes means for conserving
energy, which is important in any battery operated device and
especially so where the device is implanted for medical treatment
of a disorder, and means for providing various safety functions
such as preventing accidental reset of the device.
[0067] Features may be incorporated into the impulse generator for
purposes of the safety and comfort of the patient. In some
embodiments, the patient's comfort would be enhanced by ramping the
application of the signal up during the first two seconds. The
device may also have a clamping circuit to limit the maximum
voltage (14 volts for example) deliverable to the vagus nerve, to
prevent nerve damage. An additional safety function may be provided
by implementing the device to cease signal application in response
to manual deactivation through techniques and means similar to
those described above for manual activation. In this way, the
patient may interrupt the signal application if for any reason it
suddenly becomes intolerable.
[0068] The intermittent aspect of the blocking resides in applying
the signal according to a prescribed duty cycle. The pulse signal
is programmed to have a predetermined on-time in which a train or
series of electrical pulses of preset parameters is applied to the
vagus branches, followed by a predetermined off-time. Nevertheless,
continuous application of the electrical pulse signal may also be
effective.
[0069] Impulse generators, one supplying the right vagus and the
other the left vagus to provide the bilateral blocking or
downregulation may be used. Use of implanted impulse generator for
performing methods as described herein is preferred, but treatment
may conceivably be administered using external equipment on an
outpatient basis, albeit only somewhat less confining than complete
hospitalization. Implantation of one or more impulse generators, of
course, allows the patient to be completely ambulatory, so that
normal daily routine activities including on the job performance is
unaffected.
[0070] Signals can be applied at a portion of the nervous system
remote from the vagus nerve such as at or near the stomach wall,
for indirect regulation of the vagus nerve in the vicinity of the
sub-diaphragmatic location. Here, at least one impulse generator is
implanted together with one or more electrodes subsequently
operatively coupled to the impulse generator via leads for
generating and applying the electrical signal internally to a
portion of the patient's nervous system to provide indirect
blocking or down regulation of the vagus nerve in the vicinity of
the desired location. Alternatively, the electrical signal may be
applied non-invasively to a portion of the patient's nervous system
for indirect application of the vagus nerve at a sub-diaphragmatic
location.
[0071] The impulse generator may be programmed with an external
programmer such as a programming wand and a personal computer using
suitable programming software developed according to the
programming needs and signal parameters which have been described
herein. The intention, of course, is to permit noninvasive
communication with the electronics package after the latter is
implanted, for both monitoring and programming functions. Beyond
the essential functions, the programming software should be
structured to provide straightforward, menu-driven operation, HELP
functions, prompts, and messages to facilitate simple and rapid
programming while keeping the user fully informed of everything
occurring at each step of a sequence. Programming capabilities
should include capability to modify the electronics package's
adjustable parameters, to test device diagnostics, and to store and
retrieve telemetered data. It is desirable that when the implanted
unit is interrogated, the present state of the adjustable
parameters is displayed on the PC monitor so that the programmer
may then conveniently change any or all of those parameters at the
same time; and, if a particular parameter is selected for change,
all permissible values for that parameter are displayed so that the
programmer may select an appropriate desired value for entry into
the impulse generator.
[0072] Other desirable features of appropriate software and related
electronics would include the capability to store and retrieve
historical data, including patient code, device serial number,
number of hours of battery operation, number of hours of output,
and number of magnetic activations (indicating patient
intercession) for display on a screen with information showing date
and time of the last one or more activations.
[0073] In embodiments, the external programmer is configured to
obtain and store patient data concerning the health profile of the
patient. A health profile may include the presence or absence of
conditions in a subject selected from the group consisting of
diabetes, hypertension, cardiac condition, liver disorder, a renal
disorder and combinations thereof. A health profile may also
include age of the patient, the presence of other implantable
devices, and medications taken by the patient.
[0074] In some embodiments, the external programmer is configured
to obtain and store data about dosages and side effects of agents
that alter energy balance. The agents that alter energy balance
comprise agents that enhance the sensation of satiety, agents that
decrease appetite, agents that block the absorption of fat or other
nutrients, agents that inhibit enzymes that digest fat, agents that
are thermogenic, or combinations thereof. Examples of such agents
are described herein and include ghrelin, leptin, CNTF, amylin,
PYY,CKK, GLP-1 and analogues or antagonists thereof. Other agents
include sibutramine, fenfluramine, phenteramine, fluoxetine, and
bupropion. Side effects associated with a particular agent may
include cardiac arrhythmias, cardiac valve disease, seizures,
increased blood pressure, depression, anxiety, diarrhea, increased
fat in the stool and combinations thereof.
[0075] Diagnostics testing should be implemented to verify proper
operation of the device, and to indicate the existence of problems
such as with communication, the battery, or the lead/electrode
impedance. A low battery reading, for example, would be indicative
of imminent end of life of the battery and need for implantation of
a new device. However, battery life should considerably exceed that
of other implantable medical devices, such as cardiac pacemakers,
because of the relatively less frequent need for activation of the
pulse generator of the present invention. In any event, the nerve
electrodes are capable of indefinite use absent indication of a
problem with them observed on the diagnostics testing.
[0076] The device may utilize circadian or other programming as
well, so that activation occurs automatically at normal mealtimes
for this patient. This may be in addition to the provision for the
manual, periodic between meal, and sensing-triggered activation as
described above herein.
[0077] C. Methods
[0078] The disclosure provides a method for manufacturing a system
comprising: providing at least one electrode configured to be
implanted within a body of the patient beneath a skin layer and
placed at a vagus nerve, the electrode also configured to apply
therapy to the vagus nerve upon application of a therapy signal to
the electrode; providing an implantable component for placement in
the body of the patient beneath the skin layer, the implantable
component being coupled to an implanted antenna and the electrode,
and configuring the implantable component to generate the therapy
signal and to transmit the therapy signal to the electrode;
providing an external component to be placed above the skin layer
and adapted to communicate with the implanted antenna across the
skin layer through radiofrequency communication, the external
component including a plurality of selectable operating modules,
each operating module being associated with a different set of
operations available for selection by a user and configuring the
external component to couple to a first external antenna and to
send the therapy instructions to the implantable component via the
first external antenna and the implanted antenna; providing an
external programmer and configuring the external programmer to a)
communicatively couple to the external component via a second port,
b) to provide therapy instructions comprising parameters for each
therapy cycle to the external component, wherein the parameters
comprise a therapy signal selected to downregulate activity on the
vagus nerve with an on time period and off time period, the off
time period selected to allow partial recovery of nerve function;
and c) to allow the user to select an agent that alters energy
balance in the patient based on the health profile of the patient
and the side effects of the agent.
[0079] In other embodiments, the disclosure provides a method of
selecting parameters for a therapy cycle for an implantable device
and of selecting an agent, wherein the therapy cycle and the agent
alter energy balance in a subject comprising: selecting parameters
of a therapy cycle to be applied to a vagus nerve to provide weight
loss to the subject, wherein the parameters comprise an electrical
signal having a frequency of 300 Hz or greater, having an on time
of at least 30 seconds, and having an off time that allows partial
recovery of the nerve; communicating the selected parameters to an
implantable device such as provided in the system of claim 1 and
delivering at least 10 therapy cycles during a treatment period,
and selecting an agent and a dosage of agent that alters the energy
balance of the subject based on the health profile of the subject
and the side effects of the agent using an external programmer such
as provided in the system of claim 1.
[0080] The disclosure provides methods of treating a condition
associated with excess weight in a subject by modulating neural
activity of the vagus nerve in combination with administration of
an agent that alters the energy balance in the subject. In some
embodiments, a method comprises: applying an intermittent neural
block to the vagus nerve at a blocking site with said neural
conduction block selected to down-regulate neural activity on the
nerve and with neural activity restoring upon discontinuance of
said block; and administering a composition to the subject
comprising an effective amount of an agent that alters the energy
balance of the subject. In some embodiments, the neural block is
applied to the nerve by implanting a device as described herein.
Conditions associated with excess weight include, without
limitation, obesity, compulsive eating, and bulimia.
[0081] Down Regulating Signal Application
[0082] In embodiments of the methods described herein a signal is
applied to the vagus nerve at a site with said signal selected to
down-regulate neural activity on the nerve and with neural activity
restoring upon discontinuance of said signal. Methods and systems
for applying such a signal are been described 7, 167, 750;
US2005/0038484 which is incorporated by reference.
[0083] The signal is selected to down regulate neural activity and
allow for restoration of the neural activity upon discontinuance of
the signal. An impulse generator, as described above, is employed
to regulate the application of the signal in order alter the
characteristic of the signal to provide a reversible intermittent
signal. The characteristics of the signal include frequency of the
signal, location of the signal, and the administration cycle of the
signal. Signal characteristics are selected to enhance a sensation
of satiety, to modulate intestinal motility and rate of digestion,
and/or partial restoration of the nerve following discontinuance of
the signal. Signal characteristics selected that provide for down
regulation of neural activity and restoration of neural activity
upon discontinuance of the signal include signal frequency,
electrode placement and signal type and timing.
