[Effect of biotransformation on the receptor selectivity of muscarinic antagonists in vivo]. / Vliianie protsessov biotransformatsii na retseptornuiu izbiratel'nost' muskarinovykh antagonistov v usloviiakh tselostnogo organizma.

In the experiments in vivo it is found that the receptor selectivity of muscarine antagonist glypine is time-dependent unlike atropine, amedine, benzhexol, benactyzine, and thropacin. Using modulation of the metabolic system activity it is shown that upon biotransformation glypine forms active metabolites that differs in receptor selectivity of the action.

Carriers for skin delivery of trihexyphenidyl HCl: ethosomes vs. liposomes.

The purpose of this work was to characterize a novel ethosomal carrier containing trihexyphenidyl HCl (THP) and to investigate the delivery of THP from ethosomes versus classic liposomes. THP-ethosomal systems were shown by electron microscopy to contain small, phospholipid vesicles. As the THP concentration was increased from 0 to 3%, the size of the vesicles decreased from 154 to 90 nm. This is most likely due to the surface activity of THP (critical micelle concentration of 5.9 mg/ml), as measured in this work. In addition, the ethosome zeta potential value increased as a function of THP concentration, from -4.5 to +10.4 when the THP concentration was increased from 0 to 3%. In contrast, THP liposomes were much larger and their charge was not affected by THP. When compared with standard liposomes, ethosomes had a higher entrapment capacity and a greater ability to deliver entrapped fluorescent probe to the deeper layers of skin. The flux of THP through nude mouse skin from THP ethosomes (0.21 mg/cm2 h) was 87, 51 and 4.5 times higher than from liposomes, phosphate buffer and hydroethanolic solution, respectively (p < 0.01). The quantity of THP remaining in the skin at the end of the 18-h experiment was statistically significantly greater from the ethosomal system than from liposomes or a control hydroethanolic solution. Our results indicate that the ethosomal THP system may be a promising candidate for transdermal delivery of THP.

Influence of ammonium chloride on the tissue distribution of anticholinergic drugs in rats.

Ammonium chloride (NH4Cl) increases lysosomal pH and thereby abolishes intralysosomal accumulation of drugs. Its effect on the tissue distribution of biperiden and trihexyphenidyl in rats has been investigated. The tissue-plasma concentration ratios (Kp) of these drugs in various tissues were determined by infusion studies at steady-state in the presence or absence of NH4Cl. Treatment with NH4Cl reduced the Kp values for both drugs, causing the largest reduction in Kp in the lung (52.1 to 11.8 for biperiden and 59.5 to 18.9 for trihexyphenidyl; ratios of decrease 0.77 and 0.68, respectively), followed by the heart and kidneys, with relatively small reductions in the brain, gut, muscle and fat. Subcellular fractionation studies in the lung indicated that the subcellular fraction-plasma concentration ratio of each drug at the steady state (K(p,sf)) was reduced by treatment with NH4Cl, with the largest decrease in the post-nuclear fraction (ratio of decrease 0.82 for biperiden and 0.74 for trihexyphenidyl), followed by the nucleus, microsomes and supernatant, in that order. A strong correlation was found between the ratio of decrease in K(p,sf) after NH4Cl treatment and the specific activity of acid phosphatases, a marker of lysosomes, in each fraction (biperiden, r = 0.948; trihexyphenidyl, r = 0.945). These results suggest that acidic organelles contribute significantly to the distribution kinetics of anticholinergic drugs.

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.

Development and application of a specific and sensitive radioimmunoassay for trihexyphenidyl to a pharmacokinetic study in humans.

