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PubMed1987

Misleading T3-test values in psychiatric patients treated with orphenadrine.

Thyroid laboratory tests were assessed in 74 psychiatric patients without clinical evidence of overt thyroid disorder. In a first screening of 42 patients, 13 were found to have elevated levels of triiodothyronine uptake test (T3-test) by a Sephadex method. Ten of these patients also had an elevated free thyroxine index (fT4-index). Of the 13 patients with increased T3-test values, 10 were on orphenadrine (Disipal) treatment or had recently stopped taking the drug. In a second study, thyroid function tests were compared in 15 pairs of matched psychiatric patients treated with orphenadrine or other anticholinergic drugs. Values of T3-test and free thyroxine index were significantly higher among patients treated with orphenadrine. Finally, orphenadrine was instituted in four patients and withdrawn in six patients. T3-test values and free thyroxine indices increased gradually after orphenadrine treatment had been initiated and decreased gradually when it was withdrawn.

Adult↗

PubMed1983

The influence of orphenadrine or imipramine on the hypertensive response of physostigmine in the rat.

UNLABELLED: An intravenous infusion of orphenadrine or imipramine to artificially ventilated, urethane anaesthetized rats, completely blocked the physostigmine induced increase in blood pressure and the blood pressure increase induced by electrical stimulation of the posterior hypothalamus; effects mediated via the sympathetic nerve. The noradrenaline induced blood pressure increase was not changed during an infusion with orphenadrine but was markedly depressed during an infusion with imipramine. During an infusion with both orphenadrine or imipramine the pressor response induced by stimulation of the spinal cord were completely blocked in pithed rats. The pattern of the blockade was comparable with the blockade of the pressor response after hypothalamic stimulation. These results show that at least in rats both orphenadrine and imipramine prevents the central stimulatory sympathetic effects on the cardiovascular system by interfering with the sympathetic nervous system. The site of action is discussed. IN CONCLUSION: the present results show that although physostigmine may be helpful in the treatment of central anticholinergic effects caused by overdoses of orphenadrine and imipramine it is of no use for combating the direct toxic effects of both drugs on the cardiovascular system.

Animals↗

PubMed1985

Antinociceptive effects of orphenadrine citrate in mice.

The antinociceptive effect of orphenadrine citrate, a muscle relaxant, was investigated in mice. Four different pain tests were selected to involve different noxious stimuli. Clear antinociceptive effects were found in the formalin test. The increasing temperature hot-plate test showed a biphasic dose-response relationship with slight hyperalgesia after low doses and hypoalgesia after higher doses. No significant effects of orphenadrine (0-25 mg/kg) were found in the tail flick and constant temperature hot-plate tests. The data suggest that orphenadrine may reduce, enhance or leave unaffected different types of nociceptive transmission. Orphenadrine may also possess analgesic properties in conditions not involving muscle spasm.

Analgesics↗

PubMed2006

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).

Administration, Oral↗

PubMed1977

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.

Biological Availability↗

PubMed1975

Interactions of orphenadrine and phenobarbitone with chlorpromazine: plasma concentrations and effects in man.

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.

Adult↗

PubMed2006

Torsades de pointes in congenital long QT syndrome following low-dose orphenadrine.

We report the case of a woman, affected by congenital long QT syndrome (LQTS), who experienced three syncopal episodes shortly after the assumption of a low dose of orphenadrine. The ECG revealed a QT interval of 600 ms, and the corrected QT interval (QTc) was 537 ms. No structural cardiac disease was demonstrated by echocardiography. Orphenadrine treatment was discontinued. During the first 12 h of monitoring, three short-lasting, asymptomatic episodes of torsades de pointes occurred. No other sustained ventricular arrhythmia was revealed at Holter monitoring in the following days. During the ensuing 6 months, the patient remained asymptomatic, and the QTc did not change. Orphenadrine is an analogue of diphenhydramine, an antihistaminic drug that produces sodium channel blockade similar to that caused by quinidine and other Class Ia antiarrhythmic drugs. Our case rises the suspicion that orphenadrine could cause life-threatening arrhythmias in LQTS even at a low dose, and independently from concomitant assumption of potentially QT-prolonging drugs.

Aged↗

PubMed1986

Orphenadrine citrate increases and prolongs the antinociceptive effects of paracetamol in mice.

Orphenadrine, a muscle relaxant with antinociceptive effects, was shown to increase and prolong the antinociceptive effects of paracetamol in mice. Both in the increasing temperature hot plate test and in the formalin test, a combination of the two drugs showed a significantly improved effect compared to either of the drugs alone. The time course of the effects was tested in the increasing temperature hot plate test. The group treated with the drug combination showed a prolonged effect compared to both single drug treated groups, the effect lasting longer than 120 min. for the combination and about 80 min. for the single drugs. Orphenadrine and paracetamol increased antinociception even when orphenadrine was injected 90 min. after paracetamol, which by that time did not exert antinociceptive effects by itself. Thus the combination of orphenadrine and paracetamol enhances the antinociceptive effect of either drug in mice.