[0084] In some embodiments, electrodes applied to both anterior and
posterior vagal trunks are energized with a blocking or down
regulating signal. The signal is applied for a limited time (e.g.,
5 minutes). The speed of vagal activity recovery varies from
subject to subject. However, 20 minutes is a reasonable example of
the time needed to recover to baseline. After recovery, application
of a blocking signal again down-regulates vagal activity which can
then recover after cessation of the signal. Renewed application of
the signal can be applied before full recovery. For example, after
a limited time period (e.g., 10 minutes) blocking can be renewed
resulting in average vagal activity not exceeding a level
significantly reduced when compared to baseline.
[0085] In embodiments, the implantable component is configured to
deliver a therapy cycle comprising an electrical signal having a
frequency of at least 300 Hz, an on time of at least 30 seconds,
and an off time that allows for partial recovery of the nerve
function. The implantable component may be configured to generate
therapy signals for a treatment period. In some cases, the
treatment period is at least 8 hours. In some embodiments, the
frequency of the electrical signal ranges from 300 to 10,000 Hz,
about 500 to 8000 Hz, or about 1000 to about 5000 Hz. In some
embodiments, the frequency of the electrical signal is about 2500
to 5000 Hz. An on time for the signal of a therapy cycle can range
from 30 seconds to 3 minutes, 30 seconds to 2 minutes, or from 30
seconds to 1 minute. The on time can optionally include a ramp up
and a ramp down time of about 2 to 60 seconds. The off times of the
electrical signal in the therapy cycle are selected to allow at
least a partial recovery of nerve function. The off times can be
selected from 1 minute to about 20 minutes, 1 minute to 10 minutes,
or 1 minute to 5 minutes.
[0086] In other embodiments, the external programmer is configured
to provide therapy instructions comprising parameters for the
therapy cycle to the external component, wherein the parameters of
the therapy cycle comprise an electrical signal with a frequency of
at least 300 Hz with an on time of at least 30 seconds and an off
time that allows partial recovery of nerve function. The parameters
can vary as described above. The external programmer can be
configured to provide therapy instructions to the external
component comprising multiple therapy cycles in a treatment period.
In embodiments, a treatment period is from 1 hour to 24 hours, 1
hour to about 12 hours, 1 hour to 8 hours, or 1 hour to 4 hours. In
embodiments, the external programmer is configured to provide
therapy instructions that include multiple therapy cycles per
treatment period. In some embodiments, at least ten therapy cycles
are delivered per treatment period. In other embodiments, 10 to
600, 20 to 250, or 50 to 100 cycles are delivered in a treatment
period.
[0087] Recognition of recovery of vagal activity (and recognition
of the significant variability between subjects) permits a
treatment therapy and apparatus with enhanced control and enhanced
treatment options. FIG. 6 illustrates vagal activity over time in
response to application of a blocking signal as described above and
further illustrates recovery of vagal activity following cessation
of the blocking signal. It will be appreciated that the graph of
FIG. 6 is illustrative only. It is expected there will be
significant patient-to-patient variability. For example, some
patients' responses to a blocking signal may not be as dramatic as
illustrated. Others may experience recovery slopes steeper or
shallower than illustrated. Also, vagal activity in some subjects
may remain flat at a reduced level before increasing toward
baseline activity. However, based on the afore-mentioned animal
experiments, FIG. 6 is believed to be a fair presentation of a
physiologic response to blocking.
[0088] In FIG. 6, vagal activity is illustrated as a percent of
baseline (i.e., vagal activity without the treatment of the present
invention). Vagal activity can be measured in any number of ways.
For example, quantities of pancreatic exocrine secretion produced
per unit time are an indirect measurement of such activity. Also,
activity can be measured directly by monitoring electrodes on or
near the vagus. Such activity can also be ascertained qualitatively
(e.g., by a patient's sensation of bloated feelings or normalcy of
gastrointestinal motility).
[0089] In FIG. 6, the vertical axis is a hypothetical patient's
vagal activity as a percent of the patient's baseline activity
(which varies from patient to patient). The horizontal axis
represents the passage of time and presents illustrative intervals
when the patient is either receiving a blocking signal as described
or the blocking signal is turned off (labeled "No Blocking"). As
shown in FIG. 6, during a short period of receiving the blocking
signal, the vagal activity drops dramatically (in the example
shown, to about 10% of baseline activity). After cessation of the
blocking signal, the vagal activity begins to rise toward baseline
(the slope of the rise will vary from patient to patient). The
vagal activity can be permitted to return to baseline or, as
illustrated in FIG. 6, the blocking signal can be re-instituted
when the vagal activity is still reduced. In FIG. 6, the blocking
signal begins when the vagal activity increases to about 50% of
baseline. As a consequence, the average vagal activity is reduced
to about 30% of the baseline activity. It will be appreciated that
by varying the blocking time duration and the "no blocking" time
duration, the average vagal activity can be greatly varied.
[0090] The block may be intermittent or continuous. The preferred
nerve conduction block is an electronic block created by a signal
at the vagus by an electrode controlled by the implantable impulse
generator (such as impulse generator 104 or an external
controller). The nerve conduction block can be any reversible
block. For example, ultrasound, cryogenics (either chemically or
electronically induced) or drug blocks can be used. An electronic
cryogenic block may be a Peltier solid-state device which cools in
response to a current and may be electrically controlled to
regulate cooling. Drug blocks may include a pump-controlled
subcutaneous drug delivery.
[0091] With such an electrode conduction block, the block
parameters (signal type and timing) can be altered by impulse
regulator and can be coordinated with the pacing signals to block
only during pacing. A representative blocking signal is a 500 Hz
signal with other parameters (e.g., timing and current) matched to
be the same as the pacing signal. While an alternating current
blocking signal is described, a direct current (e.g., -70 mV DC)
could be used.
[0092] The foregoing specific examples of blocking signals are
representative only. Other examples and ranges of blocking signals
are described in the afore-mentioned literature. For example, the
nerve conduction block is preferably within the parameters
disclosed in Solomonow, et al., "Control of Muscle Contractile
Force through Indirect High-Frequency Stimulation", Am. J. of
Physical Medicine, Vol. 62, No. 2, pp. 71-82 (1983). Particularly,
the nerve conduction block is applied with electrical signal
selected to block the entire cross-section of the nerve (e.g., both
afferent, efferent, myelinated and nomnyelinated fibers) at the
site of applying the blocking signal (as opposed to selected
sub-groups of nerve fibers or just efferent and not afferent or
visa versa) and, more preferably, has a frequency selected to
exceed the 200 Hz threshold frequency described in Solomonow et al.
Further, more preferred parameters are a frequency of 500 Hz (with
other parameters, as non-limiting examples, being amplitude of 4
mA, pulse width of 0.5 msec, and duty cycle of 5 minutes on and 10
minutes off). As will be more fully described, the present
invention gives a physician great latitude in selected pacing and
blocking parameters for individual patients.
[0093] For bulimic, obese, or compulsive overeating patients, the
device can be programmed so that when triggered, vagal activity is
blocked and the patient's appetite is suppressed by a feeling of
fullness (satiety). In some embodiments, manual activation by the
patient is desirable, but because the psychological pattern is
difficult to control, the use of circadian programming and
detection of overeating by measuring quantity of food consumed
during a given interval serves as an important backup in the
therapeutic modality.
[0094] As discussed above, the impulse generator may also be
activated manually by the patient by any of various means by
appropriate implementation of the device. These techniques include
the patient's use of an external magnet, or of an external RF
signal generator, or tapping on the surface overlying the impulse
generator, to activate the impulse generator and thereby cause the
application of the desired modulating signal to the electrodes.
Upon experiencing the compulsive craving, the overweight, obese or
bulimic patient can simply voluntarily activate the impulse
generator. If the patient fails to act, the automatic detection of
the overeating and consequent application of the necessary therapy
will take place through modulation of vagal activity to produce the
sensation of satiety.
[0095] Another form of treatment of may be implemented by
programming the impulse generator to periodically deliver the vagal
activity modulation productive of satiety at programmed intervals
between prescribed normal mealtimes. This will tend to reduce
excessive snacking between meals, which may otherwise be of
insufficient quantity within a preset time interval to trigger
automatic delivery of the therapy.
[0096] The electronic energization package may, if desired, be
primarily external to the body. An RF power device can provide the
necessary energy level. The implanted components could be limited
to the lead/electrode assembly, a coil and a DC rectifier. With
such an arrangement, pulses programmed with the desired parameters
are transmitted through the skin with an RF carrier, and the signal
is thereafter rectified to regenerate a pulsed signal for
application as the stimulus to the vagus nerve to modulate vagal
activity. This would virtually eliminate the need for battery
changes.
