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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
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  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
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  • A61P19/00—Drugs for skeletal disorders
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  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P25/08—Antiepileptics; Anticonvulsants
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
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• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This invention relates to pharmaceutical compositions containing heterocyclic guanidine-type compounds and uses thereof for treating wounds. More specifically, this invention relates to tricyclic 3,4-propinoperhydropurines and uses thereof for treating wounds, particularly in for use in treating anal fissure and other ailments.
• PSP Paralytic shellfish poisoning
• DSP diarrhetic shellfish poisoning
• ASP amnesic shellfish poisoning
• NSP neurotoxic shellfish poisoning
• CP ciguatera poisoning
• CNP cyanobacterial poisoning
• the phycotoxins that produce PSP have a common structure of 3,4,6-trialquil tetrahydropurine. Twenty-six naturally occurring phycotoxins have been described. These phycotoxins are non-protein, low molecular weight compounds of between 280 and 450 daltons. The GTXs are the most abundant of these phycotoxins found in shellfish extract accounting for over 80% of the total toxin content.
• the high toxicity of these phycotoxins is due to reversible binding to a receptor site on the voltage-gated sodium channel on excitable cells, thus blocking the influx of sodium ions and preventing nerve and muscle cells from producing action potentials, thereby blocking neuronal transmission and causing death in mammals via respiratory arrest and cardiovascular shock.
• Application of small amounts of these phycotoxins can produce a flaccid paralysis of striated muscle for periods that are dose dependent.
• Muscle tension may have negative effects on the healing of tissue and is one of the chief factors in determining the degree of scar formation. Surgeons have been seeking methods of reducing excessive scar formation and ways to facilitate wound healing by taking steps to overcome the effect of muscle tension on the wound healing process, including various suturing techniques, steroid injections, undermining wound edges and placing incisions in a line parallel to relaxed skin tension lines.
• Anal fissure is a cut or crack in the anal canal that may extend from the mucocutaneous junction to the dentate line. This common problem causes substantial morbidity with nearly equal incidence in both sexes and is difficult to heal without intervention. Classical symptoms are pain during or after defecation that may be severe and last several hours. In many cases, bright blood may appear on the toilet paper. The cause of chronic fissure is unclear as is the reasons for complete healing. The main characteristics of this condition including the predilection for the posterior midline and the lack of granulation tissue at the fissure site are also unexplained.
• Nitroglycerine treatment of chronic anal fissure yields a healing rate of 36 to 60% within two to six months. Placebo treatment of chronic anal fissures yields a 50% healing rate. Treatment with nitroglycerine causes moderate to severe headaches and long term treatment (over three months) causes a decrease in the MRP ranging from 17 to 38% without a significant change in MVCP.
• Topical application of nifedipine yields a healing rate of 50 to 94.55 within six weeks. Topical application does not produce any significant side effects and reduces MRP 11% from baseline without causing any MVCP changes. Recurrence is a frequent problem in both ointment treatments with 31% relapse occurrence in nitroglycerine treated patients having relapse and 42% relapse occurrence in nifedipine patients.
• BoTox treatment is used in patients with idiopathic anal fissure with a healing rate of 60 to 96% with two to six months. The healing rate is associated with regiment dosage, which yields a 96% healing using two doses of Botox. This treatment results in reduced anal tone in all patents 5 days post-injection. Two months post-injection with BoTox MRP was reduced 28.4% without any significant change in MVCP. BoTox treatment produces a chemical denervation that lasts over 3 months along with a 10% temporal fecal incontinence and a 20% relapse occurrence.
• compositions of the invention including one or more tricyclic 3,4-propinoperhydropurines are provided.
• compositions of the invention are used in combination with an effective amount of another neurotoxin and/or a local anesthetic.
• compositions comprising heterocyclic guanidine-type compounds, and more specifically tricyclic 3,4-propinoperhydropurines, can be used for certain clinical applications, to avoid or minimize the need for surgery, or to avoid or minimize side effects, allergies, immune rejection or hematoma.
• the invention is based, in part, on the reduction or elimination of the tension acting on a wound by a muscle.
• the invention is based, in part, on the surprising, long lasting effects that are provided by certain heterocyclic guanidine-type compounds in the various methods of the invention.
• the present invention relies on administration of a chemodenervating agent to relax or paralyze muscles capable of exerting tension thereby providing improved healing of a wound or treatment of a muscle-related disorder.
