Use of carbachol for the treatment of diminished voluntary movement performance

Abstract: There is disclosed a pharmaceutic product which is adapted to radically interfere against the algic pathology phenomena. This product comprises parasympathicmimetic drugs, in particular carbachol or methacholine and it has a broad application in the medical and neurology clinic field.

Description: BACKGROUND OF THE INVENTION The present invention relates to a pharmaceutical product comprising a parasymapathomimetic drug having therapeutic properties on the pathology of human sensitivity and of the motor system in general. Parasympathomimetic drugs are already known, the effect of which is similar to that which is obtained by stimulating the parasympathetic postganglionic fibres. For example J.E.F. Reynolds "Martindale The Extra Pharmacopoeia" 1989, The Pharmaceutical Press, London, "Parasympathomimetics" discloses pharmaceutical compositions comprising carbachol. However these prior carbachol drugs are at present rarely used since their action throughout the sensory periphery is little known. SUMMARY OF THE INVENTION Thus, the aim of the present invention is to disclose a novel use of carbachol for the manufacture of a medicament for the treatment of diseases deriving from parasympathetic denervation of normal mechanoceptors, nociceptors and proprioceptors, and resulting in a diminished or absent voluntary movement performance and/or muscle spasticity. In arriving at the invention, the applicant has elaborated a theory about a "sympathetic-sensory coupling" (SSC), by postulating ubiquitous sympathetic inhibitions throughout the sensory periphery. Considering the well-known sympathetic-parasympathetic parallelism on smooth muscle, glands and myocardium, the same applicant has experimentally exploited the parasympathetic denervation supersensitivity of familial dysautonomia (Riley-Day disease) and he has reversed with parasympathomimetic drugs the skin and corneal analgesia, the ageusia, anosmia and proprioceptive and vestibular areflexia of this disease, thus experimentally showing for the first time the existence of excitatory "parasympathetic-sensory couplings" (PSC). Moreover, he has integrated this discovery into the general theory of the "sympathetic- and parasympathetic-sensory coupling" (SPSC), and into the essential distinction between the following peripheries: 1) normechanoceptive, nornociceptive, norproprioceptive; and 2) dysmechanoceptive, dysnociceptive, dysproprioceptive. This theory postulates the existence of normal normechanoceptors, nornociceptors and norproprioceptors which are excited by the parasympathetic system and inhibited by the sympathetic one; and that, in the case of a parasympathetic denervation, parasympathomimetic drugs can replace the excitatory action of the parasympathetic system thereon. Vice versa, in the case of a biochemical alteration of the axoplasmic flow of the primary sensory neurons, due to a central or peripheral cause, these neurons may display membrane dysmetabolic characteristics which transform normechanoceptors into dysmechanoceptors, nornociceptors into dysnociceptors and norproprioceptors into dysproprioceptors. On these dysmechanoceptors, dysnociceptors and dysproprioceptors, the parasympathetic nervous system becomes inhibitory , whereas it was excitatory on to normechanoceptors, nornociceptors and norproprioceptors. However, the parasympathetic action on such dysmechanoceptors, dysnociceptors and dysproprioceptors becomes very small or absent because of the prevalence of an excitatory action of the sympathetic nervous system thereon. The same applicant has pointed out a broad applicability of this theoretical innovation particularly in the medical and neurological field. Within this general heuristic concept, this applicant has exploited the denervation supersensitivity of parasympathetic denervation on sensory receptors, and he has elevated it to a conspicuous indication of the general principle of ubiquitous "parasympathetic-sensory couplings", which up to now have been almost unknown in the neurological field, because of the dogmatic and exclusive ideology of the unidirectionality of "sense" (from-periphery-to-center) and of "motion" (from-center-to-periphery). Substantially, by means of classical and modern aesthesiometric tests, such as the Stockholm thermotest (which measures the pain on the skin due to warm and cold), the "Zottmeter" (a new quick skin algometer) and by means of other aesthesiometric devices, such as that of Cochet-Bonnet and the "Leibnizmeter" for corneal aesthesia, the von Frey bristles for skin and mucuous aesthesia,and the geusimeter for gustatory aesthesia, the applicant has experimentally verified the above- mentioned SPSC theory in several clinical situation of cutaneous and corneal nornociceptive and normechanoceptive hypoaesthesia- anaesthesia and also of the oral mucosa. In addition to more or less frequent neurological situations, but of great theoretical interest for verifying the SPSC theory, such as the above-mentioned Riley-Day disease, ectodermal dysplasia, corneal hypoaesthesia due to acoustic neurinoma or to invasive pathology of the ponto-cerebellar