Effect of typical and atypical anxiolytics on the behavior and electrophysiological parameters of rats with model cerebrovascular pathology

The influence a series of anxiolytics (tranquilizers) on behavioral disturbances was studied in outbread white male rats with cerebrovascular pathology modeled by ligation of common carotid arteries. All studied anxiolytics (diazepam, buspirone, mexidol) exhibited more of less pronounced protective action with respect to the pathology studied. The most significant protective effect was produced by the atypical anxiolytic mexidol. Special features of the effect of mexidol are probably explained by combination of several effects (anxiolytic, nootrope, antioxidant, and antihypoxant). in the pharmacological activity spectrum of this drug.     

Characteristics of the action of non-narcotic analgesics in diabetics

Patients with diabetes mellitus were examined for the action of non-narcotic analgesics during oral cavity sanitation. All the drugs under study (amidopyrine, pyranal, baralgin, probon) taken per os increased the threshold of tactile painful sensitivity and the threshold of pain endurance in patients with diabetes mellitus to a greater degree than in normal subjects. No such differences were recorded after diazepam intake under the same conditions.     

Combined administration of mexidol and anti-arrhythmia agents

The influence of mexidol on the acute toxicity and electrophysiological effects of nibentan, propranolol, and verapamil was experimentally studied. It was found that mexidol potentiates the ability of propranolol and verapamil to inhibit automatism of the sinus node and suppresses the ability of all the three drugs to increase the refractory period of myocardium. It is suggested that these effects are related to the action of mexidol upon ion channels.     

Antistressor and analgesic effects of mexidol, diazepam, paracetamol, and their combinations

Mexidol (100 and 200 mg/kg) and diazepam (1 and 2 mg/kg) exhibit a dose-dependent antistressor effect in the pain expectation stress test in rats (conditional emotional reflex). The effect is manifested by the normalization of both motor and somatovegetative characteristics. Paracetamol in a dose of 50 and 100 mg/kg does not possess antistressor properties. Both mexidol and paracetamol increase the threshold of pain sensitivity in the test with electric stimulation of tail in rats. Diazepam does not reduce the pain threshold in this test. The combined administration of mexidol or diazepam with paracetamol does not change the antistressor effect as compared to that of each drug alone. Mexidol, but not diazepam, enhances the effect of paracetamol on the pain threshold.     

Pain-alleviating action of gidifen and its combinations with analgesics

The analgesic effect of gidifen, a new tranquilizer belonging to the group of organophosphorus compounds, manifests itself in relatively high doses (1/3 of the LD50). The quantitative characteristics of the analgesic action depends on the method for evaluating the analgesic action of the drug. On combined use of gidifen and analgesics applied in a definite dosage range the analgesic effect is potentiated. If the tranquilizer under study is combined with non-narcotic analgesics, the above potentiation is accompanied with an increase in the toxicity and myorelaxant activity of gidifen. On combination of the latter with morphine the parameters under consideration are unchanged. According to the pattern of interaction with analgesics gidifen does not differ in principle from benzodiazepine tranquilizers. However, the drug is not superior to benzodiazepines in this respect.     

Effects of narcotic analgesics and antagonists on the in vivo release of acetylcholine from the cerebral cortex of the cat

1. In cats under light allobarbitone anaesthesia, the effects of intravenous injections of narcotic and non-narcotic analgesics, of a general depressant, and of narcotic antagonists were investigated on the spontaneous release of acetylcholine (ACh) from the surface of the sensorimotor cortex.2. The narcotic analgesics morphine (0.1, 1.0 and 5 mg/kg), meperidine (1.0 and 2.0 mg/kg), methadone (1.0 mg/kg) and codeine (5.0 and 10.0 mg/kg) greatly reduced ACh release.3. The non-narcotic analgesics pentazocine (1.0 and 2.0 mg/kg) and propoxyphene (5.0 and 10.0 mg/kg) as well as the depressant chlorpromazine (0.25, 0.5 and 1.0 mg/kg) also greatly reduced ACh release.4. Two of the three narcotic antagonists examined, levallorphan (0.1, 1.0 and 5 mg/kg) and nalorphine (1.0 mg/kg) had the property of reducing ACh release. They were thus partial agonists. With levallorphan the greatest reduction occurred with the smallest dose injected and the effect was regularly obtained, whereas with nalorphine a reduction was obtained in some experiments only. The third, naloxone, was a specific narcotic antagonist and did not reduce the ACh release in any dose (0.01, 0.1, 0.5 and 1.0 mg/kg) examined. In a dose of 1.0 mg/kg it actually produced a small increase in Ach release.5. Naloxone (0.1-1.0 mg/kg) restored the reduction in ACh release produced by the narcotic analgesics and by the partial agonist levallorphan. It partially restored the reduction produced by the non-narcotic analgesics and by nalorphine, but had no effect on the reduction produced by chlorpromazine.6. The relevance of these results with regard to analgesia and to the narcotic abstinence syndrome is discussed.     

