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BMC Pharmacology & Toxicology Jun 2020Paracetamol/Orphenadrine is a fixed dose combination containing 35 mg orphenadrine and 450 mg paracetamol. It has analgesic and muscle relaxant properties and is... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized single-dose, two-period crossover bioequivalence study of two fixed-dose Paracetamol/Orphenadrine combination preparations in healthy volunteers under fasted condition.
BACKGROUND
Paracetamol/Orphenadrine is a fixed dose combination containing 35 mg orphenadrine and 450 mg paracetamol. It has analgesic and muscle relaxant properties and is widely available as generics. This study is conducted to investigate the relative bioavailability and bioequivalence between one fixed dose paracetamol/orphenadrine combination test preparation and one fixed dose paracetamol/orphenadrine combination reference preparation in healthy volunteers under fasted condition for marketing authorization in Malaysia.
METHOD
This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2-period crossover study with a washout period of 7 days. Paracetamol/Orphenadrine tablets were administered after a 10-h fast. Blood samples for pharmacokinetic analysis were collected at scheduled time intervals prior to and up to 72 h after dosing. Blood samples were centrifuged, and separated plasma were kept frozen (- 15 °C to - 25 °C) until analysis. Plasma concentrations of orphenadrine and paracetamol were quantified using liquid-chromatography-tandem mass spectrometer using diphenhydramine as internal standard. The pharmacokinetic parameters AUC, AUC and C were determined using plasma concentration time profile for both preparations. Bioequivalence was assessed according to the ASEAN guideline acceptance criteria for bioequivalence which is the 90% confidence intervals of AUC, AUC and C ratio must be within the range of 80.00-125.00%.
RESULTS
There were 28 healthy subjects enrolled, and 27 subjects completed this trial. There were no significant differences observed between the AUC, AUC and C of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC (100.92-111.27%), AUC (96.94-108.08%) and C (100.11-112.50%) for orphenadrine (n = 25); and AUC (94.29-101.83%), AUC (94.77-101.68%) and C (87.12-101.20%) for paracetamol (n = 27) for test preparation over reference preparation were all within acceptable bioequivalence range of 80.00-125.00%.
CONCLUSION
The test preparation is bioequivalent to the reference preparation and can be used interchangeably.
TRIAL REGISTRATION
NMRR- 17-1266-36,001; registered and approved on 12 September 2017.
Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Cross-Over Studies; Drug Combinations; Fasting; Healthy Volunteers; Humans; Male; Muscle Relaxants, Central; Orphenadrine; Therapeutic Equivalency; Young Adult
PubMed: 32576287
DOI: 10.1186/s40360-020-00416-3 -
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 -
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 -
RSC Advances Oct 2023Metal organic frameworks (MOFs), with structural tunability, high metal content and large surface area have recently attracted the attention of researchers in the field...
Metal organic frameworks (MOFs), with structural tunability, high metal content and large surface area have recently attracted the attention of researchers in the field of electrochemistry. In this work, an unprecedented use of multi-walled carbon nanotubes (MWCNTs)/copper-based metal-organic framework (Cu-BTC MOF) composite as an ion-to-electron transducer in a potentiometric sensor is proposed for the determination of orphenadrine citrate. A comparative study was conducted between three proposed glassy carbon electrodes, Cu-MOF, (MWCNTs) and MWCNTs/Cu-MOF composite based sensors, where Cu-MOF, MWCNTs and their composite were utilized as the ion-to-electron transducers. The sensors were developed for accurate and precise determination of orphenadrine citrate in pharmaceutical dosage form, spiked real human plasma and artificial cerebrospinal fluid (ACSF). The sensors employed β-cyclodextrin as a recognition element with the aid of potassium tetrakis(4-chlorophenyl)borate (KTpCIPB) as a lipophilic ion exchanger. The sensors that were assessed based on the guidelines recommended by IUPAC and demonstrated a linear response within the concentration range of 10 M to 10 M, 10 M to 10 M and 10 M to 10 M for Cu-MOF, MWCNTs and MWCNTs/Cu-MOF composite based sensors, respectively. MWCNTs/Cu-MOF composite based sensor showed superior performance over other sensors regarding lower limit of detection (LOD), wider linearity range and faster response. The sensors demonstrated their potential as effective options for the analysis of orphenadrine citrate in quality control laboratories and in different healthcare activities.
PubMed: 37876650
DOI: 10.1039/d3ra06710f -
Scientific Reports May 2024An experimental design and response surface methodologies using Plackett-Burman and Box-Behnken designs were applied for selecting and optimizing the most appropriate...
An experimental design and response surface methodologies using Plackett-Burman and Box-Behnken designs were applied for selecting and optimizing the most appropriate parameters which significantly affect the separation and quantitative estimation of five skeletal muscle relaxants and four analgesic drugs (baclofen, methocarbamol, dantrolene sodium, orphenadrine citrate, cyclobenzaprine hydrochloride, ketoprofen, etoricoxib, ibuprofen, and mefenamic acid) with a relatively short duration of analysis in a single run. For the separation of the nine drugs, an INERTSIL ODS-V3-5 µm C18 column (250 × 4.6 mm I.D.) was used with the optimum mobile phase conditions (45.15 mM ammonium acetate buffer pH 5.56 adjusted with acetic acid, acetonitrile, and methanol in a ratio of 30.5:29.5:40, v/v/v with a flow rate of 1.5 mL/min) and UV-detection at 220 nm. The optimized method was successfully subjected to the validation steps as described in ICH guidelines for linearity, precision, accuracy, robustness, and sensitivity. The optimized and validated method was effectively applied to determine the content of the studied drugs in their pharmaceutical preparations and to expand its applicability to the counterfeit estimation of etoricoxib in different brands of tablet dosage forms.
