Trihexyphenidyl Research Articles

Differential effects of trihexyphenidyl on place preference conditioning and locomotor stimulant activity of cocaine and methamphetamine.

Cocaine produces rewarding and locomotor stimulant effects by increasing extracellular dopamine (DA) levels in the terminal areas of the mesolimbic DA system. Our recent in vitro studies have shown that a muscarinic receptor antagonist, trihexyphenidyl (THP) inhibits the binding of a cocaine analogue to the DA transporter at concentrations that are ineffective in inhibiting 3H-DA uptake, suggesting that THP may attenuate the actions of cocaine selectively. The present study examined whether THP could affect conditioned place preference (CPP) for and locomotor stimulant activity of cocaine and methamphetamine (MAP) in mice. Mice were injected with cocaine (10 mg/kg) or MAP (1 mg/kg) in one compartment of the CPP chamber 4 times every second day. On alternate days the animals received saline in the other compartment of the CPP chamber. Pretreatment with THP was made 10 min before cocaine or MAP injection. The CPP score and locomotor activity were assessed using a novel activity monitor, SCANET. Cocaine and MAP produced CPP for the drug-paired compartment. Pretreatment with THP (0.05-5 mg/kg) had no influence on cocaine-induced CPP at any dose tested. In contrast, MAP-induced CPP was completely antagonized by THP at 5 mg/kg, which produced no CPP by itself. Another muscarinic receptor antagonist, scopolamine (SCP, 3 mg/kg) neither caused CPP by itself nor affected the development of cocaine- or MAP-induced CPP. Both THP and SCP enhanced spontaneous, cocaine- or MAP-induced locomotor activity. Though the present conditioning treatments failed to develop locomotor sensitization to cocaine, THP, but not SCP, acted cooperatively with cocaine to develop locomotor sensitization. The development of locomotor sensitization to MAP was retarded by SCP but was not affected by THP. These results suggest that, contrary to our anticipation, THP has a unique characteristic of specifically counter-acting the rewarding properties of MAP via a non-cholinergic (muscarinic) mechanism.

Enhanced delivery of drugs into and across the skin by ethosomal carriers

In dermal and transdermal delivery, the skin is used as a portal of entry for drugs, for localized and systemic treatment. Because of the barrier properties of the outer layer of the skin, in many cases, permeation-enhancing agents are needed to achieve therapeutic levels of drug. Classic liposomal systems were found to be effective at forming drug reservoir in the upper layers of the skin, for local skin therapy. Recently, it was found that ethosomal carriers, phospholipid vesicular systems containing relatively high concentrations of alcohol, were very effective at enhancing dermal and transdermal delivery of both lipophilic and hydrophilic molecules. Fluorescent probes delivered from ethosomal systems reached the deep strata of the skin. Delivery of minoxidil to the pilosebaceous units from ethosomes was much greater compared to delivery from classic liposomes. In addition, clinical studies with aciclovir showed that ethosomal formulations were superior to the currently available topical therapy at treating recurrent herpes labialis. Ethosomal systems were also highly effective at transdermal delivery of drugs. In vivo skin permeation of testosterone from patches containing ethosomal drug were more effective at delivering testosterone through rabbit pinna skin than commercially available Testoderm patches. Results using trihexyphenidyl hydrochloride ethosomes indicated that this system has the potential to be further developed into an antiparkinsonian patch. Lastly, the transdermal delivery of insulin from an ethosomal carrier resulted in lower blood glucose levels in normal and diabetic rats in vivo, with a plateau effect lasting for at least 8 h. Drug Dev. Res. 50:406–415, 2000. © 2000 Wiley-Liss, Inc.

Dose-response curves and time-course effects of selected anticholinergics on locomotor activity in rats.