Antihypoxic effect of 3-hydroxypyridine and succinic acid derivatives and their nootropic action in alloxan diabetes

Relationship between the antihypoxic effect of 3-hydroxypyridine and succinic acid derivatives (emoxipine, reamberin and mexidol) and their effect on conditional learning, glycemia, and lipidemia was studied in rats with alloxan-induced diabetes. In parallel, the analogous relationship was investigated for alpha-lipoic acid that is regarded as a "gold standard" in treatment of diabetic neuropathy. It was established that single administration of emoxipine and mexidol in mice in doses equivalent to therapeutic-range doses in humans produces antihypoxic effect manifested by increased resistance to acute hypoxic hypoxia in test animals. Alpha-lipoic acid is inferior to emoxipin and mexidol in the degree of antihypoxic action. Reamberin does not exhibit this effect. The introduction of emoxipin, reamberin, mexidol, and alpha-lipoic acid in rats with alloxan diabetes during 7 or 14 days in doses equivalent to therapeutic-range doses in humans corrects conditional learning disorders in direct relationship with the antihypoxic activity of these drugs. The development of the nootropic effect of emoxipin, mexidol, and alpha-lipoic acid is related to a decrease in hyperglycemia and hyperlipidemia in rats with alloxan diabetes. The nootropic action of reamberin is accompanied by a transient hypoglycemizing effect and aggravation of dyslipidemic disorders. The antihypoxic activity of investigated drugs determines the direction and expression of their lipidemic effect, but is not correlated with the hypoglycemizing action these drugs on test animals with alloxan diabetes.     

Effects of narcotic and non-narcotic analgesics on the abdominal or tail stimulation-induced struggling in rats

As a model, we used struggling induced by a repetitive stimulation of the tail or abdomen and two types of pseudoaffective responses were evoked in rats. The effects of narcotic and non-narcotic analgesics on these responses were alternately assessed. Narcotics were markedly effective in inhibiting struggling elicited by tail stimulation and slightly less effective in suppressing the abdominal stimulation-induced struggling. These effects on two types of struggling differed quantitatively but not qualitatively. On the other hand, non-narcotics such as aspirin (200 mg/kg, i.p.), aminopyrine (160 mg/kg, i.p.) and indomethacin (20 mg/kg, i.p.) had an inhibitory action on the struggling elicited by the tail stimulation but showed equivocal and far less inhibition on the abdominal stimulation-induced response. These two effects were quantitatively and qualitatively different because the slope of the dose-response curves were not in parallel. The action of baclofen appears to be ambiguous since it had distinctive inhibitory actions on both typed of struggling. However, baclofen can be classified into the latter group in that it exerted an inhibitory action on two types of struggling, in a quantitatively different manner. These results suggest that two types of struggling in rats provide a convenient means to assess the potency of analgesics.     

End-stage renal disease and non-narcotic analgesics: a case-control study

1. To assess the risk of end-stage renal disease (ESRD) associated with the regular use of three classes of non-narcotic analgesics, we performed a case-control study of 340 patients with ESRD on a haemodialysis maintenance program and 673 hospital controls. 2. The overall odds ratio estimate for non-narcotic analgesics taken at least every other day for 30 days or longer before the first symptom of renal disease was 2.89 (95% CI, 1.78 to 4.68). 3. The risk increased in relation to the use duration. 4. The previous regular consumption of combinations containing phenacetin was strongly associated with ESRD (odds ratio, 19.05; 95% CI, 2.31 to 157.4). The odds ratio for previous regular consumption of salicylates was 2.54 (95% CI, 1.24 to 5.20) and for pyrazolones 2.16 (95% CI, 0.87 to 5.32). 5. An analysis for possible confounding by a history of repeated headaches, arthritis, kidney stones, hypertension, and diabetes did not alter the results. 6. The odds ratio estimates for different pathological subgroups of ESRD patients in relation to previous use of any non-narcotic analgesic were glomerulonephritis. 10.57 (95% CI, 1.25 to 89.0), interstitial nephritis, 3.33 (95% CI, 1.21 to 9.17), cystic kidney disease, 0.71 (95% CI, 0.25 to 1.97), and unknown, 5.15 (95% CI, 2.29-11.57). 7. The results of this study suggest that the regular consumption of analgesics should be routinely considered as a risk factor for any non-congenital cause of chronic renal failure. They also suggest that the risk of ESRD associated with the regular consumption of phenacetin is much higher than the risk associated with other non-narcotic analgesics.     

