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Weight Loss Patent Abstract
The present invention provides methods for facilitating weight loss
in a patient. In some embodiments, the methods comprise the steps
of locally administering a botulinum toxin to a stomach tissue of
an obese patient, and deploying a gastric band around the stomach
of the patient.
Weight Loss Patent Claims
1. A method for facilitating weight loss, the method comprising
the steps of:(a) administering a botulinum toxin to a stomach tissue
of a patient; and(b) deploying a gastric band around the stomach
of the patient, thereby facilitating weight loss by the patient.
2. The method of claim 1 wherein the step of administering is administering
locally.
3. The method of claim 2 wherein the botulinum toxin is administered
locally at a site or in a vicinity of the site where the gastric
band contacts the stomach.
4. The method of claim 2 wherein the botulinum toxin is administered
locally to an upper part of the stomach.
5. The method of claim 1 wherein the botulinum toxin is administered
orally.
6. The method of claim 1 wherein the step of administering the
botulinum toxin relaxes the muscle of the stomach prior to the step
of deploying the gastric band around the stomach.
7. The method of claim 1 further comprising the step of:(c) tightening
or loosening the gastric band around the stomach.
8. The method of claim 7 wherein the step of administering the
botulinum toxin relaxes a muscle of the stomach prior to the step
of tightening or loosening of the gastric band.
9. The method of claim 1 wherein the botulinum toxin is a botulinum
toxin selected from the group consisting of botulinum toxins types
A, B, C.sub.1, D, E, F and G.
10. The method of claim 1 wherein the botulinum toxin is a botulinum
toxin type A.
11. The method of claim 1 wherein the patient is an obese patient.
12. The method of claim 1 wherein the stomach tissue is a stomach
smooth muscle.
13. A method for treating obesity, the method comprising the steps
of:(a) administering a botulinum toxin type A to a muscle of a stomach
of an obese patient; and(b) deploying a gastric band around the
stomach of the patient, thereby treating the obesity.
14. The method of claim 13 further comprising the step of:(c) tightening
or loosening the gastric band around the stomach in conjunction
with a prior injection of botulinum toxin locally to the stomach
muscle tissue.
15. A method for securing a gastric band in place around the stomach,
the method comprising the steps of:(a) locally administering a botulinum
toxin to a stomach at a site or in a vicinity of a site where the
gastric band contacts the stomach, wherein the administration of
the botulinum toxin creates a contrast muscle tone region on the
stomach;(b) deploying the gastric band around the stomach, wherein
the gastric band fits into the contrast region, thereby securing
the gastric band to the stomach.
16. The method of claim 15 wherein the site of botulinum toxin
administration is on a greater curvature side of the stomach.
17. The method of claim 15 wherein the step of locally administering
the botulinum toxin is to more than one site on the stomach.
18. The method of claim 15 wherein the botulinum toxin is a botulinum
toxin selected from the group consisting of botulinum toxins types
A, B, C.sub.1, D, E, F and G.
19. The method of claim 15 wherein the botulinum toxin is a botulinum
toxin type A.
20. The method of claim 15 wherein the gastric band is secured
to the stomach by not slipping off from the stomach.
21. A method for deploying a gastric band around a stomach, the
method comprising the steps of:(a) administering a botulinum toxin
to the stomach tissue of a patient; and(b) deploying a gastric band
around the stomach of the patient.
22. The method of claim 21 wherein the botulinum toxin is administered
locally.
23. The method of claim 21 wherein the botulinum toxin is administered
locally at a site or in a vicinity of the site where the gastric
band contacts the stomach.
24. The method of claim 21 wherein the botulinum toxin is administered
locally to an upper part of the stomach.
25. The method of claim 21 wherein the botulinum toxin is administered
orally.
26. The method of claim 21 wherein the step of administering the
botulinum toxin relaxes the muscle of the stomach prior to the step
of deploying the gastric band around the stomach.
27. The method of claim 21 further comprising the step of:(c) tightening
or loosening the gastric band around the stomach.
28. The method of claim 27 wherein the step of administering the
botulinum toxin relaxes a muscle of the stomach prior to the step
of tightening or loosening of the gastric band.
29. The method of claim 21 wherein the botulinum toxin is a botulinum
toxin selected from the group consisting of botulinum toxins types
A, B, C.sub.1, D, E, F and G.
30. The method of claim 21 wherein the botulinum toxin is a botulinum
toxin type A.
31. The method of claim 21 wherein the patient is an obese patient.
32. The method of claim 21 wherein the stomach tissue is a stomach
smooth muscle.
33. A method for facilitating weight loss, the method comprising
the steps of:(a) coating a botulinum toxin onto a surface of a gastric
band intended to contact a stomach of a patient; and(b) deploying
the gastric band around the stomach of the patient, thereby facilitating
weight loss by the patient.
34. The method of claim 33 wherein the botulinum toxin is a botulinum
toxin selected from the group consisting of botulinum toxins types
A, B, C.sub.1, D, E, F and G.
35. The method of claim 33 wherein the botulinum toxin is a botulinum
toxin type A.
Weight Loss Patent Description
BACKGROUND
[0001]The present invention relates to methods for facilitating
weight loss. In particular, the present invention relates to methods
for reducing weight loss by the use of a gastric band in conjunction
with an administration of a neurotoxin, e.g., a botulinum toxin,
at or in a vicinity of the gastric band.
[0002]Affecting weight loss is one of the key steps in the treatment
of obesity. Obesity, especially morbid obesity, is a condition that
is associated with a multitude of other hazards to health that include
reduced life expectancy and has even been associated with serious
sociopsychologic and economic problems.
[0003]Gastric Bands
[0004]An effective method that has been used to facilitate weight
loss includes the deployment of a band around a portion of the stomach
creating a stoma opening that is less in diameter than the stomach
for restricting food intake into the lower digestive portion of
the stomach. The band is commonly called a gastric band. Commercially
available gastric bands are sold by Inamed, CA, USA, under the tradename
LAP-BAND.RTM. System.
[0005]Typically, the band is made of a nonextensible material and
is located on the outside of the stomach thereby prohibiting the
stoma opening to expand. An important feature of the band deployed
around the stomach is that it is adjustable. Adjustment is accomplished
by means of a balloon that lines the inside of the band. On the
day of surgery, when the band is deployed, the balloon is empty
and this provides only a slight restriction to eating. Over the
weeks and months following surgery the balloon within the band is
gradually filled (outlet is tightened) to provide progressively
increasing restriction that is matched or "tuned" to each
patient.
[0006]The balloon adjustment is accomplished using an access port
(which is buried under the skin) to increase or decrease the amount
of saline fluid contained in the balloon. This banding procedure
has been described in articles by Solhaug, "Gastric Banding:
A New Method in the Treatment of Morbid Obesity," Current Surgery,
pp. 424-428, November-December 1983; and Check, "Yet Another
Variation on Surgery for Obesity," Journal of the American
Medical Association, Vol. 248, No. 16, pp.1939,1943, Oct. 22/29,
1982.
[0007]There are several key features that make the band an attractive
surgical technique for weight loss: laparoscopic deployment, no
division or anastomosis of stomach or bowel, removable and adjustable.
The first two of the features above probably reduce the risk of
surgery, which is especially important when operating on patients
who suffer from morbid obesity. The fact that there is no cutting
or repositioning of any intestine brings the risk of leak or obstruction
to very low levels (not impossible, as outlined in the risks section
below). The fact that the procedure is almost always done laparoscopically
may allow decreased stress on the vital organs (heart, lungs, etc.)
and may allow quicker recovery in comparison to open procedures.
[0008]Removable" in the list of key features refers to the
fact that the band can be removed from the patient with little residual
impact on the stomach. This seems to be true even when the band
has eroded into the stomach, or become infected, or slipped out
of position. This is possible because the silastic substance from
which the band is made creates essentially no tissue reaction, so
that the band is not stuck in place over time. This feature also
means that the band procedure is "reversible" in a certain
sense.
[0009]The feature of the band that deserves more attention is that
it is adjustable. This is the feature that makes the band (in many
published reports) successful in helping patients achieve significant
sustained weight loss. After all, if the band were not successful,
then the decrease in operative risk would not mean much. As long
as the patient and surgeon continue to work together, it is usually
possible to adjust the band to the patient's needs at that time.
[0010]A major advantage in using the band is that it allows for
a slower weight loss. The band aims to create slower and steadier
weight loss than the results seen after most other surgical procedures.
Most weight loss operations create very rapid weight loss in the
first few months, which then slows and stabilizes at 10-18 months
after surgery. On the other hand, band patients begin with a relatively
loose band that allows ongoing intake of nutrition, and the band
is gradually "tightened" according to the patient's weight
progress and satiety symptoms. This approach aims to achieve a weight
loss of 1-2 pounds per week that continues up to or beyond 30 months
after surgery.
[0011]The use of a gastric band for facilitating weight loss has
great promise due to its simplicity and effectiveness. However,
the step of deploying the band around the stomach and/or adjusting
(i.e., tightening/loosening) the band may be challenging due to
the stiffness of the stomach. Further, after the band is deployed
around the upper stomach, the band can slip out of its correct position.
If it slips out of position, it is likely to cause obstruction of
the stomach, requiring urgent re-operation to reposition the band.
[0012]The challenges of deploying the gastric band around the stomach
and the risk of the band possibly slipping from its correct position
may compromise the full potential use of the gastric band as a technique
for affecting weight loss.
[0013]Stomach
[0014]The stomach is an expanded section of the digestive tube
between the esophagus and small intestine. The terms used to describe
the major regions of the stomach are shown in FIG. 1. The right
side of the stomach shown in FIG. 1 is called the greater curvature
and that on the left the lesser curvature. The most distal and narrow
section of the stomach is termed the pylorus--as food is liquefied
in the stomach it passes through the pyloric canal into the small
intestine.
[0015]The wall of the stomach consists of four coats: serous, muscular,
areolar, and mucous, together with vessels and nerves.
[0016]The serous coat (tunica serosa) is derived from the peritoneum,
and covers the entire surface of the organ, excepting along the
greater and lesser curvatures at the points of attachment of the
greater and lesser omenta; here the two layers of peritoneum leave
a small triangular space, along which the nutrient vessels and nerves
pass. On the posterior surface of the stomach, close to the cardiac
orifice, there is also a small area uncovered by peritoneum, where
the organ is in contact with the under surface of the diaphragm.
