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Objective: To explore the effect of cinepazide maleate combined with promethazine hydrochloride in the treatment of emergency vertigo. Methods: 48 cases of emergency vertigo patients in our hospital from November 2017 to November 2019 were divided into experimental group (24 cases, treated with cinepazide maleate combined with promethazine hydrochloride) and control group (24 cases, treated with cinepazide maleate). The clinical efficacy, symptom relief time, adverse reactions and quality of life were compared. Results: The total effective rate of the experimental group (95.83%, 23 / 24) was higher than that of the control group (75.00%), The remission time of nausea and vomiting (1.75 ± 0.22) d, vertigo (3.54 ± 0.63) d, deafness and tinnitus (3.47 ± 0.58) d, night sweats (3.05 ± 0.33) d in the experimental group were shorter than those in the control group, P < 0.05; the incidence of adverse reactions in the experimental group (8.33%, 2 / 24) was lower than that in the control group (33.33%, The scores of social function, material life attitude, physical health and psychological function in the experimental group were 59.14 ± 7.23, 54.05 ± 8.04, 53.58 ± 8.86 and 60.11 ± 8.44 respectively, P < 0.05. Conclusion: In the process of clinical treatment of emergency vertigo patients, the combined application of cinepazide maleate and promethazine hydrochloride has definite curative effect, can relieve clinical symptoms in a short time, has less adverse reactions, and improves the quality of life of patients to a certain extent, which is worthy of promotion.

Background Ischemic stroke is a leading cause of morbidity and mortality. Thrombolytic therapy improves disability and survival rates; however, to be effective, it must be given within 4.5 h of onset. Moreover, thrombolytic therapy is frequently contraindicated. Therefore, alternative therapeutic options are required. In China, cinepazide maleate injection has been shown to improve the cerebral collateral circulation and further reduce disability in stroke patients; however, very few studies investigating this therapy have been conducted to date. Therefore, this study aimed to further confirm the efficacy and safety of cinepazide maleate injection in patients with acute ischemic stroke. Methods Patients with acute ischemic stroke were administered an intravenous infusion of 320 mg cinepazide maleate or placebo once daily for 14 days. All patients were also administered basic therapy (citicoline sodium). The primary efficacy endpoint was the proportion of patients with a modified Rankin scale (mRS) ≤2 on day 90. Secondary efficacy endpoints included Barthel Index ≥95. Safety was evaluated by recording all adverse events (AEs), monitoring laboratory parameters and vital signs, and electrocardiogram. Results In total, 937 patients with an acute ischemic stroke were included, with a mean (standard deviation, SD) National Institutes of Health Stroke Scale score of 8.8 (2.4) and a mean (SD) stroke onset of 30.9 (11.4) hours prior. Following treatment for 90 days, the proportion of patients with an mRS score ≤ 2 was significantly higher in the cinepazide maleate group than in the control group (60.9% vs. 50.1%; p = 0.0004). Moreover, the proportion of patients with a Barthel Index of ≥95 on day 90 was also significantly higher in the cinepazide maleate group than in the control group (53.4% vs. 46.7%; p = 0.0230). There were no statistically significant differences in safety parameters between the cinepazide maleate and control groups. Conclusions The results of this study show that cinepazide maleate injection is superior to placebo in improving neurological function and activities of daily living, reducing disability, and promoting functional recovery in patients with acute ischemic stroke. Cinepazide maleate injection was safe and well tolerated with no unexpected AEs reported. Trial registration Chinese Clinical Trial Registry CTR20160292 and ChiCTR1900023827. Retrospectively registered June 13, 2019.

