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 AUC0-∞, AUC0-t and Cmax 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 AUC0-∞, AUC0-t and Cmax 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 AUC0-∞, AUC0-t and Cmax of both test and reference preparations in fasted condition. The 90% confidence intervals for the ratio of AUC0-t (100.92-111.27%), AUC0-∞ (96.94-108.08%) and Cmax (100.11-112.50%) for orphenadrine (n = 25); and AUC0-t (94.29-101.83%), AUC0-∞ (94.77-101.68%) and Cmax (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.

Multidrug toxicity involving sumatriptan.

A multidrug fatality involving sumatriptan is reported. Sumatriptan is a tryptamine derivative that acts at 5-HT(1B/1D) receptors and is used for the treatment of migraines. The decedent was a 21-year-old white female found dead in bed by her spouse. No signs of physical trauma were observed and a large number of prescription medications were discovered at the scene. Toxicological analysis of the central blood revealed sumatriptan at a concentration of 1.03 mg/L. Following therapeutic dosing guidelines, sumatriptan concentrations do not exceed 0.095 mg/L. Sumatriptan was isolated by solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry in multiple reaction monitoring mode. A tissue distribution study was completed with the following concentrations measured: 0.61 mg/L in femoral blood, 0.56 mg/L in iliac blood, 5.01 mg/L in urine, 0.51 mg/kg in liver, 3.66 mg/kg in kidney, 0.09 mg/kg in heart, 0.32 mg/kg in spleen, 0.01 mg/kg in brain, 15.99 mg/kg in lung and 78.54 mg/45 mL in the stomach contents. Carisoprodol, meprobamate, fluoxetine, doxylamine, orphenadrine, dextromethorphan and hydroxyzine were also present in the blood at the following concentrations: 3.35, 2.36, 0.63, 0.19, 0.06, 0.55 and 0.16 mg/L. The medical examiner ruled the cause of death as acute mixed drug toxicity and the manner of death as accident.

Influence of orphenadrine upon the protective activity of various antiepileptics in the maximal electroshock-induced convulsions in mice.

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.

Determination of orphenadrine plasma levels using HPLC with diode array detection and a novel solid-phase extraction procedure in psychiatric patients.

Orphenadrine is an antimuscarinic agent mainly used for the treatment of parkinsonism and to alleviate the neuroleptic syndrome induced by antipsychotic drugs. A new, rapid analytical method, based on liquid chromatography with diode array detection (DAD), has been developed and applied to the determination of orphenadrine in plasma of schizophrenic patients for therapeutic drug monitoring and toxicological purposes. The chromatographic separation was performed on a pentafluorophenyl reversed phase column with a mobile phase composed of acetonitrile-phosphate buffer mixture. DAD detection was carried out at 220 nm. A careful and rapid solid-phase extraction procedure on cyanopropyl cartridges was chosen for plasma sample purification and pre-concentration obtaining good extraction yield values for the analyte (>96.0%). The assays showed a linear response for orphenadrine (30-1000 ng mL(-1)). The method is also precise and selective. Thus, the method developed seems to be suitable for routine analysis of orphenadrine in psychiatric patients. Moreover, it was applied to plasma samples from a psychotic patient who had tried to poison himself with 1000 mg of orphenadrine and was undergoing polypharmacy.

Pharmacokinetic, metabolism and withdrawal time of orphenadrine in camels (Camelus dromedarius) after intravenous administration.

The pharmacokinetics of orphenadrine (ORPH) following a single intravenous (i.v.) dose was investigated in six camels (Camelus dormedarius). Orphenadrine was extracted from the plasma using a simple sensitive liquid-liquid extraction method and determined by gas chromatography/mass spectrometry (GC/MS). Following i.v. administration plasma concentrations of ORPH decline bi-exponentially with distribution half-life (t(1/2)(alpha)) of 0.50+/-0.07h, elimination half-life (t(1/2)(beta)) of 3.57+/-0.55h, area under the time concentration curve (AUC) of 1.03+/-0.10g/hl(-1). The volume of distribution at steady state (Vd(ss)) 1.92+/-0.22lkg(-1), volume of the central compartment of the two compartment pharmacokinetic model (V(c)) 0.87+/-0.09lkg(-1), and total body clearance (Cl(T)) of 0.60+/-0.09l/hkg(-1). Three orphenadrine metabolites were identified in urine samples of camels. The first metabolite N-desmethyl-orphenadrine resulted from N-dealkylation of ORPH with molecular ion m/z 255. The second N,N-didesmethyl-orphenadrine, resulted from N-didesmethylation with molecular ion m/z 241. The third metabolite, hydroxyl-orphenadrine, resulted from the hydroxylation of ORPH with molecular ion m/z 285. ORPH and its metabolites in camel were extensively eliminated in conjugated form. ORPH remains detectable in camel urine for three days after i.v. administration of a single dose of 350mg orphenadrine aspartate.

Pharmacokinetic study of orphenadrine using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).

