A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction

J Am Geriatr Soc (1987 May) 35(5):425-30

In a double-blind clinical trial, vinpocetine, a synthetic ethyl ester of apovincamine, was shown to effect significant improvement in elderly patients with chronic cerebral dysfunction. Forty-two patients received 10 mg vinpocetine three times a day for 30 days, then 5 mg three times a day for 60 days. Matching placebo tablets were given to another 42 patients for the 90-day trial period. Patients on vinpocetine scored consistently better in all evaluations of the effectiveness of treatment including measurements on the Clinical Global Impression (CGI) scale, the Sandoz Clinical Assessment- Geriatric (SCAG) scale, and the Mini-Mental Status Questionnaire (MMSQ). There were no serious side effects related to the treatment drug.

The effect of a cerebral vasodilator, vinpocetine, on cerebral vascular resistance evaluated by the Doppler ultrasonic technique in patients with cerebrovascular diseases

Angiology (1995 Jan) 46(1):53-8

Changes in cerebral vascular resistance were examined in patients with cerebral circulatory diseases by the Doppler ultrasonic technique after administration of a cerebral vasodilator, vinpocetine, for two months. Continuous index (CI) and pulsatility index (PI) of the blood flow pattern in the internal carotid artery were used as objective parameters for changes in cerebral vascular resistance. 1. The CI and PI significantly after administration of the drug; i.e., the CI increased while the PI decreased. 2. An inverse correlation was noted between the rate of change of the CI (delta CI) and that of the PI (delta PI). 3. The results suggest that measurement of the CI and PI by the Doppler ultrasonic technique is useful in investigating the effect of drugs on the cerebral circulation.

The safety and lack of efficacy of vinpocetine in Alzheimer's disease.

J Am Geriatr Soc (1989 Jun) 37(6):515-20

Fifteen Alzheimer's patients were treated with increasing doses of vinpocetine (30, 45, and 60 mg per day) in an open-label pilot trial during a one-year period. Patients were assessed seven times both on and off drug with: the Buschke Selective Reminding Task, a letter fluency test, a category fluency test, the Boston Naming Test, a cognitive capacity screening examination, and a clinical global impression. Vinpocetine failed to improve cognition on psychometric testing or overall functioning, as measured by the clinical global impression, at any dose tested. Patients showed significant decline in most measures during the course of the study, at the same rate as a matched control group, consistent with progressive dementia. There were no significant side effects from drug therapy. We conclude that vinpocetine is ineffective in improving cognitive deficits and does not slow the rate of decline in individuals with Alzheimer's disease.

Nootropic agent vinpocetine blocks delayed rectified potassium currents more strongly than high-threshold calcium currents

Neurosci Behav Physiol (1998 Mar-Apr) 28(2):116-20

A two-microelectrode potential clamping method was used on isolated common snail neurons to measure high-threshold Ca2+ and delayed rectified K+ currents. Addition of the nootropic agent vinpocetine (VPC) to the bathing solution rapidly and reversibly inhibited both types of current. The effects of VPC were dose-dependent and were independent of the test stimulus voltage. Maximum blockade of the Ca2+ current averaged 27% at a VPC concentration of 600 microM. Maximum blockade of the K+ current averaged 76% at a VPC concentration of 30 microM It is concluded that K+ channels are more likely targets of VPC than Ca2+ channels.

On the mechanism of action of vinpocetine

Acta Pharmaceutica Hungarica (Hungary), 1996, 66/5 (213-224)

Cavinton (vinpocetine) was introduced into the clinical practice some twenty years ago in Hungary for the treatment of cerebrovascular disorders and related symptoms. Since then, its active ingredient, vinpocetine, beside its therapeutical utilization, has become a reference compound in the pharmacological research of cognitive deficits caused by hypoxia and ischaemia as well as in the cellular and biochemical investigations related to cyclic nucleotides. In this review a survey is given on the experimental data obtained with vinpocetine and an attempt is made to outline the drug's mechanism of action. Early experiments with vinpocetine indicated five main pharmacological and biochemical actions: (1) selective enhancement of the brain circulation and oxygen utilization without significant alteration in parameters of systemic circulation, (2) increased tolerance of the brain toward hypoxia and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase (PDE) enzyme and (5) improvement of rheological properties of the blood and inhibition of aggregation of thrombocytes. Later studies in various laboratories confirmed the above effects and clearly demonstrated that vinpocetine offers significant and direct neuroprotection both under in vitro and in vivo conditions. Evidence has been obtained that neuroprotective action vinpocetine is related to the inhibition of operation of voltage dependent neuronal Na+-channels, indirect inhibition of some molecular cascades initiated by the rise of intracellular Ca2+-levels and, to a lesser extent, inhibition of adenosine reuptake. Vinpocetine has been shown to be selective inhibitor of Ca2+-calmodulin dependent cGMP-PDE. It is assumed that this inhibition enhances intracellular a GMP levels in the vascular smooth muscle leading to reduced resistance of cerebral vessels and increase of cerebral flow. This effect might also beneficially contribute to the neuroprotective action.

