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Journal of Korean Neurosurgical Society Nov 2014Nefopam, a centrally acting analgesic, has been used to control postoperative pain. Reported adverse effects are anticholinergic, cardiovascular or neuropsychiatric....
Nefopam, a centrally acting analgesic, has been used to control postoperative pain. Reported adverse effects are anticholinergic, cardiovascular or neuropsychiatric. Neurologic adverse reactions to nefopam are confusion, hallucinations, delirium and convulsions. There are several reports about fatal convulsive seizures, presumably related to nefopam. A 71-year-old man was admitted for surgery for a lumbar spinal stenosis. He was administered intravenous analgesics : ketorolac, tramadol, orphenadrine citrate and nefopam HCl. His back pain was so severe that he hardly slept for several days; he even needed morphine and pethidine. At 4 days of administration of intravenous analgesics, the patient suddenly started generalized tonic-clonic seizures for 15 seconds, and subsequently, status epilepticus; these were not responsive to phenytoin and midazolam. After 3 days of barbiturate coma therapy the seizures were controlled. Convulsive seizures related to nefopam appear as focal, generalized, myoclonic types, or status epilepticus, and are not dose-related manifestations. In our case, the possibility of convulsions caused by other drugs or the misuse of drugs was considered. However, we first identified the introduced drugs and excluded the possibility of an accidental misuse of other drugs. Physicians should be aware of the possible occurrence of unpredictable and serious convulsions when using nefopam.
PubMed: 25535527
DOI: 10.3340/jkns.2014.56.5.448 -
Chemistry Central Journal Oct 2011A simple, sensitive and rapid spectrophotometric method was developed and validated for the determination of two skeletal muscle relaxants namely, tizanidine...
A simple, sensitive and rapid spectrophotometric method was developed and validated for the determination of two skeletal muscle relaxants namely, tizanidine hydrochloride (I) and orphenadrine citrate (II) in pharmaceutical formulations. The proposed method is based on the formation of a binary complex between the studied drugs and eosin Y in aqueous buffered medium (pH 3.5). Under the optimum conditions, the binary complex showed absorption maxima at 545 nm for tizanidine and 542 nm for orphenadrine. The calibration plots were rectilinear over concentration range of 0.5-8 μg/mL and 1-12 μg/mL with limits of detection of 0.1 μg/mL and 0.3 μg/mL for tizanidine and orphenadrine respectively. The different experimental parameters affecting the development and stability of the complex were studied and optimized. The method was successfully applied for determination of the studied drugs in their dosage forms; and to the content uniformity test of tizanidine in tablets.
PubMed: 21982341
DOI: 10.1186/1752-153X-5-60 -
Acta Pharmaceutica (Zagreb, Croatia) Mar 2019Twenty-five structurally diverse compounds have been tested in vitro for their pancreatic lipase (PL) inhibitory activity. Despite the diversity of tested compounds, the...
Twenty-five structurally diverse compounds have been tested in vitro for their pancreatic lipase (PL) inhibitory activity. Despite the diversity of tested compounds, the relationship comprising structural attributes of the compounds could be established to correlate with the observed inhibitory activity. Compounds that exerted inhibitory action through surface activity were of different profile from the rest of compounds. When co-incubated with orlistat (OsT), important synergistic effects for some compounds (orphenadrine, gliclazide, cefuroxime and sulfacetamide) were revealed, while antagonistic effects were demonstrated for others (camphor sulfonic acid and dinitro salicylic acid). Docking studies for the most active molecules were performed and molecular interaction forces with the PL active site were identified. The results suggested co-binding of OsT along with the other inhibitor in the binding site in cases of synergistic effect but not in the case of antagonistic effect. These results were additionally supported by affinity capillary electrophoresis. In conclusion, synergistic lipase inhibitory activity between OsT and some other pharmaceutical compounds was demonstrated for the first time, which might help improve the pharmacological effect of OsT.
