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The purpose of this review is to correlate current data on the molecular mechanisms of action of the drug Nimodipine with its clinical effects and applicability in mental disorders belonging to the spectrum of affective pathology. The article discusses the prospects for using the calcium channel blocker nimodipine as a method of both mono and combination therapy for bipolar disorders with various types of course. Nimodipine is a selective blocker of voltage-dependent calcium channels, a dihydropyridine derivative. By blocking L type calcium channels, it prevents the entry of calcium ions into the cell. Due to its pronounced ability to penetrate the blood-brain barrier, it has a selective effect on brain neurons and has a vasodilating, antihypertensive and normotimic effect. Nimodipine blocks LTCC channels in brain neurons, thereby influencing synaptic plasticity, transmitter release and excitation-transcription coupling, which makes it possible to influence various clinical conditions with pathology in the area of affect, including bipolar disorders with ultra-rapid cycling, and also, in cases with high resistance and intolerance to other mood stabilizers.

Based on the outcomes of surgical management of thirty-six patients diagnosed with atherosclerosis of carotid arteries and a further thirty-five 35 patients presenting with atherosclerotic lesions of the subclavian and vertebral arteries the authors substantiated a differentiated therapeutic policy aimed at protecting the brain from ischaemia, having demonstrated efficiency of cerebral protection with nimodipine and rheopolyglukin in patients subjected to operations on the subclavian and vertebral arteries and feasibility of combining this method with the application of a temporary puncture carotid-artery bypass graft during carotid endarterectomy. Functional possibilities of puncture-mediated bypass grafting of the carotid artery was confirmed by studying the blood flow in the common, internal carotid and median cerebral arteries on the operated side and ipsilateral side in patients with and without a bypass graft applied.

Ultralow doses of antibodies to S-100 protein increased rat survival, reduced neurological deficit, eliminated myorelaxation, and improved movement coordination and cognitive functions in rats with experimental hemorrhagic stroke; the efficiency of the preparation was not inferior to that of nimodipine. In contrast to nimodipine, ultralow doses of antibodies to S-100 protein exhibited pronounced anxiolytic properties.

The influence of nimodipine on the cerebral circulation of rats under conditions of global transient cerebral ischemia, myocardial ischemia, and combined disorders of cerebral and coronary circulation was experimentally studied in rats, in comparison to the intact and sham operated animals. It is shown that nimodipine (0.03 mg/kg) enhances circulation in the parietal region of the cerebral cortex to the same extent in both intact rats and those after global transient cerebral ischemia. Under conditions of experimental myocardial infarction, the cerebrovascular effect of nimodipine was significantly decreased in comparison to that in intact and sham operated animals. In contrast to intact and sham operated rats and the rats with myocardial infarction, there were no signs of cerebrovascular activity of nimodipine in animals with combined disorders of coronary and cerebral circulation. A new approach to the search for and investigation of pharmacological agents for the treatment of combined disturbances of cerebral and cardiac circulation is proposed.

A scheme of complex administration of drugs in the order neuroprotector + neuroactivator + neuroretarder for the treatment of neurodegenerative processes in the brain has been elaborated and tested on a model object representing neurodegenerative mutants of Drosophila melanogaster. The appearance of changes in the brain was delayed when drugs were used separately: donepezil hydrochloride (arisept), 10 - 11 days, epinephrine and nimodipine, 1 - 2 days. The treatment of flies with the same drugs in the order arisept + epinephrine + nimodipine leads to the complete regeneration of D. melanogaster brain tissue to within 15 days of imago life.

The study included 31 patients with constrictive and stenotic angiopathy (CSAP) that had developed due subarachnoidal hemorrhage. All the patients were operated on within the first 4 days after the moment of blood bleeding. Since the onset of CSAP, Groups 1 (n = 14) 2 (n = 17) received normovolemic and hypervolemic infusion therapy, respectively. In both groups, cerebral circulatory changes were found to depend primarily on cardiac productive parameters. The nature of infusion therapy had no impact on the results of treatment (according to the Glasgow scale). Hypervolemia used in such patients has no advantages over normovolemic water load when hyperdynamic circulation is created when inotropic agents are used.