Nootropic drugs have different effects on kindling-induced learning deficits in rats

Pharmacological Research (United Kingdom), 1995, 32/3 (115-122)

Kindling represents an accepted model of human epileptogenesis. Furthermore, it has been demonstrated that kindled rats show a diminished learning performance in an active avoidance task. In our study we administered different nootropic drugs to kindled rats to test their effects on learning a two-way active avoidance task in the shuttle-box. Kindling was induced by repeated intraperitoneal injections of 45 mg kg-1 pentylenetetrazol (PTZ) once every 48 h. The substances vinpocetine (0.1 and 1.0 mg kg-1), methylglucamin orotate (225 and 450 mg kg-1), piracetam (100 mg kg-1, and meclofenoxate (100 mg kg-1) were administered during kindling development and after kindling completion prior to each session in the learning experiment. The nootropic drugs had little if any effect on severity of seizures. Concerning their effect on learning the substances each acted in a specific manner. Methylglucamin orotate enhanced the learning deficit induced by kindling. Meclofenoxate injected prior to the kindling stimulation was ineffective, whereas administration prior to the learning test improved the learning performance effectively. A complementary action was shown in experiments with vinpocetine. Only piracetam prevented the occurrence of kindling-induced learning deficits regardless the administration schedule.

Clinical and immunological signs of retinal involvement and potentialities of its drug correction in patients with chronic diffuse viral diseases of the liver and in Australian antigen carriers

Vestnik Oftalmologii (Russian Federation), 1994, 110/4 (27-29)

A total of 133 subjects aged 15 to 55 were followed up, the main group (n = 87), patients with chronic diffuse diseases of the liver caused by hepatitis B virus, and two reference groups, 26 patients with uveitis and 20 normal subjects, 13 and 4 subjects of each group, respectively, were Australian antigen (HBsAg) carriers. Functional disorders of the retina were detected in 93.2% of group 1 patients, as well as intensified local (tears) and total system (blood) autoimmune reactions to tissue-specific retinal S-antigen (mol.mass 48 kD). An increased detection rate of antibodies to S-antigen and its higher titers were found in healthy virus carriers as compared to HBsAg-seronegative donors. These data may be regarded as evidence of an increased risk of uveoretinal pathology in subjects infected with hepatitis B virus, this being confirmed by a higher ),incidence (50%) of latent virus carriership in the group of patients with uveoretinitis. Stabilizing effect of cavinton in functional changes of the retina was revealed, this recommending this drug for combined therapy of patients with chronic diffuse diseases of the liver and for prevention of ocular diseases. The majority of the examinees in whom retinal abnormalities were found being young, the authors draw attention to the social aspect of the problem.

Study on the absorption of vinpocetine and apovincaminic acid

EUR. J. DRUG METAB. PHARMACOKINET. (Switzerland), 1993, 18/4 (317-321)

The absorption of vinpocetine (Cavinton) and apovincaminic acid, compounds showing a marked difference in their physico-chemical properties, was studied in rats in in situ loop experiments by using radiolabelled compounds. In the case of apovincaminic acid, the investigations also involved the estimation of the portion of radioactivity excreted in urine and faeces after i.v. and p.o. administration of the compound. According to our results, it can be concluded that both vinpocetine and apovincaminic acid are absorbed from the gastrointestinal tract - apovincaminic acid mainly from the stomach, while vinpocetine is absorbed from the small intestine.