Background: We investigated neuroprotective treatment strategies for patients with acute myocardial infarction (AMI) complicated with hypoxic ischemic encephalopathy (HIE) in the ICU. Methods: The 83 cases diagnosed with secondary AMI were, for the first time, divided into an observation group (n = 43) and control group (n = 40). All of the patients underwent emergency or elective PCI. Patients in the control group were treated with mannitol to reduce intracranial pressure and cinepazide maleate to improve microcirculation in the brain as well as given a comprehensive treatment with oxygen inhalation, fluid infusion, acid-base imbalance correction and electrolyte disturbance. Patients in the observation group underwent conventional treatment combined with neuroprotective therapeutic strategies. The effects of the different treatment strategies were compared. Results: Consciousness recovery time, reflex recovery time, muscle tension recovery time and duration of ICU stay were significantly shorter in the observation group compared with the control group (P < 0.05). After treatment, the jugular vein oxygen saturation (SjvO2) and blood lactate (JB-LA) levels of both groups were lower than before treatment and the cerebral oxygen utilization rate (O2UC) increased, with a significantly higher increase in the observation group (P < 0.05). After treatment, the activities of daily living (ADL) score was higher for both groups and the neural function defect (NIHS) score was lower. Conclusion: The neuroprotective strategies of hypothermia and ganglioside administration assisted with hyperbaric oxygen was effective for treating AMI patients with HIE and may be worth clinical promotion. Keywords: ICU, Acute myocardial infarction, Hypoxic ischemic encephalopathy, Neural protection

Objective: To analyze the effect of cinepazide combined with mecobalamine on nerve conduction velocity, vibration perception threshold and serum indexes in patients with diabetic peripheral neuropathy. Methods: 90 patients with diabetic peripheral neuropathy treated in our hospital between March 2013 and March 2016 were selected and divided into observation group and control group (n=45) according to random number table, control group received mecobalamine treatment alone and observation group accepted the cinepazide combined with mecobalamine therapy. Differences in nerve conduction velocity, vibration perception threshold as well as serum oxidative stress indexes and nerve injury marker molecules were compared between two groups of patients 2 weeks after treatment. Results: 2 weeks after treatment, median nerve, ulnar nerve and peroneal nerve sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) levels of observation group were higher than those of control group (P

Effects of edaravone combined with cinepazide maleate on neurocyte autophagy and neurological function in rats with subarachnoid hemorrhage were investigated. Eighty SD rats were selected to establish subarachnoid hemorrhage (SAH) rat models, which were divided into sham operation group, SAH group, MCI group and combined group. Hippocampal tissue of each group was taken to observe the number of neurocytes. The expression levels of Beclin-1 and (light chain LC3)-II of rats in each group were detected by ELISA. Pearson's correlation factors were used to analyze the correlation between Beclin-1 and LC3-11, and neurological function tests were carried out on rats of each group 14 and 28 days after administration. The morphological and structural damage of nerve cells in the combined group was further alleviated, and the survival rate of neurons significantly increased at all time points (P

An efficient synthesis of cinepazide has been carried out in four steps with an overall yield of 51%. The synthesis was started from a commercially available 3,4,5-tri-methoxy benzaldehyde. All the reactions were very clean and the isolation of products was also very easy.

This is a study based on hospital intensive monitoring to explore medication use of Diemailing Kudiezi injection(one Chinese herbal medicine injection) in real word in the patients with cerebral infarction. The active monitoring model was adopted and hospital intensive monitoring on safety of 7 189 cases of patients with cerebral infarction was conducted to obtain the drug use information of Diemailing injection. The results were analyzed by using statistical description and association rule method. The statistical description and association rule analysis were conducted based on patients' basic demographic characteristics, use of Diemailing injection and combined use of drugs. Sixty-two percent(4 437/7 189) of the patients were from traditional Chinese medicine hospitals as compared with 39%(2 752/7 189) from western medicine hospitals; 84%(6 003/7 189) of the patients were from tertiary hospitals as compared with 16%(1 186/7 189) from second-class hospitals. The hospitals were mostly located in north China. Drug related indicators such as a single dripping speed, stash time after allocating transfusion, duration of injection, and injecting room temperature were not noted in instruction manual. It was also found that there were off label use in the practice, for instance, non-intravenous infusion, >14 d treatment course, use of non-designated solvent, and a single dose>40 mL or

The photoinduced tautomerisation of cinepazide maleate (1), an effective vasodilator widely used in clinical therapy, had been investigated. It was found that (i) the higher the concentration of cinepazide maleate (1), the more stable it was; (ii) the effect of light on the photoisomerism of cinepazide maleate (1) was obvious in a suitable wavelength (e.g., 365 nm); (iii) solvents (e.g., acetone) with carbonyl chromophore absorbing UV could inhibit the generation of cis-isomer; (iv) anthranilic acid could be used as an effective ultraviolet absorbent and (v) the cinepazide maleate (1) could be properly stored under the airtight, light-free and room temperature conditions.