[0017]The muscular coat (tunica muscularis) (FIGS. 1B and 1C) is
situated immediately beneath the serous covering, with which it
is closely connected. It consists of three sets of smooth muscle
fibers: longitudinal, circular and oblique.
[0018]The longitudinal fibers (stratum longitudinale) are the most
superficial, and are arranged in two sets. The first set consists
of fibers continuous with the longitudinal fibers of the esophagus;
they radiate in a stellate manner from the cardiac orifice and are
practically all lost before the pyloric portion is reached. The
second set commences on the body of the stomach and passes to the
right, its fibers becoming more thickly distributed as they approach
the pylorus. Some of the more superficial fibers of this set pass
on to the duodenum, but the deeper fibers dip inward and interlace
with the circular fibers of the pyloric valve.
[0019]The circular fibers (stratum circulare) form a uniform layer
over the whole extent of the stomach beneath the longitudinal fibers.
At the pylorus they are most abundant, and are aggregated into a
circular ring, which projects into the lumen, and forms, with the
fold of mucous membrane covering its surface, the pyloric valve.
They are continuous with the circular fibers of the esophagus, but
are sharply marked off from the circular fibers of the duodenum.
[0020]The oblique fibers (fibr.ae butted.obliqu.ae butted.) internal
to the circular layer, are limited chiefly to the cardiac end of
the stomach, where they are disposed as a thick uniform layer, covering
both surfaces, some passing obliquely from left to right, others
from right to left, around the cardiac end.
[0021]The areolar or submucous coat (tela submucosa) consists of
a loose, areolar tissue, connecting the mucous and muscular layers.
[0022]The mucous membrane (tunica mucosa) is thick and its surface
is smooth, soft, and velvety. In the fresh state it is of a pinkish
tinge at the pyloric end, and of a red or reddish-brown color over
the rest of its surface. In infancy it is of a brighter hue, the
vascular redness being more marked. It is thin at the cardiac extremity,
but thicker toward the pylorus. During the contracted state of the
organ it is thrown into numerous plaits or rug.ae butted., which,
for the most part, have a longitudinal direction, and are most marked
toward the pyloric end of the stomach, and along the greater curvature.
These folds are entirely obliterated when the organ becomes distended.
[0023]Botulinum Toxin
[0024]The genus Clostridium has more than one hundred and twenty
seven species, grouped according to their morphology and functions.
The anaerobic, gram positive bacterium Clostridium botulinum produces
a potent polypeptide Clostridial toxin, botulinum toxin, which causes
a neuroparalytic illness in humans and animals referred to as botulism.
The spores of Clostridium botulinum are found in soil and can grow
in improperly sterilized and sealed food containers of home based
canneries, which are the cause of many of the cases of botulism.
The effects of botulism typically appear 18 to 36 hours after eating
the foodstuffs infected with a Clostridium botulinum culture or
spores. The botulinum toxin can apparently pass unattenuated through
the lining of the gut and attack peripheral motor neurons. Symptoms
of botulinum toxin intoxication can progress from difficulty walking,
swallowing, and speaking to paralysis of the respiratory muscles
and death.
[0025]Botulinum toxin type A is the most lethal natural biological
agent known to man. About 50 picograms of a commercially available
botulinum toxin type A (purified Clostridial toxin complex).sup.1
is a LD.sub.50 in mice (i.e. 1 unit). One unit of BOTOX.RTM. contains
about 50 picograms (about 56 attomoles) of botulinum toxin type
A complex. Interestingly, on a molar basis, botulinum toxin type
A is about 1.8 billion times more lethal than diphtheria, about
600 million times more lethal than sodium cyanide, about 30 million
times more lethal than cobra toxin and about 12 million times more
lethal than cholera. Singh, Critical Aspects of Bacterial Protein
Toxins, pages 63-84 (chapter 4) of Natural Toxins II, edited by
B. R. Singh et al., Plenum Press, New York (1996) (where the stated
LD.sub.50of botulinum toxin type A of 0.3 ng equals 1 U is corrected
for the fact that about 0.05 ng of BOTOX.RTM. equals 1 unit). One
unit (U) of botulinum toxin is defined as the LD.sub.50 upon intraperitoneal
injection into female Swiss Webster mice weighing 18 to 20 grams
each.
[0026]Seven immunologically distinct botulinum Clostridial toxins
have been characterized, these being respectively botulinum Clostridial
toxin serotypes A, B, C.sub.1, D, E, F and G each of which is distinguished
by neutralization with type-specific antibodies. The different serotypes
of botulinum toxin vary in the-animal species that they affect and
in the severity and duration of the paralysis they evoke. For example,
it has been determined that botulinum toxin type A is 500 times
more potent, as measured by the rate of paralysis produced in the
rat, than is botulinum toxin type B. Additionally, botulinum toxin
type B has been determined to be non-toxic in primates at a dose
of 480 U/kg which is about 12 times the primate LD.sub.50 for botulinum
toxin type A. Moyer E et al., Botulinum Toxin Type B: Experimental
and Clinical Experience, being chapter 6, pages 71-85 of "Therapy
with Botulinum Toxin", edited by Jankovic, J. et al. (1994),
Marcel Dekker, Inc. Botulinum toxin apparently binds with high affinity
to cholinergic motor neurons, is translocated into the neuron and
blocks the release of acetylcholine.
[0027]Regardless of serotype, the molecular mechanism of toxin
intoxication appears to be similar and to involve at least three
steps or stages. In the first step of the process, the toxin binds
to the presynaptic membrane of the target neuron through a specific
interaction between the heavy chain, H chain, and a cell surface
receptor; the receptor is thought to be different for each type
of botulinum toxin and for tetanus toxin. The carboxyl end segment
of the H chain, H.sub.c, appears to be important for targeting of
the toxin to the cell surface.
[0028]In the second step, the toxin crosses the plasma membrane
of the poisoned cell. The toxin is first engulfed by the cell through
receptor-mediated endocytosis, and an endosome containing the toxin
is formed. The toxin then escapes the endosome into the cytoplasm
of the cell. This step is thought to be mediated by the amino end
segment of the H chain, H.sub.N, which triggers a conformational
change of the toxin in response to a pH of about 5.5 or lower. Endosomes
are known to possess a proton pump which decreases intra-endosomal
pH. The conformational shift exposes hydrophobic residues in the
toxin, which permits the toxin to embed itself in the endosomal
membrane. The toxin (or at a minimum the light chain) then translocates
through the endosomal membrane into the cytoplasm.
[0029]The last step of the mechanism of botulinum toxin activity
appears to involve reduction of the disulfide bond joining the heavy
chain, H chain, and the light chain, L chain. The entire toxic activity
of botulinum and tetanus toxins is contained in the L chain of the
holotoxin; the L chain is a zinc (Zn++) endopeptidase which selectively
cleaves proteins essential for recognition and docking of neurotransmitter-containing
vesicles with the cytoplasmic surface of the plasma membrane, and
fusion of the vesicles with the plasma membrane. Tetanus Clostridial
toxin, botulinum toxin types B, D, F, and G cause degradation of
synaptobrevin (also called vesicle-associated membrane protein (VAMP)),
a synaptosomal membrane protein. Most of the VAMP present at the
cytoplasmic surface of the synaptic vesicle is removed as a result
of any one of these cleavage events. Botulinum toxin serotype A
and E cleave SNAP-25. Botulinum toxin serotype C.sub.1was originally
thought to cleave syntaxin, but was found to cleave syntaxin and
SNAP-25. Each of the botulinum toxins specifically cleaves a different
bond, except botulinum toxin type B (and tetanus toxin) which cleave
the same bond.
[0030]Although all the botulinum toxins serotypes apparently inhibit
release of the neurotransmitter acetylcholine at the neuromuscular
junction, they do so by affecting different neurosecretory proteins
and/or cleaving these proteins at different sites. For example,
botulinum types A and E both cleave the 25 kiloDalton (kD) synaptosomal
associated protein (SNAP-25), but they target different amino acid
sequences within this protein. Botulinum toxin types B, D, F and
G act on vesicle-associated protein (VAMP, also called synaptobrevin),
with each serotype cleaving the protein at a different site. Finally,
botulinum toxin type C.sub.1 has been shown to cleave both syntaxin
and SNAP-25. These differences in mechanism of action may affect
the relative potency and/or duration of action of the various botulinum
toxin serotypes. Apparently, a substrate for a botulinum toxin can
be found in a variety of different cell types. See e.g. Gonelle-Gispert,
C., et al., SNAP-25a and -25b isoforms are both expressed in insulin-secreting
cells and can function in insulin secretion, Biochem J.1;339 (pt
1):159-65:1999, and Boyd R. S. et al., The effect of botulinum Clostridial
toxin-B on insulin release from a .E-backward.-cell line, and Boyd
R. S. et al., The insulin secreting .E-backward.-cell line, HIT-15,
contains SNAP-25 which is a target for botulinum Clostridial toxin-A,
both published at Mov Disord, 10(3):376:1995 (pancreatic islet B
cells contains at least SNAP-25 and synaptobrevin).
[0031]The molecular weight of the botulinum toxin protein molecule,
for all seven of the known botulinum toxin serotypes, is about 150
kD. Interestingly, the botulinum toxins are released by Clostridial
bacterium as complexes comprising the 150 kD botulinum toxin protein
molecule along with associated non-toxin proteins. Thus, the botulinum
toxin type A complex can be produced by Clostridial bacterium as
900 kD, 500 kD and 300 kD forms. Botulinum toxin types B and C.sub.1
are apparently produced as only a 700 kD or 500 kD complex. Botulinum
toxin type D is produced as both 300 kD and 500 kD complexes. Finally,
botulinum toxin types E and F are produced as only approximately
300 kD complexes. The complexes (i.e. molecular weight greater than
about 150 kD) are believed to contain a non-toxin hemaglutinin protein
and a non-toxin and non-toxic nonhemaglutinin protein. These two
non-toxin proteins (which along with the botulinum toxin molecule
comprise the relevant Clostridial toxin complex) may act to provide
stability against denaturation to the botulinum toxin molecule and
protection against digestive acids when toxin is ingested. Additionally,
it is possible that the larger (greater than about 150 kD molecular
weight) botulinum toxin complexes may result in a slower rate of
diffusion of the botulinum toxin away from a site of intramuscular
injection of a botulinum toxin complex.