We developed and validated a simple, rapid, and accurate HPLC-MS/MS method with simple protein precipitation for the determination of orphenadrine. Injection-to-injection running time was 3 min with a retention time of orphenadrine of 1.1 min. The linear assay range was 1-200 ng/mL (r2 > 0.99). The intra- and inter-assay imprecisions were CV 0.6-4.2% and CV 1.6-6.1%, respectively. The accuracy, extraction recovery, specificity and stability were satisfactory. Using the measured plasma concentrations of orphenadrine in 24 healthy subjects, pharmacokinetic profiles of orphenadrine were evaluated (AUC(0-72,) 1565+/-731 ng h/mL, Cmax 82.8+/-26.2 ng/mL, Tmax 3.0+/-0.9 h, elimination half-life 25.8+/-10.3 h).

Acute intoxication with orphenadrine and clozapine.

This report describes a fatal intoxication with two different drugs: clozapine and orphenadrine. A 38-year-old man was found dead in the bedroom of his residence. Near the body were found various empty pharmaceutical boxes, employed in schizophrenic therapy, two of them containing clozapine and orphenadrine. High concentrations of clozapine and orphenadrine detected in blood, urine and gastric content were related to death. These compounds were identified and quantitated by liquid-liquid extraction followed by gas chromatographic/mass spectrometry (GC/MS) analysis.

Stepwise binary gradient high-performance liquid chromatographic system for routine drug monitoring.

Drug therapy is usually optimized by concentration measurement in patient serum. High-performance liquid chromatography (HPLC) is one of the most important analytical techniques used for therapeutic drug monitoring (TDM) of drugs for which no immunoassay kits are available. HPLC has been frequently used for screening purposes in toxicology, too. The Merck Tox Screening System (MTSS) has been developed for the identification of substances by a combination of gradient HPLC with diode-array detection and identification with a database system. For routine TDM an isocratic HPLC system is more suitable because of shorter analysis time, better reproducibility of retention index and better precision of results. Therefore we defined a set of methods in steps of 10% of the two MTSS eluents. Three examples are shown: Amiodarone, Indometacine and Thiopental. New applications to test for other substances can be transferred to an isocratic system after a complete MTSS gradient run.

Combined levodopa-anticholinergic therapy in the treatment of Parkinson's disease. Effect on levodopa bioavailability.

The effect of chronic intake of the anticholinergic drug orphenadrine on the bioavailability of levodopa was studied in six patients with Parkinson's disease. Plasma levodopa profiles and corresponding motor response to a standard dose of levodopa plus an inhibitor of peripheral L-aromatic aminoacid decarboxylase (benserazide) were followed, over a 5-h period, on two different sessions, with and without anticholinergic cotherapy. Six control patients were also included in the study for assessment of intrasubject variability in levodopa absorption under identical conditions. A considerable delay in levodopa absorption was found in one patient, and decreased absorption in an additional two patients while on anticholinergic. Patients' clinical performance corresponded well to plasma levodopa profiles. A significant impairment of basal clinical state was observed in two cases on anticholinergic withdrawal, probably as a result of pharmacodynamic interactions. Our observations suggest that chronic anticholinergic intake may contribute to a less predictable pattern of levodopa absorption and related therapeutic response in some subjects.

Residual neuroleptic-induced parkinsonian symptoms in schizophrenia. A naturalistic study with orphenadrine.

A naturalistic study was performed on 44 schizophrenic outpatients diagnosed according to DSM III-R and presenting neuroleptic-induced extrapyramidal side-effects. All patients had been treated continuously for the previous 10-12 weeks with haloperidol (HL) combined with orphenadrine (ORD). The dosages of HL and ORD remained unchanged for at least four weeks before the evaluations. All patients were assessed for depressive features (HRS-D), extrapyramidal (EPSE) and anticholinergic (ACS check list) side-effects. The plasma levels of ORD and its metabolite tofenacine (TOF) were determined by gas chromatography. There was a positive relationship between HRS-D and EPSE total scores, while there was a negative relationship between age and EPSE total scores. No relationship between the administered dose and plasma levels of ORD was found. The HL daily dose (mg/kg), ORD plasma levels and the TOF/ORD plasma level ratio seem to influence significantly the severity of residual extrapyramidal side-effects.

Mechanisms of orphenadrine-induced antinociception in mice: a role for serotonergic pathways.

The possible involvement of central serotonergic pathways in the mechanism of action of orphenadrine citrate was investigated in male albino mice. Orphenadrine (20 mg/kg) did not alter the concentration of 5-hydroxytryptamine (5-HT) or its metabolite 5-hydroxyindole acetic acid in the frontal cortex or spinal cord, nor did it, in moderate concentrations, inhibit the uptake of [14C]5-HT, [3H]noradrenaline ([3H]NA) or [3H]dopamine ([3H]DA) into crude synaptosomal preparations from the cortex. The antinociceptive effect of orphenadrine was studied in the formalin test and in the increasing temperature hot plate test. No sensorimotor impairment was observed for doses of 30 mg/kg or lower. A general depletion of serotonin by means of p-chlorophenylalanine significantly reduced the effect of orphenadrine in both tests, while lesion of the ascending serotonergic systems by means of p-chloroamphetamine did not affect the analgesia. It is concluded that the antinociceptive effect of orphenadrine may be mediated in part via the raphe-spinal serotonergic systems.