A liquid chromatography tandem mass spectrometry method employing electrospray ionization has been developed for the determination of cinepazide maleate in rat plasma using alprazolam as the internal standard. Liquid–liquid extraction was used for sample preparation and the analysis was achieved on a C18 reversed phase column. The method was validated over the concentration range 1–2,000 ng mL−1 in rat plasma. The intra-day and inter-day precision of cinepazide maleate expressed as RSD

Background The severity of cerebral infarction is associated with the increase of blood viscosity caused by hyperfibrinogenemia and hyperlipidemia, etc. Thus it has become one of the target for treating cerebral infarction to decrease blood viscosity by integrated Chinese and western medicine. Objective To investigate the influence and clinical therapeutic effects of cinepazide maleate combined with tanshinone ? A sodium sulfonate on the hemorrheologic indexes and blood lipids of patients with acute cerebral infarction, and compare the results with those of simple cinepazide maleate treatment. Design A non-randomized case-controlled observation. Settings Hebei North University; the Second Affiliated Hospitals of Hebei North University; the Third Affiliated Hospitals of Hebei North University. Participants Eighty-six inpatients with cerebral infarction were selected from the infirmary, the Second and Third Affiliated Hospitals of Hebei North University from September 2004 to October 2006. They were all diagnosed to have acute cerebral infarction by CT or MRI, and accorded with the diagnostic standards for acute cerebral infarction set by the Fourth National Academic Meeting for Cerebrovascular Disease in 1995. Meanwhile, 40 teachers and medical staff of voluntary physical examinees were selected as the control group. Informed contents were obtained from all the patients and their relatives. Methods The patients were divided into combined treatment group (n=43) and simple treatment group (n=43). In the combined treatment group, the patients were administrated with 160 mg cinepazide maleate injection (Beijing Four-ring Pharmaceutical, Co.,Ltd, No. H200220125; 80 mg/2 mL) added in 5% glucose, and 40 mg tanshinone II sodium sulfonate (Shanghai No.1 Biochemical & Pharmaceutical Co.,Ltd., No. H31022558, 10 mg/2 mL) added in 250 mL normal saline. In the simple treatment group, the patients were only administrated with cinepazide maleate 320 mg added in 5% glucose or 250 mL normal saline. They were treated for 1 or 2 courses, once a day, and 14 days as a course. The patients were detected before treatment and at 14 and 28 days after treatment respectively. Determination of hemorrheologic indexes: Whole blood viscosity was determined with LBY-N6B automatic hemorrheologic meter; Plasma viscosity with LBY-F200B automatic plasma viscosity meter; Volume of fibrinogen was determined by the method of 12.5% sodium nitrate depositing biuret reaction. Determination of blood lipids: The serum levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were determined. Severity of neurological deficit: The total score of neurological deficit score (NDS) ranged from 0 to 45 points, 0–15 points was taken as mild, 16–30 points as moderate and 31–45 points as severe. Evaluation of curative effects: Generally cured: NDS decreased by 91%–100%, and disabled severity of grade 0; Significantly improved: NDS decreased by 46%–90%, and disabled severity of grades 1–3; Improved: NDS decreased by 18%–45%; No change: NDS decreased by less than 18%; Aggravated: NDS increased by more than 18%. Generally cured and significant improved were taken as significant effect. The adverse events and side effects after medication were observed. Main outcome measures Results of hemorrheologic indexes and blood lipids; NDS results in the combined treatment group and simple treatment group; Therapeutic effects and adverse events. Results All the 86 patients with cerebral infarction and 40 healthy controls were involved in the analysis of results. Results of hemorrheologic indexes and blood lipids: The hemorrheologic indexes and blood lipids before treatment were manifested as abnormalities to different extents in both the combined treatment group and simple treatment group; The hemorrheologic indexes after treatment were obviously improved in both groups. But the hemorrheologic indexes were improved more obviously in the combined treatment group as compared with those in the simple treatment group (P 0.05). NDS results: The NDS scores at 14 and 28 days after treatment in the combined treatment group [(6.23±2.34), (4.27±1.83) points] were obviously lower than those in the simple treatment group [(8.76±3.41), (6.65±2.49) points, P Therapeutic effects and side effects: The total significant effective rates in the combined treatment group and simple treatment group were 93% and 81% respectively. In the combined treatment group, 1 case suffered from palpitation, dizziness and agrypnia. In the simple treatment group, 1 case suffered from palpitation, dizziness and agrypnia, 1 case had itch of skin. All the above symptoms disappeared gradually after the transfusing speed was adjusted to be slower. No drug withdrawal occurred in the patients due to the adverse events. Conclusion Cinepazide maleate combined with tanshinon can obviously improve the abnormalities of hemorrheologic indexes and blood lipids and nerve function in patients with acute cerebral infarction, and its curative effect is faster than that of simple cinepazide maleate treatment.