• a chemodenervating agent to relax or paralyze muscles capable of exerting tension thereby providing improved healing of a wound or treatment of a muscle-related disorder.
• treating and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.
• the present method of “treating” a patient, as the term is used herein, thus encompasses both prevention of one or more symptoms or underlying causes in a predisposed individual, as well as treatment of one or more symptoms or underlying causes in a clinically symptomatic individual.
• active active agent
• drug drug
• pharmaceutically active agent refers to a chemical material or compound that induces a desired effect, and include agents that are therapeutically effective, prophylactically effective, or cosmetically effective. Also included are derivatives, metabolites and analogs of those compounds or classes of compounds specifically mentioned which also induce the desired effect.
• terapéuticaally effective amount is meant a nontoxic but sufficient amount of an active agent to provide the desired therapeutic effect.
• transdermal drug delivery is meant administration of a drug to the skin surface of an individual so that the drug passes through the skin tissue and into the individual's blood stream, thereby producing a systemic effect.
• transdermal is intended to include “transmucosal” drug administration, i.e., administration of a drug to the mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of an individual so that the drug passes through the mucosal tissue and into the individual's blood stream.
• topical administration is used in its conventional sense to mean delivery of a topical drug of a pharmacologically active agent to the skin or mucosa, as in, for example, the treatment of various skin disorders.
• Topical drug administration in contrast to transdermal administration, provides a local rather than a systemic effect.
• transdermal drug administration Unless otherwise stated or implied, the terms “topical drug administration” and “transdermal drug administration” are used interchangeably.
• an effective amount is that amount sufficient to interfere with neuronal transmission by blocking at least some of the presynaptic release of the neurotransmitter acetylcholine in the neuromuscular plate, thus interfering with transmission, paralyzing the muscle and preventing it from contracting, or producing a relaxation of contracted muscles.
• Amounts are given in units of activity.
• One unit of activity corresponds to an amount of the composition of the invention necessary to block the muscular contractions of the crural biceps of a 20 gram CF1 albino or a BALB-C strain mouse leg for 1.5 to 2.0 hours.
• the toxin is intramuscularly injected in the crural biceps of the mouse right leg in a volume of 0.5 ml.
• the left leg is used as a control.
• HPLC-FLD High Performance Liquid Chromotography
• Carriers or “vehicles” as used herein refer to carrier materials suitable for transdermal drug administration. Carriers and vehicles useful herein include any such materials known in the art, which is nontoxic and does not interact with other components of the composition in a deleterious manner.
• aqueous refers to a formulation or drug delivery system that contains water or that becomes water-containing following application to the skin or mucosal tissue.
• the methods of the invention may be used for wound healing. More specifically, the methods of the invention are useful for the treatment of conditions including, but not limited to, improving wound healing, achalasia and anal fissure.
• compositions of the invention comprise an effective amount of at least one tricyclic 3,4-propinoperhydropurine (represented by formula (I) set forth below: wherein R 1 and R 5 are independently selected from the group consisting of —H and —OH; R 2 and R 3 are independently selected from the group consisting of —H and —SO 3 ; and R 4 is selected from the group consisting of —H, —OH, —COONH 2 , —COONHSO ⁇ 3 and —COOCH 3 , with the proviso that either one of R 2 and R 3 must be —OSO ⁇ 3 , or R 4 must be —COONHSO ⁇ 3 , and a pharmacologically acceptable topical carrier.
• formula (I) represented by formula (I) set forth below: wherein R 1 and R 5 are independently selected from the group consisting of —H and —OH; R 2 and R 3 are independently selected from the group consisting of —H and —SO 3 ; and R 4 is selected
• Preferred tricyclic 3,4-propinoperhydropurines in accordance with the present invention are the gonyautoxins (hereinafter “GTX”) of the formula (I) as set forth in the table below.
• GTX gonyautoxins
• Compound R 1 R 2 R 3 R 4 R 5 Gonyautoxin 1 —OH —H —OSO ⁇ 3 —COONH 2 —OH Gonyautoxin 2 —H —H —OSO ⁇ 3 —COONH 2 —OH Gonyautoxin 3 —H —OSO ⁇ 3 —H —COONH 2 —OH Gonyautoxin 4 —OH —OSO ⁇ 3 —H —COONH 2 —OH Gonyautoxin 5 —H —H —H —COONHSO ⁇ 3 —OH
• the pharmaceutical compositions of the invention comprise at least one GTX compound selected from GTX 1, GTX 2, GTX 3, GTX 4 and GTX 5.