Topics: Animals; Enzyme Inhibitors; Lipase; Orlistat; Pancreas; Pharmaceutical Preparations; Structure-Activity Relationship; Swine
PubMed: 31259721
DOI: 10.2478/acph-2019-0010 -
Journal of Pharmacy & Pharmaceutical... 2010This study was performed to find which types of hepatic CYP isoforms are responsible for the metabolism of mirodenafil (a new erectogenic) and one of its metabolite,...
Pharmacokinetics of mirodenafil, a new erectogenic, and its metabolite, SK3541, in rats: involvement of CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 for the metabolism of both mirodenafil and SK3541.
PURPOSE
This study was performed to find which types of hepatic CYP isoforms are responsible for the metabolism of mirodenafil (a new erectogenic) and one of its metabolite, SK3541, using various hepatic CYP inducers and inhibitors in rats.
METHODS
Mirodenafil at a dose of 20 mg/kg was administered intravenously to control rats and rats pretreated with various CYP inducers and inhibitors. The disappearance of SK3541 was also measured in vitro hepatic microsomes of rats with and without CYP inducer and inhibitors.
RESULTS
Compared to controls, in rats pretreated with 3-methylcholanthrene, orphenadrine, and dexamethasone (main inducers of CYP1A1/2, 2B1/2, and 3A1/2, respectively), the non-renal clearances (CLNRs) of mirodenafil were significantly faster (by 39.4%, 59.3%, and 63.9%, respectively). However, compared to controls, in rats pretreated with quinine and troleandomycin (main inhibitors of CYP2D subfamily and 3A1/2, respectively), the CLNRs of mirodenafil were significantly slower (by 36.1% and 33.2%, respectively). In rat hepatic microsomes spiked with furafylline, quinine, and troleandomycin (main inhibitors of CYP1A2, 2D subfamily, and 3A1/2, respectively), the intrinsic clearances (CLints) for the disappearance of SK3541 were significantly slower (by 18.4%, 35.3%, and 51.5%, respectively) than controls. Also in rat hepatic microsomes pretreated with orphenadrine (a main inducer of CYP2B1/2), the CLint for the disappearance of SK3541 was significantly faster (by 55.5%) than controls.
CONCLUSIONS
The above data suggest that hepatic CYP1A1/2, 2B1/2, 2D subfamily, and 3A1/2 are involved in the metabolism of both mirodenafil and SK3541 in rats.
Topics: Animals; Cytochrome P-450 Enzyme System; Enzyme Induction; Enzyme Inhibitors; Male; Microsomes, Liver; Phosphodiesterase 5 Inhibitors; Pyrimidinones; Rats; Rats, Sprague-Dawley; Sulfonamides
PubMed: 20456834
DOI: 10.18433/j3688m -
British Journal of Clinical Pharmacology Jun 19751 Two studies were carried out on acutely psychotic patients receiving chlorpromazine (100 mg) 8-hourly. 2 In the pilot study on five patients, plasma chlorpromazine... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
1 Two studies were carried out on acutely psychotic patients receiving chlorpromazine (100 mg) 8-hourly. 2 In the pilot study on five patients, plasma chlorpromazine concentrations fell over the course of 3 weeks of treatment and parallel changes were noted in the plasma half-life of antipyrine, salivation rate and handwriting length. 3 In the main study involving twelve patients treated for 15 weeks, the above findings were confirmed and were interpreted as indicating that chlorpromazine accelerated its own metabolism by inducing liver microsomal oxidising enzymes. No metabolites of chlorpromazine were detected in plasma. 4 The addition of phenobarbitone (50 mg) 8-hourly for 3 weeks, or orphenadrine (100 mg) 8-hourly for 3 weeks, resulted in a lowering of plasma chlorpromazine concentrations together with a further shortening of plasma antipyrine half-life. 5 Physiological effects of the additional treatments suggested that phenobarbitone lessens the effects of chlorpromazine by lowering body concentrations. However, orphenadrine acts more by virtue of its anticholinergic effects. 6 It was concluded that phenobarbitone and orphenadrine should not be prescribed routinely in patients receiving major tranquillisers. The need for the addition of orphenadrine should be assessed in each individual case.