A simple and reliable high performance liquid chromatographic (HPLC) method has been developed and validated to quantify cinepazide maleate, a calcium blocker, in rat plasma. Cinepazide maleate and Tinidazole (internal standard) have been extracted by a simple liquid–liquid extraction before injection into chromatographic system. Chromatographic separation was achieved on a reversed phase C 18 column with a mobile phase consisted of a water mixture of 10 mM potassium dihydrogen phosphate (pH = 4.5):methanol (40:60, v/v), pumped at flow rate of 1.0 mL/min, and detected at 303 nm. The method exhibited a linear range of 0.12–120 μg/mL in blank rat plasma, with the lower detection limit of 0.06 μg/mL. The method was statistically validated for linearity, accuracy, precision, selectivity and stability following FDA guidelines. The intra- and inter-assay coefficients of variation did not exceed ±15% from the nominal concentration. The accuracy of cinepazide maleate was within ±15% of the theoretical value. The assay has been applied successfully in a pharmacokinetic study of cinepazide maleate after a single intravenous at three doses in rat. And cinepazide maleate injection can improve the bioavailability of cinepazide maleate greatly, and has a dose-dependence profile in rats.

Our previous study showed that cinepazide maleate (CM) was as effective and safe as mildronate in the treatment of acute ischemic stroke in a randomized, double-blind, active-controlled phase II multicenter trial, but underlying mechanism(s) is not well understood. As an extending study, here we demonstrated that CM could protect neuronal cells by affecting mitochondrial functions. PC12 cells were exposed to 2.5 h oxygen-glucose deprivation (OGD) followed by a 24 h reoxygenation, and then treated with different concentrations (1, 10, 100 μM) of CM. Among various concentrations, 10 μM CM exhibited most significant protection on PC12 cells against OGD injury. CM was found to suppress OGD-induced oxidative stress, as supported by its capability of reducing intracellular reactive oxygen species and malondialdehyde production and enhancing superoxide dismutase activity. Importantly, our results showed that CM could preserve mitochondrial functions, as revealed by its capability of stabilizing mitochondrial membrane potential, improving OGD-induced suppression of mitochondrial respiratory complex activities and enhancing ATP production. In summary, our present study provides the first evidence that CM can protect neuronal cells against OGD injury by preserving mitochondrial functions.

The risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs were estimated in a population-based case-control study conducted in Israel and Europe (total population, 23 million). Cardiovascular drug use in the week before onset of illness was compared between 270 patients hospitalized with agranulocytosis and 1870 hospitalized control subjects. Propranolol (relative risk, 2.5), dipyridamole (3.8), digoxin (2.5), and acetyldigoxin (9.9) were significantly associated with agranulocytosis. The excess risks attributable to these drugs ranged from one to three cases per 10 million persons exposed for up to 1 week. Increased risks were also observed for cinepazide (used by six cases and no control subjects), procainamide (7, 1), and aprindine (5, 1); based on crude relative risk estimates, the excess risks for the latter two drugs were approximately three per million persons exposed for up to 1 week. The use of cardiovascular drugs in a 5-month period ending 1 month before hospital admission was compared between 152 patients with aplastic anemia and 2180 control subjects. Furosemide was the only significantly associated drug (relative risk, 3.1); the excess risk attributable to any exposure in a 5-month interval was 1.7 per million.