Acetaminophen↗

PubMedDate not supplied

Clinical and pharmacological review of the efficacy of orphenadrine and its combination with paracetamol in painful conditions.

Orphenadrine citrate, a monomethylated derivative of diphenhydramine, has been used as a muscle relaxant and as an analgesic both alone or as a constituent of combination products. Data on the efficacy of orphenadrine alone and in combination with paracetamol for painful conditions are evaluated in the present review. From the available animal data it is concluded that the antinociceptive effect of orphenadrine has been clearly demonstrated but data have also clearly indicated that it has muscle relaxant properties. Human placebo-controlled studies have shown some support for the view that orphenadrine on its own acts as a mild analgesic in painful conditions associated with muscle spasm. Although only a small number of well-controlled studies have been completed with the combination product of orphenadrine/paracetamol, each supports the view that the combination has superior efficacy over paracetamol alone. There is no doubt that the combination product is more efficacious than placebo.

Acetaminophen↗

PubMed1999

Assessment of the adrenergic effects of orphenadrine in rat vas deferens.

The peripheral adrenergic effects of orphenadrine, an antiparkinsonian drug, have been evaluated in the rat vas deferens to investigate whether these properties are the same as those of other phencyclidine ligands. In the low micromolar range, orphenadrine enhanced electrically-evoked and exogenous noradrenaline contractile responses in the epididymal portion of rat vas deferens. It also induced spontaneous activity that was inhibited by prazosin (1 microM) but not by atropine (20 nM). It inhibited accumulation of [3H]noradrenaline in rat vas deferens (IC50 = 14.2+/-2.3 microM). Orphenadrine competitively inhibited [3H]nisoxetine binding in rat vas deferens membranes (Ki = 1.05+/-0.20 microM). It can be concluded that orphenadrine, at low micromolar concentrations, interacts with the noradrenaline reuptake system inhibiting its functionality and thus potentiating the effect of noradrenaline.

Adrenergic Agents↗

PubMed1983

Product inhibition in orphenadrine metabolism as a result of a stable cytochrome P-450-metabolic intermediate complex formed during the disposition of mono-N-desmethylorphenadrine (tofenacine) in the rat.

Product inhibition is thought to be involved in unexpected accumulation of orphenadrine, which occurs during chronic medication with this anti-Parkinson drug in man. In previous studies (Biochem. Pharmacol. 31, 2745-2753 (1982) we established the formation of reactive metabolic intermediates (MI) during metabolism of orphenadrine and its mono-N-demethylated metabolite tofenacine, which may block cytochrome P-450 (MI-complex). In this study we investigated the role of MI-complexation in product inhibition. Three different assays were used to establish the amount of cytochrome P-450 involved in MI-complexation, which was induced by tofenacine (30 mg/kg i.p.) in phenobarbital pretreated rats. If liver microsomes were prepared 3 hours after tofenacine injection, both spectral titration of oxidized cytochrome P-450, determination of loss of metyrapone binding sites at reduced cytochrome P-450 as well as ferricyanide oxidation of the MI-complex revealed 8-13% complexation of cytochrome P-450. Our data also suggest that MI-complexation is generated on phenobarbital induced cytochrome P-450 species. Phenobarbital induction was also shown to activate orphenadrine metabolism in vitro. Moreover, with a newly developed capillary GLC method, using nitrogen detection, we showed inhibition of orphenadrine- and tofenacine metabolism in vitro, by MI-complexation. This study therefore showed that MI-complexation may produce product inhibition.

Animals↗

PubMed1992

Solid-state structure of orphenadrine hydrochloride and conformational comparisons with diphenhydramine hydrochloride and nefopam hydrochloride.

The solid-state structure of (+-)-orphenadrine hydrochloride [(CH3)2NCH2CH2OCH(o-CH3C6H4)(Ph).HCl], a skeletal muscle relaxant drug, was determined by single-crystal X-ray diffraction analysis. Orphenadrine hydrochloride gave crystals belonging to the monoclinic P2(1)/n space group, and at low temperature (92 K), the following parameters were found: a = 6.923 (4), b = 7.508 (5), c = 33.22 (3) A, V = 1720 (3) A3, Z = 4, R(F) = 0.109, and Rw(F) = 0.131. Data were collected from poor crystalline material because of the low volume of the needle-shaped crystals (0.025 x 0.025 x 0.15 mm3). A molecular mechanics model was calculated by using an input structure based on atomic coordinates of the crystallographically determined molecular structure. The resulting molecular mechanics model and the structure determined by X-ray crystallography have the same molecular conformation. Whereas both solid-state (+-)-orphenadrine hydrochloride and diphenhydramine hydrochloride [(CH3)2NCH2CH2OCH(Ph)2.HCl] have synclinal N-C-C-O and antiperiplanar NC-C-O-CAr2 torsion angles, the former has a helical arrangement for Ar2CH, as expected, and the phenyl rings in the latter are disposed in a nonhelical, "open-book" arrangement.

