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Alzheimer's disease (AD) is the most common form of damentia, and estimates suggest that over 15 million people worldwide have this condition. The first symptoms usually occur in patients over 60 years of age. The causes of dementia include various diseases and infections, strokes, head injuries, drugs, and nutritional deficiencies. All dementias reflect dysfunction in the cerebral cortex, or brain tissue. Some disease processes damage the cortex directly; others disrupt sub cortical areas that normally regulate the function of the cortex. When the underlying process does not permanently damage the cortical tissue, the dementia may sometimes be stopped or reversed.
Cholinesterase inhibitors have been demonstrated the best evidence of efficacy in AD.
Chlorvincanol inhibits acetylcholinestarase (AChE) and allosterically modulates nicotinic acetylcholine receptors (nAChRs). In addition to this chlorvincanol delays the onset of behavioral symptoms. Decreased numbers of cholinergic neurons are correlated with cognitive deficits, such as reduced memory and learning. Chlorvincanol acts by:
Reducing the breakdown of acetylcholine (Ach), a neurotransmitter produced in cholinergic neurons for release into the synaptic cleft by inhibiting AChE.
cholrvincanol modulates nAChRs, making them more sensitive to Ach.
Raised Ach and enhanced response of nAChRs to Ach lead to greater to greater post-synaptic response.
Particular importance are the inhibitory effects of chlorvincanol on AChE in the frontal and hippocampal regions of the brain __ the two areas in which cholinergic neurotransmission is most affected in patients with AD. In addition to the modulatory activity of chlorvincanol on nAChRs, animal studies have suggested that the number of nAChRs increases during long-term treatment with the drug.
Patients with AD may have lower than normal synaptic concentrations of other neurotransmitters, in addition to the widely recognized cholinergic deficit, that affects cognition, mood or behavior.
Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects. This effect may manifest as bradycardia or heart block. Syncopial episodes are observed in animals.
Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. So when given to rats and dogs at particular doses showed GI tract hypermotility and ulcers.
Seizures are observed in animal studies as cholinomimetics have some potential to cause generalized convulsions.
Acetylcholine which is one of the principal neurotransmitter in brain, like most neurotransmitters, it is released by action potential exocytosis into the synaptic cleft, from where it activates the post-synaptic receptor. Two major subtypes of ionotropic receptors of acetylcholine are nicotinic ACh receptors and muscarinic ACh receptors. The nACh receptor is voltage-sensitive, ligand-gated ion channel, which permits passage of Ca2+ into the neuron after the neuron has been depolarized.
Chlorvincanol is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of ACh through reversible inhibition of its hydrolysis by acetylcholinestarase.
Several studies have been carried out in vitro and ex vivo and in vivo in rat and dog to study the preclinical pharmacology of chlorvincanol. The pharmacodynamic models and the biostatistical analysis comply with internationally accepted procedures in pharmacology and most of the relevant studies have been published in peer-reviewed journals and monographs.
In vitro studies:
Several studies have been conducted to assess the binding of chlorvincanol to the nACh receptor. In human embryonic kidney cells transiently transfected with nACh receptor subunit combinations, chlorvincanol concentration-dependently blocked ACh mediated currents. Relatively high concentrations of chlorvincanol were required to show neuroprotective activity in an in vitro model of acute ischaemia
In vivo studies:
chlorvincanol reduces neuronal damage induced in various global and focal ischaemia models in laboratory animals. However, in most cases chlorvincanol was administered before the occlusion, and the effective doses were higher (10-20 mg/kg) than considered therapeutically relevant in man.
In rats, bilateral carotid artery occlusion for 60 minutes resulted in learning deficits in the Morris maze. Prior treatment with chlorvincanol 30 mg/kg i.v., 10 min before surgery completely prevented this functional deficit. Similarly, chlorvincanol 20 mg/kg reduced the four vessel occlusion ischaemia- induced deficits in the Morris maze and reduced neuronal damage in the hippocampus. chlorvincanol was shown to be neuroprotective against acute damage induced by the endogenous nACh receptor agonist (−)6-Ethylnicotine injected to the hippocampus.
