Internet for Pharmaceutical and Biotech Communities
| Newsletter | Advertising |
 
 
 

  

Pharm/Biotech
Resources

Outsourcing Guide

Cont. Education

Software/Reports

Training Courses

Web Seminars

Jobs

Buyer's Guide

Home Page

Pharm Patents /
Licensing

Pharm News

Federal Register

Pharm Stocks

FDA Links

FDA Warning Letters

FDA Doc/cGMP

Pharm/Biotech Events

Consultants

Advertiser Info

Newsletter Subscription

Web Links

Suggestions

Site Map
 

 
   

 

  Pharmaceutical Patents  

 

Title:  Application of topical anesthetics for modulation of neurogenic tremor
United States Patent: 
7,695,733
Issued: 
April 13, 2010

Inventors:
 Zasler; Nathan D. (Richmond, VA), Carpenter; Jeffrey (Fairfax, VA)
Appl. No.:
 11/707,144
Filed:
 February 16, 2007


 

Web Seminars -- Pharm/Biotech/etc.


Abstract

A method of ameliorating neurogenic tremor in mammals, which comprises topically administering to a mammal, which has been diagnosed with a neurogenic tremor, an effective amount of a topical anesthetic.

Description of the Invention

FIELD OF THE INVENTION

The present invention is directed to a method of modulating neurogenic tremor by administering a topical anesthetic. The present invention may be used for the modulation of tremor associated with neurological disorder and is relevant to a broad range of impairments seen by clinicians in the neuroscience related fields, in particular neurology and neurorehabilitation.

BACKGROUND OF THE INVENTION

"Tremor" refers to rhythmic shaking of a body part. Tremor is one of the most common involuntary movement disorders seen in clinical practice. In addition to consideration of a detailed history, the differential diagnosis of tremor is mainly clinically based on the distinctions made at rest, postural or intention; activation condition; frequency; and topographical distribution. The causes of tremor are heterogeneous and a tremor can present alone (e.g., as with essential tremor) or as a part of a neurological syndrome, such as traumatic brain injury, hypoxic brain injury, cerebrovascular accident, and/or multiple sclerosis, etc. This latter type of tremor is referred to as "neurogenic tremor".

Essential Tremor (ET) is the most common type of tremor. Although it is called a "benign" condition, essential tremor may be far from benign. Essential tremors may be frustrating, embarrassing, or even disabling to the patient. Essential tremor is a very common and complex neurological movement disorder. One characteristic of essential tremor is that it is not caused by another neurological condition or the side effect of a medication. ET usually affects the hands, but it may also affect the head and neck (causing shaking), face, jaw, tongue, voice (causing a shaking or quivering sound), the trunk and, rarely, the legs and feet. The tremor movement associated with ET may be a rhythmic "back-and-forth" or "to-and-fro" movement produced by involuntary contractions of the muscle. It is a syndrome characterized by a slowly progressive postural and/or kinetic tremor, usually affecting both upper extremities. The pathophysiology of ET is not known. No pathological findings are known to be associated consistently with ET. Essential tremors are characteristically postural (occurring with voluntary maintenance of a position against gravity) and kinetic (occurring during voluntary movement) and usually resolve when the body part relaxes. ET probably represents a syndrome and multiple etiologies have been identified. Most or all of these causes are probably genetic as evidenced by the fact that ET is familial in at least 50-70% of cases. Severity of the tremors can vary greatly from hour to hour and day to day. Some people experience ET only in certain positions, i.e. as a postural tremor. Tremor that worsens while writing or eating is called kinetic or action-specific tremor. Most people with ET have both postural and kinetic tremor.

Neurogenic tremors, on the other hand, occur as a part of a neurological syndrome, such as with traumatic brain injury, hypoxic brain injury, cerebrovascular accident, and/or multiple sclerosis, etc. As far as physical impairments following brain injury and/or neurological diseases are concerned, neurogenic tremors can be particularly debilitating. Neurogenic tremor is a movement disorder that is associated with rhythmic, involuntary muscular contractions of reciprocally innervated, antagonistic muscle groups characterized by rhythmic oscillations ("to-and-fro" movements) of a part of the body about a fixed plane in space. The most common of all involuntary movements, neurogenic tremor can affect various body parts such as the hands, head, facial structures, vocal cords, trunk and legs, although most tremors occur in the distal upper extremities; e.g. hands. Given that the upper extremities are most commonly affected, various aspects of activities of daily living (ADLs) can be adversely affected including self-feeding, fine motor manipulation, writing, and dressing, etc. Although neurogenic tremor is by no means life threatening, it can be the cause of significant functional disability and therefore require use of either adaptive aids and/or assistance from others to compensate for the impairment.

Generally, neurogenic tremors are manifest as the following sub-classifications of tremor "type": resting, postural and kinetic.

1) "Resting tremor" occurs when the muscle is at rest, for example, when the hands on left lying on a surface. This type of tremor is normal 4 to 6 hertz in frequency with medium amplitude. This type of tremor is often seen in patients with Parkinson's disease. Currently treatment of resting tremors is predominantly focused in pharmacotherapies involving dopamine agonist drugs such as L-dopa, amantadine, and parlodel, etc., and anticholinergic agents, such as benztropine and trihexyphenidyl.