Objective: To study influence of cinepazide maleate on vascular endothelial function of patients with acute myocardial infarction. Methods: 150 cases of patients with acute myocardial infarction were divided into the observation group and the control group, two groups were treated by conventional therapy about acute myocardial infarction, the observation group added 5%GS250 mL + cinepazide maleate 160 mg IV drip q.d, the control group added 5%GS250 mL IV drip q.d, the treatment course were 3 weeks, changes of vascular endothelial function and the blood serum no level before and after treatment were detected. Result: vascular endothelial function after treatment in observation group were obviously improved than that before treatment (p = 0.03) , blood serum no level was obviously increased (p ﹤ 0.05); about 3 weeks after treatment, vascular endothelial function in the observation group was obviously better than that of the control group (p = 0.04), the blood serum no level of the observation group was obviously higher than that of the control group (p ﹤ 0.05). Conclusion: Cinepazide maleate remarkably improves vascular endothelial function of patients with acute myocardial infarction.

Background Since the publication of a major international case-control study on the risk of agranulocytosis associated with the use of medicines in the 1980s, many new drugs have been introduced in therapeutics. Methods Seventeen units of hematology contribute to the case-control surveillance of agranulocytosis and aplastic anemia in Barcelona, Spain. After a follow-up of 78.73 million person-years, 177 community cases of agranulocytosis were compared with 586 sex-, age, and hospital-matched control subjects with regard to previous use of medicines. Results The annual incidence of community-acquired agranulocytosis was 3.46:1 million, and it increased with age. The fatality rate was 7.0%, and the mortality rate was 0.24:1 million. The drug most strongly associated with a risk of agranulocytosis was ticlopidine hydrochloride with an odds ratio (OR) of 103.23 (95% confidence interval [CI], 12.73-837.44), followed by calcium dobesilate (OR, 77.84 [95% CI, 4.50-1346.20]), antithyroid drugs (OR, 52.75 [95% CI, 5.82-478.03]), dipyrone (metamizole sodium and metamizole magnesium) (OR, 25.76 [95% CI, 8.39-179.12]), and spironolactone (OR, 19.97 [95% CI, 2.27-175.89]). Other drugs associated with a significant risk were pyrithyldione, cinepazide, aprindine hydrochloride, carbamazepine, sulfonamides, phenytoin and phenytoin sodium, β-lactam antibiotics, erythromycin stearate and erythromycin ethylsuccinate, and diclofenac sodium. Individual attributable incidences for all these drugs, which collectively accounted for 68.6% of cases, were less than 1:1 million per year. Conclusions Agranulocytosis is rare but serious. A few drugs account for two thirds of the cases. Our results also provide reassurance regarding the risk associated with a number of newly marketed drugs.

There are various drugs which are used to improve functions of the brain disturbed by stroke or senile dementia of Alzheimer type (SDAT) in Japan. Usually they are divided into two groups by the different mechanisms of action (Otomo, 1989). One group acts mainly on the vascular system of the brain; i.e., increasing blood flow of the brain, promoting antiplatelet coagulation or lowering blood viscosity. The drugs in this group are nicardipine, ifenprodil, pentoxifylline, dilazep, trapidil, vinpocetine, moxisylate, brovincamine, nicergoline and cinepazide. The other group acts directly on the brain; i.e., as neurotransmitters or activators of energy metabolism. These include dihydroergotoxine, Ca hopantenate, idebenone, bifemelane, amantadine, tiapride and indeloxazine.

The effects of cinepazide, 1-[(1-pyrrolidinylcarbonyl)methyl]-4-(3,4,5-trimethoxycinnamoyl )piperazine hydrogen maleate, were studied in isolated dog cerebral arteries. Cinepazide in concentrations ranging from 10(-6) to 10(-5) M augmented the relaxing responses to ATP, adenosine and cAMP. However, this agent did not affect the relaxations induced by isoproterenol and papaverine and the contractions induced by 5-HT, prostaglandin F2 alpha and ATP. In the basilar artery preloaded with 3H-norepinephrine or 3H-adenosine, electrical transmural stimulation resulted in a marked increase in 3H-efflux. This efflux accompanied an initial transient contraction followed by a relaxation. Cinepazide slightly reduced the 3H-efflux evoked by electrical stimulation. However, the relaxing response was mostly augmented by the treatment with cinepazide. The relaxing responses to ATP, adenosine, cAMP and electrical transmural stimulation were attenuated by theophylline. These results suggest that cinepazide selectively potentiates the relaxing response mediated through purinergic P1-receptors.