Protective action of vinpocetine against experimentally induced gastric damage in rats

ARZNEIM.-FORSCH. DRUG RES. (Germany), 1993, 43/9 (981-985)

The efficacy of vinpocetine (CAS 42971-09-5) to prevent gastric mucosal damage induced by several noxious agents and its antisecretory effect were studied in rats. Vinpocetine administered orally or intraperitoneally inhibited the development of gastric lesions induced by 96% ethanol in a dose-dependent way. The highest protective activity was observed when vinpocetine was given intraperitoneally 30 min before ethanol, and its effect was still significant when administered 120 min before ethanol exposure. Oral administration of vincamine also displayed gastroprotective action in this model. Pretreatment with indometacin counteracted the protective action of vinpocetine against ethanol-induced damage, suggesting the involvement of a prostaglandin-mediated mechanism. The protective effect of vinpocetine was compared with that of prostaglandin E2, ),sucralfate, and tripotassium dicitrate bismuthate. The antiulcer activity of vinpocetine was demonstrated also in gastric injury induced by phenylbutazone and in chronic gastric ulcer induced by acetic acid. Histamine-stimulated gastric acid secretion in pylorus-ligated rats was partially inhibited by vinpocetine administered intraduodenally. The activity of vinpocetine established in these experiments is indicative of its potential clinical value as a gastroprotective agent.

Microcirculation, rheological properties of blood and their correction in ischemic disorders of cerebral circulation

ZH. NEVROPATOL. PSIKHIATR. IM. S. S. KORSAKOVA (USSR), 1991, 91/11 (67-70)

A study was made of microcirculation using bulbar biomicroscopy and of the aggregation properties of platelets in 94 patients with initial manifestations of cerebral circulatory failure and dyscirculatory encephalopathy before and after the treatment with vasoactive drugs and actovegin. It has been recorded that the impairment of hemomicrocirculation progresses with the rise of the disease stage, being more pronounced in patients with vegetovascular crises. To correct microcirculatory disorders and the rheological properties of blood, the authors provide evidence for administering cavinton, euphylline and nicotinic acid combined with actovegin.

Cavinton in the prevention of the convulsive syndrome in children with a history of birth trauma

ZH. NEVROPATOL. PSIKHIATR. IM. S. S. KORSAKOVA (USSR), 1991, 91/8 (21-22)

The authors studied the efficacy of cavinton as an agent helpful in preventing neurologic disorders in the newborn with hypoxic ischemic encephalopathy due to intracranial birth trauma. The short-term results of the treatment were elucidated in 61 children. In group I including 20 persons given conventional therapy, the disappearance of seizures was recorded in 6 patients; out of 41 children (group II) given additionally cavinton, in 27. Twenty-nine children were followed up for a year. In group ),I, convulsive paroxysms recurred in 4 patients, whereas in the group II children, no convulsive syndrome was recorded on the follow-up. The group II children also showed a decrease of the phenomena of intracranial hypertension and normalization of the psychomotor development. The preventive effect of cavinton seen in children with a history of birth trauma may be accounted for by its capacity of normalizing cerebrovascular disorders and by its own anticonvulsive properties.

Effect of ethyl apovincaminate on the utilization of 14C-glucoses by rat brain in vitro

ARZNEIM.-FORSCH. DRUG RES. (Germany, Federal Republic of), 1991, 41/2 (107-108)

The effect of the presence of 500 microg ethyl epovincaminate (Cavinton (R)) on the aerobic metabolism of 14C-labelled glucoses was studied in vitro. The drug tested increased the metabolism of (1-14C)-D-glucose first of all, which indicated a significant activation of pentose-phosphate shunt.

Vinpocetin protects against excitotoxic cell death in primary cultures of rat cerebral cortex

EUR. J. PHARMACOL. (Netherlands), 1990, 187/3 (551-553)

The protective effect of vinpocetin, a drug clinically useful in brain hypoxia/ischemia, was examined in vitro on cerebrocortical cultures treated with glutamate and related excitotoxins. The extent of cell death was quantified by measuring lactic dehydrogenase activity released from damaged cells into the culture medium. Vinpocetin partially protected the cortical cells against cell death induced by N-methyl-D-aspartate, quisqualate and kainate, indicating that the drug exerts a direct protective action on cerebrocortical cells bearing excitatory amino acid receptors.

Effect of vinpocetine on noradrenergic neurons in rat locus coeruleus

EUR. J. PHARMACOL. (Netherlands), 1990, 187/3 (537-539)

Conventional extracellular single unit recordings were used to investigate the effect of vinpocetine on locus coeruleus noradrenergic neurons in chloral hydrate-anesthetized rats. Vinpocetine produced a significant and dose-dependent increase in the firing rate of locus coeruleus neurons (ED30 = 0.75 mg/kg i.v.) up to 1 mg/kg i.v., followed by a complete blockade of spiking activity at doses higher than this. The effective dose range was in very good agreement with the dose range corresponding to the memory-enhancing effects of the compound. Our results supplied direct electrophysiological evidence that vinpocetine increases the activity of ascending noradrenergic pathways. This effect can be related to the cognitive-enhancing characteristics of the compound.