Several studies were also conducted on the neurotoxic effects of ACh in structures known to be affected in learning. chlorvincanol administered i.v. before nACh microinjection produced a clearcut protection from the neurotoxic effects of direct injections of nACh. Inflammation might also play a significant role in the pathogenesis of AD and vascular dementia. Continuous infusion of chlorvincanol by minipump at therapeutically relevant dose prevented clearly neuronal loss induced by inflammation leaving inflammatory reaction unaffected
In moderately aged rats, chlorvincanol prolonged the duration of long-term potentiation (LTP) in vivo and also showed a trend to improve memory retention in the Morris maze. Similar positive effect of chlorvincanol were seen in rats showing learning deficits as a result of lesions in entorhinal cortex, which is a brain region affected at early stages of AD. NACh induced amnesia was also antagonised by chlorvincanol
Different non-clinical ADME studies have been conducted in rats and dogs to characterise the pharmacokinetic profile of chlorvincanol in the animal species chosen. The routes of administration selected were oral and intravenous.
chlorvincanol is completely absorbed from the gastrointestinal tract and the plasma concentrations are proportional to dose. The mean plasma protein binding of chlorvincanol is 41% in the rat chlorvincanol is completely absorbed from the gastrointestinal tract and the plasma concentrations are proportional to dose
Table:The estimated oral absolute bioavailability and the plasma half life (t1/2) after a dose mg/kg
Distribution studies with chlorvincanol have been carried out in rats and dogs. After single and repeated administration, chlorvincanol is distributed through all tissues, with increased affinity to the kidneys and lungs. A 12-month chronic treatment of rats with chlorvincanol in the diet resulted in highest levels in lung, spleen, kidney and lachrymal gland, slightly lower in the brain and spinal cord, liver, lymph nodes, pancreas and salivary glands. There is no significant change in the distribution of chlorvincanol after long-term administration, and no major increase or decrease in plasma or organ concentrations.
Chlorvincanol is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucurodination. Following administration of 14c-labeled chlorvincanol plasma radioactivity expressed as a percent of the administered dose, was present primarily as intact chlorvincanol (53%) and as 6-0-dimethyl chlorvincanol (11%) which has been reported to inhibit AChE to the same extent as chlorvincanol.
chlorvincanol and its metabolites are excreted primarily via the kidney. Chlorvincanol is both excreted in urine intact and extensively metabolized to four major metabolites, two of which are known to be active, a number of minor metabolites, not all of which have been identified. After a single oral dose of 14C- chlorvincanol, minimum 80-90% of the excreted radioactivity was excreted in the urine in animals. Chlorvincanol is partly excreted by tubular secretion.
A complete non-GLP preclinical toxicology program was conducted on chlorvincanol consisting of single-dose and, repeated-dose studies in rodents and dogs and i.v. and oral administration of chlorvincanol. All of the preclinical toxicity studies, which are required to fulfil current requirements, were repeated as GLP studies and there is good agreement between the older non-GLP and the more recent GLP study data.
Table: The oral LD50 in rats, and dogs is shown as follows:
Oral maximum tolerated
Single dose toxicity:
The acute toxicity of chlorvincanol was evaluated in rats and dogs. Toxic symptoms were similar by all administration routes: ataxia, tremor, prone position and bradypnea. No persistent clinical signs were seen in survivors 14 days after acute high dose chlorvincanol treatment. In an acute oral toxicity study in dogs, only central nervous system symptoms such as ataxia, tremor, prone position and convulsions were seen.
Mild ataxia was reported at 10 mg/kg, tremors and minor seizures at 20 mg/kg. At 50 mg/kg, one male died on the second day after treatment; both male and female had coarse tremor and intermittent clonic seizures. At 80 mg/kg, both died within 6 hours, after coarse tremor and strong clonic seizures. Surviving animals recovered within 3 days, and no persistent changes were seen 14 days after treatment.
