Clonazepam is long-acting benzodiazepine agonist used in short-acting benzodiazepine withdrawal; however, recent observations suggest the existence of its abuse. We demonstrate a 40-year-old man with a 20-year history of psychiatric care with recently benzodiazepine dependence (daily intake of ∼60 mg of clonazepam and 10 mg of alprazolam). High serum levels of both drugs were analyzed 3 weeks before admission to hospitalization (clonazepam 543.9 ng/mL, alprazolam 110 ng/mL) and at the time of admission (clonazepam 286.2 ng/mL, alprazolam 140 ng/mL) without any signs of benzodiazepine intoxication. Gradual withdrawal of clonazepam with monitoring of its serum levels and increase of gabapentin dose were used to minimize physical signs and symptoms of clonazepam withdrawal. Alprazolam was discontinued promptly. Clinical consequences of the treatment were controllable tension, intermittent headache, and rarely insomia. It is the first case report showing utilization of therapeutic drug monitoring during withdrawal period in the patient with extreme toleration to severe benzodiazepine dependence.

• MeSH
• abstinenční syndrom etiologie   MeSH
• dospělí MeSH
• GABA modulátory aplikace a dávkování   škodlivé účinky   krev   MeSH
• klonazepam aplikace a dávkování   škodlivé účinky   krev   MeSH
• lidé MeSH
• monitorování léčiv * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• GABA modulátory MeSH
• klonazepam MeSH

The purpose of our study was to determine whether a single administration of anticonvulsant doses of two ligands of benzodiazepine receptors, clonazepam and Ro 19-8022, leads to development of rebound phenomena in immature 12-day-old rats. Three tests were used: pentylenetetrazole (PTZ)-induced seizures, isolation-induced ultrasonic vocalizations, and motor performance. Susceptibility to the convulsant effects of PTZ decreased 24 hours, but increased 48 hours, after clonazepam administration. Ultrasonic vocalizations were completely suppressed 30 minutes and 3 hours after clonazepam; a moderate inhibitory effect persisted even at 48 hours. Motor abilities were slightly compromised up to 3 hours. Similar effects of Ro 19-8022 on PTZ-induced seizures and ultrasonic vocalizations were observed 24 and 48 hours after administration; motor performance was not affected. Rebound proconvulsant effects followed different time courses after administration of the two benzodiazepine receptor ligands in developing animals. Anxiolytic-like effects of these drugs were still present at the time when animals exhibited rebound proconvulsant effects.

• MeSH
• analýza rozptylu MeSH
• chinoliziny farmakologie   MeSH
• GABA modulátory farmakologie   MeSH
• klonazepam farmakologie   MeSH
• krysa rodu Rattus MeSH
• náchylnost k nemoci chemicky indukované   MeSH
• novorozená zvířata MeSH
• pentylentetrazol MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Wistar MeSH
• pyrrolidiny farmakologie   MeSH
• receptory GABA-A metabolismus   MeSH
• vokalizace zvířat účinky léků   MeSH
• záchvaty chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chinoliziny MeSH
• GABA modulátory MeSH
• klonazepam MeSH
• pentylentetrazol MeSH
• pyrrolidiny MeSH
• receptory GABA-A MeSH
• Ro 19-8022 MeSH Prohlížeč

The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by previously prepared allopregnanolone with a 16alpha-bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 16alpha with the goal of increasing water solubility, brain accessibility, and potency of neuroactive steroids. The Michael addition to derivatives of pregn-16-en-20-one was the key reaction step. The link between the steroid skeleton and the new side chain was either a methylene group (when diethyl malonate was added) or an oxygen atom (when a hydroxy derivative was added). [(35)S]TBPS displacement was used to evaluate the products. Several carbamates (but not their parent alcohols) displaced TBPS from the picrotoxin binding site on GABA(A) receptors. Although none of them was more potent than the above ammonium salt, which stimulated this study, their nonionic nature should not prevent their passage into the brain.

• MeSH
• GABA modulátory chemická syntéza   farmakologie   MeSH
• krysa rodu Rattus MeSH
• mozek metabolismus   MeSH
• potkani Wistar MeSH
• pregnanolon analogy a deriváty   chemická syntéza   farmakologie   MeSH
• radioligandová zkouška MeSH
• receptory GABA-A metabolismus   MeSH
• techniky in vitro MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• GABA modulátory MeSH
• pregnanolon MeSH
• receptory GABA-A MeSH

Sleep deprivation is a useful therapeutic option in the treatment of depressive disorders, especially in pharmacoresistant disorders. Its therapeutic efficacy in other indications has not, however, been confirmed. According to current knowledge, application of sleep therapy requires concomitant therapy to prevent early relapses of depression. Total sleep deprivation is the classic variant of its clinical use. Partial sleep deprivation has a somewhat less pronounced antidepressant effect, and the duration of sleep deprivation rather than application timing determines its therapeutic effect. The most reliable predictors of sleep deprivation efficacy are marked diurnal fluctuations of depressive mood, patient locomotor activity, and limbic hyperactivity in the central nervous system. The mechanism of the antidepressant effect of sleep deprivation remains unknown.