• the pharmaceutical compositions comprise a mixture of tricyclic 3,4-propinoperhydropurines.
• mixtures of two or more GTX compounds are contemplated.
• One embodiment of the invention employs a mixture of GTX 2 and GTX 3, in approximately a 2:1 ratio, respectively.
• Another embodiment of the invention employs a mixture of GTX 1, GTX 2, GTX 3 and GTX 4. It should be understood by those of skill in the art that, subject to the conditions set forth with respect to the formula (I) above, other mixtures and combinations of tricyclic 3,4-propinoperhydropurines are within the scope of this invention.
• these preparations are stable at room temperature, do not require refrigeration, are sterilizable, are substantially non-allergenic, are not peptide in nature, act substantially immediately, and may be applied repeatedly without significant, adverse side effects.
• the compounds of the formula (I) may be purified from dinoflagellates or cyanobacterias, and also may be accumulated by highly-contaminated mollusks, from which they may also be purified.
• Any pharmacologically acceptable carrier may be employed, including, but not limited to, water, acetic acid, and saline solutions. Acetic acid and 0.09% sodium chloride solution are preferred carrier materials.
• compositions of the invention include at least GTX compound, as discussed above, and additionally comprise at least one compound selected from the group consisting of saxitoxin (STX), neosaxitoxin, decarbamoylsaxitoxin, tetanus toxin, and Botulin A toxin.
• STX saxitoxin
• neosaxitoxin neosaxitoxin
• decarbamoylsaxitoxin decarbamoylsaxitoxin
• tetanus toxin tetanus toxin
• Botulin A toxin Botulin A toxin
• compositions of the invention are used in combination with an effective amount of a local anesthetic.
• the pharmaceutical compositions of the invention comprise an effective amount of a local anesthetic such as enzocaine, tetracaine, mepivacaine, prilocaine, etidocaine, bupivacaine, lidocaine or similar local anesthetics and combinations thereof and an effective amount of at least one tricyclic 3,4-propinoperhydropurine.
• Compositions of the invention may also be used in combination with one or more neurotoxins and one or more local anesthetics, if desired.
• these compounds when applied locally, these compounds appear to effect the antispasmodic action by blocking the spreading of nervous impulse, or neuronal transmission, by reversibly binding to the sole biological molecular receptor, i.e. the voltage gated sodium channel, present in all neurons and excitable cells. By binding to this channel, there is no entry of sodium to the neuronal cell; depolarization does not occur and, therefore, propagation of the impulse is stopped.
• This action mechanism blocks at least some of the presynaptic release of the neurotransmitter acetylcholine in the neuromuscular plate, thus interfering with neuromuscular transmission, paralyzing the muscle and preventing it from contracting, or producing a relaxation of muscles contracted by pathological problems.
• the pharmaceutical preparations of the invention may be applied in any suitable manner, such as topically, transdermally or by injection.
• the preparations of the invention are applied locally in the vicinity of the muscle that is to be paralyzed or prevented from contracting.
• the application should be in amounts sufficient to provide from 1-1000 units of activity to the muscle, per dose, more preferably, from 10-1000 units of activity, per dose.
• the effect is immediately apparent, generally occurring within a maximum of 30 seconds to five minutes after penetration of the active compound through the skin.
• the maximum effect is generally achieved within 15 minutes of penetration of the active compound through the skin. Its effective duration depends on the dose administered, the muscle in question, as well as the volume and specific composition administered. This is the pattern for all clinical applications and pathologies.
• certain methods of the present invention not only provide practically immediate anesthetic and muscle relaxant effects, but also provide beneficial muscle relaxation effects over an unexpectedly long period.
• certain methods of the present invention are particularly well-suited to wound healing and treatment of the other indications mentioned above, since the unexpected longer term muscle relaxation effects have been found to facilitate the healing process.
• each dose includes more than 32 units of activity up to a maximum of about 5000 units of activity. Even more preferably, each dose includes more than 32 to about 1000 units of activity, more preferably, from more than 40 to about 1000 units of activity, and even more preferably, from about 50 to about 500 units of activity. Most preferably, each dose includes about 75 to about 200 units of activity. Doses may be repeated from time-to-time, as needed, to continue muscle relaxation until the desired effect is obtained.