angle, uremic neuropathy and leprosy, the same applicant has moreover reversed, by means of parasympathomimetic drugs (in particular with carbachol and/or methacholine chloride and/or ethylether beta-methylcholine chloride and/or bethanechol chloride) normechanoceptive and nornociceptive hypoaesthesias, in 315 out of 337 cases of diabetic neuropathy. Moreover, the same applicant has reversed, by means of the above-mentioned drugs, skin normechanoceptive and/or nornociceptive hypoaesthesias and anesthesias in 36 senile subjects, both male and female (having an average age of 74.3 years), non-affected by relevant pathologies. It was found that also their reaction times were improved. The duration of the effect of a single dose was found to vary from 26 hours to 15 days depending on the cases. That same effect, in particular, could be restored by means of a new administration. The applicant has moreover experimentally verified the SPSC theory also on 31 paraplegic patients and, by means of parasympathomimetic drugs, has reversed skin nornociceptive and normechanoceptive anaesthesias (in three cases also of the glans, with an orgastic restitution). The sensory receptors of such anaesthetic skin were obviously still transynaptically connected with the sensory cortex, but removed from the facilitatory parasympathetic tonic action thereon -which is the presently established mandatory condition for sensory transduction- because of the spinal interruption of descending excitatory pathways on the parasympathetic preganglionic neurons. Seven of these pararaplegic patients recovered variable degrees of voluntary movement of toes, dorsi- flexion of the foot, abduction and adduction as well as extension and flexion of the lower limbs. By means of the above-mentioned experimental verifications, the applicant has been able to further consider, and to exploit, the possible presence of parasympathetic fibres, near the sympathetic ones, in the muscle spindle, after parasympathomimetic drugs had reversed the proprioceptive areflexia of the Riley-Day disease. Thus the applicant has been able to verify the motor aspect of the SPSC theory,by restoring: 1) several degrees of voluntary motor capability, sometimes even a near complete restitution ad integrum of the whole limbs, of the hand, foot, fingers or toes, starting from an absolute inability of movement, or, moreover, 2) non-assisted deambulation in patients who could walk but with means of support or who were not able to walk at all. This has been obtained in 147 out of 172 hemiplegic patients by using the above-mentioned parasympathomimetic drugs, and, more specifically: in 3 out of 5 acute hemiplegic patients (up to 21 days from the cerebral damage); in 11 out of 15 subacute hemiplegic patients (from 22 days to 6 months); in 120 out of 137 stabilized chronic hemiplegic patients (from 7 months to 8.4 years); in 13 out of 15 hemiplegic patients with post-hemiplegic shoulder-hand syndrome, in all of whom the dysnociceptive pain was also removed. In 81 out of 102 of these hemiplegic patients , tested ad hoc, in particular , cutaneous normechanoceptive and nornociceptive hypoaesthesias or anaesthesias were reversed by the above-mentioned parasympathomimetic drugs. By using the above-mentioned parasympathomimetic drugs, moreover, normechanoceptive and nornociceptive skin anaesthesias or hypoaesthesias were also reversed in 25 out of 26 cases of multiple sclerosis, by also restituting to the treated patients the two above-mentioned patterns of motor reinitiation obtained in the hemiplegic patients. The applicant has found in three patients affected by the Strumpell-Lorraine syndrome, and who had been treated with the above-mentioned parasympathomimetic drugs, a very good recovery of deambulation, which was reversed from an assisted status to a non-assisted one, as well as an improvement of their tactile and pain sensitivity. The applicant has moreover treated 3 patients affected by amyotrophic lateral sclerosis by the above-mentioned parasympathomimetic drugs. Two of the patients were affected in their lower limbs, which drastically improved, passing from an assisted deambulation to a non-assisted one. One patient affected in his upper limbs also recovered a reasonable manual work activity. Also the tactile and pain sensitivity of these patients were improved. An improvement of movement, sometimes with a restoration of non-assisted deambulation, has been obtained by treating with the above-mentioned parasympathomimetic drugs patients affected by the Eaton-Lambert syndrome (5 cases), patients affected by myasthenia gravis (9 cases) and patients affected by muscular distrophy (in particular Duchenne disease, 11 cases). Also the tactile and pain sensitivity of these patients were greatly improved. The applicant has moreover found a drastic parasympathomimetic reduction, sometimes up to a disappearance of muscle spasticity, even resistant to antispastic treatment, in patients affected by paraplegia, hemiplegia and multiple sclerosis. These parasympathomimetic drugs were moreover advantageously used to inhibit pain pathology resulting from dysnociceptos and dysmechanoceptors, due to a biochemical lesion of the axoplasmic