Pharmacological treatment strategies in dementia disorders

PHARMACOPSYCHIATRY SUPPL. (Germany, Federal Republic of), 1989, 22/2 (129-134)

Pharmacological treatment strategies in dementia disorders concern the use of vasodilators, nootropics, psychostimulants, acetylcholinergic drugs, monoaminergic drugs, and neuropeptides. The substitution of essential nutrients and the use of gangliosides and phosphatidylserine may also be considered. On the whole, drugs with vasodilator effects were unsuccessful in the past. However, new drugs have been introduced which also enhance the metabolism in the neurons. These drugs, the nootropics, often combine a vasodilator effect with the activation of brain metabolism and the protection of the brain from toxic effects. The effect of nootropics has mainly been demonstrated in animal experiments, whereas the drugs have been less effective in the treatment of demented patients. The use of psychostimulants should be tested carefully before ruling out their potential benefit. Acetylcholinergic drugs have attracted great interest in dementia treatment but, altogether, trials with these drugs have shown disappointing results. This may be due to the drugs not being effective enough, and therefore continued trials with this type of drug are necessary. Studies of drugs affecting monoaminergic function have offered interesting results. Selective 5-hydroxytryptamine (5-HT) reuptake blockers have been found to improve disturbed emotional functions, which seems to be of importance for the patients. Neuropeptides have shown effects on learning and memory paradigms in animal studies. However, their effect on ),dementia syndroms in humans has not been very promising as yet. Vitamin B12 deficiency in patients with late onset dementia may indicate reduced efficacy in transport over membranes in the elderly. Other essential nutrients might be transported in reduced quantities. Substitution therapy of vitamin B12 has to be carefully studied in the elderly. Gangliosides and phosphatidylserine are drugs that are still in the experimental stage, but these drugs offer an interesting approach to the treatment of dementia disorders.

Comparison of the effects of vinpocentine, vincamine, and nicergoline on the normal and hypoxia-damaged learning process in spontaneously hypertensive rats

DRUG DEV. RES. (USA), 1988, 15/1 (75-85)

Vinpocetine (Cavinton (R)), vincamine, and nicergoline (Sermion (R)) were evaluated for the ability to protect cognitive function of spontaneously hypertensive rats from the damaging effect of hypoxia. Normobaric hypoxia (6% oxygen) was applied during the acquisition of a two-way active avoidance task (3 sessions, 50 trials/session). Hypoxia decreased the percentage of conditioned avoidance responses by 50% on day 3. Vinpocetine (1.25-10 mg/kg) administered orally 60 min prior to the daily sessions did not significantly improve learning in normoxic conditions; however, it prevented hypoxia-induced learning deficit (1.25 mg/kg peak effect dose). The dose-response relationship for the compounds is an inverted U-shaped curve. Vincamine (2.5-20 mg/kg p.o.) did not facilitate learning under normoxic conditions, but afforded protection against hypoxia at the 20-mg/kg dose. Nicergoline (2.5-20 mg/kg p.o.) did not increase acquisition of the normoxic avoidance response, and it also showed a moderate antihypoxic effect. Vinpocetine, and to a lesser degree vincamine and nicergoline - drugs useful in the therapy of cognitive disturbances following cerebral ischemic-hypoxic states - proved effective in the prevention of a hypoxia-induced learning deficit.

A double-blind placebo controlled evaluation of the safety and efficacy of vinpocetine in the treatment of patients with chronic vascular senile cerebral dysfunction

J. AM. GERIATR. SOC. (USA), 1987, 35/5 (425-430)

In a double-blind clinical trial, vinpocetine, a synthetic ethyl ester of apovincamine, was shown to effect significant improvement in elderly patients with chronic cerebral dysfunction. Forty-two patients received 10 mg vinpocetine three times a day (tid) for 30 days, then 5 mg tid for 60 days. Matching placebo tablets were given to another 42 patients for the 90 day trial period. Patients on vinpocetine scored consistently better in all evaluation of the effectiveness of treatment including measurements on the Clinical Global Impression (CGI) scale, the Sandoz Clinical Assessment-Geriatric (SCAG) scale, and the Mini-Mental Status Questionnaire (MMSQ). There were no serious side effects related to the treatment drug.