• MeSH
• antipsychotika terapeutické užití   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• depresivní poruchy patofyziologie   terapie   MeSH
• flumazenil terapeutické užití   MeSH
• GABA modulátory terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• recidiva MeSH
• sloučeniny lithia terapeutické užití   MeSH
• spánek REM fyziologie   MeSH
• spánková deprivace * MeSH
• transkraniální magnetická stimulace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antipsychotika MeSH
• flumazenil MeSH
• GABA modulátory MeSH
• sloučeniny lithia MeSH

Neurosteroids are steroid structure hormones with neuroactive function. Neurosteroids have rapid, non-genomic actions in CNS. Non-conjugated metabolites of progesterone such as allopregnanolone, are potent positive modulators of GABAA receptors. They open ion channels for Cl- with analgetic, hypnotic, anxiolytic and anticonvulsant effects. By sulphatation the modulation on GABAA receptors is changed to negative with opposite effect. 19-C-steroids as dehydroepiandrosterone and its sulphate are negative modulators of GABAA receptors acting as an excitant and proconvulsant. They are able to modulate positively N-methyl-D-aspartate (NMDA) receptors and open ion canals for Ca2+. Changed (lowered) neurosteroid levels can be involved in many pathological processes as premenstrual syndrome, stress, depression, some forms of epilepsy, Alzheimer disease etc. Future study targeted on regulation of their production and metabolism and understanding of the mechanism of their actions will help to use them therapeutically.

• MeSH
• centrální nervový systém fyziologie   MeSH
• dehydroepiandrosteron metabolismus   fyziologie   MeSH
• GABA modulátory metabolismus   MeSH
• lidé MeSH
• pregnanolon fyziologie   MeSH
• receptory GABA-A metabolismus   MeSH
• steroidy fyziologie   MeSH
• vápníkové kanály metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• dehydroepiandrosteron MeSH
• GABA modulátory MeSH
• pregnanolon MeSH
• receptory GABA-A MeSH
• steroidy MeSH
• vápníkové kanály MeSH

The reports of analgesic effects of benzodiazepines are inconsistent. There is evidence of a hyperalgesic effect induced by activation of supraspinal GABAA receptors and an antinociceptive effect induced by activation of receptors located in the spinal cord (dorsal horns). The aim of the study was to discover whether the systemic administration of a benzodiazepine agent alprazolam increases the systemic analgesic efficacy of non-opioid analgesic ibuprofen. Experimental studies combining these agents have not yet been published. We used three experimental methods - writhing test (with acetic acid), tail-flick test and plantar test to assess analgesic action. The drugs were administered orally. Augmentation of the analgesic effect of ibuprofen by alprazolam was proved for the writhing test at a dose of 30 mg/kg of ibuprofen and alprazolam 1 mg/kg. The reaction time of the combination was significantly prolonged in comparison with ibuprofen alone. The results of the tail-flick test and plantar test were negative. The effect of ibuprofen was not enhanced by alprazolam in tests of acute thermal pain. Our results have demonstrated that the analgesic action of ibuprofen is only weakly enhanced by alprazolam.

• MeSH
• akutní nemoc MeSH
• alprazolam farmakologie   MeSH
• aplikace orální MeSH
• bolest chemicky indukované   farmakoterapie   MeSH
• GABA modulátory farmakologie   MeSH
• ibuprofen farmakologie   MeSH
• inbrední kmeny myší MeSH
• kyselina octová MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• neopioidní analgetika farmakologie   MeSH
• nociceptory účinky léků   MeSH
• receptory GABA-A fyziologie   MeSH
• synergismus léků MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alprazolam MeSH
• GABA modulátory MeSH
• ibuprofen MeSH
• kyselina octová MeSH
• neopioidní analgetika MeSH
• receptory GABA-A MeSH

In mice, the elevated plus-maze paradigm was used to investigate the effect of scopolamine hydrobromide and diazepam and their interaction with oxiracetam on the retrieval of spatial memory trace. This paradigm measures (using the transfer latency) an animal's capacity to escape from the open arm to the enclosed one. The retention session followed 24 h after the acquisition one. Experiment 1: Scopolamine (0.25 and 0.5 mg/kg) and diazepam (0.5 and 1.0 mg/kg) given 30 min before the retention session significantly prolonged the transfer latency as compared with the saline treated mice and those given the lowest dose of scopolamine (0.125 mg/kg) and diazepam (0.25 mg/kg). Experiment 2: Oxiracetam administered at doses of 3, 10 and 30 mg/kg immediately after the acquisition session prevented the scopolamine induced prolongation of the transfer latency. Thus, oxiracetam forestalled the impairment of retrieval of memory trace: the animals were able to remember the spatial configuration of the plus-maze. On the contrary, oxiracetam was not effective in the diazepam treated mice. We suggest that beneficial effect of oxiracetam might be confounded or blocked by the anxiolytic effect of diazepam.

