A GC-MS procedure has been developed for the quantitation in plasma and urine of rimantadine, an antiviral drug effective against type A influenza. The assay utilizes selective ion monitoring, methane negative ion chemical ionization (NCI) and stable isotope dilution. Sensitivity to NCI is effected by derivation of rimantadine with pentafluorobenzoyl chloride. The method has been used to quantitate plasma concentrations of rimantadine over a range from 4.2 ng/ml to 416 ng/ml, and urinary concentrations of rimantadine over a range of 21 ng/ml to 2077 ng/ml.
Abstract A gas chromatographic/mass spectrometric procedure has been developed for the quantiation in human plasma of the enatiomers of rimanatadine and its three hydroxylated metabolites. The assay utilized derivatization of all analytes with the optically active reagent S‐α‐methyl‐α‐methoxy(pentafluorpheyl)acetic acid, selective ion monitoring, methane negative ion chemical ionization mass spectrometry and stable isotope dilution techniques. This method has been used to meausure plasma concentrations of the enantiomers of rimantadine, m ‐hydroxyrimantadine and p ‐hydroxyrimantadine (equatorial and axial epimers) in the ranges 2.5‐250, 2.5‐50, 1.25–62.5 and 1.25–62.5 ng/mL, respectively, in six subjects given a single 200 mg dose of racemic rimantadine. Although there are no significant differences in the concentration‐time profiles of R ‐ and S ‐rimantadine, large stereospecific differences in the disposition of their metabolites are observed.
The pharmacokinetics and pharmacodynamics of midazolam and diazepam were compared after intravenous infusions of 0.03 and 0.07 mg/kg midazolam and 0.1 and 0.2 mg/kg diazepam on four separate occasions in 12 healthy male subjects in a randomized four-way crossover design. The Digit Symbol Substitution Test (DSST) was used as a measure of drug effect. Subjects performed three practice tests before dosing to account for any effects caused by familiarization (“learning curve”) with the testing procedure. Pharmacokinetic and pharmacodynamic data were simultaneously fitted to a semiparametric model. In this model, a pharmacokinetic model related dose to plasma concentrations, a link model related plasma concentrations to the concentration at the effect site, and a pharmacodynamic model related the effect site concentration to the observed effect. The plasma—effect site equilibrium half-life was approximately 2½ times longer for midazolam than for diazepam, which is in good agreement with previously published data. Based on the estimated effect site concentration at which half of the maximal effect was reached, midazolam had approximately a sixfold greater intrinsic potency than diazepam. This difference in potency was also observed in a previous study that used transformed electroencephalographic (EEG) data to assess pharmacodynamic activity. The findings reported here with a clinically relevant pharmacodynamic marker (DSST) confirm the utility of surrogate drug effect measures such as EEG. This work also shows the feasibility of conducting pharmacokinetic pharmacodynamic analysis during the drug development process. Clinical Pharmacology & Therapeutics (1995) 58, 35–43; doi: 10.1016/0009-9236(95)90070-5
Abstract Background Experiencing behavioural symptoms such as aggression, agitation and psychosis contribute significantly to reduced quality of life amongst people with dementia. These behavioral symptoms can be considered more detrimental to overall well‐being than cognitive impairment. In the UK, risperidone is the sole approved atypical antipsychotic for treating these symptoms, despite its notable risk of serious side effects, including stroke. This project aims to develop personalized stroke risk prediction models based on individual clinical features upon introducing risperidone. Methods This research will use data from 358,406 patient records contained in the Clinical Practice Research Datalink (CPRD). These data sets include individuals diagnosed with dementia after age 65 after January 1, 1990. The CPRD data will serve as the primary source of information for our study and will facilitate the analysis of stroke risk associated with risperidone use in this specific patient population. Our analysis will focus on two distinct groups, individuals diagnosed with dementia who have been prescribed risperidone and individuals diagnosed with dementia who have never been prescribed risperidone. To achieve our research objectives, we will analyze and compare the incidence of stroke within these two groups. We will then examine whether risk is moderated by individual clinical history. This thorough investigation will form the basis for our predictive models. Results Preliminary findings from the data show a well‐defined cohort of dementia cases with an average age of 82 years at diagnosis, consisting predominantly of females (64%). Of the cohort, 87,858 individuals fall into the 75‐84 age category. Over the study period, 47.0% of the cohort died during the study period. The median survival time is approximately 4.4 years for males and 3.7 years for females in the study cohort. This median survival time increases to 6.8 years for people diagnosed at the age of 65‐74 years. Conclusions This project’s success could significantly enhance the safety and efficacy of risperidone prescriptions for people with dementia. By leveraging personalized prediction models based on individual clinical features, our research aims to equip clinicians with tools for more informed and patient‐specific decisions concerning risperidone treatment.
Twenty-three healthy male and female subjects received single 100-mg oral doses of rimantadine hydrochloride on two occasions in an open-label, sequential design with a 6-day washout between doses. The first dose of rimantadine was administered alone, and the second dose was administered concomitantly with cimetidine (300 mg four times a day for 6 days). Blood and urine samples were collected, and rimantadine concentrations were determined by a gas-chromatographic--mass-spectrometric method. There were no changes in the rate of absorption and the renal clearance of rimantadine when it was administered with cimetidine. Both parametric and nonparametric tests showed significant differences in the area under the concentration-time curve, apparent total clearance, and elimination rate constant between the treatments (P less than 0.01). The apparent total clearance was reduced by 18%, resulting in higher values for the area under the concentration-time curve in the presence of cimetidine. However, the wide therapeutic index of rimantadine renders these changes of little, if any, clinical consequence.
Twenty-four healthy adult male volunteers were randomly assigned to one of two rimantadine regimens. The 12 volunteers assigned to regimen 1 orally received a single 100-mg rimantadine tablet followed 5 days later by 100 mg of rimantadine twice a day for 10 days. Volunteers assigned to regimen 2 ingested a single 100-mg rimantadine tablet followed 5 days later by 100 mg once a day for 10 days. The results of the study suggest that the pharmacokinetics of rimantadine are linear and accumulation of the drug during repetitive multiple doses is predictable.
A gas chromatographic/mass spectrometric procedure has been developed for the quantification of a diltiazem analog, naltiazem, in human plasma. The assay utilizes an extraction at neutral pH with hexane:ethylene dichloride:methyl-t-butyl ether (70:20:10), selective ion monitoring, methane or ammonia positive chemical ionization mass spectrometry and stable isotope dilution. The method has been used to analyze plasma concentrations of naltiazem in clinical samples over a range of 2–200 ng ml−1, using 1 ml of plasma.
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