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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 -
Clinical Toxicology (Philadelphia, Pa.) Mar 2024Orphenadrine overdoses can cause antimuscarinic toxicity, respiratory failure, refractory seizures and cardiotoxicity. The dose-toxicity relationship is poorly defined....
INTRODUCTION
Orphenadrine overdoses can cause antimuscarinic toxicity, respiratory failure, refractory seizures and cardiotoxicity. The dose-toxicity relationship is poorly defined. Orphenadrine is marketed as immediate and sustained release formulations, and it is not known how the formulation impacts on toxicity. We determined the clinical toxicity of orphenadrine in patients referred to a regional poisons centre.
METHODS
Retrospective case series of patients in New South Wales with orphenadrine deliberate self-poisoning from January 2016 to April 2022 referred to the New South Wales Poisons Information Centre. Demographics, history of exposure, treatment and outcomes were extracted from clinical databases. Receiver-operating characteristic curves were constructed to determine thresholds predicting toxicity.
RESULTS
Forty-eight patients were identified, with information on clinical outcomes in 46 patients and doses in 41 patients. All patients were older than 12 years. The median orphenadrine dose was 770 mg (range 210-10,000 mg), 59 per cent as the immediate release formulation, and 67 per cent reported coingestants. Doses of sustained release formulations were significantly greater than immediate release formulations, median 2,750 mg versus 595 mg. Common clinical features were drowsiness (59 per cent), sinus tachycardia (37 per cent) and confusion (33 per cent). Three patients had mild hypotension, three were intubated for coma, and two had seizures; no patients suffered ventricular dysrhythmias. All patients survived, with 75 per cent being medically cleared within 24 hours of presentation. A dose-toxicity relationship was observed, but conclusions are limited by the small number of cases with moderate or severe toxicity.
DISCUSSION
All patients survived, and severe cardiac and neurological toxicity were not observed. This contrasts to published case reports noting severe poisoning at similar or lower doses. Formulation may have an impact on outcomes, with lesser toxicity from sustained release products.
CONCLUSIONS
Orphenadrine doses up to 10 g were associated with antimuscarinic toxicity and sedation, but not severe cardiotoxicity. More research exploring the effect of dose and formulation on outcomes is required.
Topics: Humans; Retrospective Studies; Female; Male; Poison Control Centers; Adult; Middle Aged; Drug Overdose; Young Adult; Adolescent; Orphenadrine; Suicide, Attempted; Child; New South Wales; Delayed-Action Preparations; Muscarinic Antagonists; Aged; Dose-Response Relationship, Drug
PubMed: 38525870
DOI: 10.1080/15563650.2024.2323678 -
Environmental Science and Pollution... Dec 2021In some Brazilian coastal cities, it is common to observe 'black tongues' in beaches, i.e. a mixture of urban runoff and untreated domestic sewage containing pollutants...
Occurrence and ecological risk assessment of pharmaceuticals and cocaine in the urban drainage channels of Santos beaches (São Paulo, Brazil): a neglected, but sensitive issue.
In some Brazilian coastal cities, it is common to observe 'black tongues' in beaches, i.e. a mixture of urban runoff and untreated domestic sewage containing pollutants of emerging concern, namely pharmaceutical and personal care products (PPCPs), flowing into the South Atlantic Ocean. Such diffuse loads of pollutants might expose nontarget aquatic organisms to harmful compounds. In this work, the occurrence and preliminary ecological risk of 27 PPCPs of various therapeutic classes (including cocaine and its primary metabolite, benzoylecgonine) were investigated, for the first time, in seven urban drainage channels whose diffuse loads flow continuously to the beaches of Santos Bay, São Paulo, Brazil. Of these, 21 compounds were detected using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS), and nine of them were consistently quantified in all urban channels of Santos, suggesting that those pollutants are ubiquitous in this region: caffeine (143.4-516.0 ng/L), losartan (4.2-21.8 ng/L), atenolol (1.1-18.2 ng/L), acetaminophen (1.5-13.8 ng/L), benzoylecgonine (1.0-4.8 ng/L), carbamazepine (1.1-4.0 ng/L), diclofenac (1.9-3.5 ng/L), cocaine (0.5-1.7 ng/L), and orphenadrine (0.1-0.8 ng/L). Moreover, twelve compounds were found below the limit of quantification (
Topics: Brazil; Chromatography, Liquid; Cocaine; Environmental Monitoring; Illicit Drugs; Pharmaceutical Preparations; Risk Assessment; Tandem Mass Spectrometry; Water Pollutants, Chemical
PubMed: 34322794
DOI: 10.1007/s11356-021-15249-8 -
Environmental Science and Pollution... Mar 2021The aim of this study was to screen and quantify 23 pharmaceutical compounds (including illicit drugs), at two sampling points near the diffusers of the Guarujá...