[0032]All the botulinum toxin serotypes are made by Clostridium
botulinum bacteria as inactive single chain proteins which must
be cleaved or nicked by proteases to become neuroactive. The bacterial
strains that make botulinum toxin serotypes A and G possess endogenous
proteases and serotypes A and G can therefore be recovered from
bacterial cultures in predominantly their active form. In contrast,
botulinum toxin serotypes C.sub.1, D, and E are synthesized by nonproteolytic
strains and are therefore typically unactivated when recovered from
culture. Serotypes B and F are produced by both proteolytic and
nonproteolytic strains and therefore can be recovered in either
the active or inactive form. However, even the proteolytic strains
that produce, for example, the botulinum toxin type B serotype only
cleave a portion of the toxin produced. The exact proportion of
nicked to unnicked molecules depends on the length of incubation
and the temperature of the culture. Therefore, a certain percentage
of any preparation of, for example, the botulinum toxin type B toxin
is likely to be inactive, possibly accounting for a lower potency
of botulinum toxin type B as compared to botulinum toxin type A.
The presence of inactive botulinum toxin molecules in a clinical
preparation will contribute to the overall protein load of the preparation,
which has been linked to increased antigenicity, without contributing
to its clinical efficacy.
[0033]Botulinum toxins and toxin complexes can be obtained from,
for example, List Biological Laboratories, Inc., Campbell, Calif.;
the Centre for Applied Microbiology and Research, Porton Down, U.K.;
Wako (Osaka, Japan), as well as from Sigma Chemicals of St Louis,
Mo. Commercially available botulinum toxin containing pharmaceutical
compositions include BOTOX.RTM. (Botulinum toxin type A Clostridial
toxin complex with human serum albumin and sodium chloride) available
from Allergan, Inc., of Irvine, Calif. in 100 unit vials as a lyophilized
powder to be reconstituted with 0.9% sodium chloride before use),
Dysport.RTM. (Clostridium botulinum type A toxin haemagglutinin
complex with human serum albumin and lactose in the formulation),
available from Ipsen Limited, Berkshire, U.K. as a powder to be
reconstituted with 0.9% sodium chloride before use), and MyoBloc.TM.(an
injectable solution comprising botulinum toxin type B, human serum
albumin, sodium succinate, and sodium chloride at about pH 5.6,
available from Elan Corporation, Dublin, Ireland).
[0034]The success of botulinum toxin type A to treat a variety
of clinical conditions has led to interest in other botulinum toxin
serotypes. Additionally, pure botulinum toxin has been used to treat
humans. See e.g. Kohl A., et al., Comparison of the effect of botulinum
toxin A (BOTOX (R)) with the highly-purified Clostridial toxin (NT
201) in the extensor digitorum brevis muscle test, Mov Disord 2000;15(Suppl
3):165. Hence, a pharmaceutical composition can be prepared using
a pure botulinum toxin.
[0035]The type A botulinum toxin is known to be soluble in dilute
aqueous solutions at pH 4-6.8. At pH above about 7 the stabilizing
nontoxic proteins dissociate from the Clostridial toxin, resulting
in a gradual loss of toxicity,. particularly as the pH and temperature
rise. Schantz E. J., et al Preparation and characterization of botulinum
toxin type A for human treatment (in particular pages 44-45), being
chapter 3 of Jankovic, J., et al, Therapy with Botulinum Toxin,
Marcel Dekker, Inc (1994).
[0036]The botulinum toxin molecule (about 150 kDa), as well as
the botulinum toxin complexes (about 300-900 kDa), such as the toxin
type A complex are also extremely susceptible to denaturation due
to surface denaturation, heat, and alkaline conditions. Inactivated
toxin forms toxoid proteins which may be immunogenic. The resulting
antibodies can render a patient refractory to toxin injection.
[0037]In vitro studies have indicated that botulinum toxin inhibits
potassium cation induced release of both acetylcholine and norepinephrine
from primary cell cultures of brainstem tissue. Additionally, it
has been reported that botulinum toxin inhibits the evoked release
of both glycine and glutamate in primary cultures of spinal cord
neurons and that in brain synaptosome preparations botulinum toxin
inhibits the release of each of the neurotransmitters acetylcholine,
dopamine, norepinephrine (Habermann E., et al., Tetanus Toxin and
Botulinum A and C Clostridial toxins Inhibit Noradrenaline Release
From Cultured Mouse Brain, J Neurochem 51(2);522-527:1988) CGRP,
substance P and glutamate (Sanchez-Prieto, J., et al., Botulinum
Toxin A Blocks Glutamate Exocytosis From Guinea Pig Cerebral Cortical
Synaptosomes, Eur J. Biochem 165;675-681:1987. Thus, when adequate
concentrations are used, stimulus-evoked release of most neurotransmitters
is blocked by botulinum toxin. See e.g. Pearce, L. B., Pharmacologic
Characterization of Botulinum Toxin For Basic Science and Medicine,
Toxicon 35(9); 1373-1412 at 1393; Bigalke H., et al., Botulinum
A Clostridial toxin Inhibits Non-Cholinergic Synaptic Transmission
in Mouse Spinal Cord Neurons in Culture, Brain Research 360;318-324:1985;
Habermann E., Inhibition by Tetanus and Botulinum A Toxin of the
release of [.sup.3H]Noradrenaline and [.sup.3H]GABA From Rat Brain
Homogenate, Experientia 44;224-226:1988, Bigalke H., et al., Tetanus
Toxin and Botulinum A Toxin Inhibit Release and Uptake of Various
Transmitters, as Studied with Particulate Preparations From Rat
Brain and Spinal Cord, Naunyn-Schmiedeberg's Arch Pharmacol 316;244-251:1981,
and; Jankovic J. et al., Therapy With Botulinum Toxin, Marcel Dekker,
Inc., (1994), page 5.
[0038]Botulinum toxin type A can be obtained by establishing and
growing cultures of Clostridium botulinum in a fermenter and then
harvesting and purifying the fermented mixture in accordance with
known procedures. All the botulinum toxin serotypes are initially
synthesized as inactive single chain proteins which must be cleaved
or nicked by proteases to become neuroactive. The bacterial strains
that make botulinum toxin serotypes A and G possess endogenous proteases
and serotypes A and G can therefore be recovered from bacterial
cultures in predominantly their active form. In contrast, botulinum
toxin serotypes C.sub.1, D and E are synthesized by nonproteolytic
strains and are therefore typically unactivated when recovered from
culture. Serotypes B and F are produced by both proteolytic and
nonproteolytic strains and therefore can be recovered in either
the active or inactive form. However, even the proteolytic strains
that produce, for example, the botulinum toxin type B serotype only
cleave a portion of the toxin produced. The exact proportion of
nicked to unnicked molecules depends on the length of incubation
and the temperature of the culture. Therefore, a certain percentage
of any preparation of, for example, the botulinum toxin type B toxin
is likely to be inactive, possibly accounting for the known significantly
lower potency of botulinum toxin type B as compared to botulinum
toxin type A. The presence of inactive botulinum toxin molecules
in a clinical preparation will contribute to the overall protein
load of the preparation, which has been linked to increased antigenicity,
without contributing to its clinical efficacy. Additionally, it
is known that botulinum toxin type B has, upon intramuscular injection,
a shorter duration of activity and is also less potent than botulinum
toxin type A at the same dose level.
[0039]High quality crystalline botulinum toxin type A can be produced
from the Hall A strain of Clostridium botulinum with characteristics
of .gtoreq.3.times.10.sup.7 U/mg, an A.sub.260/A.sub.278 of less
than 0.60 and a distinct pattern of banding on gel electrophoresis.
The known Schantz process can be used to obtain crystalline botulinum
toxin type A, as set forth in Schantz, E. J., et al, Properties
and use of Botulinum toxin and Other Microbial Clostridial toxins
in Medicine, Microbiol Rev. 56;80-99:1992. Generally, the botulinum
toxin type A complex can be isolated and purified from an anaerobic
fermentation by cultivating Clostridium botulinum type A in a suitable
medium. The known process can also be used, upon separation out
of the non-toxin proteins, to obtain pure botulinum toxins, such
as for example: purified botulinum toxin type A with an approximately
150 kD molecular weight with a specific potency of 1-2.times.10.sup.8
LD.sub.50 U/mg or greater; purified botulinum toxin type B with
an approximately 156 kD molecular weight with a specific potency
of 1-2.times.10.sup.8 LD.sub.50 U/mg or greater, and; purified botulinum
toxin type F with an approximately 155 kD molecular weight with
a specific potency of 1-2.times.10.sup.7 LD.sub.50 U/mg or greater.
[0040]Either the pure botulinum toxin (i.e. the 150 kilodalton
botulinum toxin molecule) or the toxin complex can be used to prepare
a pharmaceutical composition. Both molecule and complex are susceptible
to denaturation due to surface denaturation, heat, and alkaline
conditions. Inactivated toxin forms toxoid proteins which may be
immunogenic. The resulting antibodies can render a patient refractory
to toxin injection.
[0041]As with enzymes generally, the biological activities of the
botulinum toxins (which are intracellular peptidases) is dependant,
at least in part, upon their three dimensional conformation. Thus,
botulinum toxin type A is detoxified by heat, various chemicals
surface stretching and surface drying. Additionally, it is known
that dilution of the toxin complex obtained by the known culturing,
fermentation and purification to the much, much lower toxin concentrations
used for pharmaceutical composition formulation results in rapid
detoxification of the toxin unless a suitable stabilizing agent
is present. Dilution of the toxin from milligram quantities to a
solution containing nanograms per milliliter presents significant
difficulties because of the rapid loss of specific toxicity upon
such great dilution. Since the toxin may be used months or years
after the toxin containing pharmaceutical composition is formulated,
the toxin can stabilized with a stabilizing agent such as albumin
and gelatin.
[0042]A commercially available botulinum toxin containing pharmaceutical
composition is sold under the trademark BOTOX.RTM. (available from
Allergan, Inc., of Irvine, Calif.). BOTOX.RTM. consists of a purified
botulinum toxin type A complex, albumin and sodium chloride packaged
in sterile, vacuum-dried form. The botulinum toxin type A is made
from a culture of the Hall strain of Clostridium botulinum grown
in a medium containing N-Z amine and yeast extract. The botulinum
toxin type A complex is purified from the culture solution by a
series of acid precipitations to a crystalline complex consisting
of the active high molecular weight toxin protein and an associated
hemagglutinin protein. The crystalline complex is re-dissolved in
a solution containing saline and albumin and sterile filtered (0.2
microns) prior to vacuum-drying. The vacuum-dried product is stored
in a freezer at or below -5.degree. C. BOTOX.RTM. can be reconstituted
with sterile, non-preserved saline prior to intramuscular injection.
