Zolpidem stimulant effect: Induced mania case report and systematic review of cases.

INTRODUCTION: Zolpidem is the most widely prescribed hypnotic agent worldwide. This easy-access drug seems to have a high addictive potential among specific populations and is now listed by the World Health Organization (WHO) as being as dangerous as benzodiazepines for dependence and abuse. Many side effects have been reported, but drug-induced mania is still extremely rare. We conducted a systematic review to study the zolpidem-induced stimulation, euphoric or manic effects. METHODS: MEDLINE, PsycINFO, Science Direct, and Google Scholar were searched for articles in English, French, German, Italian and Spanish published up to the 15th October 2018. RESULTS: Eighteen relevant cases were identified, highlighting the need for more reports; therefore, one case that occurred in our department was included. The mean usual dose was 363.31 mg (± 292.2), the minimum dose was 10 mg, the maximum dose was 2000 mg, and the mean intake duration was 35.20 months (±48.0). We found that 89.4% of cases were euphoric and 15.7% had drug-induced mania with delusions. A total of 15.7% of cases took zolpidem for relaxant and stimulant effects, 47% of cases suffered various depression or anxiety disorders, of which 62.5% used zolpidem to cope with depression or an anxiety disorder. A total of 26.3% of cases had concomitant drug dependence or abuse. Seventy-five percent of cases suffering from depression consumed zolpidem for more than 1 year, with significantly more increased daily doses than in non-depressed cases (p < .5). CONCLUSIONS: The latest FDA recommendations for lowering zolpidem doses should be adopted by all countries. Zolpidem prescriptions should be contraindicated for populations with identified risk factors.

Effect of agmatine on experimental vascular endothelial dysfunction.

This study was designed to investigate the effect of agmatine sulfate (AG, CAS2482-00-0) in nicotine (NIC)-induced vascular endothelial dysfunction (VED) in rabbits. NIC was administered to produce VED in rabbits with or without AG for 6 weeks. Serum lipid profile, serum thiobarbituric acid reactive substances, reduced glutathione, superoxide dismutase generation, serum nitrite/nitrate, serum vascular cellular adhesion molecule-1 (VCAM-1), and aortic nuclear factor κB (NF-κB) levels were analyzed.Treatment with AG markedly improves lipid profile and prevented NIC-induced VED and oxidative stress. The mechanism of AG in improving NIC-induced VED may be due to the significant reduction in serum VCAM-1 levels and aortic NF-κB. Thus, it may be concluded that AG reduces the oxidative stress, nitric oxide production, VCAM-1 levels, and aortic NF-κB expression, thereby consequently improving the integrity of vascular endothelium.

Comparative study of the contractile activity evoked by ATP and diadenosine tetraphosphate in isolated rat urinary bladder.

The present study was designed to investigate the effect and possible mechanism(s) of action of ATP and diadenosine tetraphosphate (AP(4)A) on the isolated rat urinary bladder rings. ATP ( 0.1- 1 x 10(-3)M) or AP(4)A ( 0.01- 0.1 x 10(-3)M) produced contractions of the isolated bladder rings in a concentration-dependent manner. The contraction-induced by AP(4)A in the bladder rings was approximately ten times more potent than that produced by ATP. Addition of ATP prior to addition of AP(4)A or vice versa desensitized bladder tissue to the second agonist with great reduction in the contraction produced. Electrical field stimulation (EFS, 40 V, 0.5 ms, 2 Hz) produced contraction (79.8 +/-7.1 g tension x g(-1)tissue) in the bladder rings that can be greatly reduced by prior addition of ATP or AP(4)A. Theophylline, a P(1)-purinoceptor antagonist, significantly reduced the contraction-induced by AP(4)A and did altered that produced by ATP in bladder rings. Atropine, a non-selective muscarinic receptor antagonist, or indomethacin, a cyclo-oxygenase inhibitor, significantly suppressed the contractions of the bladder rings to ATP or AP(4)A. Similarly, nifedipine, an l -type Ca(2+)channel blocker, significantly attenuate the contractions induced by ATP and AP(4)A in the isolated rat urinary bladder rings. In conclusion, the results of the present study show that ATP, AP(4)A, and EFS evoked contractions in the rat urinary bladder rings and that the contractions induced by AP(4)A was more potent than that produced by ATP. Furthermore, the contractions evoked by ATP or AP(4)A were Ca(2+)-dependent and mediated at least in part through one of the cyclo-oxygenase products. Also, the present results suggested the involvement of the P(1)-purinoceptor in mediating the contractions evoked by AP(4)A but not ATP in the bladder rings.