2) "Postural tremor" occurs when a patient attempts to maintain posture such as holding the hands outstretched. Postural tremors include physiological tremor, tremor associated basal ganglia disease/injury, cerebellar postural tremor, tremor with peripheral neuropathy, and alcoholic tremor. There is no established drug treatment for this type of tremor, although beta-blockers, isoniazid, anticonvulsants and other drugs have been used with some limited success.

3) "Kinetic tremor" occurs during purposeful movement, for example, during finger-to-nose testing. Kinetic tremors tend to be low frequency tremors and tend to occur ipsilateral to the side of cerebellar involvement, including but not limited to, the cerebellar outflow tracts. This type of tremor can also be seen with certain degenerative brain diseases. Numerous medications have been used, albeit with quite limited success, including but not limited to: beta-blockers, anticonvulsants, benzodiazepines, anticholinergics, and buspirone.

Symptomatic drug therapy is available for several types of neurogenic tremors. For example, for some types of neurogenic tremors there are specific pharmacological approaches to management of the tremors, such as anti-Parkinsonian drugs for Parkinson-related resting tremor. However, the majority of tremors do not have well established drug treatments, as determined either by practitioner consensus nor evidence based research. In addition, many of the drugs that are currently used to modulate tremor have also been noted to have potential and significant deleterious side effects including sedation, metabolic toxicities and/or cognitive depressant actions.

For those cases of tremor in which there is no effective drug treatment, physical measures such as teaching the patient to brace the affected limb during the tremor are sometimes useful. Physical treatments such as limb weighting have also been advocated for modulating certain types of tremor such as cerebellar postural tremor and kinetic tremor; however, these interventions tend to be cumbersome with difficulty maintaining patient compliance due to the perceived "socially unacceptability" of these modalities.

In addition, surgical intervention such as thalamotomy or deep brain stimulation may be useful in certain cases (Bogey et al: "Rehabilitation of movement disorders", Arch Phys Med Rehabil. 85(Suppl 1): S41-45, 2004.

An intervention that is effective, easily transportable and has an acceptably low side effect profile would be ideal for modulating this type of disabling condition. Based on available evidence, the novel application of topical anesthetics for modulation of neurogenic tremor meets these criteria.

To date, topical anesthetics have never been proposed for use in treatment of neurogenic (e.g. neurological) tremors. The first study to suggest that tremor might be reduced, in any fashion, through treatment with anesthetics, although not through topically to the skin, was published in 1993 in Parrent et al., "Tremor Reduction by Microinjection ofLidocaine During Stereotactic Surgery", Acta Neurochirurgica, 58:45-47 (1993). This study examined the effects of lidocaine microinjections into the thalami of ten patients undergoing stereotactic thalamotomy for the treatment of Parkinsonian or Parkinsonian tremor. In overall 2/3 of cases, the test, microinjection of the lidocaine replicated the effects of microstimulation. The authors concluded that longer term follow-up would be required to determine whether lesions made on the basis of lidocaine induced tremor suppression would result in a lower rate of tremor recurrence than those based on stimulation induced tremor suppression.

A study by Levy et al. "Lidocaine and Muscimol Microinjectionand Subthalamic NucleusReversed Parkinsonian Symptoms", Brain 124(Pt10):2105-2118 (2001) demonstrated that application of lidocaine centrally in the subcortical areas of the brain ameliorated tremor through the inactivation of neuronal activity in the subthalamic nucleus; thereby, improving motor symptoms, possibly by alternating the oscillatory activity of neurons located beyond the inhibited area.

Finally, Pozos et al., "Effective Topical Anesthesiaon Essential Tremor", Electromyography and Clinical Neurophysiology, 32(7-8): 369-72 (1992), looked at the effects of skin desensitization on essential tremor in study that used a single-blinded approach. The researchers found that topical anesthetic significantly suppressed essential tremor amplitude and associated electrical activity in all patients with the mean tremor amplitude being reduced by 40%. However, there was no apparent follow up study that has either replicated this finding and unfortunately treatments developed for the treatment of essential tremor have not proved to be indicative of efficacy in treating neurogenic tremors.

SUMMARY OF THE INVENTION

The present invention is directed to a method of ameliorating neurogenic tremor in mammals, by topically administering to a mammal, which has been diagnosed with a neurogenic tremor, an effective amount of a topical anesthetic. The present invention is further directed to the treatment of neurogenic tremors, which are manifest as kinetic, postural, task-specific, or resting tremors. The method of the present invention preferably uses a topical anesthetic that is a member of the "caine" class of anesthetics. In particular, the present invention uses a transdermal patch to administer the topical anesthetic to the patient.