In order to facilitate direct comparisons of anticholinergic drug effects on activity, nine drugs were tested in one laboratory using a standardized procedure. The present study compared the effects of aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide, and trihexyphenidyl hydrochloride on activity levels in rats. Both fine motor activity (reflecting smaller movements) and ambulatory activity (reflecting larger movements) were recorded for 23 h following drug administration in food-restricted rats. All drugs were administered during the light period of the photocycle. Atropine, azaprophen, biperiden, scopolamine, and trihexyphenidyl increased both ambulations and fine motor activity significantly during the first hour post-injection, but the increased activity levels returned to vehicle control levels within 2-6 h post-injection. Benactyzine and procyclidine only increased fine motor activity significantly above vehicle control levels and activity levels returned to vehicle control levels within 2-3 h. Finally, aprophen and diazepam generally did not increase measures of activity significantly above vehicle controls at the dose ranges examined. Based on potencies relative to scopolamine, the potency of the drugs could be ranked as follows: scopolamine > trihexyphenidyl > biperiden > azaprophen > procyclidine > benactyzine > atropine > aprophen. The comparison of drug effects on activity may be useful in selecting anticholinergic drug therapies with a minimal range of side effects. In addition, these data may reduce the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.

Stereoselective determination of trihexyphenidyl in human serum by LC–ESI–MS

The antiparkinsonian drug trihexyphenidyl (THP) is currently manufactured and administered as a racemate. However, stereochemistry can play significant role in the drug’s pharmacokinetics, biotransformation, metabolism, interaction with cellular and tissue components and overall effect on human body. It is necessary to consider such a drug as a mixture of two compounds (drug enantiomers), with their own effect on the human body. The present paper describes a simple and sensitive LC–MS method for the stereoselective determination of THP in human serum. In this study, the sample was prepared by a solid-phase extraction (SPE) procedure. The enantiomer separation was done using native β-cyclodextrin stationary phase LC column. The combination of ESI–MS detection and SPE showed excellent sensitivity and selectivity of the method. The limits of detection of <0.1 ng/ml can be easily achieved, which is 7000 times lower than the detection limits achievable by a UV detection method. The method has at least a 3-order of magnitude linear dynamic range for both enantiomers (concentrations up to 1323 ng/ml were tested). This is 24 times wider than the therapeutic range of THP (peak THP plasma concentration of 55 ng/ml was previously reported). The recoveries of THP enantiomers from the human serum were >95%.

Stability of trihexyphenidyl in stored blood and urine specimens.

Trihexyphenidyl (THP) is an anticholinergic agent with forensic toxicological interest. The stability of THP was studied in postmortem blood and urine samples at a concentration of 0.25 microgram/ml under different storage temperatures. After solid phase extraction (SFE), THP was measured by gas chromatography. On day zero and at intervals over a 6 months period, there was no significant loss of THP at the storage temperatures -20 degrees C and 4 degrees C in the spiked and authentic samples. Blood and urine samples stored at 25 degrees C showed a maximum recovery loss (about 14%) of THP after 3 months of storage. This loss was considered a significant change and corresponded to a P value < 0.046. The study demonstrates that the analysis of blood and urine samples containing THP would produce consistent results when they are stored for 6 months at -20 or 4 degrees C and for 3 months at 25 degrees C.

Characteristic subcellular distribution, in brain, heart and lung, of biperiden, trihexyphenidyl, and (-)-quinuclidinyl benzylate in rats.

The subcellular distribution of biperiden (BP), trihexyphenidyl (TP) and (-)-quinuclidinyl benzylate (QNB) in brain, heart and lung following high dose (3.2 mg/kg) i.v. administration was investigated in rats. The subcellular distribution of BP or TP used clinically conformed with that of QNB, a typical potent central muscarinic antagonist. The concentration-time courses of the brain subcellular fractions for these drugs were of two types which decreased slowly and in parallel to the plasma concentration. The subcellular distribution in the brain and heart was dependent on the protein amount of each fraction. The percent post-nuclear fraction (P2) of the total concentration in the lung was characteristically about 3-5 times larger than that in the heart. It was elucidated that the distribution in the lung differs from that in the brain and heart, with high affinity which is not dependent on the protein amount in the P2 fraction containing lysosomes. On the other hand, at a low dose (650 ng/kg) of 3H-QNB, each fraction as a percentage of the total concentration in the brain increased in synaptic membrane and synaptic vesicles and decreased in nuclei and cytosol as compared with the high dose. These results show that although the tissue concentration-time courses of anticholinergic drugs appear to decrease simply in parallel to plasma concentration, the subcellular distribution exhibits a variety of patterns among various tissues.