A double-blind clinical trial of vinpocetine in the treatment of cerebral insufficiency of vascular and degenerative origin

CURR. THER. RES., CLIN. EXP. (USA), 1986, 40/4 (702-709)

We used vinpocetine, a synthetic ethyl ester of apovincamine, to treat 22 elderly patients with central nervous system degenerative disorders, in a double-blind clinical trial. Patients received 10-mg vinpocetine TID for 30 days, then 5 mg TID for 60 days. Another 18 elderly patients were given matching placebo tablets for the 90-day trial. Vinpocetine-treated patients scored consistently better in all evaluations of the effectiveness of treatment, including measurements on the Clinical Global Impressions (CGI) and Sandoz Clinical Assessment - Geriatric (SCAG) scales, and the Mini-Mental Status Questionnaire. According to CGI assessments, severity of illness decreased in 73% of the patients in the vinpocetine group at day 30 and 77% at day 90, and improvement was seen in 77% and 87% of the patients at days 30 and 90, respectively. Patients also showed statistically significant improvement for all SCAG items but one, at days 30 and 90. The physician rated the improvement in 59% of the vinpocetine-treated patients as 'good' to 'excellent'. No serious side effects were related to the treatment drug.

Experimental assessment of selected antimotion drugs

AVIAT. SPACE ENVIRON. MED. (USA), 1984, 55/4 (281-286)

Space motion sickness (SMS) has been a perplexing problem in both the Soviet and U.S. manned space programs. Both the sensory conflict theory (neuronal signal mismatch) and the cephalad fluid shift concept explain the mechanism. This paper reviews the mechanism of action of various drugs that primarily affect brain blood flow or brain metabolism. In particular, ),Cavinton (apovincamic acid ethyl ester) has been used successfully in offsetting SMS in experimental test subjects.

Mechanism of vasodilative action of cavinton on brain vessels

FARMAKOL. TOKSIKOL. (USSR), 1983, 46/6 (36-39)

Experiments on human middle cerebral and cat internal maxillary arteries have shown high vasodilative activity of cavinton. The mechanism of the vasodilative action of the drug involves inhibition of the ingress of exocellular calcium via electrogenic and chemosensitive channels, suppression of calcium mobilization from the intracellular depot with depolarization of the membranes of vascular smooth cells and a decrease in phosphodiesterase activity.

Cerebral regulation and cerebral regulators

THER. HUNG. (HUNGARY), 1980, 28/3 (103-110)

The epidemiology and pathogenic mechanisms of disorders due to cerebral ischemia are described and the therapeutic use of Vinca minor alkaloids is reviewed with reference to their indications in neuropsychiatry, otology and ophthalmology. The literature on Devincan and Cavinton is reviewed. Devincan exerts a mild hypotensive action, while Cavinton improves the circulation and the oxygen consumption of the brain cells, a valuable effect in the treatment of cerebrovascular disease of ischemic etiology (one of its main indications).

Cavinton, a new cerebral vasodilator

THER. HUNG. (HUNGARY), 1979, 27/1 (15-16)

Vincamine, an alkaloid isolated from Vinca minor, exerts not only a moderate antihypertensive effect but also increases the cerebral blood flow c.q. significantly decreases resistance of cerebral vessels. The substance is a potent cerebral vasodilator which gives particularly good results in ),disorders of the cerebral circulation in which hypertension is present. It proved possible by chemical alteration of the vincamine molecule to synthetize a number of derivatives. Among these, cavinton proved to be the apovincamine acid ethylester with the most intensive action. Experiments in animals showed that cavinton increases the cerebral blood flow without significantly altering the blood pressure or cardiac effort.

Comparative study of the effect of ethyl apovincaminate and xantinol nicotinate in cerebrovascular diseases; immediate drug effects on the concentrations of carbohydrate metabolites and electrolytes in blood and CSF

ARZNEIMITTEL-FORSCH. (GERMANY, WEST), 1976, 26/10A (1980-1984)

Randomly selected 34 cerebrovascular patients were treated with ethyl apovincaminate (RGH 4405, Cavinton) and 109 with xantinol nicotinate. The effects of drugs given in slow i.v. infusions on the concentration of carbohydrate metabolites and electrolytes in serum and CSF were observed. Cavinton improved the paresis in 60.6% of patients while xantinol nicotinate did so only in 47.1%. On the basis of the biochemical changes, it can be concluded that Cavinton enhances both the glycolytic and the oxidative glucose breakdown in CNS.