DETAILED DESCRIPTION OF INVENTION

The instant invention is directed to a method of modulating neurological tremors through the application of local/topical anesthetics. More specifically, the instant invention is directed to a method of modulating neurogenic tremors by reducing the effects of the tremor on upper extremity motor skills. Based on the data acquired to date, the effects of the intervention are rather significant and are maintained for the duration of drug action/application. Generally, a period of 20-30 minutes is required for onset of drug action once applied. Surprisingly, while the present method is directed to a method of modulating neurological tremors through the local/topical application of anesthetics, the drug effects appear to be systemic and not local, as evidenced by the fact that the application of the anesthetic to a part of the body distant from the affected limb is effective for treating the affected limb. The medication can be applied with any topical administration system, e.g. in the form aerosol solution, cream, lotion, film-forming gel, jelly, ointment, or spray solution or through a transdermal delivery system (e.g. drug patch).

Based on the concentrations used in studies thus far, there is little to no risk of systemic or local side effects. The effect of topical anesthetics on tremor modulation is a class effect; that is, that all topical anesthetic agents, both shorter and longer acting, have some ameliorating effect on the degree of tremor related impairment.

The present invention may be used in a variety of different types of tremors that are consequential to neurological disease and/or injury, (i.e. neurogenic tremors) and may be used for the treatment of neurogenic tremors which are manifest as kinetic, postural, task-specific, or resting tremors.

Any topical anesthetic may be used in the present invention. Topical anesthetics that may be used in the instant invention include, but are not limited to, anesthetics of the "caine" family. Included in the caine family of anesthetics are benzocaine, bupivacaine, butacaine, carbisocaine, chloroprocaine, ciprocaine, dibucaine, etidocaine, heptacaine, levobupivacaine, lidocaine, lidocaine hydrochloride, mepivacaine, mesocaine, prilocaine, procaine, propanocaine, ropivacaine, and tetracaine.

With the method of the present invention, once a patient has been diagnosed with a form of a neurogenic tremor, a topical/local anesthetic may be administered to the patient either prior to or after the onset of a tremor episode. The present method may be used prophylactically with a patient diagnosed with a neurogenic tremor disorder, in the sense that the topical anesthetic may be applied at regular interviews over extended periods of time to prevent or decrease tremor episodes from reoccurring. For example, the topical anesthetic may be applied on a daily basis. With the present invention the topical anesthetic is typically administered to the patient for at least 30 minutes. However, the topical anesthetic may be administered for any period of time recommended and approved for the topical anesthetics for other indications, including over a period of several hours, e.g. many transdermal patches may be worn of up to 12 hours. If the anesthetic is applied in the form of a cream, the anesthetic is topically applied and left on the skin. The anesthetic may be reapplied as soon as deemed necessary. The topical anesthetics used in the present invention are well known for other indications. The dosages used and routes of administration for the present invention are the tested and approved doses for the treatment of such other indications. For example, the anesthetic may be lidocaine administered at 2-10% by weight. With the invention, two or more topical anesthetics may also be administered together. For example, common commercially available transdermal patches, which are suitable for use in the present invention include a mixture of lidocaine 0.1-5% and prilocaine 0.1-5% by weight or lidocaine 2.5% and prilocaine 2.5% by weight.

As determined through the experiments detailed below, it is not necessary that the anesthetic be topically/locally applied to the extremity which is most desired to have a reduction in tremor, e.g. the hand with which the patient is dominant and performs most fine motor actions such as writing or the extremity most effected by the tremor. The anesthetic may be applied in a location that is convenient for the patient and doctor, since even though the anesthetic is applied locally/topically the ameliorating effect on neurogenic tremors is systemic.

For purposes of the present method, the local anesthetic may be formulated into any commonly accepted topical formulation. For example, the delivery system for the anesthetic may be in the form of a cream, aerosol solution, lotion, film-forming gel, jelly, ointment, spray or patch. The topical anesthetic may also be administered with a topically applied liposome delivery system. A preferred form of delivery is through the use of a long-acting transdermal patch containing the topical anesthetic.

The present method may also be used in combination with other methods of treating neurogenic tremors. For example, the present method may be used in combination with the drugs that are already in use for the treatment of specific neurogenic tremor types, e.g. Parkinson-related tremor medications, for an additive or synergistic effect on the treatment of the neurogenic tremor.

The present method of treating neurogenic tremors may be applied to animals as well as humans. Many non-human mammals, such as cats, dogs and horses also suffer from the same or an equivalent form of neurogenic tremors as humans. As such, the present method is also applied to the treatment of neurogenic tumors in non-human mammalians species suffering from neurogenic tremor.
 

Claim 1 of 16 Claims

1. A method of ameliorating neurogenic tremor in mammals, which comprises: topically administering to a mammal, which has been diagnosed with a neurogenic tremor, an effective amount of a topical anesthetic, wherein the topical anesthetic is a member of the caine class of anesthetics.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.
 

 

     
[ Outsourcing Guide ] [ Cont. Education ] [ Software/Reports ] [ Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ]

[ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ]
[ Pharm Stocks ] [ FDA Links ] [ FDA Warning Letters ] [ FDA Doc/cGMP ]
[ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ]
[ Site Map ]