Twenty six patients, used home-made ephedrine like psychostimulators were examined. Nervous system pathology in these cases was characterized by short (several months) period of the pathological process formation, young patient's age, absence of family psychiatric history, pronounced systemic and multilevel affection of the organism, severity of psychic defects and patients disability. Electrophysiological study revealed essential changes of neurodynamics manifesting with insufficiency of non-specific activating brain system, diencephalic stem structure dysfunction, deep structure irritation that might correspond to clinical picture of multisystem CNS lesions. An involvement of limbic reticular structures in pathological process on the background of neurophysiological immaturity was detected as well. In patients disorders of brain homeostatic mechanisms and cognitive functions were also found. Deprivation of reactivity of upper-segmental autonomic system regulation can determine rigidity and pathological adaptation of such patients. Insufficiency of activating systems of reticular formation, arrhythmia, disturbances of cognitive functions and cerebral homeostasis dictate a need for nootropics prescription for these patients. Clinical experience justifies including drug nimotop in complex treatment and rehabilitation schemes.

Forty three patients with chronic alcoholism of stage II with secondary affective disorders (anxiety, subdepression) and actualization of pathological drive for alcohol in remission period were divided into 3 groups: patients were treated with nimodipine (90 mg/day during 10 days), patients were treated with nifedipine (45 mg/day during 10 days) and patients of control group (they received a placebo for 10 days). The study was double blind. The results revealed that both calcium channels antagonists reduced a level of depression measured with the Hamilton scale and Zung test. Ten-day nimodipine (but not nifedipine) course also caused a significant decrease of anxiety evaluated by the Spilberger test. Both medications, being significantly more efficient comparing to placebo, led to desactualization of pathological drive for alcohol in parallel with affective disorders reduction. Because of the absence of the depriming effect of these compounds on CNS as well as of dependence phenomenon, calcium channels antagonists may be used in narcology for stopping secondary affective disorders and actualization of pathological drive for alcohol in remission period.

The influence of the calcium entry blocker dilceren (nimodipine) on the local and regional circulation was studied in rats and cats. In the majority of experiments on intact animals, dilceren increased the local and regional blood flow. However, in some cases, the circulation decreased or remained unchanged, which was accompanied by pronounced hypotension. Administered after global brain ischemia, dilceren improved the cerebral hemodynamics in all experiments.

A comparative study of pharmacodynamics and clinical efficacy of nimodipine, nifedipine and foridon in ischemic stroke (late recovery and residual period) was performed in 97 patients with ischemic stroke. It was found that nimodipine, nifedipine and foridon at late recovery or residual stages significantly improved higher psychic functions, promoted regression of neurologic disorders and optimized social rehabilitation. Nimodipine, primarily, decreased the intensity of neurological disorders, improved higher psychic functions and had a positive impact on cerebral hemodynamics. Nifedipine primarily improved central hemodynamics (increased stroke output and ejection fraction). Foridon is most effective selective pharmacodynamic impact on peripheral hemodynamics (stimulated arteriolar blood flow, diminished venous capacity and spasticity), i.e. normalized peripheral blood flow.

A clinical and paraclinical monitoring was conducted of the condition of those patients presenting with cerebral hemorrhage using X-ray computerized tomography, ultrasound dopplerography of extra- and intracranial arteries. Shown in the study is a positive effect of nimodipine on the risk of development of clinically significant neurological deficit with no regression undergone against the background of paraclinically recordable objective signs of constrictive-stenotic artheriopathy and formation of unfavourable (gross invalidism, vegetative state, case mortality) outcome according to the Glasgow Outcome Scale and low level of functional activity according to the Barthel Index at day 30 after the development of hemorrhage. The drug can be recommended for use in the treatment of aneurysmatic cerebral hemorrhages.

The relationship between lipid peroxidation products and the severity of arterial spasm was studied in 86 patients. For this, the level of radical production, the content of the end lipid peroxidation product malonic dialdehyde and the overall antioxidative activity of lumbar cerebrospinal fluid were determined during 24-hour Doppler monitoring of blood flow in the middle cerebral and internal carotid arteries. Following subarachnoidal hemorrhage, the activation of lipid peroxidation processes was shown to correlate with the severity of arterial spasm and it is likely to contribute to the development of late ischemias. Nimotop used to treat patients with significant arterial spasm caused a reduction in the rate of free radical lipid peroxidation to that characteristic for patients with moderate spasm. The findings suggest that it is expedient of including antioxidants into the combined therapy of patients with acute subarachnoidal hemorrhage.