Topics: Chromatography, High Pressure Liquid; Analgesics; Neuromuscular Agents; Reproducibility of Results; Chromatography, Reverse-Phase; Research Design
PubMed: 38710733
DOI: 10.1038/s41598-024-58381-4 -
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 -
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 -
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 -
International Journal of Molecular... Mar 2024Cisplatin (CDDP) stands out as an effective chemotherapeutic agent; however, its application is linked to the development of significant adverse effects, notably nephro-...
Cisplatin (CDDP) stands out as an effective chemotherapeutic agent; however, its application is linked to the development of significant adverse effects, notably nephro- and ototoxicity. The human organic cation transporter 2 (hOCT2), found in abundance in the basolateral membrane domain of renal proximal tubules and the Corti organ, plays a crucial role in the initiation of nephro- and ototoxicity associated with CDDP by facilitating its uptake in kidney and ear cells. Given its limited presence in cancer cells, hOCT2 emerges as a potential druggable target for mitigating unwanted toxicities associated with CDDP. Potential strategies for mitigating CDDP toxicities include competing with the uptake of CDDP by hOCT2 or inhibiting hOCT2 activity through rapid regulation mediated by specific signaling pathways. This study investigated the interaction between the already approved cationic drugs disopyramide, imipramine, and orphenadrine with hOCT2 that is stably expressed in human embryonic kidney cells. Regarding disopyramide, its influence on CDDP cellular transport by hOCT2 was further characterized through inductively coupled plasma isotope dilution mass spectrometry. Additionally, its potential protective effects against cellular toxicity induced by CDDP were assessed using a cytotoxicity test. Given that hOCT2 is typically expressed in the basolateral membrane of polarized cells, with specific regulatory mechanisms, this work studied the regulation of hOCT2 that is stably expressed in Madin-Darby Canine Kidney (MDCK) cells. These cells were cultured in a matrix to induce the formation of cysts, exposing hOCT2 in the basolateral plasma membrane domain, which was freely accessible to experimental solutions. The study specifically tested the regulation of ASP uptake by hOCT2 in MDCK cysts through the inhibition of casein kinase II (CKII), calmodulin, or p56 tyrosine kinase. Furthermore, the impact of this manipulation on the cellular toxicity induced by CDDP was examined using a cytotoxicity test. All three drugs-disopyramide, imipramine, and orphenadrine-demonstrated inhibition of ASP uptake, with IC values in the micromolar (µM) range. Notably, disopyramide produced a significant reduction in the CDDP cellular toxicity and platinum cellular accumulation when co-incubated with CDDP. The activity of hOCT2 in MDCK cysts experienced a significant down-regulation under inhibition of CKII, calmodulin, or p56 tyrosine kinase. Interestingly, only the inhibition of p56 tyrosine kinase demonstrated the capability to protect the cells against CDDP toxicity. In conclusion, certain interventions targeting hOCT2 have demonstrated the ability to reduce CDDP cytotoxicity, at least in vitro. Further investigations in in vivo systems are warranted to ascertain their potential applicability as co-treatments for mitigating undesired toxicities associated with CDDP in patients.
Topics: Humans; Animals; Dogs; Organic Cation Transporter 2; Organic Cation Transport Proteins; Cisplatin; Disopyramide; Calmodulin; Imipramine; Orphenadrine; Ototoxicity; Madin Darby Canine Kidney Cells; Protein-Tyrosine Kinases; Cysts
PubMed: 38474165
DOI: 10.3390/ijms25052922 -
Microbiological Research Jan 2015Staphylococcus aureus strains harboring QacA, QacB, QacC, QacG transporters and norA promoter up-regulating mutations were characterized by phenotype microarray (PM),...
Staphylococcus aureus strains harboring QacA, QacB, QacC, QacG transporters and norA promoter up-regulating mutations were characterized by phenotype microarray (PM), standard methods for susceptibility testing, and ethidium bromide efflux assays, in order to increase knowledge on phenotypes associated to efflux pumps and their substrates. PM data and standard susceptibility testing lead to the identification of new potential efflux targets, such as guanidine hydrochloride or 8-hydroxyquinoline for QacA and QacC pumps, respectively. The identification of compounds to which the presence of efflux pumps induced increased susceptibility opens new perspectives for potential adjunct anti-resistance treatment (i.e. strains bearing QacB transporters showed increased susceptibility to thioridazine, amitriptyline and orphenadrine). Although the tested isolates were characterized by high degree of heterogeneity, a hallmark of clinical isolates, direct ethidium bromide efflux assays were effective in highlighting differences in efflux efficiency among strains. These data add to characterization of substrate specificity in the different classes of staphylococcal multidrug efflux systems conferring specific substrate profiles and efflux features to each of them.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Cluster Analysis; Drug Resistance, Bacterial; Genotype; Humans; Membrane Transport Proteins; Microbial Sensitivity Tests; Multidrug Resistance-Associated Proteins; Phenotype; Staphylococcal Infections; Staphylococcus aureus
PubMed: 25081379
DOI: 10.1016/j.micres.2014.07.001