Effects of aminoguanidine and desferrioxamine on some vascular and biochemical changes associated with streptozotocin-induced hyperglycaemia in rats.

The effects of aminoguanidine (AG; 100 mg x kg(-1)) and desferrioxamine (DFO; 50 mg x kg(-1)) on some vascular and biochemical changes associated with streptozotocin (STZ; 65 mg x kg(-1); i.p.)-induced hyperglycaemia were investigated in rats. Both AG and DFO were administered i.p., once daily, for 14 consecutive days to normal and hyperglycaemic animals. The responsiveness of the isolated aortic rings to phenylephrine (PE) was tested. In addition, biochemical markers for oxidative stress such as plasma levels of lipid peroxides and total thiols, as well as the activities of erythrocytic superoxide dismutase (SOD) and whole blood glutathione peroxidase (GSH-Px) were assessed. Results of the present study indicated that induction of hyperglycaemia was associated with increased aortic ring responsiveness to PE, loss in body weight, increase in urine volume, elevation of plasma total thiols and lipid peroxide levels and elevated SOD and GSH-Px enzymatic activities. Treatment of normal rats with AG reduced the response of their aortae to PE. Furthermore, a profound increase in body weight without any significant change in the measured biochemical parameters was observed. In hyperglycaemic animals, AG tended to normalize the enhanced aortic response to PE and modulated STZ-induced biochemical changes without affecting the elevated plasma glucose level. Treatment of normal rats with DFO reduced the response of their aortae to PE and decreased their body weight without altering any of the chosen biochemical parameters. In hyperglycaemic animals, DFO attenuated the responsiveness of their aortae to PE and at the same time, did not affect the loss in body weight and the elevation of plasma glucose level observed in the hyperglycaemic group. Additionally, DFO normalized the elevated plasma level of total thiols and exerted a modulatory influence on the enhanced activities of SOD and GSH-Px as well as on the increased levels of lipid peroxides. Our data lend further credence for the contribution of oxidative stress in the vascular and biochemical changes associated with STZ-induced hyperglycaemia. It is also apparent that advanced glycosylation end products and nitric oxide might be involved. Until clinical studies prove the efficacy and safety of these drugs, specific agents which could scavenge free radicals and block protein glycosylation seem beneficial as a helpful adjunct to the therapy of diabetes.

Ginkgo biloba extract (EGb 761) modulates bleomycin-induced acute lung injury in rats.

The effect of Ginkgo biloba extract (EGb 761) on bleomycin (BLM)-induced acute lung injury was studied in rats. The responsiveness of isolated pulmonary arterial rings to 5-hydroxytryptamine (5-HT) as well as the levels of some relevant biochemical markers in the lung tissue were taken as evidence for the acute lung injury. BLM was given intraperitoneally at a dose of 15 mg/kg/day for five consecutive days. It was found that BLM treatment attenuated the vasoconstrictor effect of 5-HT on the isolated pulmonary arteries. In lung tissues BLM also elevated the level of lipid peroxides and enhanced the activity of glutathione peroxidase. On the other hand, the level of glutathione and the activity of alkaline phosphatase were reduced. Body weight, lung weight and tissue glutathione-S-transferase activity were, however, not altered. Oral administration of EGb 761 at a dose of 100 mg/kg/day for five consecutive days did not alter any of the chosen biochemical parameters in the lung tissue except for a slight reduction in alkaline phosphatase activity. However, treatment with EGb 761 reduced the responsiveness of the pulmonary artery to 5-HT. Administration of EGb 761 (100 mg/kg/day; po) two hours prior to BLM (15 mg/kg/day; ip), for five consecutive days blunted the occurrence of further reduction in the vasoconstrictor response of the pulmonary artery to 5-HT. Furthermore, EGb 761 tended to normalize BLM-induced alterations in the measured biochemical markers in the lung tissue. The apparent modulatory influence of EGb 761 on BLM-induced acute lung injury stems, at least in part, from its beneficial free radical scavenging properties that provide the extract with antioxidant activity.

Thymoquinone-induced relaxation of guinea-pig isolated trachea.