A radioimmunoassay (RIA) for trihexyphenidyl was developed through the use of a bovine thyroglobulin conjugate of trihexyphenidyl hemisuccinate. Immunization of New Zealand white rabbits with this drug-protein conjugate yielded antisera, for which the antibody titer and specificity were evaluated. An antiserum that had the highest titer and minimal cross-reactivities to major metabolites of trihexyphenidyl, such as trihexyphenidyl N-oxide (2%), hydroxytrihexyphenidyl (1%), and the antipsychotic drugs fluphenazine (< 1%), flupenthixol (< 1%), chlorpromazine (< 1%), and haloperidol (< 1%), was selected for development of a RIA. The described RIA enables the quantitation of 7.8 pg of trihexyphenidyl in 200 microL of human plasma with a mean coefficient of variation of < 6% across the range of the standard curve. Assay specificity was further demonstrated by comparison of results obtained directly and after selective extraction of trihexyphenidyl from replicate samples. This RIA procedure was applied to the analysis of steady state plasma samples obtained from patients undergoing treatment with trihexyphenidyl (2-8 mg) and plasma samples obtained from eight healthy male volunteers after administration of a single 4 mg oral dose of the drug. The results of the latter single dose studies demonstrated that the mean +/- SD for the peak concentration (Cmax), the time to Cmax (Tmax), the rate of absorption (Ka), and the area under the curve from 0 to 72 h (AUC0-72) were found to be 7.15 +/- 2.58 ng/mL, 1.32 +/- 0.58 h, 2.07 +/- 0.93 1/h, and 201 +/- 71 ng h/mL, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Death due to benzhexol toxicity.

A rare case of death due to benzhexol toxicity is reported in a 48-year-old schizophrenic male with a resolving empyema and underlying patchy, mild bronchopneumonia. Toxicological analysis revealed the benzhexol blood and liver concentrations to be 0.12 mg/l and 0.5 mg/kg, respectively. Gastric contents contained 0.4 mg of benzhexol. Other drugs were not detected. It is suggested that for fatalities to occur following benzhexol intoxication, secondary contributory factors, which probably further alter the patient's conscious state, are necessary.

Quantitation of trihexyphenidyl from plasma using a mass-selective detector and electron-impact ionization.

A method is described for the measurement of plasma concentrations of trihexyphenidyl, an anti-parkinsonian drug. The drug was extracted from human plasma samples. Then, gas chromatography-mass spectrometry with electron-impact ionization and selected-ion monitoring allowed the specific quantitation of trihexyphenidyl, with bupivacaine used as an internal standard. Linear calibration curves were obtained in the concentration range 5-100 ng/ml. Precision and accuracy were found acceptable for quantitation during pharmacokinetic trials of the drug. This method has been successfully applied to bioavailability studies after Parkinane and Artane administration to humans.

Capillary gas chromatography of trihexyphenidyl, procyclidine and cycrimine in biological fluids.

A sensitive (50-100 pg/ml) method is described for the analysis of the anticholinergic drugs cycrimine, procyclidine and trihexyphenidyl by capillary gas chromatography with flame thermionic detection. Since these anticholinergic drugs are frequently administered in combination with antipsychotic medication for the treatment of mental illness, the potential interference by antipsychotic drugs in this assay was examined. No interference was observed from a series of antipsychotic drugs in the quantitation of cycrimine, procyclidine or trihexyphenidyl. The use of this technique to study trihexyphenidyl pharmacokinetics in man is described.

Pharmacokinetic evaluation of a sustained-release formulation of trihexyphenidyl in healthy volunteers.

Twenty-four male subjects were randomized to receive two oral dosage forms of trihexyphenidyl HCl (alpha-cyclohexyl-alpha-phenyl-1-piperidinepropanol HCl). The dosage regimens were (1) a 5-mg immediate release (IR) tablet given twice daily at time zero and 12 h later, and (2) two 5-mg sustained-release (SR) capsule formulations given daily. The number of adverse experiences following the SR formulation were approximately 50% of those for the IR formulation, the peak concentration (Cmax) after the SR formulation was significantly lower (p less than 0.05) than that after the first dose of the IR formulation, and the time to reach Cmax (tmax) was significantly longer after the SR formulation (p less than 0.05). The SR formulation maintained serum concentrations above 50, 60, and 70% of Cmax values for average time periods of 11.7, 9.4, and 5.9 h, respectively, compared with values of 1.8, 1.2, and 0.9 h after the IR formulation; the differences were all significant (p less than 0.05). The mean elimination half-life (t1/2) was similar (p greater than 0.05) after the SR (10.1 h) and IR (8.7 h) formulations. The statistical power of the study was 98.1% to detect a 20% difference in the area under the curve from time zero to time infinity (AUC0----infinity) between formulations. Although the AUC0----infinity after the SR formulation was statistically smaller (p less than 0.05) than after the IR tablet, the difference was less than 20%. Therefore, the SR formulation was bioequivalent to the IR tablet formulation of trihexyphenidyl.