Each vial of BOTOX.RTM. contains about 100 units (U) of Clostridium
botulinum toxin type A purified Clostridial toxin complex, 0.5 milligrams
of human serum albumin and 0.9 milligrams of sodium chloride in
a sterile, vacuum-dried form without a preservative.
[0043]To reconstitute vacuum-dried BOTOX.RTM., sterile normal saline
without a preservative; (0.9% Sodium Chloride Injection) is used
by drawing up the proper amount of diluent in the appropriate size
syringe. Since BOTOX.RTM. may be denatured by bubbling or similar
violent agitation, the diluent is gently injected into the vial.
For sterility reasons BOTOX.RTM. is preferably administered within
four hours after the vial is removed from the freezer and reconstituted.
During these four hours, reconstituted BOTOX.RTM. can be stored
in a refrigerator at about 2.degree. C. to about 8.degree. C. Reconstituted,
refrigerated BOTOX.RTM. has been reported to retain its potency
for at least about two weeks. Neurology, 48:249-53:1997.
[0044]Botulinum toxins have been used in clinical settings for
the treatment of neuromuscular disorders characterized by hyperactive
skeletal muscles. Botulinum toxin type A (BOTOX.RTM.) was approved
by the U.S. Food and Drug Administration in 1989 for the treatment
of essential blepharospasm, strabismus and hemifacial spasm in patients
over the age of twelve. In 2000 the FDA approved commercial preparations
of type A (BOTOX.RTM.) and type B botulinum toxin (MyoBloc.TM.)
serotypes for the treatment of cervical dystonia, and in 2002 the
FDA approved a type A botulinum toxin (BOTOX.RTM.) for the cosmetic
treatment of certain hyperkinetic (glabellar) facial wrinkles. Clinical
effects of peripheral intramuscular botulinum toxin type A are usually
seen within one week of injection and sometimes within a few hours.
The typical duration of symptomatic relief (i.e. flaccid muscle
paralysis) from a single intramuscular injection of botulinum toxin
type A can be about three months, although in some cases the effects
of a botulinum toxin induced denervation of a gland, such as a salivary
gland, have been reported to last for several years. For example,
it is known that botulinum toxin type A can have an efficacy for
up to 12 months (Naumann M., et al., Botulinum toxin type A in the
treatment of focal, axillary and palmar hyperhidrosis and other
hyperhidrotic conditions, European J. Neurology 6 (Supp 4): S111-S115:1999),
and in some circumstances for as long as 27 months. Ragona, R. M.,
et al., Management of parotid sialocele with botulinum toxin, The
Laryngoscope 109:1344-1346:1999. However, the usual duration of
an intramuscular injection of BOTOX.RTM. is typically about 3 to
4 months.
[0045]It has been reported that a botulinum toxin type A has been
used in diverse clinical settings, including for example as follows:
[0046](1) about 75-125 units of BOTOX.RTM. per intramuscular injection
(multiple muscles) to treat cervical dystonia;
[0047](2) 5-10 units of BOTOX.RTM. per intramuscular injection
to treat glabellar lines (brow furrows) (5 units injected intramuscularly
into the procerus muscle and 10 units injected intramuscularly into
each corrugator supercilii muscle);
[0048](3) about 30-80 units of BOTOX.RTM. to treat constipation
by intrasphincter injection of the puborectalis muscle;
[0049](4) about 1-5 units per muscle of intramuscularly injected
BOTOX.RTM. to treat blepharospasm by injecting the lateral pre-tarsal
orbicularis oculi muscle of the upper lid and the lateral pre-tarsal
orbicularis oculi of the lower lid.
[0050](5) to treat strabismus, extraocular muscles have been injected
intramuscularly with between about 1-5 units of BOTOX.RTM., the
amount injected varying based upon both the size of the muscle to
be injected and the extent of muscle paralysis desired (i.e. amount
of diopter correction desired).
[0051](6) to treat upper limb spasticity following stroke by intramuscular
injections of BOTOX.RTM. into five different upper limb flexor muscles,
as follows: [0052](a) flexor digitorum profundus: 7.5 U to 30 U
[0053](b) flexor digitorum sublimus: 7.5 U to 30 U [0054](c) flexor
carpi ulnaris: 10 U to 40 U [0055](d) flexor carpi radialis: 15
U to 60 U [0056](e) biceps brachii: 50 U to 200 U. Each of the five
indicated muscles has been injected at the same treatment session,
so that the patient receives from 90 U to 360 U of upper limb flexor
muscle BOTOX.RTM. by intramuscular injection at each treatment session.
[0057](7) to treat migraine, pericranial injected (injected symmetrically
into glabellar, frontalis and temporalis muscles) injection of 25
U of BOTOX.RTM. has showed significant benefit as a prophylactic
treatment of migraine compared to vehicle as measured by decreased
measures of migraine frequency, maximal severity, associated vomiting
and acute medication use over the three month period following the
25 U injection.
[0058]Additionally, intramuscular botulinum toxin has been used
in the treatment of tremor in patients with Parkinson's disease,
although it has been reported that results have not been impressive.
Marjama-Lyons, J., et al., Tremor-Predominant Parkinson's Disease,
Drugs & Aging 16(4);273-278:2000.
[0059]Treatment of certain gastrointestinal and smooth muscle disorders
with a botulinum toxin are known. See e.g. U.S. Pat. Nos. 5,427,291
and 5,674,205 (Pasricha). Additionally, transurethral injection
of a botulinum toxin into a bladder sphincter to treat a urination
disorder is known (see e.g. Dykstra, D. D., et al, Treatment of
detrusor-sphincter dyssynergia with botulinum A toxin: A double-blind
study, Arch Phys Med Rehabil 1990 January;71:24-6), as is injection
of a botulinum toxin into the prostate to treat prostatic hyperplasia.
See e.g. U.S. Pat. No. 6,365,164 (Schmidt).
[0060]U.S. Pat. No. 5,766,605 (Sanders) proposes the treatment
of various autonomic disorders, such as excessive stomach acid secretion,
hypersalivation, rhinittis, with a botulinum toxin. Additionally,
It is known that nasal hypersecretion is predominantly caused by
over activity of nasal glands, which are mainly under cholinergic
control and it has been demonstrated that application of botulinum
toxin type A to mammalian nasal mucosal tissue of the maxillary
sinus turbinates can induce a temporary apoptosis in the nasal glands.
Rohrbach S., et al., Botulinum toxin type A induces apoptosis in
nasal glands of guinea pigs, Ann Otol Rhinol Laryngol 2001 November;110(11):1045-50.
Furthermore, local application of botulinum toxin A to a human female
patient with intrinsic rhinitis resulted in a clear decrease of
the nasal hypersecretion within five days. Rohrbach S., et al.,
Minimally invasive application of botulinum toxin type A in nasal
hypersecretion, J Oto-Rhino-Laryngol 2001 November-December.;63(6):382-4.
[0061]Various afflictions, such as hyperhydrosis and headache,
treatable with a botulinum toxin are discussed in WO 95/17904 (PCT/US94/14717)
(Aoki). EP 0 605 501 B1 (Graham) discusses treatment of cerebral
palsy with a botulinum toxin and U.S. Pat. No. 6,063,768 (First)
discusses treatment of neurogenic inflammation with a botulinum
toxin.
[0062]In addition to having pharmacologic actions at the peripheral
location, botulinum toxins can also have inhibitory effects in the
central nervous system. Work by Weigand et al, (.sup.125I-labelled
botulinum A Clostridial toxin:pharmacokinetics in cats after intramuscular
injection, Nauny-Schmiedeberg's Arch. Pharmacol. 1976; 292, 161-165),
and Habermann, (.sup.125I-labelled Clostridial toxin from clostridium
botulinum A: preparation, binding to synaptosomes and ascent to
the spinal cord, Nauny-Schmiedeberg's Arch. Pharmacol. 1974; 281,
47-56) showed that botulinum toxin is able to ascend to the spinal
area by retrograde transport. As such, a botulinum toxin injected
at a peripheral location, for example intramuscularly, may be retrograde
transported to the spinal cord.
[0063]In vitro studies have indicated that botulinum toxin inhibits
potassium cation induced release of both acetylcholine and norepinephrine
from primary cell cultures of brainstem tissue. Additionally, it
has been reported that botulinum toxin inhibits the evoked release
of both glycine and glutamate in primary cultures of spinal cord
neurons and that in brain synaptosome preparations botulinum toxin
inhibits the release of each of the neurotransmitters acetylcholine,
dopamine, norepinephrine, CGRP and glutamate.
[0064]U.S. Pat. No. 5,989,545 discloses that a modified Clostridial
toxin or fragment thereof, preferably a botulinum toxin, chemically
conjugated or recombinantly fused to a particular targeting moiety
can be used to treat pain by administration of the agent to the
spinal cord.
[0065]A botulinum toxin has also been proposed for the treatment
of hyperhydrosis (excessive sweating, U.S. Pat. No. 5,766,605),
headache, (U.S. Pat. No. 6,458,365), migraine headache (U.S. Pat.
No. 5,714,468), post-operative pain and visceral pain (U.S. Pat.
No. 6,464,986), pain by intraspinal administration (U.S. Pat. No.
6,113,915), Parkinson's disease by intracranial administration (U.S.
Pat. No. 6,306,403), hair growth and hair retention (U.S. Pat. No.
6,299,893), psoriasis and dermatitis (U.S. Pat. No. 5,670,484),
injured muscles (U.S. Pat No. 6,423,319, various cancers (U.S. Pat.
No. 6,139,845), pancreatic disorders (U.S. Pat. No. 6,143,306),
smooth muscle disorders (U.S. Pat. No. 5,437,291, including injection
of a botulinum toxin into the upper and lower esophageal, pyloric
and anal sphincters), prostate disorders (U.S. Pat. No. 6,365,164),
inflammation, arthritis and gout (U.S. Pat. No. 6,063,768), juvenile
cerebral palsy (U.S. Pat. No. 6,395,277), inner ear disorders (U.S.