flow in primary sensory nociceptive and mechanoceptive neurons, due either to a peripheral or a central cause (as in the above-mentioned post-hemiplegic shoulder-hand syndrome and in the dysnociceptive and dysmechanoceptive dysaesthesias resulting from a central lesion in general,as well as in paraplegic patients and in those affected by multiple sclerosis). In this connection it should be pointed out that the applicant has experimentally verified his SPSC and his centroperipherorecursive theory in pains from chronic dysnociceptors of a peripheral cause, by greatly reducing, and also zeroing, by means of the above-mentioned parasympathomimetic drugs, pain also of the drug-resistant type in: 25 out of 28 patients affected by chronic rheumatoid arthritis; 18 out of 19 patients affected by chronic arthrosis; 22 out of 25 patients affected by chronic coxarthrosis and chronic relapsing sciatica. Moreover, after using the above-mentioned parasympathomimetic drugs, aesthesiometric tests were carried out that reversed cutaneous hypoaesthesias-anesthesias of 32 patients affected by arterial hypertension whose antihypertensive therapies had been suitably suspended. The applicant has detected significant reductions of their systolic and diastolic blood pressure down to normal values. These reductions in blood pressure values could be repeated in a causal relation so as to guarantee a control of blood pressure without the use of any other anti-hypertensive drug, for the whole period of treatment, up to four weeks of observation. Likewise, during further aesthesiometric tests done to cause a reversal, by the above-mentioned parasympathomimetic drugs, of cutaneous hypoaesthesias and anesthesias- in 15 patients affected by an arteriopathy of the upper limbs (Raynaud disease and syndrome, and sclerodermia in particular) and of the lower limbs, the applicant found, in addition to the aesthesiometric reversal of hypoaesthesia-anaesthesia, a remarkable improvement of the vasculopathic status, as detected pletysmographically, which was accompanied by a drastic reduction and also by a disappearance of intermittent claudication pain. Finally, after tests reversing normechanoceptive and nornociceptive hypoaesthesias-anesthesias by using the above-mentioned parasympathomimetic drugs, it was possible to improve the reaction times in 21 patients affected by Down disease, 9 patients affected by Alzheimer disease and 11 patients affected by autism. These results were replicated in a causal relation,for the whole time of treatment, up to four weeks. In 12 out of 21 patients affected by Down disease, the applicant found a drastic improvement of muscle tone and movement. From the above disclosure there results that the applicant's claim about the use of parasympathomimetic drugs in general, in particular carbachol and/or methacholine chloride and/or ethylether beta-metylcholine chloride and/or bethanechol chloride in the medical and neurological clinical fields is broadly justified. With respect to the optimum doses of parasympathomimetic drugs which have been found to be active in the diseases disclosed above, the following daily doses are indicated: 1) CARBACHOL: 0.3 ÷9 mg supra cutem and/or 0.25 ÷ 0.75 mg i.m. pro die; 2) METHACHOLINE CHLORIDE: 0.3÷9 mg supra cutem and/or 0.25 ÷ 0.75 mg i.m. pro die; 3) ETHYLETHER BETA-METHYLCHOLINE CHLORIDE: 0.3÷9 mg supra cutem pro die; 4) BETHANECHOL CHLORIDE: 0.3 ÷15 mg supra cutem and/or 5÷15 mg i.m. pro die Within these dose ranges no side effect was ever found, either topically on the skin, or systemically. It should be pointed out that while the best pharmacological and therapeutic results have been obtained by using the four above-mentioned chemical compounds, it has been experimentally found that the whole spectrum of parasympathomimetic drugs exhibited similar therapeutic characteristics. From the above it should be apparent that the invention is intended to also encompass, with respect to the above-disclosed therapeutic uses and indications, all the classes of the parasympathomimetic compounds.

Claims: Use of carbachol for the manufacture of a medicament for the treatment of diseases deriving from parasympathetic denervation on normal mechanoceptors, nociceptors and proprioceptors, and resulting in a diminished or absent voluntary movement performance and/or muscle spasticity. Use according to claim 1 in which the disease is hemiplegia. Use according to Claim 1 in which the disease is multiple sclerosis. Use according to Claim 1 in which the disease is paraplegia. Use according to Claim 1 in which the disease is Strumpell-Lorraine disease. Use according to Claim 1 in which the disease is amyotrophic lateral sclerosis. Use according to Claim 1 in which the disease is myasthenia gravis. Use according to Claim 1 in which the disease is Eaton-Lambert syndrome. Use according to Claim 1 in which the disease is muscular dystrophy. Use according to Claim 1 in which the disease is Duchenne disease. Use according to Claim 1 in which the disease is Down syndrome.

Inventors: SANTINI MAURIZIO, SANTINI, MAURIZIO
Applicants: SANTINI MAURIZIO, SANTINI, MAURIZIO
Application year: 1992
Main classification: A61K31
IPC codes: A61K31