Study on the vasodilator effects of ethyl apovincaminate in neurosurgical patients

ARZNEIMITTEL-FORSCH. (GERMANY, WEST), 1976, 26/10A (1956-1962)

Studies have been performed in a series of 44 neurosurgical cases. The patients were subjected to detailed neurological examination and EEG after admission and before being discharged. The effect of ethyl apovincaminate (RGH 4405, Cavinton) on cortical electric activity was investigated after the administration of 10 mg i.v. Cavinton. In cases on long term courses of three times daily 5 mg Cavinton in tablets, control EEG was performed one and two mth, resp., after the start of medication. The state of vessels of the eye ground was also checked. In cerebral angiography attention was concentrated on width of the vascular lumen and visualization of Cavinton effect on vessels which on account of narrowing or spasm had not filled up with contrast medium prior to Cavinton. During angiography the patients ),were given i.v. 10 mg Cavinton diluted to 10 ml with physiological saline. In the cases where investigations failed to reveal any change requiring neurosurgical intervention and insufficient cerebral circulation had to be held responsible for the patient's condition, 3 times 10 mg Cavinton i.v. was administered daily as long as the patient was at our Department. After having been discharged these patients took 3 times daily 5 mg Cavinton in tablets. Duration of the course of oral Cavinton depended on the degree of improvement in the patient's condition. Cavinton was used with success in cases where cerebral circulation was damaged for functional or organic reasons. Allergic hypersensitivity did not occur in any of the cases, either on single doses or long term use of parenteral or oral Cavinton.

Rheoencephalographic and psychological studies with ethyl apovincaminate in cerebral vascular insufficiency

ARZNEIMITTEL-FORSCH. (GERMANY, WEST), 1976, 26/10A (1947-1950)

The effect of ethyl apovincaminate (RGH 4405, Cavinton) on the rheoencephalogram and memory functions was studied in 50 patients with ischaemic disturbances of cerebral circulation. The drug was administered in a single i.v. dose of 10 mg and orally three times daily 5 mg for a month. Improvement of cerebral circulation was observed after i.v. and oral medication. Blood flow was most markedly increased in the gray matter. The effect on arterial pressure was negligible. Improvement of memorizing capacity evaluated by psychological tests was recorded after one month of Cavinton treatment, associated with alleviation or complete disappearance of symptoms. No side effects attributable to the drug were observed. It is pointed out that Cavinton is indicated in the treatment of ischaemic disorders of the cerebral circulation, particularly in chronic insufficiency.

Effect of ethyl apovincaminate on the cerebral circulation; studies in patients with obliterative cerebral arterial disease

ARZNEIMITTEL-FORSCH. (GERMANY, WEST), 1976, 26/10A (1945-1947)

The effect of ethyl apovincaminate (RGH 4405, Cavinton) on the cerebral and systemic circulations has been studied in detail in ten cases of cerebrovascular disease. 10 mg doses of Cavinton were given as infusion within 4-6 min; circulatory tests were carried out prior to administration of the drug and 3-6 min after. The principal results showed the following: On Cavinton cerebral vascular resistance was strongly reduced, while cerebral fraction of cardiac output significantly increased. On acute ),effect of the drug arterial mean pressure slightly decreased but cerebral blood flow nevertheless increased in general. Total vascular resistance also decreased but this decrease was less marked than that registered in cerebral vascular resistance.

Biochemical effects of ethyl apovincaminate

ARZNEIMITTEL-FORSCH. (GERMANY, WEST), 1976, 26/10A (1923-1926)

Some cerebrobiochemical effects of a new cerebrovasodilatory agent, ethyl apovincaminate (RGH 4405, Cavinton) were studied. Changes of biogenic amines, 5 hydroxyindole acetic acid (5 HIAA) levels, serotonin (5 HT) turnover rate, and the effect on 3',5' cyclic nucleotide phosphodiesterase (PDE; E.C. 3.1.4.c) activity, isolated from different tissues, were determined. Lasting increase of cerebral 5 HIAA level was observed after treatment with the compound, 5 HT levels were transitorily enhanced 2 hr following i.p. treatment. At later periods (4-6 hr) after treatment catecholamine levels were significantly raised. 5 HT turnover was practically uninfluenced by the compound. Activities of PDE preparations isolated from cerebral tissues were markedly inhibited. Various hypotheses are suggested in order to explain the biochemical mechanism of action of the compound.