Pat. No. 6,265,379), thyroid disorders (U.S. Pat. No. 6,358,513),
parathyroid disorders (U.S. Pat. No. 6,328,977). Additionally, controlled
release toxin implants are known (U.S. Pat. Nos. 6,306,423 and 6,312,708).
[0066]It has been reported that that intravenous injection of a
botulinum toxin causes a decline of pentagastrin stimulated acid
and pepsin secretion in rats. Kondo T., et al., Modification of
the action of pentagastrin on acid secretion by botulinum toxin,
Experientia 1977;33:750-1. Additionally it has been speculated that
a botulinum toxin can be used to reduce a gastrointestinal secretion,
such as a gastric secretion. See pages 16-17 of WO 95/17904. Furthermore,
a botulinum toxin has been proposed for the treatment of disorders
of gastrointestinal muscle in the enteric nervous system disorder
(U.S. Pat. No. 5,437,291) and well as to treat various autonomic
disorders (U.S. Pat. No. 5,766,605). Botulinum toxin has been injected
into the fundus of the stomach of dogs. Wang Z., et al., Effects
of botulinum toxin on gastric myoelectrical and vagal activities
in dogs, Gastroenterology 2001 April;120(5 Suppl 1):A-718. Additionally,
intramuscular injection of a botulinum toxin into the gastric antrum
has been proposed as a treatment for obesity. See e.g. Gui D., et
al., Effects of botulinum toxin on gastric emptying and digestive
secretions. A possible tool for correction of obesity?, Naunyn Schmiedebergs
Arch Pharmacol 2002 June;365(Suppl 2):R22; Albanese A., et al.,
The use of botulinum toxin on smooth muscles, Eur J Neurol 1995
November;2(Supp 3):29-33, and; Gui D., et al., Botulinum toxin injected
in the gastric wall reduces body weight and food intake in rats,
Aliment Pharmacol Ther 2000 June; 14(6):829-834 . Furthermore, botulinum
toxin type A has been proposed as a therapeutic application for
the control of secretion in the stomach. Rossi S., et al., Immunohistochemical
localization of SNAP-25 protein in the stomach of rat, Naunyn Schmiedebergs
Arch Pharmacol 2002;365(Suppl 2):R37.
[0067]Significantly, it has been reported that injection of a botulinum
toxin into the lower esophageal sphincter for the treatment of achalasia
results in the formation of ulcers in the esophagus. Eaker, E. Y.,
et al., Untoward effects of esophageal botulinum toxin injection
in the treatment of achalasia, Dig Dis Sci 1997 April;42(4):724-7.
It is know to inject a botulinum toxin into a spastic pyloric sphincter
of a patient with a prepyloric ulcer in order to permit the pyloric
muscle to open. Wiesel P. H. et al., Botulinum toxin for refractory
postoperative pyloric spasm, Endoscopy 1997;29(2): 132.
[0068]It is known to inject a botulinum toxin into the stomach
wall of a patient to treat obesity by reducing stomach muscle contractions
(see e.g. Rolnik J., et al., Antral Injections of botulinum toxin
for the treatment of obesity, Ann Intern Med 2003 February, 18;138(4):359-360;2003,
Miller L., WO 02/13854 A1, Obesity controlling method, published
Feb. 21, 2002; Gui, D. et al., Botulinum toxin injected in the gastric
wall reduces body weight and food intake in rats, Aliment Pharmacol
Ther 2000 June; 14(6):829-834; Gui D. et al., Effects of botulinum
toxin on gastric emptying and digestive secretions. A possible tool
for correction of obesity?, Naunyn Schmiedebergs Arch Pharmacol
2002 June; 365(Suppl 2): R22; Albanese A., et al., The use of botulinum
toxin on smooth muscles, Eur J Neurol 1995 November; 2 (Supp 3):
29-33; Albanese A. et al., Review article: the use of botulinum
toxin in the alimentary tract, Ailment Pharmacol Ther 1995; 9: 599-604.
[0069]Tetanus toxin, as wells as derivatives (i.e. with a non-native
targeting moiety), fragments, hybrids and chimeras thereof can also
have therapeutic utility. The tetanus toxin bears many similarities
to the botulinum toxins. Thus, both the tetanus toxin and the botulinum
toxins are polypeptides made by closely related species of Clostridium
(Clostridium tetani and Clostridium botulinum, respectively). Additionally,
both the tetanus toxin and the botulinum toxins are dichain proteins
composed of a light chain (molecular weight about 50 kD) covalently
bound by a single disulfide bond to a heavy chain (molecular weight
about 100 kD). Hence, the molecular weight of tetanus toxin and
of each of the seven botulinum toxins (non-complexed) is about 150
kD. Furthermore, for both the tetanus toxin and the botulinum toxins,
the light chain bears the domain which exhibits intracellular biological
(protease) activity, while the heavy chain comprises the receptor
binding (immunogenic) and cell membrane translocational domains.
[0070]Further, both the tetanus toxin and the botulinum toxins
exhibit a high, specific affinity for gangliocide receptors on the
surface of presynaptic cholinergic neurons. Receptor mediated endocytosis
of tetanus toxin by peripheral cholinergic neurons results in retrograde
axonal transport, blocking of the release of inhibitory neurotransmitters
from central synapses and a spastic paralysis. Contrarily, receptor
mediated endocytosis of botulinum toxin-by peripheral cholinergic
neurons results in little if any retrograde transport, inhibition
of acetylcholine exocytosis from the intoxicated peripheral motor
neurons and a flaccid paralysis.
[0071]Finally, the tetanus toxin and the botulinum toxins resemble
each other in both biosynthesis and molecular architecture. Thus,
there is an overall 34% identity between the protein sequences of
tetanus toxin and botulinum toxin type A, and a sequence identity
as high as 62% for some functional domains. Binz T. et al., The
Complete Sequence of Botulinum Clostridial toxin Type A and Comparison
with Other Clostridial toxins, J Biological Chemistry 265(16);9153-9158:1990.
[0072]Acetylcholine
[0073]Typically only a single type of small molecule neurotransmitter
is released by each type of neuron in the mammalian nervous system.
The neurotransmitter acetylcholine is secreted by neurons in many
areas of the brain, but specifically by the large pyramidal cells
of the motor cortex, by several different neurons in the basal ganglia,
by the motor neurons that innervate the skeletal muscles, by the
preganglionic neurons of the autonomic nervous system (both sympathetic
and parasympathetic), by the postganglionic neurons of the parasympathetic
nervous system, and by some of the postganglionic neurons of the
sympathetic nervous system. Essentially, only the postganglionic
sympathetic nerve fibers to the sweat glands, the piloerector muscles
and a few blood vessels are cholinergic as most of the postganglionic
neurons of the sympathetic nervous system secret the neurotransmitter
norepinephrine. In most instances acetylcholine has an excitatory
effect. However, acetylcholine is known to have inhibitory effects
at some of the peripheral parasympathetic nerve endings, such as
inhibition of heart rate by the vagal nerve.
[0074]The efferent signals of the autonomic nervous system are
transmitted to the body through either the sympathetic nervous system
or the parasympathetic nervous system. The preganglionic neurons
of the sympathetic nervous system extend from preganglionic sympathetic
neuron cell bodies located in the intermediolateral horn of the
spinal cord. The preganglionic sympathetic nerve fibers, extending
from the cell body, synapse with postganglionic neurons located
in either a paravertebral sympathetic ganglion or in a prevertebral
ganglion. Since the preganglionic neurons of both the sympathetic
and parasympathetic nervous system are cholinergic, application
of acetylcholine to the ganglia will excite both sympathetic and
parasympathetic postganglionic neurons.
[0075]Acetylcholine activates two types of receptors, muscarinic
and nicotinic receptors. The muscarinic receptors are found in all
effector cells stimulated by the postganglionic, neurons of the
parasympathetic nervous system as well as in those stimulated by
the postganglionic cholinergic neurons of the sympathetic nervous
system. The nicotinic receptors are found in the adrenal medulla,
as well as within the autonomic ganglia, that is on the cell surface
of the postganglionic neuron at the synapse between the preganglionic
and postganglionic neurons of both the sympathetic and parasympathetic
systems. Nicotinic receptors are also found in many nonautonomic
nerve endings, for example in the membranes of skeletal muscle fibers
at the neuromuscular junction.
[0076]Acetylcholine is released from cholinergic neurons when small,
clear, intracellular vesicles fuse with the presynaptic neuronal
cell membrane. A wide variety of non-neuronal secretory cells, such
as, adrenal medulla (as well as the PC12 cell line) and pancreatic
islet cells release catecholamines and parathyroid hormone, respectively,
from large dense-core vesicles. The PC12 cell line is a clone of
rat pheochromocytoma cells extensively used as a tissue culture
model for studies of sympathoadrenal development. Botulinum toxin
inhibits the release of both types of compounds from both types
of cells in vitro, permeabilized (as by electroporation) or by direct
injection of the toxin into the denervated cell. Botulinum toxin
is also known to block release of the neurotransmitter glutamate
from cortical synaptosomes cell cultures.
[0077]A neuromuscular junction is formed in skeletal muscle by
the proximity of axons to muscle cells. A signal transmitted through
the nervous system results in an action potential at the terminal
axon, with activation of ion channels and resulting release of the
neurotransmitter acetylcholine from intraneuronal synaptic vesicles,
for example at the motor endplate of the neuromuscular junction.
The acetylcholine crosses the extracellular space to bind with acetylcholine
receptor proteins on the surface of the muscle end plate. Once sufficient
binding has occurred, an action potential of the muscle cell causes
specific membrane ion channel changes, resulting in muscle cell
contraction. The acetylcholine is then released from the muscle
cells and metabolized by cholinesterases in the extracellular space.
The metabolites are recycled back into the terminal axon for reprocessing
into further acetylcholine.
[0078]As discussed above, the challenges of deploying the gastric
band around the stomach and the risk of the band possibly slipping
from its intended position may compromise the full potential use
of the gastric band as a technique for affecting weight loss.
[0079]What is needed therefore is an improved method for facilitating
weight loss.
SUMMARY
[0080]The present invention meets this need and provides for improved
methods for facilitating the successful use of a gastric band leading
weight loss in a patient. For example, the present invention allows
the surgeon to maneuver the gastric band around the stomach more
easily and/or to secure the band and prevent it from slipping off
from the stomach.