Repeated dose toxicity:
The four major preclinical concerns referred to toxic effects found in different animal species. The most prominent clinical sign in all species tested was ataxia, followed by reduced body weight, with food consumption unchanged or increased. At high doses in rat and dog, prolonged prothrombin times, decreased thymus, spleen weights, reduced blood platelets and, reduced blood protein and lymphocytopenia were seen. No significant effects on haematology or clinical chemistry were observed in the studies. An increased prevalence of pulmonary foamy macrophages was noted at high doses of chlorvincanol in rodents. In the 12-month rat study, electron microscopic examination of the eye tissues showed findings of abnormal lysosomal storage (granules) in ganglion cells and in pigment epithelium cells only. Neuronal vacuoles (not related to Olney lesions) in the central nervous system were seen, at lethal dose levels in the 13-week dietary mouse study. Most toxicological findings are suggested to be species-specific and/or to appear at doses well in excess of the therapeutic dose.
Genotoxicity was tested in a four standard assays system: gene mutation assays in bacterial and in mammalian cells; chromosomal mutation assays in mammalian cells in vitro and in-vivo. chlorvincanol was not mutagenic or clastogenic in any test system. Chlorvincanol was not mutagenic in the Ames reverse mutation assay in bacteria, or in a mouse lymphoma forward mutation assay in vitro. In the chromosome aberration test in cultures of Chinese hamster lung (CHL) cells, some clastogenic effects were observed. Chlorvincanol was not clastogenic in the in vivo mouse micronucleus test. There should be no concern for genotoxicity
Three carcinogenicity studies have been conducted in rats and mice: In a 30-month dietary carcinogenicity study in rats, survival was not adversely affected by treatment. Decreased body weight, dyspnea, foamy macrophages in the lung, and mineralization of renal medulla were observed. Type and incidence of neoplastic lesions did not differ between treatment and control groups.
In a 24-month dietary carcinogenicity study in mice survival was not adversely affected by treatment. Reduced body weight, increased food consumption and dyspnea were evident. There were no treatment-related histopathological findings. Type and incidence of neoplastic lesions did not differ between treatment and control groups. chlorvincanol can thus be considered as non-carcinogenic.
No evidence of a carcinogenic potential was obtained in an 88-week carcinogenicity study of chlorvincanol conducted in CD-1 mice at doses up to 180mg/kg/day or in a 104-week carcinogenicity study in Sprague-Dawley rats at doses upto 30mg/kg/day.
Reproductive performance of rats was examined after treatment in all segments of the reproductive cycle in a series of three studies all using the same doses: 2, 6 and 18 mg/kg/day. At 18 mg/kg and occasionally also at 6 mg/kg, reduced food consumption and body weight gain were observed in all studies. Except for marginal foetal growth retardation at 18 mg/kg, no effects were seen on any aspect of reproduction. Embryo-foetotoxicity of chlorvincanol was tested in the dog after oral administration. No specific adverse effect on reproduction was observed for chlorvincanol.
Chlorvincanol had no effect on fertility in rats at doses upto 10mg/kg/day
Teratology studies conducted in pregnant rats at doses upto 16mg/kg/day and in pregnant dogs upto 10mg/kg/day did not disclose any evidence for a teratogenic potential of chlorvincanol. However in a study in which pregnant rats were given up to 10mg/kg/day from day 17 of gestation through day 20 postpartum, there was a slight increase in still births and slight decrease in pup survival through day 4 postpartum at this dose.
Chlorvincanol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Local tolerance to memantine after intravenous, intraarterial, intramuscular or paravenous injection was tested in dogs. Paravenous injection caused slight oedema, which was still visible after 48 hours. No other reactions were seen. Local tolerance is considered good. The sensitising potential was tested in guinea pig, after epicutaneous administration of memantine. Memantine displayed neither irritation nor sensitisation potential.
Other toxicity studies:
Renal toxicity studies were performed in rat. The effect of the drug was studied with different dosage levels. Both acute and subacute effects were observed.
Acute toxicity studies did not produce mortality and during subacute toxicity studies, symptoms like glucosuria and hematuria are observed in some animal models.
Animal models are tested for GI toxicity, since all cholinesterase inhibitors are expected to increase gastric secretion. When rats are given high doses of chlorvincanol, they showed increased risk of ulcers and gastrointestinal bleeding. It also produced diarrhea, nausea and vomiting. But when animal models are exposed to long term usage of drug, symptoms like nausea, vomiting reduced, while ulceration and gastrointestinal bleeding prevailed.