Trihexyphenidyl (Artane) Dependence: A Controlled Investigation between Users and Abusers

This controlled study aims to identify the socioclinical factors predisposing psychiatric patients to abuse trihexyphenidyl (artane) and to document the extrapyramidal symptoms in artane abusers and users. Thirty patients (n=30), with mainly two major functional psychoses and who were abusing trihexyphenidyl, were compared with 90 artane user patients (n=90), who were matched for both the diagnosis and treatment. Besides a detailed clinical interview, each patient was assessed by using DSM-IIIR criteria, Brief Psychiatric Rating Scale, Simpson and Angus Scale, and Abnormal Involuntary Movement Scale. The analysis of data showed that, compared with users, trihexyphenidyl abusers were significantly characterized by being unmarried, unemployed, smokers and having past and concurrent history of multiple drug abuse, and genetic loading of mental disorders. Both groups of patients were prescribed antipsychotic drugs and trihexyphenidyl on a longer basis. Besides other socioclinical parameters, premorbid personalities, stressful life events and extrapyramidals, including tardive dyskinesias, we did not differentiate between the two groups. Artane abusers, when compared with users, were significantly characterized by less negative psychopathology. However, other psychopathological domains, in particular, the positive symptoms and depression, did not differentiate between abusers and users. In conclusion, patients having these socioclinical profiles tend to develop trihexyphenidyl abuse. The mental health professionals should not prescribe trihexyphenidyl indiscriminately or for a long time to such patients, who indeed require long-term antipsychotic maintenance medications.

Trihexyphenidyl withdrawal

Trihexyphenidyl withdrawal

Effects of antimuscarinic antiparkinsonian drugs on brightness discrimination performance in rats

Biperiden (BPR) and trihexyphenidyl (THP), the current antimuscarinic drugs of choice in the management of parkinsonism, have been shown to exert anticonvulsant effects induced by poisoning by the organophosphorus compound soman. The present study was undertaken to evaluate the effects of these drugs on performance of a simple light-intensity discrimination task in rats under a tandem schedule of fixed-ratio (FR) reward/ differential-reinforcement-of-low-rate (DRL) nonreward contingencies, for water reinforcement in 2-h experimental sessions. Both BPR (0.125–2.0 mg/kg, SC) and THP (0.25–8.0 mg/kg, SC) in general decreased overall reinforcement rates in a similar dose dependent and parallel manner, concurrent with increased overall nonreinforced responses in an inverted U-shaped dose-response relationship. Lower doses of BPR (0.125–0.5 mg/kg) and and THP (0.25–2.0 mg/kg) produced a moderate reduction in reinforcement (>−50% of baseline controls), which was correlated well with increases in nonreinforced responses emitted, whereas, higher doses of BPR (> 0.5 mg/kg) and TPH (>−2.0 mg/kg) markedly decreased reinforcements, which mainly resulted from the pausing of responding in the presence of stereotyped behavior. The behavioral disruption induced by BPR was much more rapid than that induced by THP. The ED 50 values (0.6 mg/kg vs. 1.3 mg/kg, respectively) and parallel dose-effect curves suggest that these drugs have similar efficacy, and that BPR is about twice as potent as THP, a ranking that corresponds with their binding affinity at M-1 muscarinic acetylcholine receptors in rat cerebral cortex. Based on the similarity between the anticonvulsant doses of these drugs and the maximal doses that in this study did not disrupt operant responses (0.125 mg/kg vs. 0.25 mg/kg, respectively), it is suggested that both drugs may be useful in protection against seizures produced by the cholinesterase inhibitor soman. Overall, these results suggest that this multiple schedule operant contingency may have promise as a behavioral model to identify the therapeutic or toxic potentials of centrally acting antimuscarinic antiparkinsonian drugs based on their congnitive side effects.