The effect of semax and mexidol on the course of acute pancreatitis in rats

The effect of semax and mexidol on the course of acute pancreatitis in rats was studied in comparison with the action of contrical, fluorouracil, and dibunol. It was established that a single intraductal or intraperitoneal administration of semax or mexidol markedly reduces the loss of experimental animals (to 10-13%), decreases hyperfermentemia, lipid peroxidation activation, and vascular permeability, improves microcirculation, and accelerates healing of the damaged pancreatic zones by substitutional repair of pancreatic acini not accompanied by coarse fibrous changes in the parenchyma. Upon the intraductal administration, semax and mexidol were more effective than contrical, fluorouracil, and dibunol.     

The effect of flupirtine, various analgesics and muscle relaxants on skeletal muscle tone in the conscious rat

The influence of the skeletal muscle tone by flupirtine (D-9998, Katadolon; CAS 56995-20-1), some selected analgesics and muscle relaxants was investigated in conscious rats after intraperitoneal administration. Benzodiazepines (diazepam and tetrazepam), baclofen, dantrolene and mephenesine reduced the tone of the skeletal muscle. Opiate analgesics, such as morphine, codeine and tramadol, enhanced the muscle tone. Flupirtine reduced the skeletal muscle tone at doses comparable with its antinociceptive effective doses. In this dose range no sedative side effects as ataxia or decrease of spontaneous motor activity could be observed. The mode of this muscle relaxing effect of flupirtine is not known in all details. It is, however, likely that flupirtine is able to inhibit the mono- and/or polysynaptic reflexes at the spinal level.     

Use and abuse of non-narcotic analgesics

The definition of abuse and dependence of non-narcotic analgesics should take into consideration the interaction of drug and personality. Usually, definitions are based on qualitative aspects of the risk-benefit ratio in the use of psychotropic drugs. By means of modern research methods in epidemiology and clinical psychology, quantitative aspects might be integrated in the process of defining persons and drugs when evaluating their risk of abuse or dependence. In a prospective field study with working housewives of north-western Switzerland who showed objective evidence of intake of non-narcotic analgesics and a control group, the interaction of drug use and personality features has been investigated. There was significant evidence that heavy use of non-narcotic analgesics was paralleled with a high risk of depression, emotional liability and disturbance in sexual identity. Using urine analysis, the study group was divided into two subgroups showing low or high intake of drugs, respectively. Special attention was focused on persons shifting from the study group into the control group and vice versa.     

Tazadolene: A centrally-acting,non-narcotic analgesic

Intravenous tazadolene elevated the threshold stimulus for rabbits to respond to electrical tooth-pulp stimulation. Systemic tazadolene also increased the latency for mice to lick their paws in the hot-plate analgesic test. However, tazadolene did not alter the mouse tail flick, a spinal reflex most sensitive to analgesics acting at spinal sites. Tazadolene analgesia was not antagonized by naloxone. Intracranial (i.c.), but not intraspinal (i.s.), injections of tazadolene were more effective than systemic injections in producing analgesic effects in the hot-plate test. It is concluded that tazadolene is a centrally-acting, non-narcotic analgesic.     

Diphenylhydantoin potentiates the protective effect of diazepam against pentylenetetrazol but not against bicuculline and isoniazid-induced seizures in mice

The anticonvulsant activity of diazepam alone, or in combination with diphenylhydantoin was studied in pentylenetetrazol-, bicuculline- and isoniazid-induced Scizures. Alone, diphenylhydantoin did not influence the chemically-induced convulsions but enhanced the antipentylenetetrazol action of diazepam whilst failing to affect the protective effect of the benzodiazepine against bicuculline- and isoniazid-induced convulsions. It is suggested that a diphenylhydantoin-induced increase in the total number of specific benzodiazepine binding sites might be responsible for the enhancement of the antipentylenetetrazol activity of diazepam. The anticonvulsant action of diazepam against bicuculline and isoniazid-induced Scizures does not seem to involve an interaction with benzodiazepine receptors.     

Comparative study of alpha-lipoic acid and mexidol effects on affective status, cognitive functions and quality of life in diabetes mellitus patients

Short-term, prospective placebo-controlled simple blind randomized study of the effects of alpha-lipoic acid and mexidol on the dynamics of affective status disorders, cognitive functions, and quality of life in parallel with changes in carbohydrate metabolism and lipidemia has been conducted in diabetic patients. It is established that two-week administration of alpha-lipoic acid (600 mg once a day, i.v.) and mexidol (300 mg once a day, i.v.) reduced hyperglycemia by 13.00 with simultaneous decrease of depressive "feelings of guilt". In case of mexidol, these effects were accompanied by positive "vitality" dynamics established with SF-36 questionnaire and reflecting improvement in patients' quality of life. Additionally, course administration of alpha-lipoic acid increased attention as studied with Schulte tables. Favorable psychotropic effects of alpha-lipoic acid and mexidol were unrelated to changes in lipidemia and "lipid peroxidation - antioxidant protection" system indicators.     

