Blood pressure control among patients with hypertension and newly diagnosed diabetes.

AIMS: To determine the proportion of patients who achieved blood pressure control during the 2 years following new diabetes diagnosis. METHODS: A retrospective cohort of veterans ≥ 18 years with hypertension who initiated a diabetes medication from 2000 to 2007 in the Veterans Administration Mid-South Network was assembled. Blood pressure control at diabetes treatment initiation (baseline) was compared with blood pressure control 6, 12, 18 and 24 months later. The Veterans Affairs and American Diabetes Association definitions of control, ≤ 140/90 and ≤ 130/80 mmHg, respectively, were primary and secondary outcomes. RESULTS: At baseline, 59.5% of 16,182 patients had controlled blood pressure according to the Veterans Affairs guideline (31.5% using American Diabetes Association definition). Six months following initiation of diabetes treatment, 65.7% had their blood pressure controlled (P < 0.001). Blood pressure control was sustained but not further improved between 6 months and 2 years, with 66.5% controlled at 2 years following baseline. Higher initial systolic blood pressure, black race and hospitalization in the previous year were associated with higher likelihood of uncontrolled blood pressure at 6 months; whereas baseline cardiovascular disease, baseline dementia and later year of cohort entry were associated with lower likelihood of uncontrolled blood pressure. CONCLUSION: We found an increase in blood pressure control in the 6 months following initiation of diabetes treatment. However, overall blood pressure control remained suboptimal and with no further improvement over the next 18 months.

Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam.

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 2 1/2 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.

Quantitation of the enantiomers of rimantadine and its hydroxylated metabolites in human plasma by gas chromatography/mass spectrometry.

A gas chromatographic/mass spectrometric procedure has been developed for the quantitation in human plasma of the enantiomers of rimantadine and its three hydroxylated metabolites. The assay utilized derivatization of all analytes with the optically active reagent S-alpha-methyl-alpha-methoxy(pentafluorophenyl)acetic acid, selective ion monitoring, methane negative ion chemical ionization mass spectrometry and stable isotope dilution techniques. This method has been used to measure 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.

Determination of rimantadine and its hydroxylated metabolites in human plasma and urine.

A gas chromatographic-mass spectrometric procedure has been developed for the quantitation of the antiviral agent rimantadine and its meta- and para-hydroxylated metabolites in human plasma and urine. The assay utilizes an extractive pentafluorobenzoylation at alkaline pH with cyclohexane saturated with triethanolamine-chloroform (2:1) containing pentafluorobenzoyl chloride, selective ion monitoring, methane negative ion chemical ionization mass spectrometry and stable isotope dilution. The method has been used to measure plasma concentrations of rimantadine, m-hydroxyrimantadine and the two epimers of p-hydroxyrimantadine between 5-250, 5-100 and 2.5-50 ng/ml, respectively. Similarly, the urine concentrations of these analytes measured were between 25-1250, 25-500 and 12.5-250 ng/ml, respectively.

Quantitative determination of naltiazem in human plasma by gas chromatography/mass spectrometry.

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.

Quantitation of the benzodiazepine antagonist flumazenil in human plasma by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric procedure has been developed for the quantitation of the benzodiazepine antagonist flumazenil in human plasma. The assay utilizes an extraction at alkaline pH with benzene-dichloroethane (80:20), selective ion monitoring, isobutane positive-ion chemical ionization mass spectrometry and stable isotope dilution. The method has been used to measure plasma concentrations of flumazenil in over 1500 clinical samples over a range of 0.5-200 ng/ml (using 2 ml of plasma).

Effect of cimetidine on the disposition of rimantadine in healthy subjects.

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.

Quantitation of the enantiomers of rimantadine in human plasma and urine by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric procedure has been developed for the quantitation in plasma and urine of the enantiomers of rimantadine, an antiviral drug effective against type A influenza. The assay utilizes derivatization with an optically active reagent, selective ion monitoring, methane negative-ion chemical ionization (NICI) mass spectrometry and stable isotope dilution. The method has been used to measure concentrations of each rimantadine enantiomer over a range of 2.5-250 and 12.5-1250 ng/ml in the plasma and urine, respectively, of four male volunteers administered rimantadine. In plasma and urine, no differences were observed in the disposition of the unconjugated enantiomers. In urine, one enantiomer, but not both, was released following enzymatic hydrolysis.

Relative bioavailability of rimantadine HCl tablet and syrup formulations in healthy subjects.

Twenty healthy male subjects completed an open-label randomized crossover design to assess the bioavailability of 100 mg of rimantadine HCl in tablet and syrup forms relative to an oral solution. Blood samples were drawn and rimantadine plasma concentrations were determined by a GC-MS method. The maximum plasma concentration (Cmax), the time to Cmax (tmax), the area under the plasma concentration-time curve (AUC), and k were compared among treatments using an analysis of variance and the Hauck-Anderson test for bioequivalence. The Hauck-Anderson test was satisfied when the syrup and solution were compared. The relative bioavailability of the syrup was 96%. Both Cmax and AUC were significantly (p less than 0.05) increased (23 and 17%, respectively) when the tablet was compared with the solution. The relative bioavailability of the tablet was 117%. This outcome was unusual and could not be explained. However, this was not anticipated to be of clinical consequence since the majority of the safety and efficacy of rimantadine HCl was established using a tablet.

Gorham's syndrome: a case report and review of the literature.

Gorham's syndrome is a rare disorder involving a proliferation of vascular channels associated with extensive loss of bony matrix. A case report is presented with a review of the 97 previously reported cases. The age of patients at presentation has ranged from less than one to 75 years (mean: 27 years). Sixty-four percent have been men. Fifty-seven percent have had a history of prior trauma. Laboratory values for systemic measures have usually been normal. The disease usually arrests spontaneously, but this is unpredictable. Sixteen patients (16 percent) have died of the disorder, with 10 deaths due to chest wall involvement, three to spinal cord transection, two to sepsis, and one to asphyxia and aspiration. Although the mechanism of bone loss is unknown, osteoclasts were focally increased in the case described herein. Further information and investigation are needed to better understand this unusual disorder.

Quantitative determination of rimantadine in human plasma and urine by GC-MS.

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.

Rimantadine pharmacokinetics after single and multiple doses.

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.