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Movement Disorders : Official Journal... Nov 2014Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity...
Broad-spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short- and long-term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock-in (Tor1a(+/Δgag) ) mice heterozygous for ΔE-torsinA and their controls (Tor1a(+/+) mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M1 antagonist, VU0255035. Tor1a(+/Δgag) mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short-term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long-term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M1 -preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M1 receptors was further demonstrated by their ability to counteract the M1 -dependent potentiation of N-methyl-d-aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M1 muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder.
Topics: Animals; Biophysics; Cholinergic Antagonists; Corpus Striatum; Electric Stimulation; Excitatory Postsynaptic Potentials; In Vitro Techniques; Long-Term Potentiation; Mice; Mice, Transgenic; Molecular Chaperones; Mutation; Neurons; Patch-Clamp Techniques; Synapses; Thalamus
PubMed: 25195914
DOI: 10.1002/mds.26009 -
Acta Crystallographica. Section E,... Feb 2010The asymmetric unit of the title compound N,N-dimethyl-2-[(2-methyl-phen-yl)phenyl-meth-oxy]ethanaminium picrate picric acid, C(18)H(24)NO(+)·C(6)H(2)N(3)O(7)...
The asymmetric unit of the title compound N,N-dimethyl-2-[(2-methyl-phen-yl)phenyl-meth-oxy]ethanaminium picrate picric acid, C(18)H(24)NO(+)·C(6)H(2)N(3)O(7) (-)·C(6)H(3)N(3)O(7), contains one orphenadrinium cation, one picrate anion and one picric acid mol-ecule. In the orphenadrine cation, the two aromatic rings form a dihedral angle of 70.30 (7)°. There is an intra-molecular O-H⋯O hydrogen bond in the picric acid mol-ecule, which generates an S(6) ring motif. In the crystal structure, the orphenadrine cations, picrate anions and picric acid mol-ecules are connected by strong inter-molecular N-H⋯O hydrogen bonds, π⋯π inter-actions between the benzene rings of cations and anions [centroid-centroid distance = 3.5603 (9) Å] and weak C-H⋯O hydrogen bonds, forming a three-dimensional network.
PubMed: 21580426
DOI: 10.1107/S1600536810006379 -
Pharmacological Reports : PR 2009Orphenadrine is an anticholinergic drug used in the treatment of Parkinson's disease, and is also known to exert nonspecific antagonistic activity at the phencyclidine... (Comparative Study)
Comparative Study
Orphenadrine is an anticholinergic drug used in the treatment of Parkinson's disease, and is also known to exert nonspecific antagonistic activity at the phencyclidine binding site of the N-methyl-D-aspartate (NMDA) receptor. The aim of this study was to assess the anticonvulsant properties of orphenadrine and to evaluate its effect on the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures in mice. Orphenadrine given at a dose of 5.65 mg/kg elevated the electrical seizure threshold from 5.7 (5.4-6.1) to 6.8 (6.3-7.3) mA, while a dose of 2.8 mg/kg was ineffective. The ED(50) values of orphenadrine administered 10, 30 and 120 min before maximal electroshock-induced convulsions were 16.8 (11.3-25.1), 17.8 (15.7-20.0) and 25.6 (23.3-28.3) mg/kg, respectively. Orphenadrine at a sub-threshold dose of 2.8 mg/kg significantly enhanced the anticonvulsant activity of valproate by reducing its ED(50) value from 315.8 (270.0-369.4) to 245.9 (207.1-292.0) mg/kg without affecting the free plasma levels of valproate. However, orphenadrine failed to enhance the protective activity of carbamazepine, phenytoin, phenobarbital, lamotrigine, topiramate, or oxcarbazepine against maximal electroshock-induced seizures.
Topics: Animals; Anticonvulsants; Drug Synergism; Electroshock; Male; Mice; Neuroprotective Agents; Orphenadrine; Random Allocation; Seizures
PubMed: 19815957
DOI: 10.1016/s1734-1140(09)70127-6 -
Pilot study of orphenadrine as a novel treatment for muscle cramps in patients with liver cirrhosis.United European Gastroenterology Journal Apr 2018Muscle cramps markedly affect the quality of life in cirrhotic patients with no available highly effective treatment. The aim of this study was to assess the safety and...
BACKGROUND AND AIMS
Muscle cramps markedly affect the quality of life in cirrhotic patients with no available highly effective treatment. The aim of this study was to assess the safety and efficacy of orphenadrine in the treatment of muscle cramps in cirrhotic patients.