[0097] However, the external component transmitter must be carried
on the person of the patient, which is inconvenient. Also,
detection is more difficult with a simple rectification system, and
greater power is required for activation than if the system were
totally implanted. In any event, a totally implanted system is
expected to exhibit a relatively long service lifetime, amounting
potentially to several years, because of the relatively small power
requirements for most treatment applications. Also, as noted
earlier herein, it is possible, although considerably less
desirable, to employ an external impulse generator with leads
extending percutaneously to the implanted nerve electrode set. The
major problem encountered with the latter technique is the
potential for infection. Its advantage is that the patient can
undergo a relatively simple procedure to allow short term tests to
determine whether the condition associated with excess weight of
this particular patient is amenable to successful treatment. If it
is, a more permanent implant may be provided.
[0098] Signal Frequency
[0099] In some embodiments, the signal has a frequency of at least
200 Hz and up to 5000 Hz. In other embodiments, the signal is
applied at a frequency of about 500 to 5000 Hz. Applicant has
determined a most preferred blocking signal has a frequency of
3,000 Hz to 5,000 Hz or greater applied by two or more bi-polar
electrodes. Such a signal has a preferred pulse width of 100
micro-seconds (associated with a frequency of 5,000 Hz). It is
believed this frequency and pulse width best avoid neural recovery
from blocking and avoid repolarization of the nerve by avoiding
periods of no signal in the pulse cycle. A short "off" time in the
pulse cycle (e.g., between cycles or within a cycle) could be
acceptable as long as it is short enough to avoid nerve
repolarization. The waveform may be a square or sinusoidal waveform
or other shape. The higher frequencies of 5,000 Hz or more have
been found, in porcine studies, to result in more consistent neural
conduction block. Kilgore, et al., "Nerve Conduction Block
Utilizing High-Frequency Alternating Current", Medical &
Biological Engineering & Computing, Vol. 24, pp. 394-406
(2004). Preferably the signal is bi-polar, bi-phasic delivered to
two or more electrodes on a nerve.
[0100] In some embodiments, a signal amplitude of 0.5 to 8 mA is
adequate for blocking. Other amplitudes may suffice. Other signal
attributes can be varied to reduce the likelihood of accommodation
by the nerve or an organ. These include altering the power,
waveform or pulse width.
[0101] Location of Signal Application
[0102] Electrodes can be positioned at a number of different sites
and locations on or near the vagus nerve. In some embodiments, the
electrode is positioned to apply a signal to a branch or trunk of
the vagus nerve. In other embodiments, the electrode is positioned
to apply a signal to an anterior trunk, posterior trunk or both.
The electrode may also be positioned to apply a signal to an organ
in proximity to the vagus nerve such as the esophagus or stomach.
In some embodiments, the electrode is positioned to apply an
electrical signal to the vagus nerve at a location near or distal
to the diaphragm of the subject.
[0103] For example, FIG. 2 illustrates placement of a blocking
electrode. Referring to FIG. 2, the baseline vagal activity is
illustrated by the solid line of the proximal vagus nerve segment
VNP. The remainder of the vagus and enteric nervous system are
shown in reduced thickness to illustrate down-regulation of tone.
The pancreo-biliary output (and resulting feedback) is also
reduced. In FIG. 2, the blocking electrode BE is shown high on the
vagus relative to the GI tract innervation (e.g., just below the
diaphragm), the sole blocking electrode could be placed lower
(e.g., just proximal to pancreo/biliary innervation VN5). Blocking
of the entire vagus as described above can be used to down-regulate
the vagus for various benefits including treating a condition
associated with excess weight.
[0104] In other embodiments, alternative designs for placing
electrodes on or near the vagus nerve in a region of the esophagus
E either above or below the diaphragm are provided. Two paired
electrodes may connect to a pulse generator for bi-polar pacing. In
other embodiments, a portion of the vagus nerve VN is dissected
away from the esophagus E. An electrode is placed between the nerve
VN and the esophagus E. The electrode is placed overlying the vagus
nerve VN on a side of the nerve opposite electrode and with
electrodes axially aligned (i.e., directly across from one
another). Not shown for ease of illustration, the electrodes may be
carried on a common carrier (e.g., a PTFE or silicone cuff)
surrounding the nerve VN. Other possible placements of electrodes
are described herein US 2005/0131485 published Jun. 16, 2005, which
patent publication is hereby incorporated by reference.
[0105] While any of the foregoing electrodes could be flat metal
pads (e.g., platinum), the electrodes can be configured for various
purposes. In an embodiment, an electrode is carried on a patch. In
other embodiments, the electrode is segmented into two portions
both connected to a common lead and both connected to a common
patch. A flexible patch permits articulation of the portions of the
electrodes to relieve stresses on the nerve VN.
[0106] Signal Type and Timing
[0107] Selection of a signal that downregulates neural activity
and/or allows for recovery of neural activity can involve selecting
signal type and timing of the application of the signal. For
example, with an electrode conduction block, the block parameters
(signal type and timing) can be altered by the impulse generator
and can be coordinated with the pacing signals to block only during
pacing. A representative blocking signal is a 500 Hz signal with
other parameters (e.g., timing and current) matched to be the same
as the pacing signal. The precise signal to achieve blocking may
vary from patient to patient and nerve site. The precise parameters
can be individually tuned to achieve neural transmission blocking
at the blocking site.
[0108] In some embodiments, the signal has a duty cycle including
an ON time during which the signal is applied to the nerve followed
by an OFF time during which the signal is not applied to the
nerve.
[0109] In some embodiments, subjects receive an implantable impulse
generator component 104. (FIG. 3) The electrodes 212, 212a are
placed on the anterior vagus nerve AVN and posterior vagus nerve
PVN just below the patient's diaphragm. The external antenna (coil
102) is placed on the patient's skin overlying the implanted
receiving coil 105. The external control unit 101 can be programmed
for various signal parameters including options for frequency
selection, pulse amplitude and duty cycle. The frequency options
include 2500 Hz and 5000 Hz (both well above a threshold blocking
frequency of 200 Hz). The vast majority of treatments are at 5,000
Hz, alternating current signal, with a pulse width of 100
microseconds. The amplitude options are 1-8 mA. Duty cycle could
also be controlled. A representative duty cycle is 5 minutes of
blocking frequency followed by 5 minutes of no signal. The duty
cycle is repeated throughout use of the device.
[0110] FIG. 21 shows a typical duty cycle. Each ON time includes a
ramp-up where the 5,000 Hz signal is ramped up from zero amperes to
a target of 8 mA. Each ON time further includes a ramp-down from
full current to zero current at the end of the ON time. For about
50% of the patients, the ramp durations were 20 seconds and for the
remainder the ramp durations were 5 seconds. In some embodiments,
the on time is elected to have a duration of no less than 30
seconds or no more than 180 seconds or both.
[0111] The use of ramp-ups and ramp-downs are conservative measures
to avoid possibility of patient sensation to abrupt application or
termination of a full-current 5,000 Hz signal. An example of a
ramp-up for a high frequency signal is shown in U.S. Pat. No.
6,928,320 to King issued Aug. 9, 2005.
[0112] In some embodiments, a mini duty cycle can be applied. In an
embodiment, a mini duty cycle comprises 180 millisecond periods of
mini-ON times of 5,000 Hz at a current which progressively
increases from mini-ON time to mini-ON time until full current is
achieved (or progressively decreases in the case of a ramp-down).
Between each of such mini-ON times, there is a mini-OFF time which
can vary but which is commonly about 20 milliseconds in duration
during which no signal is applied. Therefore, in each 20-second
ramp-up or ramp-down, there are approximately one hundred mini-duty
cycles, having a duration of 200 milliseconds each and each
comprising approximately 180 milliseconds of ON time and
approximately 20 milliseconds of OFF time.
[0113] Normally a patient would only use the device while awake.
The hours of therapy delivery can be programmed into the device by
the clinician (e.g., automatically turns on at 7:00 AM and
automatically turns off at 9:00 PM). In the RF-powered version of
the impulse generator, use of the device is subject to patient
control. For example, a patient may elect to not wear the external
antenna. The device keeps track of usage by noting times when the
receiving antenna is coupled to the external antenna through
radio-frequency (RF) coupling through the patient's skin.
[0114] In some cases, loss of signal contact between the external
component 101 and implanted impulse generator 104 due occurs in
large part to misalignment between coils 102, 105. (See FIG. 8). It
is believed coil misalignment results from, at least in part,
changes in body surface geometry throughout the day (e.g., changes
due to sitting, standing or lying down). These changes can alter
the distance between coils 102, 105, the lateral alignment of the
coils 102, 105 and the parallel alignment of the coils 102,
105.