Simple and rapid GLC method for the determination of orphenadrine in human plasma.

A rapid and specific method has been developed for the determination of orphenadrine concentration in plasma. It involves a one-step sample preparation using n-hexane/isopropyl alcohol (98:2) extraction, and analysis by gas chromatography on a wide bore capillary column using nitrogen/phosphorus detection. This procedure considerably simplifies previously reported assays and is specific and sensitive enough for the determination of orphenadrine in plasma of patients on chronic therapy.

Orphenadrine serum levels in a poisoned patient.

A patient ingested about 5 g of orphenadrine hydrochloride. He had gastric lavage and oral administration of activated charcoal. The main symptoms were neuropsychiatric in nature. Possible relation between serum levels of the drug and time course of the toxic effects are described.

Quantitative determination of diphenhydramine and orphenadrine in human serum by capillary gas chromatography.

Diphenhydramine has been in medical use for 35 years as an antihistamine and hypnotic. We evaluated the pharmacokinetic parameters, which are not only important for disposition studies, in the serum of 10 volunteers who received a single dose of 31 mg diphenhydramine. For this purpose a suitable capillary GC-method was developed, which has a detection limit of 2 micrograms/l (serum); the calibration curve is linear between 2.5 and 120 micrograms/l, the reproducibility is always better than 3.6% and the average recovery is about 100.1%. The combination of a relatively non-polar extraction solvent, a selective detector (N-FID) and a fused silica, bonded-phase capillary column led to a more rapid sample clean-up procedure (no back-extraction needed) and is sensitive and specific enough for the quantitative determination of diphenhydramine, orphenadrine or other ethanolamines in human serum.

A report on the analysis of orphenadrine in post mortem specimens.

A discussion of the methods reported for the analysis of orphenadrine is given. The drug levels in biological specimens and the methods reported vary widely. The stability and extractability of orphenadrine is investigated and a method suggested, which uses subtilisin digestion of tissue followed by extraction with 1-chlorobutane. Body fluids are extracted directly by 1-chlorobutane after pH adjustment. Analysis is performed by gas chromatography with a nitrogen selective detector and no interferences are observed from bland specimens. The following levels are results from a case of a 19-year-old male who was found dead 2.5 hours after last being seen alive. This laboratory analysed the case using diphenhydramine as an internal standard: blood 18.1 micrograms/mL, liver 242 micrograms/g, urine 7.0 micrograms/mL, stomach contents 1452 mg.

Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man.

Plasma concentrations of orphenadrine were measured by a specific gas chromatographic method in 5 healthy male volunteers after a single oral dose of orphenadrine hydrochloride 100mg. The single dose pharmacokinetic profile of orphenadrine was evaluated from these data. The elimination half-life ranged from 13.2-20.1h after the commercial tablet formulation. Plasma concentrations, determined in volunteers and patients under different conditions of repeated oral administration of the same formulation of orphenadrine hydrochloride exceeded the theoretical values, predicted from the single dose pharmacokinetics, by a factor 2 to 3. The elimination half-lives after discontinuation of treatment showed a 2 to 3-fold increase over the single dose values. This demonstrates a clear discrepancy between the multiple and single dose pharmacokinetics of orphenadrine. Experiments in dogs suggested competition for biotransformation between orphenadrine and its metabolite N-demethylorphenadrine. Product inhibition of this type could explain the observed discrepancy.

The bioavailability of orphenadrine hydrochloride after intramuscular and oral administration.

The bioavailability of orphenadrine hydrochloride after a single intramuscular injection was compared to that after a single oral dose by following serial plasma concentration estimations of the unchanged drug. Eight subjects received 40 mg orphenadrine HCl intramuscularly and 50 mg orally on separate occasions 1 week apart. The bioavailability of orphenadrine from the intramuscular dosage form proved to be equal to or even greater than that from the tablet. The first hour plasma concentrations after intramuscular doses were significantly higher than those after oral doses, supporting the clinical use of the intramuscular route in those indications where rapid effects of the drug are required.

Sensitive and specific gas chromatographic and extraction method for the determination of orphenadrine in human body fluids.

A gas chromatographic and extraction method for the assay of orphenadrine in plasma and urine has been developed, in which diphenhydramine is used as the internal standard. The procedure involves extraction with isopentane and alkali flame ionization (nitrogen) detection. Orphenadrine N-oxide and N-dealkylated orphenadrine did not interfere with the analysis. Orphenadrine concentrations down to 1 ng/ml can be determined. Application in a pharmacokinetic/bioavailability study is reported.