Further study on identification of metabolites of cinepazide, 4-(3,4,5-trimethoxycinamoyl)-1-(1-pyrrolidinyl)carbonylmethylpiperazine, in rats and men was carried out. New metabolites of cinepazide in rat urine were 4-[1-[4-(3,4,5-trimethoxycinnamoyl)-piperazinly]acetamidol-1-butanol (M-II), 4-(3,4,5-trimethoxycinnamoyl)-1-[1-(hydroxypyrrolidinyl)]carbonylmerthylpiperazine (M-IV) and 4-[1-[4-(3,4,5-trimethoxycinnamoyl)piperazinyl]acetamidol]-1-butyric acid (M-VI). Structures of two mono-O-demethylated metabolites of cinepazide predicted in the previous paper were assigned as 3-hydroxy-4,5-dimethoxycinnamoyl and 4-hydroxy-3,5-dimethoxycinnamoyl compounds (M-III and M-V) by the FT-NMR spectrometry measured in a mixture of CDC13-C6D6 (1:1, v/v) after methylation with dimethylsulfare-d6. The corresponding pyrrolidone metabolite of cinepazide was undetectable in rat urine. New metabolites of cinepazide in rat feces were found to be 4-(3,5-dihydroxy-phenethylcarbonyl)-1-(1-pyrrolidinyl)carbonylmethylpiperazine (M-VIII) and 4-(3,5-dihydroxycinnamoyl)-1-(1-pyrrolidinyl)carbonylmethylpiperazine (M-IX). Metabolites of cinepazide in human urine were studied by both methods--high performance liquid chromatography and mass spectrometry with ion cluster technique. Unchanged drug was mainly excreted in the urine, and M-VI was the major urinary metabolite. The existence of M-IV and M-V was suggested by high performance liquid chormatography. The corresponding pyrrolidone was also undetectable in human urine.

1. An oral dose of the coronary vasodilator 4-(3,4,5-trimethoxy[14C]cinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was well absorbed and more than 60% of the dose was excreted within 24 h. In 5 days, rats, dogs, and man excreted in the urine and faeces respectively 36.7% and 58.3%, 33.4% and 68.6%, and 61.3% and 38.1% dose. Faecal radioactivity was probably excreted via the bile. 2. Plasma concentrations of radioactivity reached a maximum within about 1 h in all three species and declined fairly rapidly (t0.5 less than 3 h). For several hours, more than 50% of the plasma radioactivity was due to unchanged drug. After correction for dose and body weight (normalization), peak plasma concentrations of unchanged drug in man, rat and dog were in the approximate ratio 100 :30:1. 3. Similar metabolites were excreted by the three species, but the relative proportions differed. Rats and man excreted 17.2% and 15.9% respectively as unchanged drug in the urine whereas dogs excreted only 3.6%. Rat bile and urine contained 4.3% and 9.8% dose respectively as glucuronides of the mono-O-demethylated compounds and dog and human urine contained 9.0% and 2.6% respectively of these metabolites. The corresponding pyrrolidone accounted for 2.5%, 5.5% and 5.1% respectively in rat, dog and human urine. Complete O-demethylation also occurred since 4-(3,4,5-trihydroxycinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was present in rat faeces (22.1% dose).

I. V. self-administration of cinepazide by rats and the preference of the animals for this drug were studied; and the following were found: 1. I. V. self-administration of cinepazide to rats at dosages of 4, 15, 30, and 60 mg/kg/injection for 7 consecutive days resulted in no self-administration by the animals of the drug far beyond the operant level. 2. Rats undertook the self-administration of cocaine at 1 mg/kg/injection continuously, unlike that of saline or cinepazide. 3. Cross application of cinepazide at dosages of 4, 15, 30 and 60 mg/kg/injection to rats on i. v. self-administration of cocaine failed to substitute itself for the latter. These findings suggested that cinepazide was not a positive reinforcer. 4. Rats exhibited preference for morphine, codeine and pethidine but not for cinepazide. 5. The rats exhibiting preference for morphine also exhibited preference for codeine and pethidine in cross choice trials with these drugs but not for cinepazide in the cross choice trial with this drug. The findings in 4 and 5 suggested that rats showed no preference for cinepazide and that cinepazide failed to maintain the rats' preference for morphine.