[0115] FIG. 7 illustrates a desired alignment. Coil 105 is
implanted beneath the skin 103 at a preferred depth D.sub.1 (e.g.,
about 2 cm to 3 cm beneath the skin 103), and with a plane of the
coil 105 parallel to the surface of the skin 103. Each coil 102,
105 is a circular coil surrounding a central axis X-X and Y-Y. As
shown in FIG. 7, in an ideal alignment, the axes X-X, Y-Y are
collinear so that there is no lateral offset of the axes X-X, Y-Y
and the coils 102, 105 are parallel. Such an alignment may be
attained when the external coil 102 is applied when the patient is
lying flat on his back.
[0116] FIG. 8 illustrates misalignment between the coils 102, 105
resulting from posture changes. When the patient stands, excess fat
may cause the skin 103 to roll. This increases the spacing between
the coils 102, 105 to increase to a distance D.sub.2. Also, the
axes X-X and Y-Y may be laterally offset (spacing T) and at an
angular offset A. These changes may be constantly occurring
throughout the day. As a result of coil misalignment, there may be
a significant variance in the power received by the implanted coil
105. In the case of an implant receiving both power and command
signals, in extreme cases, the power of a signal received by the
implanted circuit 150 may be so weak or the communication link
between the controller 101 and impulse generator 104 may be so poor
that therapy is lost. Misalignment can be detected by the device
and alignment of the coils adjusted to ensure that the signals are
restored. The device may include a notification to the patient or
physician if there has been a misalignment.
[0117] In some embodiments, the external component 101 can
interrogate the impulse generator component 104 for a variety of
information. In some embodiments, therapy times of 30 seconds to
180 seconds per duty cycle are preferred to therapy times of less
than 30 seconds per duty cycle or greater than 180 seconds per duty
cycle.
[0118] During a 10 minute duty cycle (i.e., intended 5 minutes of
therapy followed by a 5 minute OFF time), a patient can have
multiple treatment initiations. For example, if, within any given
5-minute intended ON time, a patient experienced a 35-second ON
time and 1.5 minute actual ON time (with the remainder of the
5-minute intended ON time being a period of no therapy due to
signal interruption), the patient could have two actual treatment
initiations even though only one was intended. The number of
treatment initiations varies inversely with length of ON times
experienced by a patient.
[0119] The flexibility to vary average vagal activity gives an
attending physician great latitude in treating a patient. For
example, in treating obesity, the blocking signal can be applied
with a short "no blocking" time to reduce weight as rapidly as
possible. If the patient experiences discomfort due to dysmotility,
the duration of the "no blocking" period can be increased to
improve patient comfort. Also, the reduction of enzyme production
can result in decreased fat absorption with consequential increase
of fat in feces. The blocking and no blocking duration can be
adjusted to achieve tolerable stool (e.g., avoiding excessive fatty
diarrhea). The control afforded by the present invention can be
used to prevent the enteric nervous system's assumption of control
since vagal activity is not completely interrupted as in the case
of a surgical and permanent vagotomy.
[0120] While patient weight loss and comfort may be adequate as
feedback for determining the proper parameters for duration of
blocking and no blocking, more objective tests can be developed.
For example, the duration of blocking and no blocking can be
adjusted to achieve desired levels of enzyme production and
nutrient digestion. In one example of drug therapy for obesity,
orlistat blocks the action of lipase. Lipase is a fat-digesting
enzyme. As a consequence of this reduction in lipase, the fat
content of feces increases. It is generally regarded as desirable
to modulate drug intake so that fecal fat does not exceed 30% of
ingested fat. Similarly, the blocking and no blocking durations can
be modulated to achieve the same result. Such testing can be
measured and applied on a per patient basis or performed on a
statistical sampling of patients and applied to the general
population of patients.
[0121] In some embodiments, a sensing electrode SE is added to the
system to monitor vagal activity as a way to determine how to
modulate the block and no block durations. While sensing electrode
can be an additional electrode to blocking electrode, it will be
appreciated a single electrode could perform both functions. The
sensing and blocking electrodes can be connected to a controller as
shown in FIG. 3. Such a controller is the same as controller 102
previously described with the additive function of receiving a
signal from sensing electrode (which yields the actual vagal
activity of the graph of FIG. 6). When the sensing electrode SE
yields a signal representing a targeted maximum vagal activity or
tone (e.g., 50% of baseline as shown in FIG. 6) the controller with
the additive function of receiving a signal from sensing electrode
energizes the blocking electrode BE with a blocking signal. As
described with reference to controller 102, controller with the
additive function of receiving a signal from sensing electrode can
be remotely programmed as to parameters of blocking duration and no
blocking duration as well as targets for initiating a blocking
signal.
[0122] The apparatus and method described herein use recovery of
the vagus nerve to control a degree of down-regulation of vagal
activity. This gives a physician enhanced abilities to control a
patient's therapy for maximum therapeutic effectiveness with
minimum patient discomfort. Therefore, while obesity is
particularly described as a preferred treatment, the vagal neural
block of the present invention can be used as treatment for other
conditions associated with excess weight.
[0123] Agents that Alter the Energy Balance of the Subject
[0124] The disclosure provides methods for treating a condition
associated with excess weight that include administering to a
subject a composition comprising an agent that alters an energy
balance in a subject. The disclosure also provides systems and
methods that provide for selecting an agent that alters energy
balance of the subject based on the health profile of the subject
and the side effects of the agent.
[0125] In some embodiments, the agent will increase energy expended
and/or decrease the amount of energy consumed. Agents that alter
energy balance in a subject are known to have certain
characteristics, for example, some agents enhance the sensation of
satiety, other agents decrease appetite (anorexic), others block
the absorption of fat or other nutrients, others inhibit enzymes
that digest fat, some agents are thermogenic, and some have
combinations of effects.
[0126] Several pathways are known to affect energy balance.
Pathways include gut-hypothalamic axis (e.g. ghrelin),
gut-hindbrain axis (e.g. vagus nerve), peripheral tissue (adipose
tissue, skeletal muscle)-hypothalamic axis (e.g. leptin), and
hypothalamic-hindbrain axis (neural projections). In particular,
the hypothalamus (forebrain) and the area postrema (hindbrain) are
2 regions of the central nervous system which are thought to play
orchestrating roles in the human energy homeostasis. It has been
documented that there are neural connections between these two
regions enabling communications and complimentary, as well as,
redundant effects on body energy balance. Numerous hormones,
enzymes, neurotransmitters, and other mediators are released from
different parts of these pathways and can have influences on these
regions of the central nervous system. These interactions, in turn,
ultimately produce orexigenic or anorexic behavior thereby altering
the energy balance of a patient. Utilization of distinct treatment
modalities that involve different parts of these pathways and brain
regions, thus altering the communication between the hypothalamus
and area postrema, may be of importance in combinatorial therapy
that is highly effective, robust, and durable.
[0127] Agents that alter energy balance can be selected based on an
ability to complement treatment of applying a signal to
downregulate neural activity of the vagal nerve. Drugs that have
been approved by the FDA to treat obesity include sibutramine and
orlistat for long term use; and phentermine for short term use.
However, the excess weight loss associated with administration of
these drugs is limited to a maximum of about 10% when compared with
loss due to diet and exercise alone. As described herein, an agent
is selected that may provide a complementary or synergistic effect
with the application of signal to modulate neural activity on the
vagus nerve. A synergistic or complementary effect can be
determined by determining whether the patient has an increase in
excess weight loss as compared to one or both treatments alone. In
some embodiments, agents that act at a different site (e.g.
hypothalamus or pituitary) or through a different pathway may be
selected for use in the methods described herein. Agents that
complement treatment are those that include a different mechanism
of action for affecting the excess weight of the subject.
[0128] An agent may also or in addition be selected to administer
that may have undesirable side effects at the recommended dosage
that prevents use of the agent, or that prevents compliance by the
patient. In addition, patients that have excess weight as well as
hypertension, cardiac conditions, liver disease, or renal disease
may not be able to tolerate treatment with one or more of the
agents at the recommended dosage due to adverse side effects.
Agents that have undesirable side effects include fenfluramine, and
dexfenfluramine which have been shown to have adverse effects on
blood pressure and to be associated with valvular heart disease.
Other drugs such as bupropion can cause seizures. Drugs that
inhibit fat absorption, such as orlistat, can cause diarrhea, soft
and oily stools, and flatulence. Other drugs may cause central
nervous system symptoms such as anxiety, cognitive deficits,
depression, and/or nervousness.
[0129] Combining administration of a drug with undesirable side
effects with modulating neural activity on the vagus nerve may
allow for administration of the drugs at a lower dose thereby
minimizing the side effects. In addition, a drug may be selected
that has altered pharmacokinetics when absorption is slowed by a
delay in gastric emptying due to neural downregulation as described
herein. In other embodiments, the recommended dosage may be lowered
to an amount that has fewer adverse side effects. In some
embodiments, the therapeutic window may be increased. In some
embodiments, a drug that may be useful for short term use may be
administered for long term use at the lowered dosage. For example,
a drug such as rimonabant at 20 mg per dose may be lowered to a 5
mg dose and still be effective for weight loss. In embodiments, it
is expected that the recommended dosage may be able to be lowered
at least 25%. In other embodiments, the dosage can be lowered to
any percentage of at least 25% or greater of the recommended dose.