• mammals are treated by direct, local injection of a composition of the invention into a muscle or in the vicinity of a muscle.
• the muscle at the location of injection exhibits elevated tone or spasms, though this is not necessary for the effectiveness of all treatments.
• Each injection may be limited to not more than two milliliters of composition, including solvents, adjuvants and/or carrier materials. Administration may be accomplished, for example, using a one milliliter, tuberculin-type disposable syringe with a twenty-seven to thirty gauge needle. Alternatively, for certain methods, it may be desirable to administer the dosage using an endoscope such as that described in U.S. Pat. No. 5,674,205, the disclosure of which is hereby incorporated by reference for the purpose of providing details of an endoscope suitable for use in the method of the present invention.
• an endoscope such as that described in U.S. Pat. No. 5,674,205, the disclosure of which is hereby incorporated by reference for the purpose of providing details of an endoscope suitable for use in the method of the present invention.
• the pharmaceutical compositions of the invention may be applied locally in the form of a topical preparation.
• a topical preparation an effective amount of the pharmaceutical composition of the invention is added to a pharmacologically acceptable topical carrier.
• the composition when applied topically, may be in any form suitable for application to the body surface, and may comprise, for example, a cream, lotion, solution, gel, ointment, paste or the like, and/or may be prepared so as to contain liposomes, micelles, and/or microspheres.
• the topical preparation may include from about 0.0001% to about 0.01% by weight of the GTX compounds, based on the weight of the preparation.
• the topical preparation may include from about 0.001% to about 0.01% by weight of the GTX compounds, based on the weight of the preparation.
• compositions may be directly applied to the body surface or may involve use of a drug delivery device.
• a formulation or drug reservoir may be aqueous, i.e., contain water, or may be nonaqueous and used in combination with an occlusive overlayer so that moisture evaporating from the body surface is maintained within the formulation or transdermal system during drug administration.
• a non-aqueous formulation may be used with or without an occlusive layer.
• dose refers to the amount of toxin used during one administration to a patient.
• a dose may be applied to one or more sites.
• Treatment refers to the total number of doses given to a patient to achieve the desired effect. 100 units of the mixture of GTX 2 and GTX 3, determined by mouse assay, is equivalent to 25 ⁇ g of GTX 2 and GTX 3, as determined by HPLC-FLD.
• test subjects Ten healthy male adults between 24 and 48 years old with normal sphincter tone (pressure at rest less than 72 mmHG as determined by anorectal manometry) were studied. The test subjects had no anorectal pathologies like hemorrhoids, fistula or abscesses. Before intervention, tests were performed including anorectal manometry, electromyography, a hemogram, a basic metabolic panel and a urinalysis.
• a dosage of 100 units of activity of a combination of GTX-2 and GTX-3, in approximately a 2:1 ratio, in a total volume of 1.0 ml was locally infiltrated into both sides of the anal internal sphincter (0.5 ml each side) with an insulin syringe (25 gauge).
• the mixture of GTX-2 and GTX-3 was purified from shellfish collected in the Chilean Patagonia fjord that was found to be highly-contaminated with PSP toxins using standard purification methods.
• Table 1 is a summary of the test results. As shown in Table 1, all participants showed anal sphincter relaxation within 30 seconds after injection, as determined by clinical anorectal examination during the injection and then after two minutes using anorectal manometry. The participants all stated that they felt the anal anesthesia for an average time of 59.5 minutes ⁇ 7.12 minutes (mean value ⁇ Stand. Dev.) and sphincter hypotonical sensation for 40.0 ⁇ 4.20 minutes. None of the participants showed flatus incontinence or transitory fecal incontinence.
• Table 2 is a summary of the anorectal manometric recordings.
• Manometric recording showed a significant decrease in the anal maximal voluntary contraction pressure. Two minutes after injection the pressure was 55.2 ⁇ 6.2% (mean value ⁇ standard dev.) of the base line values, a diminishing of 44.8%. Twenty-four hours after injection, the drop in the anal maximal voluntary contraction pressure increased to 53% of the baseline value. Fifteen days after injection all of the anal maximal voluntary contractions had returned to the base line values.
• the local peripheral application of toxins interferes with neuromuscular transmission, altering the action potential which results in a temporarily paralysis of the sphincter.