METHODS
The study enrolled 30 liver cirrhosis patients complaining of frequent muscle cramps (≥3 per week), who were randomized to receive either orphenadrine 100 mg or calcium carbonate 500 mg twice daily as a control for one month. Severity, frequency, and duration of the muscle cramps were assessed before and after treatment as well as recurrence after washout of the drug for two weeks. Side effects were recorded.
RESULTS
One month after treatment with orphenadrine; the frequency of muscle cramps decreased significantly to 0.6 ± 0.74 per week compared to 12.53 ± 6.01 at baseline ( < 0.001), the duration of muscle cramps decreased from 1 min to 0.1 min after treatment ( < 0.001). The pain score improved significantly from a score of 8/10 to 0/10 ( < 0.001). The side effects were few, such as dry mouth, drowsiness, and nausea, with no significant difference between their occurrences in the two groups.
CONCLUSION
Orphenadrine is safe and effective in treatment of muscle cramps in patients with liver cirrhosis.
PubMed: 29774156
DOI: 10.1177/2050640617731261 -
Frontiers in Neurology 2015Human dopamine (DA) transporter (hDAT) regulates dopaminergic signaling in the central nervous system by maintaining the synaptic concentration of DA at physiological...
Human dopamine (DA) transporter (hDAT) regulates dopaminergic signaling in the central nervous system by maintaining the synaptic concentration of DA at physiological levels, upon reuptake of DA into presynaptic terminals. DA translocation involves the co-transport of two sodium ions and the channeling of a chloride ion, and it is achieved via alternating access between outward-facing (OF) and inward-facing states of DAT. hDAT is a target for addictive drugs, such as cocaine, amphetamine (AMPH), and therapeutic antidepressants. Our recent quantitative systems pharmacology study suggested that orphenadrine (ORPH), an anticholinergic agent and anti-Parkinson drug, might be repurposable as a DAT drug. Previous studies have shown that DAT-substrates like AMPH or -blockers like cocaine modulate the function of DAT in different ways. However, the molecular mechanisms of modulation remained elusive due to the lack of structural data on DAT. The newly resolved DAT structure from Drosophila melanogaster opens the way to a deeper understanding of the mechanism and time evolution of DAT-drug/ligand interactions. Using a combination of homology modeling, docking analysis, molecular dynamics simulations, and molecular biology experiments, we performed a comparative study of the binding properties of DA, AMPH, ORPH, and cocaine and their modulation of hDAT function. Simulations demonstrate that binding DA or AMPH drives a structural transition toward a functional form predisposed to translocate the ligand. In contrast, ORPH appears to inhibit DAT function by arresting it in the OF open conformation. The analysis shows that cocaine and ORPH competitively bind DAT, with the binding pose and affinity dependent on the conformational state of DAT. Further assays show that the effect of ORPH on DAT uptake and endocytosis is comparable to that of cocaine.
PubMed: 26106364
DOI: 10.3389/fneur.2015.00134 -
The Journal of Toxicological Sciences 2013Phenobarbital (PB) and orphenadrine (ORPH) are cytochrome P450 (CYP) 2B inducers and have liver tumor-promoting effects in rats. In this study, we performed a rat...
Phenobarbital (PB) and orphenadrine (ORPH) are cytochrome P450 (CYP) 2B inducers and have liver tumor-promoting effects in rats. In this study, we performed a rat two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of PB and ORPH co-administration. Twelve male rats per group were given an intraperitoneal injection of N-diethylnitrosamine (DEN) for initiation. Two-week after DEN administration, rats were given PB (60 or 120 ppm in drinking water), ORPH (750 or 1,500 ppm in diet) or 60 ppm PB+750 ppm ORPH for 6-week. One-week after the PB/ORPH treatment, all rats were subjected to two-thirds partial hepatectomy. To evaluate the effect of the combined administration, we used two statistical models: a heteroadditive model and an isoadditive model. In the heteroadditive model, the net values of the number and area of glutathione S-transferase placental form (GST-P) positive foci, Cyp2b1/2, Gstm3 and Gpx2 mRNA levels, microsomal reactive oxygen species (ROS) production and thiobarbituric acid-reactive substances level in the PB+ORPH group were significantly higher than the sum of the net values of those in the Low PB and Low ORPH groups. In the isoadditive model, the average values of the area of GST-P positive foci and PCNA positive hepatocyte ratio and Gstm3 mRNA level in the PB+ORPH group were significantly higher than the average values of those in the High PB and High ORPH groups. These results suggest that PB and ORPH co-administration causes synergistic effects in liver tumor-promoting activity in rats resulting from oxidative stress due to enhanced microsomal ROS production.