In some embodiments, the dosage is lowered at least 25, 30, 35, 40,
45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% of the
recommended dosage.
[0130] In an embodiment, a method provides a treatment for a
condition associated with excess weight such as obesity. A method
comprises selecting a drug useful for treating excess weight or
obesity and having a recommended dosage for efficacy where a
patient is likely to experience disagreeable side effects at said
recommended dosage; and treating the patient with a concurrent
treatment comprising: applying an intermittent neural block to a
vagus nerve of the patient at multiple times per day and over
multiple days with the block selected to down-regulate afferent
and/or efferent neural activity on the nerve and with neural
activity restoring upon discontinuance of said block; and
administering said drug to the patient at a dosage less than said
recommended dosage. In some embodiments, the effective dosages for
treating a condition associated with excess weight for such a
patient are associated with disagreeable side effects contributing
to said patient not complying with a drug treatment. In some
embodiments, patients are those that have an eating disorder,
hypertension, cardiac conditions, liver, or renal disorder and may
not be able to tolerate treatment with one or more of the agents
that alter energy balance at the recommended dosage due to adverse
side effects.
[0131] Agents that affect the hypothalamic or neuroendocrine
function such as ghrelin, ghrelin agonists, ghrelin antagonists,
leptin agonist, leptin antagonists, ciliary neurotrophic factor
(CNTF), CNTF analogues, amylin, and amylin analogues may complement
effects on the vagus nerve. In addition, agents that enhance the
sensation of satiety and reduce appetite and act on
neurotransmitters in the brain may complement the effects of neural
downregulation on the vagus nerve. Such agents include
neurotransmitter releasers, inhibitors of the uptake of serotonin,
norepinephrin, and dopamine. These agents include, for example,
sibutramine, fenfluramine, phentermine, dexphenfluoramine,
flouxetine, and bupropion. Agents that are thermogenic increase
energy expenditure of the patient and would have a complementary
effect to that of modulating the neural activity of the vagus
nerve. These agents include, for example, sibutramine, leptin,
leptin agonists, leptin analogues, CNTF, and CNTF analogues. Agents
that suppress appetite and enhance the feeling of satiety include
incretins including GLP-1, PYY, CKK, and oxyntomodulin.
[0132] In the methods of the disclosure, an anorexic agent may be
administered. Several anorexic agents are known to those of skill
in the art. Anorexic agents include phentermine, fenfluramine,
dexfenfluramine, endocannabinoid receptor antagonists, ghrelin
antagonists, orexin antagonists, somatostatin receptor agonist,
GLP-1, PYY, and cholecystokinin agonists. Endocannaboid receptor
antagonists are known and include rimonabant. Phentermine has been
approved for short term treatment of obesity.
[0133] Thermogenic agents are attractive as they increase the
energy expenditure of the subject. Leptin, for example, may reduce
calorie intake and increases energy expenditure through action on
the sympathetic nerve system. Other agents that have thermogenic
characteristics include sibutramine, leptin, leptin agonist, a
leptin analogue, ciliary neurotrophic factor (CNTF), and a CNTF
analogue. Axokine is a CNTF analogue that has been shown to promote
weight loss. Sibutramine has been approved for long term treatment
of obesity.
[0134] Agents that inhibit fat absorption are more likely to have
effects similar to that of modulating neural activity of the vagus
nerve rather than complementary effects. Even though the action of
agents that inhibit fat absorption may not be complementary to
downregulation of vagal nerve activity, they have undesirable side
effects that may contribute to a lack of patient compliance. Such
side effects include diarrhea, flatulence and loose stools. Some
agents inhibit the action of lipases that break down fat in
ingested food. Agents that inhibit fat absorption include orlistat
or a lipin inhibitor. Orlistat has been approved for long term
treatment of obesity.
[0135] Agents that enhance satiety through a CNS pathway, such as a
hypothalamic or neuroendocrine pathway, would have effects
complementary to those due to treatment by modulating neural
activity on the vagus nerve. Agents that enhance satiety include
somatostatin receptor agonists, GLP-1 agonists, GLP-1 variants,
peptide PYY, POMC agonists, neuropeptide Y inhibitors, topiramate,
tegretol, bupropion, naltrexone, zonisamide, amylin, amylin
analogues, and oxyntomodulin. Pramlitidine is an amylin analogue
that has shown effectiveness in clinical trials for weight loss.
Exendin-4 is a potent and long lasting GLP-1 analogue and agonist
of GLP-1. Liraglutide is also a long acting analogue of GLP-1.
Adminstration of PYY increases propiomelanocortin activity and has
been shown to result in decreased food consumption. Oxyntomodulin
suppresses appetite and food intake.
[0136] Sequences for the polypeptides such as GLP-1, ghrelin,
leptin are known to those of skill in the art and are described in
publicly available databases. Representative sequences are: Leptin
(gI 1469860 and gI4557715); ghrelin (gI 37183224); POMC (GI
190188); GLP-1 (gI 125987831 (P01275)); CKKB receptor (gI 417029);
CNTF (gI 633830, gI 825643, gI116585); PYY (gI 71361686, gI
1172776); orexin (gI 4557635); somatostatin receptor (gI 431095, gI
307430) and amylin (gI 457131, gI 4557655).
[0137] In some embodiments, the agents that alter the energy
balance in the subject do not include prokinetic agents. Prokinetic
agents are drugs that enhance motor activity of the smooth muscle
characteristic of GI tract. These agents have been used for
treating gastroesophageal reflux disease (GERD) and are beneficial
for improving the strength of esophageal peristalsis, the resting
pressure of the LES, the strength of gastric contractions, and
improving gastric motility. Recently, cisapride, the most commonly
prescribed prokinetic agent, has been withdrawn from the US market
because of rare, but life-threatening cardiac arrhythmias.
Metoclopramide, another prokinetic agent proven effective for GERD,
is frequently associated with unpleasant side effects. In other
embodiments, prokinetic agents may be used as an agent that alters
energy balance in a subject but a dosage that provides for
alleviating a symptom of the eating disorder while minimizing the
side effects.
[0138] In some embodiments, the patient has a condition associated
with excess weight including obesity, compulsive eating, and/or
bulimia. In some embodiments, a patient may be selected that is not
yet obese but is overweight. Excess weight of at least 10 pounds or
10-20 pounds is associated with adverse health effects. Overweight
and obesity classifications include those determined by body mass
index (BMI) (calculated as weight in kilograms divided by the
square of height in meters). For example, normal weight:
BMI=18.5-24.9; overweight: BMI=25.0-29.9; obesity-class 1:
BMI=30.0-34.9; obesity-class 2: BMI=35.0-39.9; obesity-class 3:
BMI.gtoreq.40.0). Of course these ranges may vary given the height,
gender, and age of the subject. In other embodiments, the patient
at least has a body mass index (BMI) of at least 25 or greater. In
other embodiments, the patient has a BMI of at least 27 to about 30
and also has other health conditions such as hypertension,
diabetes, cardiovascular disease, liver disease, and/or renal
disease. In other embodiments, the patient is overweight at least
10 pounds and/or has a condition such as type II diabetes, asthma,
arthritis, hypertension, high cholesterol, and/or cardiovascular
disease.
[0139] Dosages for administration to a subject can readily be
determined by one of skill in the art. Guidance on the dosages can
be found, for example, by reference to other drugs in a similar
class of drugs. For example, dosages have been established for any
of the approved drugs or drugs in clinical trials and the range of
dose will depend on the type of drug. For example, pramlintide
dosages range from about 240 micrograms up to 720 micrograms per
day. A dosage of sibutramine of 5 to 20 mg per day is
recommended.
[0140] Dosages associated with adverse side effects are known or
can also be readily determined based on model studies. For example,
dosages of 30 mg per day or greater of fenfluramine in combination
with dexphenfluramine were associated with valvular heart
conditions. Risk of seizures and increase in blood pressure with
bupropion treatment increases at doses of 300 mg per day or
greater. A determination of the effective doses to achieve excess
weight loss while minimizing side effects can be determined by
animal studies.
[0141] Agents that alter the energy balance will be formulated,
dosed, and administered in a fashion consistent with good medical
practice. Factors for consideration in this context include the
particular disorder being treated, the particular mammal being
treated, the clinical condition of the individual patient, the age
of the patient, other medications that the patient is taking, the
cause of the disorder, the site of delivery of the agent, the
method of administration, the scheduling of administration, and
other factors known to medical practitioners. The agent need not
be, but is optionally formulated with one or more agents currently
used to prevent or treat the disorder in question. The effective
amount of such other agents depends on the amount of agent that
alters an energy balance of the subject present in the formulation,
the type of disorder or treatment, and other factors discussed
above. These are generally used in the same dosages and with
administration routes as used hereinbefore or about from 1 to 99%
of the heretofore employed dosages.