• the mode of action of GTX is directed to the injected muscle leaving other muscles in the area unaffected.
• the paretic effects indicate that local injection of the sphincter lasts for 12 days. As there are no side effects, the use of this toxin injected locally is safe and effective particularly for use in the anal sphincter.
• the immobilization of healing tissue is a fundamental therapeutic principle and treatments using paralytic toxins may be effective in the remission of other pathologies such as blepharospasm, tics, tremors, bruxism, hemifacial spasm, cervical dystonia, cerebral palsy, muscle spasm pain such as writer or musician cramps, hand tremors, spasmodic dystonia to list just a few conditions of muscle hypertonicity causing stiff and awkward movements.
• pathologies such as blepharospasm, tics, tremors, bruxism, hemifacial spasm, cervical dystonia, cerebral palsy, muscle spasm pain such as writer or musician cramps, hand tremors, spasmodic dystonia to list just a few conditions of muscle hypertonicity causing stiff and awkward movements.
• Patients were evaluated for the following inclusion criteria: evidence of anterior, posterior or both circumscribed ulcers, induration at the edges and posterior of horizontal fibers of the interior anal sphincter, with symptoms of post defecatory or permanent pain, bleeding or both. Patients with an anal fissure history of two or month duration were considered to be chronic. Table 3 contains a detail of the patients selected for study. Patients younger than 18 or older than 70 years of age were excluded from this study as were those patients that were pregnant or had anal fissure associated with other conditions such as hemorrhoids, fistula or anal abscess.
• the healing criteria and primary end points of the study were pain relief and fissure epithelization.
• the participants were fully informed about the action and mechanism of GTX and all included patients supplied their written consent.
• the study was a randomized double-blind trial in which the patients were diagnosed and injected with a mixture of GTX-2 and GTX-3 or placebo solution of 0.9% sodium chloride.
• the study was opened for humanitarian and ethical reasons after 15 placebo treated patients showed either no improvement or a worsening of their conditions and patients injected with GTX showed marked improvement after three weeks treatment.
• the test dosage consisted of 100 units of activity of a mixture of GTX-2 and GTX-3 in 1.0 ml volume, which was locally infiltrated into both sides of the anal fissure, in the internal anal sphincter, in equal volumes. The injection was accomplished with an insulin needle (25 gauge).
• Table 5 demonstrates a significant decrease in the maximum resting pressures (MRP) in all the patients as indicted by the manometric recordings.
• MRP maximum resting pressures
• the MRP recordings fell from 108.8 ⁇ 24.9 to 61.1 ⁇ 22.8 mmHg (Mean value ⁇ Standard Deviation) decreasing to 56.2 ⁇ 12.5 of MRP baseline values. This represents a mean reduction of 43.8%.
• maximum voluntary contraction pressure (MVCP) decreases to 74.3 ⁇ 13.1 of MVCP baseline values, a 25.7% mean reduction.
• GTX provides a safer treatment regiment for healing acute and chronic anal fissures than the current therapeutic methods such as BoTox or surgery.
• GTX treatment does not produce the inconveniences of flatus or fecal incontinence, nor does it require 5 to 7 weeks healing time.
• GTX treatment does not produce permanent sphincter damage resulting in long term hospitalization.
• One unit of activity corresponds to an amount of the composition of the invention necessary to block the muscular contractions of the crural biceps of a 20 gram CF1 albino strain mouse leg for 1.5 to 2.0 hours.
• the toxin was intramuscularly injected in the crural biceps of the mouse right leg in a volume of 0.5 ml.
• the left leg is used as a control. This was done in three mice and the paralyzing effect was tested every 30 minutes for the first two hours, and then every 2, 4, 8 hours and overnight. Depending on the dose injected, the paralyzing effect can last 24 hours or longer.
• This example confirms the reversible nature of the effect of the toxins of the present invention and demonstrates that the duration of the effect can be controlled by varying the dosage of the toxins.
• Ano-rectal manometry was performed before and 10 minutes after the application of the ointment.
• the pressure measurements showed no significant change after the application of the cream.
• Patients were sent home with the cream and instructions to apply the cream twice a day (morning and night, about every 12 hours). The patients were followed up via weekly visits to the physician. The patients started to present re-epithelialization of the fissures after the first, second and third week, and the healing was completed in between the third to the fifth week of treatment, depending of the type of anal fissure (acute or chronic or posterior, anterior, both).

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