[0081]In some embodiments, the methods comprise the steps of administering
a neurotoxin to a stomach tissue of a patient, and deploying a gastric
band around the stomach of the patient. The neurotoxin (e.g., botulinum
toxin types A, B, C.sub.1, D, E, F and G) may be locally administered
or orally administered. In some embodiments, the neurotoxin is locally
administered at or in a vicinity of the site where the gastric band
contacts the stomach, for example, the upper part of the stomach.
[0082]In some embodiments, the neurotoxin is administered to a
stomach tissue prior to the step of deploying a gastric band around
the stomach. One of the advantages in pre-administering the stomach
with a neurotoxin is that it relaxes the stomach and makes it more
malleable. When the stomach is relaxed and is more malleable, it
is easier for the surgeon to maneuver the band around the stomach,
which would result in reduced operation time and faster recovery.
[0083]Another advantage of pre-administering the stomach tissue
prior to deploying the gastric band around the stomach is that the
stomach is relaxed and it is easier to adjust (e.g., tighten or
loosen) the band around the stomach.
[0084]In some embodiments, the neurotoxin is administered at or
in the vicinity of the site where the gastric band contacts the
stomach. One of the advantages of locally administering a neurotoxin
at a site or in the vicinity of the site where the gastric band
contacts the stomach is that the band is better fitted at that site
and would tend not to slip from that site. Without wishing to limit
the invention to any theory or mechanism of operation, it is believed
that the administration of the neurotoxin at or in the vicinity
of the site where the band contacts the stomach creates a contrast
region in muscle tone that would serve to secure the gastric band
in place. For example, when the neurotoxin is administered at the
site where the band contacts the stomach, the site administered
has a relaxed muscle tone (see FIG. 2A). The gastric band would
tend to "fall" into the region with the relaxed muscle
tone--thus, the band would be secured in its intended site. In some
embodiments, the gastric band is secured in that it does not twist
around the stomach. In some embodiments, the gastric band is secured
in that it does not slip off from the stomach.
[0085]Alternatively, the neurotoxin may be administered in the
vicinity of the site where the band contacts the gastric band to
create a contrast muscle tone region that would serve to secure
the band in place. For example, a neurotoxin may be administered
at a site above and/or below the site where the gastric band contacts
the stomach (see FIG. 2B). This pattern of administration would
create a contrast in muscle tone region such that the gastric band
would tend to "fall" into the region that is not administered.
[0086]The term "neurotoxin" employed herein refers to
one or more of a toxin made by a bacterium, for example, a Clostridium
botulinum, Clostridium butyricum, Clostridium beratti, Clostridium
tetani. In some embodiments, the neurotoxin is a botulinum toxin.
The botulinum toxin may be a botulinum toxin type A, type B, type
C.sub.1, type D, type E, type F, or type G. In some embodiments,
the neurotoxin is a botulinum toxin type A. Unless stated otherwise,
the dose of the neurotoxin referenced herein is equivalent to that
of a botulinum toxin type A. The assays required to determine equivalency
to the therapeutic effectiveness of botulinum toxin type A at a
certain dosage are well established.
[0087]Further, the botulinum toxin of the present invention may
comprise a first element comprising a binding element able to specifically
bind to a neuronal cell surface receptor under physiological conditions;
a second element comprising a translocation element able to facilitate
the transfer of a polypeptide across a neuronal cell membrane, and
a third element comprising a therapeutic element able, when present
in the cytoplasm of a neuron, to inhibit exocytosis of acetylcholine
from the neuron. The therapeutic element can cleave a SNARE protein,
thereby inhibiting the exocytosis of acetylcholine from the neuron.
The SNARE protein can be selected from the group consisting of syntaxin,
SNAP-25 and VAMP.
DEFINITIONS
[0088]The following definitions apply herein.
[0089]About" means plus or minus ten percent of the value
so qualified.
[0090]Biocompatible" means that there is an insignificant
inflammatory response upon ingestion of an oral formulation of a
Clostridial toxin, as set forth herein.
[0091]Effective amount" as applied to the biologically active
compound means that amount of the compound which is generally sufficient
to effect a desired change in the subject. For example, where the
desired effect is decreasing the muscle tone of the stomach, an
effective amount of the compound is that amount which causes at
least a substantial decrease in the muscle tone of the stomach as
determined by the pressure needed to be applied to tighten the gastric
band around the stomach.
[0092]Effective amount" as applied to a non-active ingredient
constituent of an oral formulation (such as a polymer used for forming
a matrix or a coating composition) refers to that amount of the
non-active ingredient constituent which is sufficient to positively
influence the release of a biologically active agent at a desired
rate for a desired period of time. For example, where the desired
effect is muscle paralysis by using a single oral formulation, the
"effective amount" is the amount that can facilitate extending
the release over a period of between about 60 days and 6 years.
This "effective amount" can be determined based on the
is teaching in this specification and the general knowledge in the
art.
[0093]Effective amount" as applied to the amount of surface
area of an oral formulation is that amount of oral formulation surface
area which is sufficient to effect a flux of biologically active
compound so as to achieve a desired effect, such as a muscle paralysis
or a decrease in the secretory activity of a gland. The area necessary
may be determined and adjusted directly by measuring the release
obtained for the particular active compound. The surface area of
the oral formulation or of a coating of an oral formulation is that
amount of membrane necessary to completely encapsulate the biologically
active compound. The surface area depends on the geometry of the
oral formulation. Preferably, the surface area is minimized where
possible, to reduce the size of the oral formulation.
[0094]Locally administering" or "local administration"
means direct injection of a tissue, e.g., stomach tissue. For example,
local administration to a stomach tissue may be accomplished by
using an endoscope and a sclerotherapy needle (see U.S. Pat. No.
5,437,291, the disclosure of which is incorporated in its entirety
herein by reference).
[0095]Oral formulation" means a drug delivery system intended
for oral ingestion. The oral formulation can be comprised of a biocompatible
polymer or natural material which contains or which can act as a
carrier for a molecule with a biological activity.
[0096]Deploying" a gastric band around the stomach means wrapping
the band around the stomach and positioning it at a desirable location,
so that when tightened, the band pinches the stomach into an upper
and a lower portion.
[0097]Treatment" means any treatment of a disease (obesity)
in a mammal, and includes: (i) preventing the disease from occurring
or; (ii) inhibiting the disease, i.e., arresting its development;
(iii) relieving the disease, i.e., reducing the incidence of symptoms
of or causing regression of the disease.
DRAWINGS
[0098]FIGS. 1A, 1B and 1C show the general diagram of the stomach;
the longitudinal and circular muscular fibers of the stomach, viewed
from above and in front; and the oblique muscular fibers of the
stomach, viewed from above and in front, respectively.
[0099]FIGS. 2A and 2B show examples of an administration of a neurotoxin
at a site where the gastric band contacts the stomach, and in the
vicinity of the site where the gastric band contacts the stomach.
[0100]FIG. 3 shows a cross-sectional view of the torso of a patient
showing the placement of trocars for the introduction of a laparoscopic
gastric band.
[0101]FIG. 4 shows the insertion of a modified flexible endoscope
into the upper abdomen.
[0102]FIG. 5 shows a perspective view of the flexible endoscope
with a light on the tip to facilitate dissection along the lesser
curvature of the stomach.
[0103]FIG. 6 shows forceps inserted through the lumen of the endoscope
prior to grasping the tail end of a gastric band.
[0104]FIG. 7 is a perspective view of the gastric band being held
for adjustment of the stoma size during the calibration procedure.
[0105]FIG. 8 shows the gastric band in position around the stomach
with an injection port passing underneath the liver and threaded
into the space within the rectus sheath for implantation.
DESCRIPTION
[0106]The present invention is partly based upon the surprising
discovery that an administration of a neurotoxin, such as a botulinum
toxin, to a stomach tissue allows the gastric band to be more easily
maneuvered around the stomach and subsequently adjusted (e.g., tightened
or loosened). The present invention is also partly based on the
surprising discovery that an administration of a neurotoxin at or
in the vicinity of a site of the gastric band helps secure the band
and prevents it from slipping off from the stomach.
[0107]In some embodiments, the methods comprise the steps of administering
a neurotoxin to a stomach tissue of a patient, and deploying a gastric
band around the stomach of the patient. In some embodiments, the
stomach tissue is a smooth muscle of the stomach, e.g., longitudinal,
circular and/or oblique. In some embodiments, the neurotoxin is
administered to the circular muscle of the stomach.
[0108]The neurotoxin (e.g., botulinum toxin types A, B, C.sub.1,
D, E, F and G) may be locally administered. The neurotoxin may be
locally administered using an endoscopic and/or laparoscopic procedure
(see Example 2 below). In some embodiments, the neurotoxin is administered
generally around the area where the gastric band is to be deployed.
In some embodiments, the neurotoxin is administered to a stomach
tissue prior to the step of deploying a gastric band around the
stomach.
[0109]Various references have disclosed an endoscopic administration
of botulinum toxin to a stomach to treat obesity. See, for example,
Porta et al. (Mov Disord 2004, 19(9):S431 ABP1264); Albani et al.
(J. Gastroenterol 2005, 40:833-835); Garcia-Compean et al. (Gastroenterol
Clin Biol 2005, 29(8-9):789-791); U.S. Pat. App. Pub. 20040009224
to Miller; and U.S. Pat. App. Pub. 20040037865. These references
disclose that the administration of a botulinum toxin to the stomach
is effective to reduce motility of the stomach muscle (to slow down
stomach emptying) and/or reduce the secretion of ghrelin, which
presents a powerful signal of "hunger sensation" to the
hypothalamus. However, the references do not teach or suggest that
an administration of a neurotoxin, such as a neurotoxin, can be
used in conjunction with a gastric band. More specifically, these
references do not teach or suggest that an administration of a neurotoxin
to a stomach tissue allows the gastric band to be more easily maneuvered
around the stomach and subsequently adjusted (e.g., tightened or
loosened), or that an administration of a neurotoxin at or in the
vicinity of a site of the gastric band helps secure the band and
prevents it from slipping off from the stomach.
[0110]In some embodiments, the neurotoxin is orally administered.