[0142] The agent that alters energy balance of the subject can be
administered at the same time that the subject is receiving a
therapy signal treatment, after therapy signal treatment has been
administered and is ongoing, when therapy signal treatment is
providing for maintenance of weight loss. For example, the
implanatable device can be implanted and the subject undergo
therapy for a period of at least 1 month to determine the rate of
excess weight loss using the device. The rate and amount of excess
weight loss using the implantable device can be determined and if
weight loss is not adequate (e.g., less than 1% excess weight loss)
then the therapy cycle parameters may be adjusted and/or an agent
that alters energy balance can be administered. In most cases, the
implanatable device will deliver therapy for a period of time
before the agent is administered to the subject. An agent that
alters energy balance may be administered in those patients that
appear to be nonresponders or intermediate responders.
[0143] Therapeutic formulations comprising the agent are prepared
for storage by mixing the agent having the desired degree of purity
with optional physiologically acceptable carriers, excipients or
stabilizers (Remington's Pharmaceutical Sciences 16th edition,
Osol, A. Ed. (1980)), in the form of aqueous solutions, lyophilized
or other dried formulations. Acceptable carriers, excipients, or
stabilizers are nontoxic to recipients at the dosages and
concentrations employed, and include buffers such as phosphate,
citrate, histidine and other organic acids; antioxidants including
ascorbic acid and methionine; preservatives (such as
octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;
benzalkonium chloride, benzethonium chloride; phenol, butyl or
benzyl alcohol; alkyl parabens such as methyl or propyl paraben;
catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low
molecular weight (less than about 10 residues) polypeptides;
proteins, such as serum albumin, gelatin, or immunoglobulins;
hydrophilic polymers such as polyvinylpyrrolidone; amino acids such
as glycine, glutamine, asparagine, histidine, arginine, or lysine;
monosaccharides, disaccharides, and other carbohydrates including
glucose, mannose, or dextrins; chelating agents such as EDTA;
sugars such as sucrose, mannitol, trehalose or sorbitol;
salt-forming counter-ions such as sodium; metal complexes (e.g.,
Zn-protein complexes); and/or non-ionic surfactants such as
TWEEN.TM., PLURONICS.TM. or polyethylene glycol (PEG).
[0144] The formulation herein may also contain more than one active
compound as necessary for the particular indication being treated.
In certain such embodiments, the compounds have complementary
activities that do not adversely affect each other. Such molecules
are suitably present in combination in amounts that are effective
for the purpose intended.
[0145] The therapeutic agent is/are administered by any suitable
means, including parenteral, subcutaneous, orally, intradermal,
intraperitoneal, and by aerosol. Parenteral infusions include
intramuscular, intravenous, intraarterial, intraperitoneal, or
subcutaneous administration. Pumps may be utilized as well as drug
eluting devices and capsules.
Example 1
A. VBLOC-I Obesity Study
[0146] In early 2006, Assignee began a human pilot study ("VBLOC-I)
to evaluate an obesity treatment according to the present
invention. The inclusion criteria of the VBLOC-I study required the
patient have a body mass index (BMI) in a range between 35 and 50
(+/-10%). A BMI>30 is regarded as obese. A BMI>35 is
generally regarded as morbidly obese.
[0147] After receiving the implant 104, (FIG. 3) the device was
inactive for a two-week post-surgery healing period. Thereafter,
the therapy was initiated. Patients were followed at regular
periods throughout the study. The study was designed to measure
efficacy at multiple time points post-implant. Efficacy is measured
as the amount of excess weight loss (EWL) experienced by the
patient. Excess weight is the difference between the patient's
actual weight and ideal weight. The patient's excess weight is
determined prior to surgery ("baseline") as well as at multiple
time points post-implantation. The EWL is the weight loss expressed
as a percent of the baseline excess weight.
[0148] Patients enrolled in the VBLOC-I study received an
implantable component 104. All patients in the VBLOC-I study
received an RF-powered version of the impulse generator. The
electrodes 212, 212a were placed on the anterior vagus nerve AVN
and posterior vagus nerve PVN just below the patient's
diaphragm.
[0149] The external antenna (coil 102) was placed on the patient's
skin overlying the implanted receiving coil 105. The external
control unit 101 can be programmed for various signal parameters
including options for frequency selection, pulse amplitude and duty
cycle. The frequency options include 2500 Hz and 5000 Hz (both well
above a threshold blocking frequency of 200 Hz). The vast majority
of treatments were at 5,000 Hz, alternating current signal, with a
pulse width of 100 microseconds. The amplitude options are 1-8 mA.
Duty cycle could also be controlled. A representative duty cycle is
5 minutes of blocking frequency followed by 5 minutes of no signal.
The duty cycle was repeated throughout use of the device.
[0150] Normally a patient would only use the device while awake.
The hours of therapy delivery can be programmed into the device by
the clinician (e.g., automatically turns on at 7:00 AM and
automatically turns off at 9:00 PM). In the RF-powered version of
the impulse generator, use of the device is subject to patient
control. For example, a patient may elect to not wear the external
antenna. The device keeps track of usage by noting times when the
receiving antenna is coupled to the external antenna through
radio-frequency (RF) coupling through the patient's skin.
[0151] B. Weight Loss Data
[0152] As would be expected in a human weight loss study, patients
vary significantly in their response to treatment. However, overall
weight loss has been very promising. Of thirty-one patients entered
in the study, patients experienced an average weight loss of 16%
after 34 weeks. FIG. 9 is an example of a scatter graph of all
patients not otherwise excluded. "Excluded" means patient data was
excluded for reasons of not using the device for significant
periods or equipment failure. (E.g. Two patients were excluded from
the data. Their exclusion was due to their extended periods of
non-use of the device and questionable impedance data indicating
therapy was not being delivered to the patient).
[0153] In FIG. 9, the vertical axis is the excess weight loss
relative (as a percent of baseline weight). The horizontal axis is
the number of weeks following treatment. "Maestro Implant" is the
surgery date. "2 Weeks Maestro Activation" is the date of device
activation following a 2-week post-surgery healing period. The
remaining dates on the horizontal axis are post-surgery follow-up
dates measured from date of surgery "Maestro Implant".
[0154] The data are very encouraging. In any human treatment study,
one expects patient-to-patient outcome variability. That is
reflected in the data of FIG. 9. During the VBLOC-I study, patients
were intended to receive a therapy dose of 5 minutes of electrical
signal followed by 5 minutes of no signal. This duty cycle was to
be repeated throughout the day.
[0155] FIG. 21 shows a typical duty cycle. Each ON time includes a
ramp-up where the 5,000 Hz signal is ramped up from zero amperes to
a target of 8 mA. Each ON time further includes a ramp-down from
full current to zero current at the end of the ON time. For about
50% of the patients, the ramp durations were 20 seconds and for the
remainder the ramp durations were 5 seconds.
[0156] The use of ramp-ups and ramp-downs are conservative measures
to avoid possibility of patient sensation to abrupt application or
termination of a full-current 5,000 Hz signal. An example of a
ramp-up for a high frequency signal is shown in U.S. Pat. No.
6,928,320 to King issued Aug. 9, 2005.
[0157] Not shown in the drawings, each ramp-up and ramp-down in the
VBLOC-I study was broken into mini-duty cycles consisting of many
imbedded OFF times of very short duration. While the mini-duty
cycle was not completely uniform, it is approximated by 180
millisecond periods of mini-ON times of 5,000 Hz at a current which
progressively increases from mini-ON time to mini-ON time until
full current is achieved (or progressively decreases in the case of
a ramp-down). Between each of such mini-ON times, there is a
mini-OFF time which can vary but which is commonly about 20
milliseconds in duration during which no signal is applied.
Therefore, in each 20-second ramp-up or ramp-down, there are
approximately one hundred mini-duty cycles, having a duration of
200 milliseconds each and each comprising approximately 180
milliseconds of ON time and approximately 20 milliseconds of OFF
time.
[0158] Analyzing data recovered during the post-surgery follow-ups,
it was noted that, frequently, patients did not receive the full
5-minute dose. It was determined this was primarily due to loss of
signal contact between the external controller 101 and implanted
impulse generator 104 due in large part to misalignment between
coils 102, 105.
[0159] It is believed coil misalignment results from, at least in
part, changes in body surface geometry throughout the day (e.g.,
changes due to sitting, standing or lying down). These changes can
alter the distance between coils 102, 105, the lateral alignment of
the coils 102, 105 and the parallel alignment of the coils 102,
105.
[0160] FIG. 7 illustrates a desired alignment. Coil 105 is
implanted beneath the skin 103 at a preferred depth D.sub.1 (e.g.,
about 2 cm to 3 cm beneath the skin 103), and with a plane of the
coil 105 parallel to the surface of the skin 103. Each coil 102,
105 is a circular coil surrounding a central axis X-X and Y-Y. As
shown in FIG. 7, in an ideal alignment, the axes X-X, Y-Y are
collinear so that there is no lateral offset of the axes X-X, Y-Y
and the coils 102, 105 are parallel. Such an alignment may be
attained when the external coil 102 is applied when the patient is
lying flat on his back.