The effect of thymoquinone (TQ), the main constituent of the volatile oil of black seed (Nigella sativa), on the guinea-pig isolated tracheal zig-zag preparation was investigated. TQ caused a concentration-dependent decrease in the tension of the tracheal smooth muscle precontracted by carbachol. The effects of TQ were significantly potentiated by pretreatment of the tracheal preparations with quinacrine, a phospholipase A2 inhibitor, nordihydroguiaretic acid, a lipoxygenase inhibitor and by pretreatment with methylene blue, an inhibitor of soluble guanylyl cyclase. On the other hand, the effects of TQ were not influenced by pretreatment of the tracheal preparations with indomethacin, a cyclooxygenase inhibitor, propranolol, a non-selective beta-adrenoceptor blocker or by the pretreatment with theophylline, an adenosine receptors antagonist TQ totally abolished the pressor effects of histamine and serotonin on the guinea-pig isolated tracheal and ileum smooth muscles. The results of the present study suggest that TQ induced relaxation of precontracted tracheal preparation is probably mediated, at least in part, by inhibition of lipoxygenase products of arachidonic acid metabolism and possibly by non-selective blocking of the histamine and serotonin receptors. This relaxant effect of TQ, further support the traditional use of black seeds either alone or in combination with honey to treat bronchial asthma.

New pyrazolo[3,4-b]pyrazines: synthesis and biological activity.

Some new pyrazolo[3,4-b]pyrazines and related heterocycles were synthesized and evaluated for their antifungal and antiparasitic activities. The key intermediate, 6-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyrazine-5-carbonitrile (3) was obtained in a one-pot synthesis via the reaction of 5-amino-3-methyl-4-nitroso-1-phenylpyrazole 2 with malononitrile.

New polycyclic azines derived from pyrazolo[3,4-b]pyridine.

The aminoimidazolinyl derivative 3 was synthesized using the pyrazole amino aldehyde 1 as a starting material. Compound 3 has been used as a key intermediate in the synthesis of the title compounds.

Effect of streptozotocin-induced hyperglycaemia on intravenous pharmacokinetics and acute cardiotoxicity of doxorubicin in rats.

The present study was designed to investigate the pharmacokinetics and acute cardiotoxicity of doxorubicin (DOX) after intravenous (i.v.) administration (15 mg kg(-1)) to streptozotocin (STZ)-induced hyperglycaemic and normoglycaemic male Wistar albino rats. In STZ diabetic rats the area under the serum DOX time-concentration curve (AUC(0-24 h)) increased (13.35+/-1.33 compared with 7.13+/-0.71 microg h(-1) ml(-1); P<0.0001) and plasma and renal DOX clearance decreased. The DOX accumulation in STZ-induced diabetic rat heart (12.7+/-1.2 microg g(-1)) was increased (P<0.05) compared with non-diabetic hearts (11.0+/-0.9 microg/g), 24 h after DOX administration. Serum creatine phosphokinase (CPK) activity showed 25% increase in peak level in STZ diabetic rats compared to non-diabetic rats. DOX produced a reduction in heart rate of anaesthetized non-diabetic (20%) and diabetic (14%) rats 1 and 2 h after its administration, respectively. Isolated atria of diabetic rats were more sensitive to the negative chronotropic effect of DOX (150 microm). These preliminary results indicate that hyperglycaemia may alter the pharmacokinetics and acute cardiotoxicity of DOX and suggest that i.v. doses of DOX in diabetic patients may need to be modified if the present data could be extrapolated to humans.

Synthesis of 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones and their 2-imino isosteres as nonsteroidal cardiotonic agents.

Thirty new 1,2-dihydropyridine derivatives of the general formula 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-pyridinones (1-15) and 4-alkyl (aryl)-6-aryl-3-cyano-2(1H)-iminopyridines (16-30) were synthesized using one-pot multicomponent reactions of the properly substituted acetophenone, appropriate aldehyde, ammonium acetate and ethyl cyanoacetate (1-15) or malononitrile (16-30) in ethanol. These target compounds (1-30) were evaluated for their cardiotonic activity using the spontaneously beating atria model, from reserpine-treated guinea pigs. The best pharmacological profile was obtained with 3-cyano-6-(3,4-dimethoxyphenyl)-4-(4-hydroxyphenyl)-2(1H)-pyridinone (9) which displaced selectivity for increasing the force of contraction (108.7 +/- 6.7,% change over control) rather than the frequency rate (40.8 +/- 5.3,% change over control) at a 5 x 10(-4) M concentration. The effects of structural changes upon activity are reported.

Effect of adenosine on pulmonary circulation of rabbits.