MCI-2016 showed little influence on coagulation (APTT) and fibrinolysis (plasma clot lysis activated by urokinase) at doses (concentrations) as high as 300 mg/kg, p.o. or 8.6 X 10(-4) M. Hemolytic action of MCI-2016 was only observed at the concentrations above 2 mM. The drug also showed no influence on blood glucose level (30-300 mg/kg, p.o.). Effects of MCI-2016 on hemorheological properties were studied either in vitro or ex vivo. Above the doses (concentrations) of 100 mg/kg, p.o. and 10 microM, MCI-2016 suppressed the mechanical hemolysis and accelerated the membrane filtration rate. These effects of MCI-2016 were superior to those of cinepazide, Ca-hopantenate, meclofenoxate and pentoxyfylline. MCI-2016 also inhibited platelet aggregation induced by collagen with the IC 50 of 35 to 60 microM (rabbit and human platelets). Secondary aggregations of ADP and epinephrine were also inhibited by MCI-2016. As for reference drugs, bencyclane showed inhibitory patterns similar to MCI-2016. Other drugs examined exhibited little effect. In summary, it may be suggested that MCI-2016 exhibits beneficial influences in the clinical fields of cerebrovascular diseases.

Papaverine, while enhancing the force of contraction of guinea-pig atria, remarkably and dose-dependently enhanced the negative inotropic response of the atria to adenosine. It also enhanced the actions of ATP and other adenine nucleotides, but not those of 2-chloroadenosine and ACh. At similar concentrations, papaverine inhibited the uptake of adenosine by the atrial tissue during incubation with adenosine. Adenosine in the medium was degraded to inactive inosine during incubation with the atrial tissue, and papaverine reduced its degradation. The enhancing effect of papaverine on the action of adenosine on guinea-pig atria was like those of dipyridamole, 6-(2-hydroxy-5-nitrobenzyl)thioguanosine and cinepazide. The effect seemed to be due mainly to inhibition of adenosine uptake into the tissue. Inhibition of adenosine degradation may also have contributed to the action of papaverine, but this action was probably much less important than inhibition of adenosine uptake.

The concentrations of cinepazide in human plasma and urine were studied byusing high-performance liquid chromatography. Each of 7 healthy, male volunteersreceived 200 and 400 mg of cinepazide on separate occasions for single doseexperiments. In the case of the 200 mg single dose, a rapid peak of plasma concentrationat2.8-4.9μg/ml was observedat 1-3hr, and 57.6% of the cinepazidewas excreted in urine within 24 hr. The peak plasma level increased proportionallywith the dose of cinepazide, whereas the extent of cinepazide excretionincreased slightly with the dose.In multiple dose experiments, each of these volunteers received, on two separateoccasions, 200 mg of cinepazide t. i. d. at 9: 00 am, 1: 00 pm and 5: 00 pm eachday for 1 day and 5 days, respectively. The results on the peak and valley plasmalevels of multiple dose cinepazide indicated reproducible absorption in comparisonwith values predicted using a computer program describing a one compartment, open pharmacokinetic model. The extent of cumulative urinary excretion ofcinepazide was nearly constant during multiple dose experiments . No side effectswere noted.

Effects of some cerebrovasodilators on the anti-anoxic activity of indeloxazine hydrochloride [(+/-)-2[(inden-7-yloxy)methyl]morpholine hydrochloride, YM-08054] with cerebral metabolic enhancing activity, were observed in mice. Oral administration of both indeloxazine (10 mg/kg) and each of the cerebral vasodilators, such as nicardipine (10 mg/kg), cinepazide (100 mg/kg), ifenprodil (1 mg/kg), pentoxyfylline (1 mg/kg) and vinpocetine (10 mg/kg) significantly prolonged the survival time of mice subjected to anoxia, without affecting pentobarbital-induced sleeping time. The effect of indeloxazine was potentiated by a sub-effective dose of the cerebral vasodilators. The effect of a combined treatment may be due to the cerebral metabolic enhancing and vasodilating activities of both drugs. These results demonstrate the beneficial pharmacological properties of the combined treatment with indeloxazine and cerebrovasodilator and encourage combination therapy for the treatment of organic brain syndromes.