The aim of this study was to screen and quantify 23 pharmaceutical compounds (including illicit drugs), at two sampling points near the diffusers of the Guarujá submarine outfall, State of São Paulo, Brazil. Samples were collected in triplicate during the high (January 2018) and low (April 2018) seasons at two different water column depths (surface and bottom). A total of 10 compounds were detected using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Caffeine (42.3-141.0 ng/L), diclofenac (3.6-85.7 ng/L), valsartan (4.7-14.3 ng/L), benzoylecgonine (0.3-1.7 ng/L), and cocaine (0.3-0.6 ng/L) were frequently detected (75% occurrence). Orphenadrine (0.6-3.0 ng/L) and atenolol (0.1-0.3 ng/L), and acetaminophen (1.2-1.4 ng/L) and losartan (0.7-3.4 ng/L), were detected in 50% and 25% of the samples, respectively. Only one sample (12.5%) detected the presence of carbamazepine (< 0.001-0.1 ng/L). Unexpectedly a lower frequency of occurrence and concentration of these compounds occurred during the summer season, suggesting that other factors, such as the oceanographic and hydrodynamic regimes of the study area, besides the population rise, should be taken into account. Caffeine presented concentrations above the surface water safety limits (0.01 μg/L). For almost all compounds, the observed concentrations indicate nonenvironmental risk for the aquatic biota, except for caffeine, diclofenac, and acetaminophen that showed low to moderate ecological risk for the three trophic levels tested.
Topics: Brazil; Chromatography, Liquid; Cocaine; Environmental Monitoring; Pharmaceutical Preparations; Risk Assessment; Sewage; Tandem Mass Spectrometry; Water Pollutants, Chemical
PubMed: 33123891
DOI: 10.1007/s11356-020-11320-y -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2023Acute pain syndromes caused by discogenic lumbosacral radiculopathy and lumboischialgia are not uncommon in clinical practice and characterized by a high risk of...
[The use of a fixed combination of diclofenac and orphenadrine in the treatment of acute pain syndrome in patients with discogenic lumbosacral radiculopathy and lumboischialgia].
Acute pain syndromes caused by discogenic lumbosacral radiculopathy and lumboischialgia are not uncommon in clinical practice and characterized by a high risk of becoming chronic. The pathogenetic aspects, features of the clinical picture, existing approaches to conservative treatment of these conditions are analyzed in this paper. Data on the efficacy and safety of a fixed combination of diclofenac and orphenadrine (Neodolpasse) use in the treatment of vertebrogenic pain syndromes based on the NEODOLEX study results are presented, and the authors' own clinical observations are given. Possible reasons for the high efficacy of Neodolpasse in patients with discogenic radiculopathies and nonspecific back and neck pain are discussed.
Topics: Humans; Diclofenac; Radiculopathy; Orphenadrine; Acute Pain; Back Pain
PubMed: 36946408
DOI: 10.17116/jnevro2023123031122 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2021The high prevalence of dorsalgia and dorsopathy among the adult population makes a significant contribution to the structure of the financial burden of health care...
The high prevalence of dorsalgia and dorsopathy among the adult population makes a significant contribution to the structure of the financial burden of health care systems. The use of non-steroidal anti-inflammatory drugs (NSAIDs) as the basis for the pharmacotherapy of dorsopathy is recommended by most international clinical guidelines. The pharmacodynamic effects of NSAIDs underlie the clinical efficacy of this group of drugs in patients with pain of musculoskeletal origin, while monotherapy is not always accompanied by the rapid development of a persistent analgesic effect. An urgent direction in the therapy of dorsopathies may include combination of NSAIDs with analgesic drugs of other pharmacological groups capable of additive action. The fixed combination of diclofenac, 75 mg, and orphenadrine, 50 mg, allows achieving an effective analgesic effect in patients with lower back pain of various etiologies. It was demonstrated in a series of clinical cases that included 4 patients with dorsopathy who were treated at the City Clinical Hospital No. 24, Moscow in 2020.
Topics: Adult; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Humans; Moscow; Orphenadrine
PubMed: 34184488
DOI: 10.17116/jnevro2021121051126 -
Pain Medicine (Malden, Mass.) Oct 2021To examine the prevalence and duration of skeletal muscle relaxant (SMR) treatment among commercially insured adults in the United States.
OBJECTIVE
To examine the prevalence and duration of skeletal muscle relaxant (SMR) treatment among commercially insured adults in the United States.
METHODS
We used the MarketScan Research Database to identify a cohort of adults 18 to 64 years who had ≥2-year continuous enrollment between 2005 and 2018. We estimated the prevalence of SMR treatment using a repeated cross-sectional design and derived treatment duration using the Kaplan-Meier method. Analyses were stratified by age group, sex, geographic region, individual SMR agent, and musculoskeletal disorder.