Diphenhydramine↗

PubMed1999

Orphenadrine poisoning in a child: clinical and analytical data.

Orphenadrine is an anticholinergic drug used mainly in the treatment of Parkinson's disease. It has a peripheral and central effect and a known cardiotoxic effect when taken in large doses. We report the successful outcome of the treatment of a 2 1/2-year-old girl who accidentally ingested 400 mg of orphenadrine hydrochloride (Disipal). One hour after ingestion she presented neurological symptoms: confusion, ataxic walking, and periods of severe agitation. Generalized tonic-clonic seizures appeared resistant to the administration of multiple antiepileptics. They ceased after a supplementary dose of intravenous diazepam, endotracheal intubation, and mechanical ventilation. An episode of ventricular tachycardia responded well to i. v. lidocaine. Physostigmine was administered in three successive doses. The initial orphenadrine plasma level (3,55 microg/ml) was in the toxic range, associated with high mortality. The calculated elimination half-life was 10.2 h and the molecule and/or its metabolites were found up to 90 h after ingestion.

Akathisia, Drug-Induced↗

PubMedDate not supplied

Forensic toxicology of some orphenadrine-related deaths.

Toxicological data for orphenadrine in ten cases of fatal poisoning are presented together with results for a further eight cases in which orphenadrine was present in combination with alcohol or another drug. Collapse and convulsions occur within an hour of ingestion of an overdose and death supervenes soon after. Autopsy blood concentrations of orphenadrine in such acute fatal poisonings range from 5.5-37 mug/ml. The unchanged drug was found in the bile and urine and the concentrations in the liver, lung and kidney, though differing between cases, were of the same order in any one case.

Adolescent↗

PubMedDate not supplied

Reversal of orphenadrine-induced ventricular tachycardia with physostigmine.

A 3-year-old boy developed confusion, generalized tonic-clonic seizures, and sustained ventricular tachycardia following ingestion of an unknown quantity of orphenadrine (Norflex). Although refractory to precordial thump, synchronous cardioversion, and lidocaine, the ventricular tachycardia was reversed by intravenous administration of the tertiary acetylcholinesterase inhibitor physostigmine. We discuss the underlying physiology and manifestations of anticholinergic overdose, the specific manifestations of orphenadrine overdose, and the current recommendations regarding the utilization and toxicity of physostigmine in the treatment of anticholinergic syndromes and orphenadrine intoxication.

Child, Preschool↗

PubMed2001

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.

Adult↗

PubMed2000

Central anticholinergic syndrome from orphenadrine in a 3 year old.

Orphenadrine (N,N-dimethyl-2(o-methyl-alpha-phenylbenzyloxy)ethylamine) is an analog of diphenhydramine with central and peripheral anticholinergic properties. It is commonly prescribed both as a muscle relaxant and as an adjunct to antipsychotic medications to prevent parkinsonism. We report a case of orphenadrine poisoning in a 3-year-old boy following ingestion of no more than two 100-mg tablets. Central anticholinergic toxicity was prominent, manifested by hallucinations and severe agitation. Orphenadrine can cause profound toxicity in children after ingestion of small doses, and should be considered as a potential cause for acute delirium in childhood.

Child, Preschool↗

PubMed1989

Interaction of nefopam and orphenadrine with the cytochrome P-450 and the glutathione system in rat liver.

Nefopam, a cyclic analogue of orphenadrine, exhibits a type I (substrate) and a type II (ligand) interaction with ferri-cytochrome P-450 in control and phenobarbitone induced rat hepatic microsomes respectively. In-vitro metabolism of nefopam in phenobarbitone-induced microsomes leads to the production of a reactive metabolite which complexes with cytochrome P-450. In contrast to the known complexation of orphenadrine, complexation by nefopam can be inhibited by glutathione (GSH, 0.1-1.0 mM). However, in-vivo administration of nefopam to rats does not diminish the GSH content of liver cytosol nor increase oxidized glutathione levels nor alter the activities of GSH transferase and GSH peroxidase. In-vivo administration does not lead to cytochrome P-450 induction nor cytochrome P-450 complexation as has been shown for orphenadrine. Finally, nefopam inhibits the NADPH dependent endogenous H2O2 production in both control and phenobarbitone-induced microsomes.

Aminopyrine N-Demethylase↗