The neurotoxin may be administered to the stomach via an oral ingestion
of a neurotoxin oral formulation. For example, a neurotoxin oral
formulation within the scope of the present invention is capable
of releasing a effective amount of a neurotoxin into the stomach
of a patient to relax the stomach muscle. The amount of released
neurotoxin can comprise as little as about 10 units (based on the
units of botulinum toxin type A) (i.e. to relax the stomach muscle
of a patient weighing less than 50 kg) to as much as 500 units (i.e.
to relax the stomach muscle of a large adult). The quantity of botulinum
toxin required to effectively relax a stomach muscle can be varied
according to the known clinical potency of the different neurotoxins,
e.g., botulinum toxin serotypes. For example, several orders of
magnitude more units of a botulinum toxin type B are typically required
to achieve a physiological effect comparable to that achieved from
use of a botulinum toxin type A.
[0111]The specific dosage by oral formulation appropriate for administration
is readily determined by one of ordinary skill in the art according
to the factors discussed above. The dosage can also depend upon
the size of the tissue mass to be treated or denervated, and the
commercial preparation of the toxin. Additionally, the estimates
for appropriate dosages in humans can be extrapolated from determinations
of the amounts of botulinum required for effective denervation of
other tissues. Thus, the amount of botulinum A to be injected is
proportional to the mass and level of activity of the tissue to
be treated. Generally, between about 0.01 units per kilogram to
about 35 units per kg of patient weight of a botulinum toxin, such
as botulinum toxin type A, can be released by the present oral formulation
per unit time period (i.e. over a period of or once every 2-4 months)
to effectively accomplish a desired relaxation of the stomach muscle.
Less than about 0.01 U/kg of a botulinum toxin may not have a significant
therapeutic effect upon a stomach endocrine cell, while more than
about 35 U/kg of a botulinum toxin approaches a toxic dose of a
Clostridial toxin, such as a botulinum toxin type A. Careful preparation
of the oral formulation prevents significant amounts of a botulinum
toxin from appearing systemically. A more preferred dose range is
from about 0.01 U/kg to about 25 U/kg of a botulinum toxin, such
as that formulated as BOTOX.RTM.. The actual amount of U/kg of a
botulinum toxin to be administered depends upon factors such as
the extent (mass) and level of activity of the tissue to be treated
and the administration route chosen. Botulinum toxin type A is a
preferred botulinum toxin serotype for use in the methods of the
present invention.
[0112]The oral formulation may be prepared so that the neurotoxin
is substantially uniformly dispersed in a biodegradable carrier.
An alternate oral formulation within the scope of the present invention
can comprise a carrier coated by a biodegradable coating, either
the thickness of the coating or the coating material being varied.
[0113]The thickness of the oral formulation can be used to control
the absorption of water by, and thus the rate of release of a neurotoxin
from, a composition of the invention, thicker oral formulations
releasing the polypeptide neurotoxin more slowly than thinner ones.
[0114]The neurotoxin in a neurotoxin controlled release composition
can also be mixed with other excipients, such as bulking agents
or additional stabilizing agents, such as buffers to stabilize the
neurotoxin during lyophilization. Additional details regarding a
neurotoxin formulation suitable for oral delivery may be found in,
for example, U.S. Pat. No. 10/288,906 and Ser. No. 10/459,767 (Attorney
Docket Nos. 17539 and 17586, respectively), the disclosures of which
are incorporated in their entirety herein by reference.
[0115]In some embodiments, the neurotoxin is administered to the
stomach prior to deploying the gastric band around the stomach.
One of the advantages in pre-administering the stomach with a neurotoxin
is that it relaxes the stomach and makes it more malleable. When
the stomach is relaxed and is more malleable, it is easier for the
surgeon to maneuver the band around the stomach, which would result
in reduced operation time and faster recovery. For example, a standard
gastric band procedure takes about 30-45 minutes. With a pre-administration
of a neurotoxin, the procedure may be faster by about 10-40%, as
the surgeon is better able to maneuver around a more malleable stomach.
Also, a pre-administration of a neurotoxin results in a faster healing
time. For example, after a conventional gastric band procedure,
most patients are able to return to normal functions after about
5-7 days. However, an administration of a neurotoxin prior to a
gastric band procedure would result in patients being able to return
to normal functions about 10-40% faster, as compared to patients
undergoing the same procedure but without the pre-administration
of a neurotoxin.
[0116]Another advantage of administering the neurotoxin to a stomach
tissue prior to deploying the gastric band around the stomach is
that the stomach is relaxed and it is easier to adjust (e.g., tighten
or loosen) the band around the stomach. For example, after the gastric
band is deployed around the stomach, the patient is scheduled for
a regular check up. During this check up, the band may be adjusted
(tightened or loosened) to decrease or increase the size of the
stoma. This is a quick and relatively painless outpatient procedure.
Usually, the patient is x-rayed during the procedure so that the
band reservoir or "port" can be seen clearly. Then, a
fine needle is passed through the skin into the port to add or remove
saline. Adding saline tightens the band, further restricting the
amount of food the patient can eat before feeling full and satisfied.
When the stomach is administered with a neurotoxin, stomach area
forming the stoma is more malleable, allowing for more accurate
adjustment and calibration of the stoma size, and thus, better facilitation
of weight loss.
[0117]My invention also includes a method for facilitating weight
loss by deploying a gastric band around the stomach of the patient
wherein the gastric band has previously been coated, on the side
of the gastric band which will be in contact with stomach tissue,
with a botulinum toxin, such as a botulinum toxin type A. Thus upon
positioning of the gastric band in contact with the stomach, the
botulinum toxin is absorbed into or diffuses into the adjacent stomach
tissue. Technologies for coating a medical device with a botulinum
toxin are known. See eg U.S. Pat. Nos. 6,767,544 and 6,579,847.
[0118]In some embodiments, the neurotoxin is administered at or
in the vicinity of the site where the gastric band contacts the
stomach. One of the advantages of locally administering a neurotoxin
at a site or in the vicinity of the site where the gastric band
contacts the stomach is that the band is better fitted at that site
and would tend not to slip from that site. Without wishing to limit
the invention to any theory or mechanism of operation, it is believed
that the administration of the neurotoxin at or in the vicinity
of the site where the band contacts the stomach creates a contrast
in muscle tone region that would serve to secure the gastric band
in place. For example, when the neurotoxin is administered at the
site where the band contacts the stomach, the site administered
has a relaxed muscle tone (see FIG. 2A). The gastric band would
tend to "fall" into the region with the relaxed muscle
tone-thus, the band would be secured in its intended location. One
or more sites on the stomach may be administered. In some embodiments,
the neurotoxin is administered along the entire circumference of
the stomach. In some embodiments, the neurotoxin is administered
substantially on the greater curvature side of the stomach (FIG.
1 and FIG. 2A). In some embodiments, the neurotoxin is administered
on the stomach at sites that are about 1-10 cm apart. In some embodiments,
about 0.5-10 units based on botulinum toxin type A) of a neurotoxin
is administered to each site.
[0119]Alternatively, the neurotoxin may be administered in the
vicinity of the site where the band contacts the gastric band to
create a contrast muscle tone region that would serve to secure
the band in place. For example, a neurotoxin may be administered
at a site above and/or below the site where the gastric band contacts
the stomach (see FIG. 2B). This pattern of administration would
create a contrast in muscle tone such that the gastric band would
tend to "fall" into the region that is not administered.
In some embodiments, the neurotoxin is administered along the entire
circumference of the stomach. In some embodiments, the neurotoxin
is administered substantially on the greater curvature side of the
stomach (FIG. 1 and FIG. 2B). In some embodiments, the neurotoxin
is administered on the stomach at sites that are about 1-10 cm apart.
In some embodiments, about 0.5-10 units based on botulinum toxin
type A) of a neurotoxin is administered to each site.
[0120]Preferably, a neurotoxin used to practice a method within
the scope of the present invention is a botulinum toxin, such as
one of the serotype A, B, C, D, E, F or G botulinum toxins. Preferably,
the botulinum toxin used is botulinum toxin type A, because of its
high potency in humans, ready availability, and known safe and efficacious
use for the treatment of skeletal muscle and smooth muscle disorders
when locally administered by intramuscular injection.
[0121]The present invention includes within its scope: (a) Clostridial
toxin complex as well as pure Clostridial toxin obtained or processed
by bacterial culturing, toxin extraction, concentration, preservation,
freeze drying and/or reconstitution and; (b) modified or recombinant
Clostridial toxin, that is Clostridial toxin that has had one or
more amino acids or amino acid sequences deliberately deleted, modified
or redeployed by known chemical/biochemical amino acid modification
procedures or by use of known host cell/recombinant vector recombinant
technologies, as well as derivatives or fragments of Clostridial
toxins so made, and includes Clostridial toxins with one or more
attached targeting moieties for a cell surface receptor present
on a cell.
[0122]Neurotoxins, e.g., botulinum toxins, for use according to
the present invention can be stored in lyophilized or vacuum dried
form in containers under vacuum pressure. Prior to lyophilization
the botulinum toxin can be combined with pharmaceutically acceptable
excipients, stabilizers and/or carriers, such as albumin. The lyophilized
or vacuum dried material can be reconstituted with saline or water.
[0123]Methods for determining the appropriate route of administration
and dosage are generally determined on a case by case basis by the
attending physician. Such determinations are routine to one of ordinary
skill in the art (see for example, Harrison's Principles of Internal
Medicine (1998), edited by Anthony Fauci et al., 14.sup.th edition,
published by McGraw Hill).
EXAMPLES
[0124]The following examples set forth specific compositions and
methods encompassed by the present invention and are not intended
to limit the scope of the present invention.
Example 1
Laparoscopic Procedure for Deploying a Gastric Band
[0125]In the discussion that follows, reference is made to FIGS.
3-8. For clarity, the trocar cannulas have been omitted from these
figures. It should be understood, however, that all intra-abdominal
instruments or exogenous assemblies referred to in the figures pass
through a laparoscopic cannula.
[0126]The surgical technique is as follows:
[0127]Step 1. Routine procedures for laparoscopic surgical entrance
into the abdominal cavity are followed. Typically, a semicircular
incision about 20 mm in length is made at the lower edge of the
umbilicus. A trocar 11 (FIG. 3) is inserted through an incision
into the peritoneal cavity. The laparoscope 14 is inserted through
the sleeve of the trocar 11 and the abdomen insufflated to a pressure
of 14-16 mm of mercury. The pressure should never exceed 20 mm of
mercury. With abdominal distension, the intraperitoneal viscera
are visible. At this time, a video camera (not shown) may be connected
to the laparoscope 14. Once the abdomen is properly insufflated,
trocars 12 and 13 are inserted under the following guidelines: a)
each entrance port is inspected to assure it is a safe area; and
b) each insertion is observed through the laparoscope from within
to assure no viscera is injured. More additional cannulas may be
inserted as the need arises. Once the upper stomach is exposed,
adhesions, if present, are transected. The stomach is pulled down
(caudal) and the gastrophrenic ligament is opened proximal to the
short gastric vessels.