单剂量非麻醉性镇痛药预防瑞芬太尼麻醉后痛觉过敏的有效性Meta分析

目的:评价非麻醉性镇痛药(氯胺酮、帕瑞昔布钠、氟比洛芬酯)预防瑞芬太尼麻醉后疼痛过敏的有效性。方法:电子检索Pubmed,EBSCO,Springer,Ovid,CNKI等数据库,收集发表于1990-2011年的非麻醉性镇痛药物预防瑞芬太尼麻醉后疼痛过敏的临床试验性文章及相关的参考文献,按Cochrane系统评价方法对纳入的文献进行质量评价和资料提取。统计学分析采用RavMan 5.0软件。结果:共纳入24篇随机对照试验,包括1 525例患者。Meta分析显示:疼痛评分[拔管后口述疼痛评分(VRS)和停药后24 h内视觉疼痛模拟评分(VAS)]:单剂量静注氯胺酮可显著降低患者VRS和停药后1,2和4 h的VAS评分(P<0.01),静注帕瑞昔布纳可显著降低患者停药后8 h的VAS评分(P<0.01);静注氟比洛芬酯能够显著降低患者VRS和停药后1,2,4,6和8 h的VAS评分(P<0.01);其余各观察点VAS评分较对照组无明显差别。停药后清醒时间、拔管时间和再次要求镇痛的人数:单剂量静注氯胺酮、帕瑞昔布纳、氟比洛芬酯不延迟患者清醒和拔管时间,且能明显减少停药后追加其他镇痛药物的人数(P<0.01)。停药后不良反应发生率:除氯胺酮能明显患者降低停药后躁动的发生率外(P<0.01),三者对预防术后头疼、恶心、呕吐等不良反应无统计学差异。结论:单剂量静注氯胺酮、帕瑞昔布纳、氟比洛芬酯可有效预防瑞芬太尼麻醉后诱发的疼痛过敏,减少停药后再次要求镇痛的人数。     

A test for analgesics: incoordination in writhing mice

Acetic acid administered to mice resulted in post-writhing incoordination and a subsequent fall in the rota-rod test. This fall from rota-rod induced by 3% acetic acid was dose-dependently protected by the non-narcotic analgesics. While suprofen was found to be the most potent (ED50 = 15.29 mg/kg), aspirin was found to be the least potent (ED50 = 81.54 mg/kg). The model appears to be more sensitive than the conventional methods for testing non-narcotic analgesics.     

The synthesis and pharmacology of a new analgesic, ID-1229.

A new non-narcotic analgesic, 2-[3-(p-fluorobenzoyl)-n-propy]-5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan (ID-1229) has been prepared from 5alpha,9alpha-dimethyl-2'-hydroxy-6,7-benzomorphan. The analgesic activities of ID-1229 were several times more potent than those of pentazocine in the acetic acid writhing test in mice, bradykinin test in rats, Randall-Selitto's test in rats, and the electrical stimulation test in mice, while, ID-1229 showed little activity in both the tail pinch test and the hot plate test. ID-1229 did not show anti-narcotic activity in the morphine-combined test, and the Straub tail phenomenon was not observed in ID-1229. ID-1229 showed CNS activities in some tranquilizing tests, but did not show activity in several other CNS tests. The CNS potency is condiserably weaker as compared with haloperidol or diazepam, and the pattern of CNS activities in ID-1229 is quite different from those of both compounds. ID-1229 is a potent non-narcotic analgesic with tranquilizing activity, which is quite free from the undersirable side effects of morphine or morphine-like compounds including pentazocine.     

Effect of mexidol on 6beta/free hydroxycortisol ratio. Possibility of CYP3A4 activation

The influence of mexidol (2-ethyl-6-methyl-3-oxypyridine) after a single peroral administration on the levels of 6beta-hydroxycortisol (6beta-OHC) and free cortisol (FC) in human urine has been evaluated. The 6beta-OHC/FC ratio is increased (approximately 2.96 +/- 0.76 times) against the basal 6beta-OHC/FC ratio during the first 24 hour after drug administration. Data analysis on the second and third day after mexidol administration did not show evident changes in 6beta-OHC/FC ratios. It is suggested that CYP3A4 activation after mexidol administration occurred only during active drug biotransformation and excretion and ceased after full excretion from the human body.     

GABAergic mechanism of cerebrovasculareffect of mexidol

Experiments on rats showed that mexidol significantly increases local cerebral blood flow in animals under conditions of global transient brain ischemia, whereas in intact rats this drug initially causes a decrease in the blood flow, followed by its recovery. Mechanism of the cerebrovascular effect of mexidol is determined by its action on GABA receptors of cerebral vessels, which confirmed the fact that the cerebrovascular effect of mexidol is absent in the presence of bicuculline.