This literature review concerns both well known facts on mechanisms of action of calcium channels blockers and less known effects on different systems of the body. In addition to vascular dilatation, the blockers produce neuroprotective action, promote dysaggregation. Detailed information is given on usage of soluble calcium antagonist-nimotop.

A modified rat model of ischemic brain injury caused by ligation of the middle cerebral artery is proposed. The time course of morphological changes in brain tissues was studied and bilateral cerebral circulatory disorders, hypoxic cortical neurocytic damages followed by intracellular regeneration, as well as metabolic and structural changes not only in the cortical neurocytes, but in the conduction paths and synaptic terminals. Nimodipine had no effect on blood supply to the ischemic brain either early or late in ischemic brain injury after ligation of the middle cerebral artery.

The analysis of original and literature evidence on nimodipin administration in senile patients with vascular dementia and Alzheimer's disease allows the conclusion on positive effects of the drug on cognitive, motor, behavioral, neuropsychological and postural defects. Further efforts should be directed to the study of long-term regimens and elucidation of nimodipin ability to inhibit progression of dementia.

A model of spinal pain syndrome induced by a generator of abnormally increased excitation in the system of dorsal horns of the spinal cord with penicillin was used to test the calcium channel blockers OF5015 and nimotop, as well as calcium gluconate for their effects. The drugs were administered orally, intraperitoneally, intracisternally and applied to the spinal cord in combination with penicillin which was used to induce the pain syndrome. The action of the agents were compared with that of analgin. OF5015 given in a dose orally was shown to attenuate the pain syndrome to a greater extent than analgin. Nimotop and calcium gluconate given orally or intrasystematically failed to affect the pain syndrome. When applied to the spinal cord, all the drugs substantially attenuated the pain syndrome or prevented its development.

Before and after intravenous administration of 1-1.5 mg nimotop 18 patients with acute brain infarction underwent EEG, integral body rheography, computed tomography and measurement of regional volumetric cerebral circulation (RVCC). Nimotop appeared to increase RVCC in the infarction zone, especially in low initial RVCC levels. The drug induced a shift to EEG normalization and a hypotensive effect, cerebral hemodynamics remaining without changes. Nimodipine-type calcium antagonists favourably affect brain perfusion and bioelectric activity which is promising for application in acute cerebral infarction.

The experiments with unconscious cats and dogs have demonstrated that the calcium antagonist nimodipine has a profound anti-ischemic property. The drug reduces the average value of ST-segment elevation in multiple epicardial ECG leads, during acute myocardial ischemia. Nimodipine maintains cardiac pump and contractile functions, elevates ATP levels in the arbitrarily intact and ischemic myocardium of the left ventricle during 40-min occlusion and 60-min reperfusion of the coronary artery. The protective action of the drug is unassociated with enhanced collateral coronary circulation.

Experiments on rats with myocardial infarction induced by occlusion of the left coronary artery were made to explore the influence of calcium antagonists injected intraperitoneally for a long time (daily, for 21 days) on hemodynamics, contractile function and morphology of the heart muscle. It has been shown that verapamil (0.5 mg/kg), diltiazem (2 mg/kg) and nimodipine (20 micrograms/kg) do not exert under those conditions any noticeable effect on pump and contractile heart functions. Administration of verapamil in a doze of 2 mg/kg enhanced heart failure. The drugs under study normalized the response of contractile heart function to volumetric load, which is related to a considerable measure to the acceleration of reparative processes in the myocardium.

In the experiments on anesthetized cats and dogs it was shown that calcium antagonists nimodipine and flunarisine possessing the predominant action on the cerebral vessels exert a significant effect on the blood supply and the activity of the cardiac muscle. Administration of the drugs causes bradycardia, increases the total coronary blood flow. Nimodipine enhances the contractile function of the myocardium, flunarisine fails to change it. Under ischemia of the cardiac muscle the drugs increase the blood supply of only the intact zones of the left ventricle without influencing positively the blood supply of the ischemic focus itself.