Effects of anticholinergic-antiparkinsonian drugs on striatal neurotransmitter levels of rats intoxicated with soman

Antimuscarinic drugs possessing antiparkinson activity that were effective in preventing convulsions induced by the organophosphorus cholinesterase (ChE) inhibitor soman were studied for their effects on spinal cord ChE activity and striatal levels of acetylcholine (ACh) and catecholamines in soman-intoxicated rats. Either biperiden (BPR) or trihexyphenidyl (THP) was administered to rats at an anticonvulsant dose (0.125 mg/kg, IM) in the presence or absence of soman (100 μg/kg, SC). The time course (up to 2 h) for ChE activity and levels of ACh and catecholamines were measured after soman, BPR, THP, soman and BPR, or soman and THP treatment. Soman rapidly inhibited ChE activity (65–75%; 15–120 min) and increased ACh levels (35%; at 30 min). It did not affect norepinephrine or dopamine (DA), but elevated at later time points (60–120 min) levels of the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), thus indicating increased DA turnover. BPR and THP alone reduced striatal ACh level from control, but did not affect any other neurochemical parameters studied. THP and BPR each reversed the effects of soman on DOPAC and HVA levels, but neither affected ChE activity nor ACh level induced by soman. Thus, our findings suggest that the anticonvulsant effects of BPR and THP in soman poisoning may be attributed to their earlier reported muscarinic receptor blocking properties.

Memory and Cognitive Impairments in a Case of Long-Term Trihexyphenidyl Abuse

We present a case of long-term trihexyphenidyl (THP) abuse in which memory and cognitive impairments were observed 23 years after the commencement of medication. This case showed a dramatic improvement after withdrawal of THP. Clinical course during admission was followed with psychometric testing and laboratory examinations. The fact that the patient showed no evidence of lowered alertness during the clinical course raises the possibility that THP can primarily induce impairment of memory and cognitive functions. This is supported by the findings on the resting EEG of the patient. This case emphasizes the need to exercise caution in prescribing high doses of anticholinergic agents for long periods, particularly in elderly patients with underlying brain pathology.

A spin label study of the membrane effect of various psychoactive drugs in human erythrocytes

The effect of psychoactive agents with different clinical actions: three sedative neuroleptics (trifluoperazine, alimemazine tartrate, chlorpromazine), an anticholinergic agent (trihexyphenidyl hydrochloride), two tricyclic antidepressants (imipramine, desipramine) and lithium carbonate on the rotational correlation frequency (V +) of the spin label 16NS has been comparatively investigated in whole human erythrocytes. V + was about 40% increased by the three neuroleptics, the anticholinergic agent and the antidepressant molecules at 0.2mM. By contrast, lithium did not induce any significant change in V + at the same concentrations. It can be suggested that the increase in “membrane fluidity”, observed with a wide variety of drugs, is a non specific effect, unrelated to the psychotropic action, that can be ascribed to the amphiphilic properties of the tested drugs.

Neuroendocrine response to trihexyphenidyl in depressed patients.

The effect of a single dose (10 mg P.O.) of trihexyphenidyl (THP) on plasma cortisol, growth hormone (GH), and immunoreactive beta-endorphin (ir-beta-EP) was studied in seven major depressed patients and seven controls. GH secretion was suppressed (34-41%) by THP in both groups. THP did not affect cortisol secretion in depressed patients and controls. An increase (18%; p less than 0.05) in plasma ir-beta-EP levels was detected in the healthy subjects only. The results of this study do not support the hypothesized altered responsiveness to anticholinergic provocation in major depression. The inhibitory activity of THP on GH secretion indicates the involvement of the cholinergic system in the regulation of GH release in humans.