[0128]Step 2. Mid-line (2-3'') long skin incision in midway between
the xyphoid process and the umbilicus. The incision is carried out
through the subcutaneous fat to the linea alba. The right rectus
sheath is exposed but no space for implantation of the injection
port is prepared at this time.
[0129]Step 3. As shown in FIG. 4, a modified flexible endoscope
41 is inserted into the abdominal cavity. Using the flexible part
42 of the endoscope 41, blunt dissection is made at the greater
curvature. A tunnel is dissected under the stomach toward the lesser
curvature as shown by the position of the flexible end 42 of the
endoscope 41 in FIG. 5. The optical system of the scope is useful
during the dissection. In particular, at the lesser curvature, the
light on the scope will make dissection easier and safer (FIG. 5).
[0130]Step 4. When the opening next to the lesser curvature is
made, forceps 61 (FIG. 6) are inserted through the channel in the
scope 41. The tail end of the gastric band 62 is grasped with the
forceps 61 (FIG. 6); and, when withdrawing the endoscope 41, the
band is threaded under the stomach. The head and tail ends of the
gastric band are brought together.
[0131]Step 5. A pair of banding instruments 91 (FIG. 9a) are inserted
into the abdominal cavity. The head and tail ends of the gastric
band are brought together into adjustable alignment and clamped
with the respective jaws of the banding instrument 91 as shown in
FIG. 7. The balloon (not shown) on the band is pre-inflated with
saline solution.
[0132]Step 6. The calibration tube (not shown) is then inserted
into the stomach by the anesthesiologist through the mouth and the
band is tightened by hand until it is firmly in place over the calibration
tube in the manner well known in the prior art. The greater curvature
is sutured over the band to the pouch. Using the banding instruments
the band is carefully tightened until the correct stoma diameter
is obtained.
[0133]Step 7. The band holder or any other modified attachment
device is then applied. The banding instruments and calibration
tube are removed.
[0134]Step 8. The overlapping ends of the band are sutured together
in the calibrated position (or clipped with clips).
[0135]Step 9. As shown in FIG. 8, subcutaneous fat overlying the
right rectus sheath is dissected for access to the rectus sheaths
for implantation of the injection port.
[0136]Step 10. The fill tube 83 is deployed under the liver 84
to create the shortest path between the band 63 and the injection
site 82 and threaded into the previously dissected receiving space
within the rectus sheath. The fill tube 83 is connected to the injection
port 82. The incisions are closed in the usual fashion.
[0137]It is clear that the foregoing procedure may be modified
and be useful for deploying any gastric band (including the LAP-BAND.RTM.
SYSTEM) into an encircling position around the stomach.
Example 2
Injection of Botulinum Toxin Using Endoscopic Techniques
[0138]To locally administer a neurotoxin to a stomach site, an
endoscopy is performed with a standard adult forward-viewing instrument.
The site of administration on the stomach is estimated both endoscopically
as well as by a previously performed manometry. At the administration
site, a neurotoxin, e.g., botulinum toxin type A is injected via
a 4-mm sclerotherapy needle passed thorough the biopsy channel of
the endoscope. One milliliter of a 10 U/mL solution can be injected
into each site on the stomach (see U.S. Pat. No. 5,437,291, the
disclosure of which is incorporated in its entirety herein by reference).
Example 3
Method for Facilitating Weight Loss
(With Local Administration of Botulinum Toxin to the Stomach)
[0139]A male patient being at least 60-100 pounds overweight. The
patient is a good candidate for a gastric band procedure to help
him loose weight.
[0140]The patient wishes to loose weight and elects to undergo
a LAP-BAND.RTM. procedure. A few weeks prior to and/or at the time
of the actual LAP-BAND.RTM. procedure, the patient is administered
with a botulinum toxin to relax the stomach muscles. Using endoscopic
techniques, the botulinum toxin is administered to the upper part
of the stomach, preferably to or in the vicinity of a site where
the band is to be deployed ("in the vicinity" of the site
means, for example, within about less than 10 cm from the site of
where the band is to be deployed on the stomach).
[0141]The time gap between the pre-administration of the botulinum
toxin and LAP-BAND.RTM. procedure depends on the dose and botulinum
toxin type administered. Preferably, the muscle tone of the stomach
muscle is relaxed by at least more than about 50% of the maximum
contraction prior to performing LAP-BAND.RTM. procedure.
[0142]When the patient is ready for the LAP-BAND.RTM. procedure,
the patient is placed on a no fat, liquid diet for 7 days before
the surgery. The purpose of this liquid diet is to decrease the
size of the liver, which in turn will make the placement of the
LAP-BAND.RTM. safer.
[0143]The LAP-BAND.RTM. procedure performed after the stomach is
relaxed by the administration of a botulinum toxin takes less time
as compared to the same procedure where the stomach is not relaxed
by the administration of a botulinum toxin, as the surgeon can maneuver
around the stomach more easily. In this case, the LAP-BAND.RTM.
procedure is around 25 minutes, which is about 10 minutes faster
than usual. Moreover, the recovery time (time the patient is able
to resume normal daily functions) from the LAP-BAND.RTM. procedure
performed after the stomach is relaxed by the administration of
a botulinum toxin is faster as compared to that of the same procedure
where the stomach is not relaxed by the administration of a botulinum
toxin. In this case, the recovery time is about 4 days, which is
about 1 or 2 days faster than usual.
Example 4
Method for Facilitating Weight Loss
(with Oral Botulinum Toxin Formulation)
[0144]A middle age female patient with a BMI (Body Mass Index)
of between 30-60. The patient is a good candidate for a gastric
band procedure to help her loose weight.
[0145]The patient wishes to loose weight and elects to undergo
a LAP-BAND.RTM. procedure. A few weeks prior and / or at the time
of the LAP-BAND.RTM. procedure, the patient is administered with
an oral botulinum toxin formulation to relax the stomach muscles.
[0146]The time gap between the pre-administration of the botulinum
toxin and LAP-BAND.RTM. procedure depends on the dose and botulinum
toxin type administered. Preferably, the muscle tone of the stomach
muscle is relaxed to at least more than about 75% of the maximum
contraction prior to performing LAP-BAND.RTM. procedure.
[0147]The LAP-BAND.RTM. procedure is performed after the surgeon
determines that the stomach is adequately relaxed by the administration
of a botulinum toxin. The LAP-BAND.RTM. procedure takes less time
as compared to the same procedure where the stomach is not relaxed
by the administration of a botulinum toxin, as the surgeon can maneuver
around the stomach more easily. In this case, the LAP-BAND.RTM.
procedure is around 25 minutes, which is about 5 minutes faster
than usual. Moreover, the recovery time from the LAP-BAND.RTM. procedure
performed after the stomach is relaxed by the administration of
a botulinum toxin is faster as compared to that of the same procedure
where the stomach is not relaxed by the administration of a botulinum
toxin. In this case, the recovery time is about 3 days, which is
about 2-3 days faster than usual.
Example 5
Method for Making a Botulinum Toxin Tablet for Oral Ingestion
[0148]A botulinum toxin can be compounded as an oral formulation
for release of the toxin active ingredient into the stomach or duodenum.
This is easily accomplished by mixing with a mortar and pestle (at
room temperature without addition of any water or saline) 50 units
of a commercially available lyophilized botulinum toxin powder,
such as non-reconstituted BOTOX.RTM. (or 200 units of DYSPORT.RTM.
powder) with a biodegradable carrier such as flour or sugar. Alternately,
the botulinum toxin can be mixed by homogenization or sonication
to form a fine dispersion of the powdered toxin in the carrier.
The mixture can then compressed with a tablet making machine (such
as the tablet press available from Scheu & Kniss, 1500 W. Ormsby
Ave, Louisville, Ky. 40210) to make an ingestible tablet. Alternately,
the toxin can be formulated with gelatin by well known methodologies
to make an ingestible geltab.
Example 6
Method For Securing a Gastric Band In Place
[0149]One of the complications of a gastric band procedure is that
after the gastric band procedure is completed, the gastric band
can slip out of position, which may cause obstruction of the stomach.
To prevent the band from slipping out of position, the surgeon locally
administers botulinum toxin along the circumference line of where
the gastric band is to contact the stomach. In this case, the botulinum
toxin is administered at five sites (each site being about 2 cm
apart) to the greater curvature side of the stomach along the circumference
line of where the gastric band is to contact the stomach (FIG. 2A).
The administration of the botulinum toxin causes a contrast in muscle
tone between the administered and non-administered region.
[0150]Subsequent to the local administration of botulinum toxin,
the surgeon deploys the gastric band around the stomach. The band
snuggly falls into the region on the stomach that has been administered
with a botulinum toxin. Thus, the stomach effectively "traps"
the band, and prevents it from slipping off. The band remains in
place on the stomach for more than one year.
[0151]Methods according to the invention disclosed herein has many
advantages, including the following:
[0152]All references, articles, publications and patents and patent
applications cited herein are incorporated by reference in their
entireties.
[0153]Although the present invention has been described in detail
with regard to certain preferred methods, other embodiments, versions,
and modifications within the scope of the present invention are
possible. For example, a wide variety of Clostridial toxins can
be effectively used in the methods of the present invention. Additionally,
the present invention includes oral formulations where two or more
botulinum toxins, are administered concurrently or consecutively
via the oral formulation. For example, botulinum toxin type A can
be administered via an oral formulation until a loss of clinical
response or neutralizing antibodies develop, followed by administration
also by suitable oral formulation of a botulinum toxin type B or
E. Alternately, a combination of any two or more of the botulinum
serotypes A-G can be locally administered to control the onset and
duration of the desired therapeutic result. Furthermore, non-Clostridial
toxin compounds can be administered prior to, concurrently with
or subsequent to administration of the Clostridial toxin via oral
formulation so as to provide an adjunct effect such as enhanced
or a more rapid onset of denervation before the Clostridial toxin,
such as a botulinum toxin, begins to exert its therapeutic effect.
[0154]Accordingly, the spirit and scope of the following claims
should not be limited to the descriptions of the preferred embodiments
set forth above
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