Topics: Animals; Cytochrome P-450 CYP2B1; Diethylnitrosamine; Drug Combinations; Drug Synergism; Enzyme Induction; Liver Neoplasms; Male; Microsomes, Liver; Orphenadrine; Oxidative Stress; Phenobarbital; Rats; Rats, Inbred F344; Reactive Oxygen Species; Thiobarbituric Acid Reactive Substances
PubMed: 23665940
DOI: 10.2131/jts.38.415 -
Environmental Science and Pollution... Aug 2022"Wealth by the sea and poverty away from the sea breeze" is a metaphor that mirrors what happens along the Brazilian coastal zone, namely in São Vicente Island, São...
Occurrence of pharmaceuticals and cocaine in the urban drainage channels located on the outskirts of the São Vicente Island (São Paulo, Brazil) and related ecological risk assessment.
"Wealth by the sea and poverty away from the sea breeze" is a metaphor that mirrors what happens along the Brazilian coastal zone, namely in São Vicente Island, São Paulo, Brazil. Due to the high cost of the properties on this shore, the impoverished population started to migrate to the northern outskirts of the island (away from the tourist beaches), potentiating the emergence of poor housing conditions, namely stilt-house slums. Consequently, the urban drainage channels across these outskirts neighbourhoods are potentially contaminated by human wastes. In this context, the occurrence and preliminary ecological risk assessment of eleven pharmaceuticals of various therapeutic classes (including cocaine and its primary metabolite, benzoylecgonine) were investigated, for the first time, in five urban drainage channels whose diffuse loads flow continuously to the estuarine waters of São Vicente Island. The results showed the widespread presence of these environmental stressors in all urban channels analysed, namely losartan (7.3-2680.0 ng/L), caffeine (314.0-726.0 ng/L), acetaminophen (7.0-78.2 ng/L), atenolol (6.2-23.6 ng/L), benzoylecgonine (10.2-17.2 ng/L), furosemide (1.0-7.2 ng/L), cocaine (2.3-6.7 ng/L), carbamazepine (0.2-2.6 ng/L), diclofenac (1.1-2.5 ng/L), orphenadrine (0.2-1.1 ng/L) and chlortalidone (0.5-1.0 ng/L). The overall total estimated load of pharmaceuticals and personal care products flowing to the estuarine waters of São Vicente Island is on the order of 41.1 g/day. The ecological risk assessment revealed a great environmental concern for São Vicente Island, ranging between low (e.g. carbamazepine and cocaine) and moderate to high (e.g. caffeine, acetaminophen and losartan) threats for the aquatic biota. Therefore, initiatives promoting basic sanitation, land-use regularisation and population awareness are highly recommended.
Topics: Acetaminophen; Brazil; Caffeine; Carbamazepine; Cocaine; Environmental Monitoring; Humans; Losartan; Pharmaceutical Preparations; Risk Assessment; Water Pollutants, Chemical
PubMed: 35359205
DOI: 10.1007/s11356-022-19736-4 -
Communications Chemistry 2019One-pot reactions that combine non-enzymatic and biocatalytic transformations represent an emerging strategy in chemical synthesis. Some of the most powerful...
One-pot reactions that combine non-enzymatic and biocatalytic transformations represent an emerging strategy in chemical synthesis. Some of the most powerful chemoenzymatic methodologies, although uncommon, are those that form a carbon-carbon (C-C) bond and a stereocenter at one of the reacting carbons, thereby streamlining traditional retrosynthetic disconnections. Here we report the one-pot, chemoenzymatic conversion of amides to enantioenriched alcohols. This transformation combines a nickel-catalyzed Suzuki-Miyaura coupling of amides in aqueous medium with an asymmetric, biocatalytic reduction to provide diarylmethanol derivatives in high yields and enantiomeric excesses. The synthetic utility of this platform is underscored by the formal syntheses of both antipodes of the pharmaceutical orphenadrine, which rely on ketoreductase enzymes that instill complementary stereoselectivities. We provide an explanation for the origins of stereoselectivity based on an analysis of the enzyme binding pockets.