Anticholinergics: Effects on thermoregulation and performance in rats

Atropine (AT) induces a dose-dependent increase in rate of rise of core temperature (heating rate) in sedentary heat-stressed rats, a muscarinic anticholinergic (MA) effect which is quantitatively similar to the increase in heating rate seen in heat-exposed men after equivalent atropine dose. In the heat-stressed rat, scopolamine (S) was found to have 16 x the MA effect of AT and, in the present study, aprophen (AP) and trihexyphenidyl (THP) manifested 0.067 x 0.061 x the MA effect of AT. In rats exercising on a treadmill (11 m/min, 6 degrees incline, 26 degrees C), physostigmine (PH) administration resulted in reduced endurance and increased heating rate, both of which were attenuated following AT administration-hypothesized to be a nicotinic anticholinergic (NA) effect. Optimum doses of anticholinergics to reverse the PH-induced decrements were: AT-200 micrograms/kg, S-8-16 micrograms/kg, AP-3000 micrograms/kg, and THP-800 micrograms/kg. These optimum NA doses for AT, S, and AP were the same as those predicted from their MA potency relative to AT in heat-stressed rats. However, it should be noted that 800 micrograms/kg of THP is only 1/4 of the expected 3200 micrograms/kg dose of THP based on MA equivalence to AT. Relative MA activities and optimum doses in PH-treated exercising rats appear to be due to differential MA and NA activities. Thus, a combination of both sedentary heat-stressed and exercising rat models may be useful in predicting relative cholinergic effects of new drugs with both MA and NA effects in man.

Refractory variant angina relieved by denopamine. A case report.

A 48-year-old man with severe variant angina refractory to conventional treatment with calcium antagonists and nitrates, or prazosin, or trihexyphenidyl hydrochloride, became symptom free rapidly when treated with denopamine, a adrenergic beta-1 agonist. Denopamine may prove to be an additional therapeutic agent in the management of severe variant angina. Therefore the response to denopamine and the lack of response to prazosin in this patient suggests that not only the adrenergic alpha receptor but also the adrenergic beta-1 receptor plays an important role in the production of coronary spasm, at least in some patients.

Long-term behavioral and learning abnormalities produced by the irreversible cholinesterase inhibitor soman: Effect of a standard pretreatment regimen and clonidine

Previous studies in this laboratory have demonstrated that the α 2-adrenergic agonist clonidine and related drugs can offer significant protection against both the acute and chronic toxicity to soman administration in rats and mice. The purpose of this study was to determine whether addition of clonidine to a standard pretreatment protective regimen against soman toxicity could offer added protection or benefit. The standard regimen employed was a mixture of physostigmine salicylate (150 μg/kg) and artane (trihexyphenidyl hydrochloride 2 mg kg ). Rats were randomly assigned to one of 4 experimental groups: (1) those receiving i.m. sterile saline injection followed 30 min later by s.c. saline injection (normal controls); (2) saline i.m. followed 30 min later by one of several doses (60–110 μg/kg) of soman s.c.; (3) saline i.m., followed 10 min later by the standard pretreatment regimen i.m., followed by one of several doses of soman (160–300 μg/kg), s.c.; and (4) clonidine hydrochloride (1 mg kg ) i.m., followed 10 min later by the pretreatment regimen, followed 30 min later by soman. All animals were examined acutely and survivors were examined over a 3-week period following soman administration. The following observations were made: (1) Addition of clonidine to the standard pretreatment regimen did not enhance survival rate over the standard regimen alone (unless the clonidine was administered after the regimen). (2) Of the acutely toxic behavioral signs promoted by soman, clonidine addition to the standard regimen was of benefit only in reducing soman-induced tremor. (3) Addition of clonidine to the standard regimen appeared to hasten the return to normal motor behavior after soman; however, all groups exhibited normal motor behavior in 9 days. (4) Despite apparent normal motor behavior, soman-treated animals exhibited a marked per formance deficit in the passive avoidance parameter 3 weeks after injection. The standard regimen partially preserved this effect; addition of clonidine to the standard regimen completely reversed the effect. These results indicate that clonidine provides a measure of protection against chronic behavioral deficits caused by soman intoxication.