Topics: Adult; Antipyrine; Chlorpromazine; Clinical Trials as Topic; Drug Interactions; Female; Half-Life; Humans; Male; Orphenadrine; Phenobarbital; Psychotic Disorders
PubMed: 791320
DOI: 10.1111/j.1365-2125.1975.tb01576.x -
PloS One Feb 2008Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to myotonic dystrophy 1 (DM1). To understand this...
Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced aspects of the DM1 pathology, most notably nuclear accumulation of CUG transcripts, muscle degeneration, splicing misregulation, and diminished Muscleblind function in vivo. Reduced Muscleblind activity was evident from the sensitivity of CUG-induced phenotypes to a decrease in muscleblind genetic dosage and rescue by MBNL1 expression, and further supported by the co-localization of Muscleblind and CUG repeat RNA in ribonuclear foci. Targeted expression of CUG repeats to the developing eye and brain mushroom bodies was toxic leading to rough eyes and semilethality, respectively. These phenotypes were utilized to identify genetic and chemical modifiers of the CUG-induced toxicity. 15 genetic modifiers of the rough eye phenotype were isolated. These genes identify putative cellular processes unknown to be altered by CUG repeat RNA, and they include mRNA export factor Aly, apoptosis inhibitor Thread, chromatin remodelling factor Nurf-38, and extracellular matrix structural component Viking. Ten chemical compounds suppressed the semilethal phenotype. These compounds significantly improved viability of CUG expressing flies and included non-steroidal anti-inflammatory agents (ketoprofen), muscarinic, cholinergic and histamine receptor inhibitors (orphenadrine), and drugs that can affect sodium and calcium metabolism such as clenbuterol and spironolactone. These findings provide new insights into the DM1 phenotype, and suggest novel candidates for DM1 treatments.
Topics: Animals; Brain; DNA Repeat Expansion; Disease Models, Animal; Drosophila; Drosophila Proteins; Eye; Gene Dosage; Myotonic Dystrophy; Nuclear Proteins; RNA-Binding Proteins; Trinucleotide Repeats
PubMed: 18270582
DOI: 10.1371/journal.pone.0001595 -
British Medical Journal Aug 1975
Topics: Adult; Epilepsy; Humans; Male; Orphenadrine; Substance-Related Disorders
PubMed: 1156831
DOI: 10.1136/bmj.3.5981.486 -
British Journal of Clinical Pharmacology Aug 2009Extrapyramidal side-effects induced by antipsychotic drugs are treated with dose reduction or substitution with another antipsychotic drug or by the addition of...
AIMS
Extrapyramidal side-effects induced by antipsychotic drugs are treated with dose reduction or substitution with another antipsychotic drug or by the addition of anticholinergic antiparkinson agents. The withdrawal of orphenadrine from the Norwegian market provided a possibility to investigate to what degree these alternative measures were taken in clinical practice.
METHODS
Data were drawn from the Norwegian Prescription Database on the sales of antipsychotics and one of the two anticholinergic antiparkinson agents marketed in 2004, orphenadrine and biperiden, to a total of 39 758 outpatients. The patients were reinvestigated in 2007. The consequences of the withdrawal of orphenadrine from the Norwegian market in 2005 regarding dosing, switching and cessation of antipsychotics and use of anticholinergics were assessed for orphenadrine users compared with biperiden users.
RESULTS
Of the patients originally using orphenadrine, 28.4% stopped using the drug without reducing the antipsychotic dose or replacing orphenadrine with another anticholinergic agent. The corresponding number for biperiden users was 19.3%. Only 11.8% of patients switched to another antipsychotic drug, but they used significantly lower antipsychotic doses than those who stayed on the same drug.
CONCLUSION
The use of anticholinergic antiparkinson agents could be seen as superfluous for at least one-third of patients.