The effect and mechanism of action of adenosine on the pulmonary circulation of rabbits were studied. Adenosine (10(-5)-10(-3) M) produced a concentration-dependent decrease in pulmonary arterial tension of precontracted pulmonary arterial rings. Removal of endothelium (denuded) augmented the adenosine-induced vasodilation in the pulmonary arterial rings. Theophylline (5 x 10(-5) M), an adenosine receptor antagonist, reduces the vasodilation induced by adenosine in intact and denuded rings. Pretreatment of the pulmonary rings with the cyclooxygenase inhibitor indomethacin (5 x 10(-6) M) significantly attenuated the adenosine-induced relaxation in denuded but not in the intact pulmonary arterial rings. Methylene blue (5 x 10(-5) M), a guanylate cyclase inhibitor, significantly reduced the relaxation induced by adenosine in both the intact and the denuded arterial rings. Adenosine significantly attenuated the pressor responses of serotonin and acetylcholine in the intact and denuded rabbit's pulmonary arterial rings. The results of this study indicate that adenosine induces pulmonary vasodilation and that functional endothelium is not required to evoke this dilation. In addition, guanylate cyclase activity and the generation of cGMP is essential for adenosine to induce vasodilation in the rabbit lung. Furthermore, the results of this study may suggest that adenosine could be used to reduce the severity of pulmonary hypertension and possibly pulmonary edema.

Effect of captopril on doxorubicin-induced nephrotoxicity in normal rats.

Biochemical evaluations of the effects of the sulfhydryl-containing angiotensin-converting enzyme inhibitor (captopril) on the nephrotoxicity induced by doxorubicin in normal rats were carried out. A single dose of doxorubicin (15 mg kg-1) which caused nephrotoxicity was manifested biochemically by the elevation of serum urea after 24 and 48 h of administration. Also a severe decrease in total proteins and albumin after 4, 24 and 48 h was observed. Moreover, a decrease of non-protein sulfhydryl (-SH) concentrations in the kidney tissues after 24 h and an increase in the lipid peroxidation was observed after 4 h administration of doxorubicin. Captopril (60 mg kg-1 i.p.) injection did not induce any change in the biochemical parameters measured, however, captopril administered 1 h before doxorubicin ameliorated the biochemical toxicity induced by doxorubicin. This was evidenced by a significant reduction in serum urea and the lipid peroxidation after 4 and 24 h and a significant reduction in creatinine after 48 h. Also, the captopril amelioration was evidenced by an increase in total proteins and albumin after 4 and 24 h of doxorubicin administration. Captopril did not change non-protein sulfhydryl (-SH) concentrations or protein content in the kidney tissues. These results suggest that captopril may be beneficial as a protective agent against nephrotoxicity induced by doxorubicin.

Protective effect of aminoguanidine against cardiovascular toxicity of chronic doxorubicin treatment in rats.

The cardiotoxicity-induced by chronic treatment of doxorubicin have recently be attributed to free radical formation and/or release of nitric oxide. In the present study, an already established rat model of doxorubicin -induced cardiotoxicity was used. Doxorubicin in a total cumulative dose of 15 mgkg(-1) I.P. given in six equal injections over two week period was administered. After three weeks of doxorubicin administration, the blood pressure, serum lactate dehydrogenase, lipid peroxides, asites fluid and mortality rate were significantly increased. Doxorubicin-induced cardiotoxicity was further confirmed by examining the histopathology of heart sections. Myocardial fibres necrosis with prominent acute inflammatory cells were observed in rats hearts treated with doxorubicin. Aminoguanidine, an inhibitor of nitric oxide synthase, 100 mgkg(-1) injected every other day for two week was given concurrently with doxorubicin. Aminoguanidine given concurrently with doxorubicin return blood pressure, lactate dehydrogenase and lipid peroxides to normal control values. Furthermore, aminoguanidine reduces the mortality rate, ascites fluid formation- induced by doxorubicin and improved the histopathology of rats hearts treated with doxorubicin. In conclusion, inhibition of nitric oxide formation may be beneficial in protecting rat hearts against doxorubicin- induced cardiotoxicity.

Synthesis and antimicrobial activities of some new pyrrolylthieno[2,3-b]-quinoline derivatives.

2-Acetyl-4-(p-chlorophenyl)-3-(1-pyrrolyl)-5,6,7,8- tetrahydrothieno[2,3-b]quinoline (4a) and its corresponding 2-carbohydrazide derivative 5 were prepared and used as key intermediates in the synthesis of the title compounds. Some of the synthesized compounds were screened for their antibacterial and antifungal activities.

Captopril ameliorates myocardial and hematological toxicities induced by adriamycin.