[0161] FIG. 8 illustrates misalignment between the coils 102, 105
resulting from posture changes. When the patient stands, excess fat
may cause the skin 103 to roll. This increases the spacing between
the coils 102, 105 to increase to a distance D.sub.2. Also, the
axes X-X and Y-Y may be laterally offset (spacing T) and at an
angular offset A. These changes may be constantly occurring
throughout the day. As a result of coil misalignment, there may be
a significant variance in the power received by the implanted coil
105. In the case of an implant receiving both power and command
signals, in extreme cases, the power of a signal received by the
implanted circuit 150 may be so weak or the communication link
between the controller 101 and impulse generator 104 may be so poor
that therapy is lost.
[0162] Since such unintended signal interruption is undesirable,
when an indication of such misalignment is detected, the device can
and was realigned.
[0163] C. Observed Variations in Duty Cycle
[0164] a. Length of ON Times
[0165] During patient follow-up visits in the VBLOC-I study, the
external controller 101 can interrogate the implantable component
104 for a variety of information. From the collected data, a
physician can determine how often the patient is receiving the
intended therapy. For example, the physician can determine if a
patient is receiving a full five minutes of an intended 5-minute
therapy or only a portion (10 seconds, 1 minute, 4.5 minutes,
etc).
[0166] Analysis of the collected data, showed that a range of
actual therapy stood out as being surprisingly superior.
Specifically, it was noted that therapy times of 30 seconds to 180
seconds per duty cycle were significantly superior to therapy times
of less than 30 seconds per duty cycle or greater than 180 seconds
per duty cycle.
[0167] Number of Therapeutic ON Times
[0168] During a 10 minute duty cycle (i.e., intended 5 minutes of
therapy followed by a 5 minute OFF time), a patient can have
multiple treatment initiations. For example, if, within any given
5-minute intended ON time, a patient experienced a 35-second ON
time and 1.5 minute actual ON time (with the remainder of the
5-minute intended ON time being a period of no therapy due to
signal interruption), the patient could have two actual treatment
initiations even though only one was intended. The number of
treatment initiations varies inversely with length of ON times
experienced by a patient.
[0169] D. Statistical Analysis of Duty Cycle Data and Weight
Loss
[0170] A statistical analysis of collected data from the VLOC-I
study was performed. The primary analysis method employed was a
mixed model, repeated measures regression analysis. This
methodology is standard for longitudinal or serially collected
data. In the VBLOC-I study, data on delivered therapy (actual ON
times) and excess weight loss (EWL) were available for at least
some of the patients at weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20 and
24 post-therapy initiation (with therapy initiation being 2-weeks
post implantation).
[0171] Data from a particular subject patient across follow-up
visits were correlated, and the mixed model regression analysis
effectively accounted for this correlation and avoided the
situation whereby the effect size of a particular parameter was
overestimated. This analysis essentially computed an average effect
for each subject and averaged that effect across subjects, weighted
according to the amount of information each subject was
contributing.
[0172] a. Quartile Analysis
[0173] To facilitate an analysis, patients were grouped into
quartiles based on the number of ON times experienced by a patient.
For example, for any given follow-up period (e.g., 6 weeks
post-therapy initiation corresponding to 8 weeks
post-implantation), twenty-four patients may report for such
follow-up (the numbers given here are hypothetical for ease of
explanation). Interrogation of the patients' implants reveal the
patients have a wide number of different therapy initiations
(correlating inversely with a wide variety of ON time durations).
Patients are divided into quartiles based on the number of ON times
experienced by the patient. In the example given, Quartile 4 would
be the six patients (i.e., 25%) having the most number of ON times.
Quartile 1 would the six patients (i.e., 25%) having the fewest
number of ON times.
[0174] A quartile analysis can be made using, among other options,
a visit interval-defined quartile analysis or a subject-defined
quartile analysis. A visit interval-defined quartile analysis was
chosen. However, information is supplied below showing
comparability of such analysis with a subject-defined quartile
analysis.
[0175] b. Visit Interval-Defined Quartile Analysis
[0176] In FIGS. 10-12, therapeutic ON time quartiles are defined
according to visit intervals. These figures illustrate the effect
of the number of ON times of a specific duration. In these figures,
discrete ON time durations (i.e. 0-30 seconds (FIG. 10), 30-180
seconds (FIG. 11), and 180-300 seconds (FIG. 12)) are analyzed in a
repeated measures regression model to determine the duration of ON
time with the greatest effect on EWL.
[0177] In FIG. 10, there is a relationship between quartiles and
EWL as represented by the statistically significant "p-value" of
0.001. (A "p-value" of less than 0.05 is generally regarded as
significant since it represents a 95% confidence level that the
data variations are attributable to non-random events). However,
the effect of this 0-30 second ON time is an order of magnitude
less than that seen with therapeutic ON times of either 30-120 or
30-180 seconds (as discussed below) as shown by the parameter
estimates of FIG. 17.
[0178] In FIG. 11, there is a strong relationship between quartiles
of therapeutic ON times from 30-180 seconds and EWL as evidenced by
the p-value of 0.004. This therapeutic ON time duration of 30-180
seconds (which includes, as a subset, ON time durations of 30-120
seconds (FIG. 13)), represents the ON time with the greatest effect
on EWL.
[0179] In FIG. 12, there is no statistically significant quartile
effect of therapeutic ON times from 180-300 seconds as shown by the
relatively high p-value of 0.165. The frequency of longer duration
ON times is inconsequential in terms of incremental EWL. There is
no additional benefit of longer ON times, relative to shorter ON
times, with respect to EWL.
[0180] FIG. 13 analyzes a subset (30-120 seconds) of the data of
FIG. 6 (30-180 seconds). As with the analysis of 30-180 second
therapeutic ON times (FIG. 6), there is a strong relationship
between quartiles of ON times from 30-120 seconds and EWL as
evidenced by the p-value of 0.002. This therapeutic ON time
duration of 30-120 seconds represents the optimal combination of
effect on EWL (and battery longevity for a battery powered
implant).
[0181] c. Study Subject-Defined v. Visit Interval-Defined Quartile
Analyses
[0182] In a visit interval-defined quartile analysis, subjects are
allowed to move from one quartile to another over the follow-up
period. The repeated measures analysis described above adequately
accounted for the visit-to-visit movement by an individual subject
from one quartile to another by isolating the effect of ON times to
the interval preceding each study visit and calculating a slope
across visits.
[0183] By allowing movement between quartiles across visits, the
analysis addressed the fact that ON times were not necessarily
consistent across all visits for an individual study subject. For
instance, if an intermittent or inconsistent link developed during
an interval between visits but was then corrected at the next
visit, that individual subject might have a greater number of
therapeutic ON times (.gtoreq.30 seconds) for the period of time
with an inconsistent link compared with the period of time with
consistent link. If ON times are associated with EWL, there would
be a different effect on weight loss for the period of time with a
greater frequency of therapeutic ON times compared with the period
of time with consistent link.
[0184] Through the course of follow-up, that subject may have an
average or low number of ON times and a different overall weight
loss than was observed during the period of time with an
inconsistent link. By allowing for movement across quartiles, we
are able to account for such interval effects of ON times on
EWL.
[0185] There is value, though, in also examining the cumulative
frequency of therapeutic ON times through a certain follow-up visit
(e.g. 20 weeks) and dividing subjects into quartiles according to
the grand total number of ON times (corrected for total days on
study). This analysis evaluates whether or not the cumulative (over
20 weeks) total number of therapeutic ON times has an effect on
excess weight loss. The repeated measures approach in this instance
adjusts for the within-patient correlation across follow-up visits,
but does not take into account that a subject may have a variable
frequency of ON times from one visit to another. That is, only the
average frequency of ON times over the course of follow-up is
considered. This type of analysis is "study subject-defined
quartile analysis".
[0186] Study subject-defined and visit interval-defined quartile
analyses are compared in FIGS. 14 and 15. In these analyses, "ON
time" means an actual therapy time greater than or equal to 30
seconds. Quartiles are divided on the basis of frequency of ON
times.
[0187] The p-value in these analyses is the significance of the
effect across quartiles. This p-value not only incorporates a
measure of linearity, but also effect size. A non-significant
p-value would be an indication of no linear effect of therapeutic
ON times on % EWL.
[0188] A similar effect is seen in both analyses. There is a
generally linear effect of the number of ON times (according to
quartile) and the percent EWL. The significance level for both
analyses is statistically significant, though the more granular
analysis (visit interval-defined quartiles) is more significant.