PubMed: 32042928
DOI: 10.1038/s42004-019-0182-8 -
Phenotype microarray analysis of the drug efflux systems in Salmonella enterica serovar Typhimurium.Journal of Infection and Chemotherapy :... Nov 2016A large number of drug efflux transporters have been identified in Salmonella enterica serovar Typhimurium, and increased expression of these transporters confers drug...
A large number of drug efflux transporters have been identified in Salmonella enterica serovar Typhimurium, and increased expression of these transporters confers drug resistance in this organism. Here we compared the respiration activities of the wild-type strain and a mutant with nine deleted transporters by phenotype microarray analysis. The mutant was susceptible to 66 structurally unrelated compounds including many antibiotics, dyes, detergents, antihistamine agents, plant alkaloids, antidepressants, antipsychotic drugs, and antiprotozoal drugs. To investigate the effect of each transporter on the susceptibilities to these drugs, we used the single transporter mutants, several multiple deletion mutants, and the transporter overexpressor strains to determine minimum inhibitory concentrations of ampicillin, erythromycin, minocycline, ciprofloxacin, orphenadrine, amitriptyline, thioridazine, and chlorpromazine. The data indicate that the increased susceptibilities of the mutant lacking nine transporter genes are mainly dependent on the absence of the acrAB efflux genes as well as the tolC gene. In addition to the AcrAB-TolC efflux system, the results from the overexpressor strains show that AcrEF confers resistance to these compounds as well as AcrAB of Escherichia coli, MexAB-OprM and MexXY-OprM of Pseudomonas aeruginosa. The results highlight the importance of the efflux systems not only for resistance to antibiotics but also for resistance to antihistamine agents, plant alkaloids, antidepressants, antipsychotic drugs, and antiprotozoal drugs.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Escherichia coli; Membrane Transport Proteins; Microarray Analysis; Microbial Sensitivity Tests; Mutation; Phenotype; Pseudomonas aeruginosa; Salmonella typhimurium; Serogroup
PubMed: 27210311
DOI: 10.1016/j.jiac.2016.03.015 -
British Journal of Pharmacology Oct 2006The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore,... (Comparative Study)
Comparative Study
BACKGROUND AND PURPOSE
The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore, a series of experiments using various inducers and inhibitors of CYP isozymes was conducted to find out what types of CYP isozymes are involved in the metabolism of metformin in rats.
EXPERIMENTAL APPROACH
Metformin at a dose of 100 mg kg(-1) was administered intravenously to rats. The rats were pretreated with CYP inducers such as 3-methylcholanthrene, orphenadrine, isoniazid, and dexamethasone (major inducers of CYP1A1/2, 2B1/2, 2E1, and 3A1/2, respectively, in rats), or CYP inhibitors such as SKF-525 (a non-specific inhibitor of CYP isozymes), and sulfaphenazole, quinine, and troleandomycin (major inhibitors of CYP2C11, 2D1, and 3A1/2, respectively, in rats). The time-averaged non-renal clearance (CLNR) of metformin was compared with that of controls.
KEY RESULTS
In rats pretreated with dexamethasone, the CLNR was significantly faster (57% increase) than for the controls. In rats pretreated with SKF-525-A, sulfaphenazole, quinine, and troleandomycin, the CLNR was significantly slower (24.3, 62.9, 77.6, and 78.7% decrease, respectively) than for the controls. However, the CLNR values did not significantly different in the rats pretreated with 3-methylencholanthrene, orphenadrine, and isoniazid compared with the controls.
CONCLUSIONS AND IMPLICATIONS
Our data suggest that metformin was metabolized mainly via CYP2C11, 2D1, and 3A1/2 in rats. This result could contribute to understanding of the possible changes in metformin pharmacokinetics in disease models where CYP2C11 and/or 3A1/2 are altered.
Topics: Alcohol Oxidoreductases; Animals; Aryl Hydrocarbon Hydroxylases; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P450 Family 2; Dexamethasone; Enzyme Induction; Enzyme Inhibitors; Hypoglycemic Agents; Liver; Male; Membrane Proteins; Metformin; Protein Binding; Quinine; Rats; Rats, Sprague-Dawley; Steroid 16-alpha-Hydroxylase; Sulfaphenazole; Troleandomycin
PubMed: 16940989
DOI: 10.1038/sj.bjp.0706875