RESULTS
48.7 million individuals were included. Treatment prevalence ranged from 61.5 to 68.3 per 1,000. About one-third of users did not have a preceding musculoskeletal disorder diagnosis. Cyclobenzaprine was the dominant agent accounting for >50% of prescriptions. The considerable growth in the use of baclofen, tizanidine, and methocarbamol paralleled with a decline in carisoprodol and metaxalone use. The prevalence was highest in the South while lowest in the Northeast. The median treatment duration was 14 days with 4.0%, 1.9%, and 1.0% of individuals using SMRs for more than 90, 180, and 365 days, respectively. Compared with cyclobenzaprine, patients initiating baclofen, tizanidine, and carisoprodol had longer treatment duration.
CONCLUSIONS
SMRs are widely used in the United States. Their use slightly increased in recent years, but trends varied among individual agents, patient groups, and geographic regions. Despite limited evidence to support efficacy, a sizable number of U.S. adults used SMRs for long-term and off-label conditions. Further study is needed to understand determinants of treatment as well as outcomes associated with such use.
Topics: Adult; Cross-Sectional Studies; Humans; Musculoskeletal Diseases; Neuromuscular Agents; Prevalence; United States
PubMed: 33690860
DOI: 10.1093/pm/pnab088 -
Angewandte Chemie (International Ed. in... Jul 2023Advancing the development of perfecting the use of polar organometallics in bio-inspired solvents, we report on the effective generation in batch of organosodium...
Advancing the development of perfecting the use of polar organometallics in bio-inspired solvents, we report on the effective generation in batch of organosodium compounds, by the oxidative addition of a C-Cl bond to sodium, a halogen/sodium exchange, or by direct sodiation, when using sodium bricks or neopentylsodium in hexane as sodium sources. C(sp )-, C(sp )-, and C(sp)-hybridized alkyl and (hetero)aryl sodiated species have been chemoselectively trapped (in competition with protonolysis), with a variety of electrophiles when working "on water", or in biodegradable choline chloride/urea or L-proline/glycerol eutectic mixtures, under hydrous conditions and at room temperature. Additional benefits include a very short reaction time (20 s), a wide substrate scope, and good to excellent yields (up to 98 %) of the desired adducts. The practicality of the proposed protocol was demonstrated by setting up a sodium-mediated multigram-scale synthesis of the anticholinergic drug orphenadrine.
PubMed: 37166367
DOI: 10.1002/anie.202304720 -
Journal of AOAC International Jan 2020The utilization of selection methods such as genetic algorithm (GA) aims to construct better partial least squares (PLS) and principal component regression (PCR) models...
Effect of Genetic Algorithm-Based Wavelength Selection as a Preprocessing Tool on Multivariate Simultaneous Determination of Paracetamol, Orphenadrine Citrate, and Caffeine in the Presence of p-Aminophenol Impurity.
BACKGROUND
The utilization of selection methods such as genetic algorithm (GA) aims to construct better partial least squares (PLS) and principal component regression (PCR) models than those established from the full-spectrum range.
OBJECTIVE
Determination of paracetamol (PAR), orphenadrine citrate (Or.cit), and caffeine (CAF) in the presence of PAR nephrotoxic impurity [p-aminophenol (PAP)]. GA was applied to select the optimum wavelengths used.
METHODS
A calibration set was prepared in which the three drugs, together with PAP, were modeled by multilevel multifactor design. This calibration set was used to build the PLS and PCR models, either with or without preprocessing the data using GA.
RESULTS
Results were compared with and without preprocessing, and this revealed that GA can find an optimized combination of spectral wavelengths, yielding a lower root mean square error of prediction as well as a lower number of latent variables used. The results of the two models show that simultaneous determination of the aforementioned drugs can be performed in the concentration ranges of 20-60, 3-11, and 1-9 μg/mL for PAR, Or.cit, and CAF, respectively.
CONCLUSIONS
The proposed models were applied for the determination of the three drugs in their pharmaceutical formulations, and the results were verified by the standard addition technique.
HIGHLIGHTS
GA can be useful as a wavelength selection tool before applying multivariate PLS and PCR methods. GA gives an improvement in the predictive ability of the models with lower RMSEP and less number of latent variables (LVs). The proposed PLS, PCR, GA-PLS, and GA-PCR spectrophotometric methods were able to determine paracetamol, orphenadrine citrate, and caffeine in the presence of p-aminophenol and severe spectral overlapping.
Topics: Acetaminophen; Algorithms; Aminophenols; Caffeine; Calibration; Least-Squares Analysis; Orphenadrine
PubMed: 31277724
DOI: 10.5740/jaoacint.18-0393 -
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