Adriamycin has a wide spectrum of antitumor activity with dose related cardiotoxicity as a major side effect. The objective of this study was to investigate the influence of captopril, a sulphydryl containing angiotensin converting enzyme inhibitor, on the cardio- and hematotoxicity of adriamycin in normal rats. A single dose of adriamycin (15 mg/kg) caused myocardial toxicity after 24 h manifested biochemically by elevation of serum enzymes:- Aspartate transaminase (AST, EC: 2.6.1.1), lactate dehydrogenase (LDH, EC: 1.1.1.27), creatine phosphokinase (CPK, EC: 2.7.3.2) and the cardiac iso-enzymes of LDH and CPK. The hematotoxicity was characterized by severe leukopenia and anemia that appeared after 72 h of adriamycin administration. Captopril (60 mg/kg i.p.) 1 h before adriamycin injection ameliorated the biochemical toxicity induced by adriamycin. This was evidenced by a significant reduction in serum enzymes, after 24 and 48 h and a significant reduction of serum cardiac iso-enzymes after 48 h. Also restoration of the white blood cell counts as well as hemoglobin concentration occurred after 72 h of captopril administration. These results suggest that captopril may be benificial as a protective agent against cardio- and hematotoxicity induced by adriamycin.

Synthesis and anti-microbial activity of some imidazo[1',2':5,6]pyrimido[4,5-c]pyridazines and related heterocycles.

The synthesis of the title heterocycles was achieved using 3-amino-5,6-diphenylpyridazine-4-carbonitrile (4) as a starting material. This compound was converted into the corresponding 4-imidazolinyl derivative 5 which was then subjected to cyclization reactions to afford the title compounds.

Effects of Ehrlich ascites carcinoma cells on the responses of non-pregnant and pregnant uterine smooth muscles of mice to oxytocin and acetylcholine.

The effects of Ehrlich Ascites Carcinoma (EAC) cells on the responses of isolated uterine smooth muscles obtained from normal non-pregnant and pregnant mice to oxytocin and acetylcholine (ACh) were investigated. The contractions of normal uterine smooth muscles to oxytocin "0.1, 1 and 10 mU" and to ACh "0.1, 1 and 10 uM" were significantly reduced in the presence of EAC cells. On the other hand, induction of pregnancy in control non-tumor bearing mice significantly increases the sensitivity of the uterine smooth muscles to oxytocin as well as to ACh. In tumor bearing mice, the induction of pregnancy significantly reduced the sensitivity of the uterine smooth muscles to oxytocin and ACh when compared with the uterine muscles obtained from pregnant non-tumor bearing mice. The results of the present study indicate that the presence of tumor cells decreases the responses of the uterine smooth muscles to oxytocin and ACh, while pregnancy increases the uterine contractions induced by oxytocin and ACh. Furthermore, induction of pregnancy in tumor bearing animals reduces the responsiveness of uterine smooth muscles to oxytocin and ACh.

Identification of surface tegumental antigens of normal and irradiated schistosomula.

Sodium dodecyl sulphate- poly acrylamide gel electronphoresis (SDS-PAGE) fractionation of tegumental surface antigens (STEG-Ags.) of 7-day cultured normal and irradiated schistosomula showed no obvious qualitative differences. The observed polypeptide bands of both normal irradiated STEG-Ags. were almost identical and have similar corresponding molecular weights. The immunoblotting assay, using different types of mouse sera, revealed similarity between the bands of both normal and irradiated STEG-Ags. recognized by each type of mouse serum. No qualitative rather than quantitative differences have been observed. The quantitative differences were reflected in intensively staining of some bands from normal STEG-Ag. rather than their corresponding bands of the same molecular weights from irradiated STEG-Ag.

Synthesis and cardiotonic activity of certain imidazo[2,1-b]-1,3,4-thiadiazole derivatives.

A series of 5-imino-2-methyl-4-(4'-substituted phenacyl)-1,3, 4-thiadiazole derivatives 3-5 have been synthesized and further used to prepare a series of 2-methyl-6-(4'-substituted phenyl)imidazo[2, 1-b]-1,3,4-thiadiazoles 6-8 and 5-substituted-2-methyl-6-(4'-substituted phenyl) imidazo[2, 1-b]-1,3, 4-thiadiazoles 9-18. All of newly prepared imidazothiadiazole compounds were screened for their cardiotonic activity in isolated guinea pig atria. The detailed synthesis, spectroscopic and biological data are reported.

Fused pyrimidines. Synthesis of new derivatives of potential diuretic activity.

Certain derivatives of quinazoline and its bioisostere pyridopyrimidine carrying important structural features that contribute to diuretic activity, such as sulfonamido, morpholino and chlorophenyl, were prepared as potential diuretic agents. Likewise, some tricyclic 1,2,4-triazolo[3,4-b]quinazolines and pyrido[3,2-d][1,2,4]triazolo[4,3-alpha] pyrimidines with the same features were reported. Nine compounds were tested for the diuretic activity in rats and the results showed that the active compound is 7-chloro-2-methyl-3-phthalimido-4(3H)-quinazoline (4).