Physical dependence liability to cinepazide was studied, and the following were found : 1. Rats were applied cinepazide for 96 days by the cinepazide-admixed food method (DAF method) on gradedly increasing dosage schedules from low cinepazide dose; of 1/4 and 1/2 mg/g food (the average intake being 40 mg/kg/day) to 6 and 8 mg/g food (the average intake being 277 mg/kg/day) which caused toxic signs to evolve, e.g., suppressed righting reflex, urinary incontinence, dacryohemorrhed, hypothermia, and weight loss. No abstinence signs evolved on withdrawal at any dosage level. 2. The challenge with levallorphan (2 mg/kg, s.c.) at each dosage level during the application of cinepazide on the gradedly increasing dosage schedules precipitated no abstinence signs. 3. Cross-application at 3- to 6-hour intervals of 0 (the vehicle only), 10, 30, 100 and 300 mg/kg (p.o.) of cinepazide (doses prolonging the duration of hexobarbital-induced sleep) to animals with the manifestation of moderate to severe barbital abstinence signs, unlike the similar application of diazepam (10, 30 and 100 mg/kg, p.o.) as the positive control, failed to suppress but rather tended to aggravate the abstinence signs. 4. Cross-application at 3- and 6-hour intervals of 0, 10, 30, 100 and 300 mg/kg (p.o.) of cinepazide and similar s.c. application of 30 mg/kg of pethidine resulted in a significant suppression of weight loss due to withdrawal of morphine in the groups of animals treated with 100 and 300 mg/kg of cinepazide. Naloxone challenge at the stage when weight loss was suppressed significantly (p

The effects of cinepazide, a vasodilator, on the content, biosynthesis and turnover of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-FIT) in the rat brain were examined under room air and hypoxia (10% O2, 90% N2). Under room air, cinepazide had no significant effects on the content of NA, DA, 5-HT and 5-hydroxyindoleacetic acid (5-FIIAA), the accumulation of 3,4-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after central decarboxylase inhibition, and the depletion of NA, DA and 5-FIT after synthesis inhibition. After 2 hr-exposure to hypoxia, the content of NA, 5-FIT and 5-FIIAA was decreased, whereas the content of DA was unchanged. The accumulation of DOPA and 5-HTP was decreased. The depletion of DA and 5-HT was inhibited by hypoxia, whereas the depletion of NA was unaffected. Under hypoxic conditions, cinepazide had no effects on the content of NA, DA and 5-HT, the accumulation of DOPA and 5-HTP, and the depletion of NA and DA, whereas cinepazide increased both the rate of 5-HT depletion and the content of 5-HIAA. The present data suggest that cinepazide selectively stimulates the functional activities of 5-HT neurons in the brain, which are depressed by hypoxia.

A 56-year-old male parkinsonian patient developed a unique behavioral change following the oral administration of cinepazide, a cerebral vasodilator. This behavior consisted of an apparent infatuation with a ward nurse, which ceased after medication was discontinued.

Cinepazide(CP) was evaluated for its effect on cerebral circulation of SHR with acute and chronic cerebral lesions using a hydrogen clearance method. In the first experiment, CP(10 mg/ kg i.v.) increased regional cerebral blood flows(rCBFs) in the parietal cortex and basal ganglia, and reversed a decrease in rCBFs resulting from bilateral common carotid artery occlusion for 10 min followed by reperfusion. In the second experiment, in which SHR received 1% NaCl solution for 8 weeks, there was a rapid development of hypertension with a decrease in rCBFs and an acceleration of cerebral lesions, compared to salt-unloaded SHR. Repeated administration of CP(100 and 300 mg/kg p.o.) for 6-9 weeks, initiating at 9 weeks after salt loading, resulted in a dose-related improvement of reduction in rCBFs and of impairment of ocular vessels without remarkable concomitant alternation in systolic blood pressure. These effects were reflected by a low incidence of histo-pathological changes in the cerebral vasculature. These results suggest that improvement of cerebral lesions by CP may be at least in part related to its ability to protect against cerebral hypo -perf us ion.