Topics: Antipsychotic Agents; Cholinergic Antagonists; Drug Administration Schedule; Female; Humans; Male; Norway; Orphenadrine; Parkinson Disease; Practice Patterns, Physicians'; Safety-Based Drug Withdrawals; Substance Withdrawal Syndrome
PubMed: 19694744
DOI: 10.1111/j.1365-2125.2009.03446.x -
Chemical & Pharmaceutical Bulletin 2012New, simple, rapid and precise reversed-phase high-performance liquid chromatographic method was developed for the simultaneous determination of orphenadrine citrate,...
New, simple, rapid and precise reversed-phase high-performance liquid chromatographic method was developed for the simultaneous determination of orphenadrine citrate, caffeine and aspirin in presence of aspirin degradation products, orphenadrine citrate and caffeine process related impurities, and excipients. Good resolution and quantization were achieved on reversed-phase column [Phenomenex™ Luna ODS C(18) (25 cm×4.6 mm, 5 µm particles)]. Gradient elution based on; eluant [A]: 0.1% triethylamine in aqueous potassium dihydrogen phosphate buffer (50 mM; pH 3.0), while as, eluant [B]: acetonitrile, at a flow rate of 1.5 mL min(-1). UV quantitation was set at 215 nm. Linearity was exhibited for orphenadrine citrate, caffeine and aspirin within 0.5-150, 0.5-360 or 0.7-301 µg mL(-1) ranges, respectively. Satisfactory validation results were ascertained in terms of low limits of quantiation (6.33×10(-2)-7.94×10(-2)), mean percentage recovery (98.9-101.4%), precision (<2%) and robustness. The proposed method was proved to be specific, robust and accurate for the determination of cited drugs in pharmaceutical preparations in presence of their degradation products.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Caffeine; Central Nervous System Stimulants; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Limit of Detection; Muscarinic Antagonists; Orphenadrine
PubMed: 23124566
DOI: 10.1248/cpb.c12-00596 -
British Journal of Pharmacology Feb 20011. Previous studies indicate that 3-nitropropionic acid (3-NPA) neurotoxicity involves the excitotoxic activation of N-methyl-D-aspartate (NMDA) receptors. Thus, we...
1. Previous studies indicate that 3-nitropropionic acid (3-NPA) neurotoxicity involves the excitotoxic activation of N-methyl-D-aspartate (NMDA) receptors. Thus, we examined the effect of orphenadrine (an anticholinergic drug with NMDA receptor antagonist properties) on 3-NPA neurotoxicity in both cultured rat cerebellar granule cells (CGCs) and in rats. 2. Orphenadrine protected CGCs from 3-NPA-induced mortality, as assessed by both the neutral red viability assay and laser scanning cytometry, using propidium iodide staining. 3. For rats, two indirect markers of neuronal damage were used: the binding of [(3)H]-PK 11195 to the peripheral-type benzodiazepine receptor (PBR), a microglial marker, and expression of the 27 kD heat-shock protein (HSP27), a marker of activated astroglia. Systemic administration of 3-NPA (30 mg kg(-1) per day for 3 days) induced a 170% increase in [(3)H]-PK 11195 binding, and expression of HSP27. 4. Both the increase in [(3)H]-PK 11195 and HSP 27 expression were prevented by previous administration of 30 mg kg(-1) per day of orphenadrine for 3 days. Lower doses (10 and 20 mg kg(-1)) had no protective effect. Orphenadrine also reduced 3-NPA-induced mortality in a dose-dependent manner. 5. We propose that orphenadrine or orphenadrine-like drugs could be used to treat neurodegenerative disorders mediated by overactivation of NMDA receptors.
Topics: Animals; Antihypertensive Agents; Blotting, Western; Body Weight; Cell Survival; Cerebellum; Corpus Striatum; Disease Models, Animal; Drug Interactions; Isoquinolines; Male; Mortality; Muscarinic Antagonists; Neurotoxicity Syndromes; Nitro Compounds; Orphenadrine; Propionates; Radioligand Assay; Rats; Rats, Sprague-Dawley; Tritium
PubMed: 11159722
DOI: 10.1038/sj.bjp.0703869