Trihexyphenidyl withdrawal

Trihexyphenidyl withdrawal

Acetylcholinesterase Inhibition by (+)Physostigmine and Efficacy against Lethality Induced by Soman

The optical isomer (+)Physostigmine [(+)Phy] is a very weak anticholinesterase. In a recent report, pretreatment with (+)Phy, at a dose which failed to inhibit acetylcholinesterase (AChE), and atropine provided efficacy against a lethal dose of sarin (SYNAPSE:2, 139, 1988). It was of interest to see whether (+)Phy could protect against soman at a dose which caused only marginal inhibition of the whole blood (WB) AChE in guinea pigs (GPs). (-)Phy (0.15 mg/kg, im) and (+)Phy (10.0 mg/kg, im) produced nearly 70% inhibition of WB AChE at 30 min whereas (+)Phy (0.15 mg/kg, im) caused only marginal inhibition. Groups of guinea pigs (20/group) were dosed, im, with (-)Phy (0.15 mg/kg), (+)Phy (0.15 mg/kg), (+)Phy (10.0 mg/kg) or vehicle (0.5 ml/kg) respectively in one thigh while the mild anticholinergic trihexyphenidyl (THP), 2.0 mg/kg, was injected into the other thigh of 10 animals from each of the respective groups. Thirty min after pretreatment, all animals were challenged with soman (60 micrograms/kg, sc; 2 LD50s); this dose of soman is lethal in unprotected animals. (-)Phy or (+)Phy (10 mg/kg) alone protected nearly 50% from soman lethality, and in combination with THP, all animals survived. In contrast, (+)Phy (0.15 mg/kg; alone or together with THP) was completely ineffective against a 2 LD50 challenge of soman. These data support the hypothesis that protection against soman-induced lethality is related to the degree of carbamylation of the AChE just prior to challenge.

Effects of Anticholinergic Agents on Patients with Tardive Dyskinesia and Concomitant Drug-Induced Parkinsonism

Twenty-five percent of 80 consecutive patients who met research criteria for persistent tardive dyskinesia (TD) were found to have an energy peak in the parkinsonian tremor band (3-6 Hz) of the frequency spectrum of their machine-measured resting hand movements in addition to the abnormalities consistent with TD (increased energy in the 0.5-3 Hz frequency spectrum). Twelve of these patients were studied again in double-blind fashion 2 hours after receiving a placebo and again 2 hours after a single 4 mg dose of trihexyphenidyl hydrochloride (HCl). Compared with the placebo condition, the trihexyphenidyl HCl markedly diminished the measured energy in the 4 Hz band and had no effect or slightly decreased the energy at all other points on the frequency spectrum. Simultaneous Abnormal Involuntary Movement Scale ratings revealed no change in the dyskinetic movements between the conditions; there was a significant subjective improvement reported by the patients following the trihexyphenidyl HCl administration. These observations indicate that electromechanical devices identify a subpopulation of TD patients who may acutely benefit from anticholinergic treatment.

ChemInform Abstract: Syntheses of (S)‐(+)‐Trihexyphenidyl Hydrochloride and (S)‐(+)‐Procyclidine Hydrochloride, Two Anticholinergics, Using (S)‐(‐)‐3‐Cyclohexyl‐3‐hydroxy‐3‐phenylpropanoic Acid as Chiral Synthon.

AbstractThe (S)‐configuration of trihexyphenidyl hydrochloride (+)‐(Va) is established by chemical correlation with the known procyclidine hydrochloride (S)‐(Vb).