Effect of ethyl apovincaminate on cerebral circulation of dogs under normal conditions and in arterial hypoxia

ARZNEIMITTEL-FORSCH. (GERMANY, WEST), 1976, 26/10A (1920-1923)

Effects of 1, 2 and 4 mg/kg i.v. doses of ethyl apovincaminate (RGH 4405, Cavinton) on cerebral blood flow, determined in the internal carotid and vertebral artery, were studied in anaesthetized dogs under 21, 16 and 11% Osub 2 inhalation. Total cerebral blood flow was increased by 4 mg/kg Cavinton under normal Osub 2 and between 100 and 200 mmHg perfusion pressures, while 2 mg/kg doses were effective under hypoxia. Similar phenomena were observed in the carotid and vertebral flow, separately. Arterial hypoxia seems to potentiate the effect of Cavinton on cerebral blood flow.

Effect of oral pretreatment with ethyl apovincaminate on the cardiac ),output and nutritive blood flow of various organs in rats

ARZNEIMITTEL-FORSCH. (GERMANY, WEST), 1976, 26/10A (1912-1917)

Effects of ethyl apovincaminate (RGH 4405, Cavinton), administered repeatedly p.o. in doses of 0.5-1.5-4.5 mg/100 g body weight for 5 days, on cardiac output and organ fractions of cardiac output were studied in rats anesthetized with sodium pentobarbital by Evans blue dilution and the isotope fractionation technique of Sapirstein. Cardiac output, cerebral, coronary, renal, intestinal and dermal blood flow was increased by 18-42% after 4.5 mg/100 g Cavinton, while blood pressure was unaltered. Total peripheral resistance, cerebral, coronary, dermal resistance and that of the carcas decreased significantly. Organ fractions of the cardiac output were not significantly altered after treatment.

General and cerebral haemodynamic activity of ethyl apovincaminate

ARZNEIMITTEL-FORSCH. (GERMANY, WEST), 1976, 26/10A (1908-1912)

Systemic and cerebral haemodynamic effects of ethyl apovincaminate (RGH 4405, Cavinton), a new compound, have been investigated in anaesthetized dogs. The compound was administered i.v. and produced an increase in the cerebral blood flow accompanied by a decrease in cerebral vascular resistance which persisted for 15 min. The effective dose was 0.2-0.5 mg/kg. Mean arterial blood pressure, total peripheral resistance and cardiac work were decreased, heart rate and cardiac output were increased. Cerebral metabolic rate of oxygen was enhanced. It is assumed that the compound has a direct effect on cerebral metabolism. RGH 4405 has a weak antiarrhythmic and coronary dilating activity. Its effect on smooth muscle is more marked than that of papaverine. RGH 4405 appears to be a potent cerebral vasodilator enhancing cerebral metabolism.

Pharmacotherapy in Alzheimer's dementia: Treatment of cognitive symptoms Results of new studies

Fortschritte der Neurologie Psychiatrie (Germany), 1997, 65/3 (108-121)

Recent investigations have given new insights into pathogenetical determinants of Alzheimer's disease. Amyloid deposition and neurofibrillary tangles are no longer considered to be primary pathological changes. Neurobiological research tries to work out the etiopathogenital cascade that finally causes Alzheimer's disease. So far, several relevant ),pathogenetical factors have been detected, e.g. pertubated control of glucose breakdown, impairment of oxidative metabolism, impaired neuroprotection due to increased oxidative stress and non-enzymatic protein glycation as well as immunological disturbances. Thus, new strategies for the development of cognition-enhancing drugs are emerging. The authors review reports on agents, that are under investigation for the treatment of cognitive symptomatology in Alzheimer's disease. Some of these agents have already been used for treatment of other medical conditions, e.g. nimodipine, memantine as well as selegiline. Many of them are still experimental. Promising strategies include antioxidative agents (e.g. vitamin E, vitamin C, beta-carotin), acetylcholinesterase-inhibitors with central selectivity (e.g. ENA 713), M1- and M4-muscarinic receptor agonists (milameline) as well as sabeluzole, a benzothazide derivative that shows neurotrophic activities and anti-inflammatory substances like indomethacin.