Because the patient groups for the study subject-defined quartiles
is determined according to the cumulative number of ON times over a
fixed period of time (20 weeks), sample size is smaller (29 vs. 31
subjects) as data was not available at 20 weeks for two
subjects.
[0189] Defining quartiles in the described manners yield similar
results in terms of the effect of therapeutic ON times on excess
weight loss. Evaluating subject-defined quartiles has confirmed the
findings from the study visit interval-defined quartile
analysis.
[0190] From a comparison of FIGS. 14 and 15, it was determined that
the mixed model, repeated measures regression models are
appropriate for both quartile-defined analyses. A strong, linear
relationship exists between frequencies of therapeutic ON times
greater than or equal to 30 seconds and excess weight loss in the
VBLOC-I study population. Each of the two quartile analyses yield
consistent results and conclusions, and are mutually
confirmatory
[0191] d. Additional Analysis
[0192] FIGS. 16 and 17 graphically illustrate an alternative
analysis showing the observed superiority of 30 to 180 seconds
therapy per duty cycle versus other options within a 0 to 5 minute
range. FIGS. 16 and 17 represent the parameter estimates associated
with distinct ON time bins. A "bin" is an assignment of data. For
example, "Bin 1" is defined as data associated with ON times of
less than 30 seconds. The bins are reflected in Table 17.
[0193] FIGS. 16 and 17 represent the parameter estimates associated
with distinct ON time bins. Bins are retrospective groupings to
permit analyzing the correlation, if any, between length of ON
times and excess weight loss.
[0194] For each bin, a parameter estimate is given. These parameter
estimates are from a mixed model, repeated measures regression
analysis that estimates the effect of the cumulative number of ON
times of a given duration over time. Such models and analyses are
well known in statistics.
[0195] The parameter estimate represents the slope of the
regression line, and a one-unit increase in the cumulative number
of ON times for a particular bin is associated with a percent of
excess weight loss equal to the parameter estimate for that ON
time. For example, a 100 unit increase in the number of ON times
from two to three minutes in duration is associated with a -2.9%
EWL.
[0196] G. Conclusions from Statistical Analysis
[0197] From the foregoing, it was concluded that a greater number
of initiations of therapeutic ON times during any given time period
are associated with greater excess weight loss (EWL). This
therapeutic effect is greatest with therapeutic ON times of either
30-180 seconds (p=0.004) or 30-120 seconds (p=0.002). Therapeutic
ON time durations of 30-120 seconds represent the optimal
combination of effect on EWL and battery longevity. As a matter of
conjecture, the central nervous system may accommodate to a loss of
vagal neural activity after about 180 seconds, or accommodation may
be due to membrane changes and local accommodation.
[0198] In addition to a preferred ON time of 30 seconds to 180
seconds, the duty cycle preferably has a short OFF time to maximize
the number of initiations of such duty cycles per day. FIG. 18
graphically illustrates patient response to the therapy based on
the number of ON times experienced by the patient. For FIG. 18, "ON
time" means only those treatment durations between 30 to 180
seconds. If the patient experienced additional treatments of
different durations (e.g., less than 30 seconds or greater than 180
seconds), those additional treatments are ignored in FIG. 18.
[0199] In FIG. 18, the horizontal axis is the number of week's
post-activation of the implant. The vertical axis is the number of
treatment ON times (again, defined for the purpose of FIG. 18 as
between 30 and 180 seconds) experienced by the patient between
follow-up visits.
[0200] It should be noted that not the same number of patients are
in the data points for each horizontal axis location. Since
patients are implanted over a period of time, while all patients
had early follow-ups at the time of the analysis, not all such
patients had later follow-ups. Therefore, there are more data for
early weeks than for later weeks. This is also true for the other
graphs described in this application.
[0201] In FIG. 18, patients are grouped into groupings labeled
"non-responders", "intermediate responders" and "responders". For
the purpose of FIG. 18, "non-responders" is defined as patients who
experience an excess weight loss of less than or equal to zero
(includes patients who gained weight). "Intermediate responders" is
defined as patients who experience an excess weight loss greater
than zero and less than or equal to 10%. "Responders" is defined as
who patients experience an excess weight greater than 10%.
[0202] FIG. 18 further supports the surprising conclusion that 30
to 180 seconds is a preferred ON time of a duty cycle. Responders
have many more such ON times than non-responders or intermediate
responders. In addition, FIG. 18 may suggest the duty cycle should
include an OFF time (period of time when a signal is not applied to
the nerve) that is short in duration in order to maximize the
number of such 30-to-180 second ON times per day.
[0203] The OFF time should be long enough to permit at least
partial recovery of the nerve from the effect of the ON time. The
data suggest that an OFF time period less than five minutes and,
more preferably, less than two minutes permits partial recovery. By
way of non-limiting examples, improved duty cycles may be (1)
2-minutes ON followed by 1-minute OFF followed by 2-minutes ON
followed by 5 minutes OFF or (2) 1.75-minutes ON followed by
1-minute OFF followed by 2.5-minutes ON followed by 5 minutes OFF.
These examples illustrate techniques to increase the number of ON
times per day and also illustrate the duration of ON times need not
be uniform. For example, the duration could be randomly distributed
within the preferred range (30 to 180 seconds).
[0204] Specifically, the effect of blocking frequencies and
recovery times on rat nerves has been studied. A rat's cervical
vagus nerve or sciatic nerve was isolated to be used as a test
nerve for study. Bipolar hook electrodes were placed in series on
the isolated nerve. An electrode applied a neural blocking signal
(e.g., a series of alternating current pulses with a frequency in
excess of a threshold blocking frequency of 200 Hz). Another
electrode connected the nerve to recording equipment to record
neural impulses.
[0205] A blocking signal (greater than 200 Hz) was applied to the
electrode for a period of time. After such period, the nerve
impulses can be recorded by the third electrode. The frequency and
duration of the blocking signal at the second electrode were varied
to observe the effect of such variables on the recorded response at
the other electrode. The amplitude of evoked fast and slow CAP
waves was measured (at the other electrode) before and after
applying blocking pulses of selected frequency and duration.
Post-block measurements were taken at time points (e.g., 0-5, 10
and 15 minutes) after discontinuing the blocking signal.
[0206] The graph of FIG. 19 shows normal (i.e., not subject to a
blocking frequency) nerve response to a stimulation signal (i.e.,
less than 200 Hz). The nerve includes three types of nerve fibers
designated A.alpha..beta., A.delta. and C fibers. The
A.alpha..beta. and A.delta. fibers are myelinated while the
C-fibers are not myelinated. Being myelinated, the A.alpha..beta.
and A.delta. fibers have faster neural impulse propagation.
[0207] The graph of FIG. 20 shows fast and slow wave components
after application of a blocking signal of 5,000 Hz for 5 minutes.
FIG. 20 shows that fast and slow components were blocked at 5,000
Hz and 1 mA-4 mA. The graph also shows CAP recovery of 50% within
two minutes post-block and by 90% within 10 minutes post-block.
[0208] From the above, an OFF time duration of less duration
permits at least partial recovery of the nerve. Therefore, a short
OFF time duration is preferred to maximize the number of ON times
experienced by a patient per day while still permitting partial
recovery of the nerve.
[0209] H. Ramp-Ups and Ramp-Downs
[0210] As a consequence of the shortened ON times from a target of
5-minutes, not many patients in the VBLOC-I study received any
ramp-down. Only those experiencing an uninterrupted 5-minute ON
time received a ramp-down. Further, patient treatments with actual
ON-times less than 20-seconds in duration, never received treatment
other than the mini-duty cycle ramp-up described above. Treatment
durations greater than 20 seconds received a full ramp-up described
above.
[0211] From the data, it was concluded that ramp-ups and ramp-downs
are not beneficial from an efficacy perspective. For patients
groups receiving the longest actual ON times (e.g., ">4 to 5
min" in FIG. 16), these include the only patients to receive a
ramp-down. These patients experienced some of the worst efficacy
correlation. Similarly, for patients for whom the ramp-up was the
highest percent of the total ON time (group "0-30 sec" in FIG. 16),
efficacy correlation was also poor.
[0212] With the foregoing detailed description of the present
invention, it has been shown how the objects of the invention have
been attained in a preferred manner. Modifications and equivalents
of disclosed concepts such as those which might readily occur to
one skilled in the art are intended to be included in the scope of
the claims which are appended hereto. For example, while the
foregoing example is described with reference to applying blocking
signals to vagus nerves to treat obesity, the invention is
applicable to other conditions associated with excess weight
amenable to treatment by down-regulating the vagus nerve. Further,
the invention is applicable to any blocking frequency applied to an
autonomic nerve. Further, the invention is applicable to duty
cycles for applying signals to the splanchnic nerves.
[0213] In the sections of this application pertaining to teachings
of the prior art, the specification from prior art patents is
substantially reproduced for ease of understanding the embodiment
of the present invention. For the purpose of the present
application, the accuracy of information in those patents is
accepted without independent verification.
* * * * *