• MeSH
• antagonisté muskarinových receptorů farmakologie   MeSH
• bludiště - učení účinky léků   MeSH
• diazepam farmakologie   MeSH
• GABA modulátory farmakologie   MeSH
• myši MeSH
• nootropní látky farmakologie   MeSH
• poruchy paměti chemicky indukované   prevence a kontrola   MeSH
• přenos učení (psychologie) účinky léků   MeSH
• pyrrolidiny farmakologie   MeSH
• skopolamin antagonisté a inhibitory   farmakologie   MeSH
• úzkost psychologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté muskarinových receptorů MeSH
• diazepam MeSH
• GABA modulátory MeSH
• nootropní látky MeSH
• oxiracetam MeSH Prohlížeč
• pyrrolidiny MeSH
• skopolamin MeSH

The study examined the effects of the benzodiazepine receptor partial agonist, Ro 19-8022, on anxiety-like, aggressive, social and locomotor behaviours in timid ('anxious') and aggressive mice in the social conflict test. To test the hypothesis that Ro 19-8022 acts as a partial agonist in this model, i.e. it reduces anxiety-like and aggressive behaviours without affecting motor coordination, its effects were compared to those of the full agonist, nitrazepam. Both Ro 19-8022 and nitrazepam decreased anxiety-like behaviour in timid mice and aggressive behaviour in aggressive mice. The effect of the full agonist, nitrazepam, was dose-dependent while the effect of the partial agonist, Ro 19-8022, was lower in magnitude and reflected its partial agonistic properties. Both drugs stimulated social behaviour in both groups of mice, presumably due to disinhibition of anxiety or aggression. The marked difference was in their effects on motor coordination, as nitrazepam, but not Ro 19-8022, produced motor impairment at higher doses. Thus, Ro 19-8022 produces anxiolytic-like and potent anti-aggressive effects without causing muscle relaxation or ataxia in the present model. Our data confirm that the main behavioural differences between partial and full benzodiazepine receptor agonists are in their side-effect profiles.

• MeSH
• agonisté receptorů GABA-A * MeSH
• agrese účinky léků   MeSH
• anxiolytika farmakologie   MeSH
• chinoliziny farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• GABA modulátory farmakologie   MeSH
• konflikt (psychologie) * MeSH
• myši inbrední ICR MeSH
• myši MeSH
• nitrazepam farmakologie   MeSH
• pyrrolidiny farmakologie   MeSH
• sociální chování * MeSH
• úniková reakce účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté receptorů GABA-A * MeSH
• anxiolytika MeSH
• chinoliziny MeSH
• GABA modulátory MeSH
• nitrazepam MeSH
• pyrrolidiny MeSH
• Ro 19-8022 MeSH Prohlížeč

The lymphatic bioavailability (FL) of diazepam (DZ) and its major metabolite desmethyldiazepam (DDZ) was studied. DZ was administered in intravenous and intraduodenal boluses, and in intravenous infusion in three groups of rats with different total lipid (TL) content in the central lymph. The effect of a) different lipophilicity of DZ and DDZ, b) lymphatic TL content, and c) route of DZ administration on FL was determined. It was found that a) FL values of DZ exceeded the FL values of DDZ and b) FL values of DZ increased with increasing TL content in the lymph (an opposite relation was found in DDZ), and c) the highest FL value of DZ + DDZ sum after intravenous bolus administration was attained contrary to the lowest one after intraduodenal bolus administration.

• MeSH
• biologická dostupnost MeSH
• chemické jevy MeSH
• chromatografie plynová MeSH
• demethyldiazepam aplikace a dávkování   chemie   farmakokinetika   MeSH
• diazepam aplikace a dávkování   chemie   farmakokinetika   MeSH
• duodenum fyziologie   MeSH
• fyzikální chemie MeSH
• GABA modulátory aplikace a dávkování   chemie   farmakokinetika   MeSH
• injekce intravenózní MeSH
• injekce MeSH
• intravenózní infuze MeSH
• krysa rodu Rattus MeSH
• lymfa chemie   metabolismus   MeSH
• lymfatický systém metabolismus   MeSH
• metabolismus lipidů MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• demethyldiazepam MeSH
• diazepam MeSH
• GABA modulátory MeSH

Male Wistar rats were maintained on a nutritionally adequate diet and diazepam was administered in a dose of 10 mg/kg/day. Control animals were pair-fed an adequate diet. Feeding was continued for 180 days, and the effects on the liver, plasma and erythrocyte phospholipid content were studied. It was found that the contents of sphingophospholipids and phosphatidylinositol + phosphatidylserine were significantly reduced in the erythrocytes of diazepam-treated rats. There was a significantly increased content of phosphatidylcholine in the liver an erythrocytes after 180 days of diazepam treatment. Such treatment did not cause statistically significant changes in the plasma of diazepam-treated rats. These investigations are in agreement with the hypothesis that extended or chronic use of drugs such as diazepam may alter membrane-dependent processes.

• MeSH
• diazepam farmakologie   MeSH
• erytrocyty účinky léků   metabolismus   MeSH
• fosfolipidy krev   metabolismus   MeSH
• GABA modulátory farmakologie   MeSH
• hmotnostní přírůstek účinky léků   fyziologie   MeSH
• játra účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• diazepam MeSH
• fosfolipidy MeSH
• GABA modulátory MeSH