Intrathecal 6-mercaptopurine: preclinical pharmacology, phase I/II trial, and pharmacokinetic study.

For over 30 years, oral 6-mercaptopurine (6-MP) has been a mainstay of systemic maintenance therapy for acute lymphoblastic leukemia. Despite its efficacy as an antileukemic agent, 6-MP has not been previously administered by the intrathecal (IT) route. In anticipation of a clinical trial of IT 6-MP, preclinical cytotoxicity and pharmacology studies were performed to define a safe, effective dose. The optimal concentration (greater than 1 microM) and duration of exposure (greater than 12 h) to 6-MP required for cytotoxicity were determined in vitro using human leukemia cell lines. The dose required to achieve the desired cerebrospinal fluid concentrations in humans was derived from pharmacokinetic parameters determined in rhesus monkeys. A phase I/II study was then performed in pediatric patients with refractory meningeal leukemia. Nine patients (aged 3.5 to 16 years) with chronic meningeal leukemia (2 to 6 central nervous system relapses) were entered onto the study. All had previously failed, at a minimum, IT methotrexate, IT cytarabine, and cranial (+/- spinal) radiation. A 10-mg IT dose of 6-MP (calculated to produce cytotoxic cerebrospinal fluid levels for 12 h) was administered twice weekly for 4 weeks. There were four complete responses and three partial responses. The duration of complete responses ranged from 7 to 22 weeks. Observed toxicities were not dose limiting and included mild headache (three patients) and minimal nausea (two patients). Pharmacokinetic studies performed in patients confirmed that cerebrospinal fluid concentrations of 6-MP were greater than 1 microM for 12 h. These results indicate that the IT administration of 6-MP is feasible, is not associated with significant toxicity, and has definite activity in patients with refractory meningeal leukemia.

Clinical and biochemical effects of verapamil administration to schizophrenic patients.

We administered verapamil hydrochloride, a calcium channel antagonist, to seven chronically ill schizophrenic patients for five weeks under double-blind, placebo-controlled conditions. No therapeutic effect was noted. Worsening in hostile and uncooperative behaviors and a syndrome of heightened emotional tone was observed during verapamil treatment and during the postverapamil placebo period. Verapamil produced significant increases in cerebrospinal fluid (CSF) and plasma levels of homovanillic acid and in plasma levels of prolactin, as well as significant decreases in plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol. Verapamil and its active metabolite, norverapamil, were partitioned into CSF with CSF/plasma ratios of 0.06 and 0.04, respectively. The lack of therapeutic effects of verapamil in schizophrenic patients differs from earlier reports of its usefulness in treating manic patients. The biochemical and clinical data from our study suggest the possibility that verapamil exerts behaviorally relevant central nervous system activity in schizophrenic patients.

Steady-state cerebrospinal fluid transfer of verapamil and metabolites in patients with schizophrenia.

Cerebrospinal fluid (CSF) and plasma levels of verapamil and its two metabolites, norverapamil and D-620, were measured in seven patients with schizophrenia under steady-state conditions. Simultaneous sampling of CSF and plasma just before the dose during week 4 of the trial showed that verapamil, norverapamil, and D-620 partition in the CSF and reflect 7%, 5%, and 12% of the corresponding levels in plasma, respectively. There was a significant decrease in the mean unbound fraction of verapamil in schizophrenic patients as compared with normal subjects (0.058 vs. 0.11; p less than 0.001). Estimates of the mean unbound fraction obtained from CSF/plasma verapamil concentrations and the pH partition hypothesis showed excellent agreement with that measured by equilibrium dialysis (0.055 vs. 0.058) in these patients. Although systemic pool protein concentrations in schizophrenic patients were within normal range, an excellent positive correlation was observed between the ratio of the bound/free verapamil concentration and alpha 1-acid glycoprotein levels (r = 0.86; p less than 0.05). Determination and development of correlations between plasma and CSF may enhance our understanding of the central nervous system effects of verapamil.

Rifabutin absorption in humans: relative bioavailability and food effect.

The relative bioavailability of the capsule dose form (150 mg) and the effect of high-fat food were assessed in a randomized, three-way crossover trial of rifabutin in 12 healthy male volunteers. Each subject received a single 150 mg dose as a solution (treatment A, fasted) or a capsule with food (treatment B) and without food (treatment C), with a 2-week washout period. Serial plasma and urine samples were obtained for 168 and 48 hours, respectively, and rifabutin and its active metabolite, 25-O-deacetyl-rifabutin, quantitated by a validated HPLC procedure. The mean +/- SD maximum concentration for rifabutin in plasma was 238 +/- 65, 156 +/- 52, and 188 +/- 50 ng/ml, time to reach peak concentration was 2.5 +/- 0.4, 5.4 +/- 1.6, and 3.0 +/- 1.1 hours, and the area under the plasma concentration-time curve from zero to infinity [AUC(0-infinity)] was 2989 +/- 726, 2640 +/- 891, and 2516 +/- 601 ng.hr/ml for the solution and the capsule during the fed and fasted states, respectively. Percentage of dose excreted in the urine as unchanged rifabutin was 11.0% +/- 2.4%, 11.4% +/- 4.9%, and 9.1% +/- 2.1% for treatments A, B, and C, respectively. The corresponding AUC(0-infinity) values for the equiactive metabolite 25-O-deacetyl-rifabutin, were 400 +/- 184, 361 +/- 187, and 298 +/- 102 ng.hr/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Vancomycin disposition: the importance of age.

We examined the influence of age on vancomycin kinetics in 12 normal healthy men (six young and six elderly) after an intravenous infusion of 6 mg/kg. Serial blood and urine samples were collected for up to 2 days after dosing and were assayed for unchanged drug by a specific radioimmunoassay. Serum concentrations of vancomycin after infusion declined in a multiphasic manner. Both serum and urinary excretion data were simultaneously fit by a three-compartment model with SAAM-27 computer programs. Estimates of mean t1/2 obtained from the terminal phase of the drug disposition profile showed the t1/2 to be longer in the elderly than in the young subjects (12.1 and 7.2 hr). Although there was no change in the initial distribution volume of the central compartment, total systemic and renal clearances were reduced in the elderly and did not correlate with renal function. The increase in the vancomycin volume of distribution at steady state was ascribed to enhanced tissue binding of drug in the elderly, since the mean fraction of vancomycin bound in systemic pool of the young and elderly did not differ (0.53 and 0.56). In-depth analysis of excretion data tends to support suggestions of vancomycin excretion solely by glomerular filtration. Our data strongly suggest the need for adjustment or modification of recommended vancomycin dosing schedules in the elderly.

Lidocaine and its active metabolites.

It has been shown that the antiarrhythmic and toxic effects of lidocaine may be in part dependent on its two active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX). Presently available gas liquid chromatographic analytic methods require long and tedious steps or sophisticated equipment such as gas liquid chromatography-mass spectrometry. The assay method reported here with the use of high-performance liquid chromatography is rapid and allows accurate, precise determination of lidocaine, MEGX, and GX in biologic fluids. On the 3 patients studied extensively with the use of this assay, one patient had MEGX concentrations almost twice those of lidocaine. At 83% lidocaine potency, the contribution of MEGX in this patient was about 1.5 times that of lidocaine. The second patient studied on two consecutive days had a 20% increase in serum lidocaine concentration and an equivalent decrease in MEGX concentration on the second day. In the third patient lidocaine was stopped with a resulting half-life of 3.8 hr, which is consistent with previously reported values for patients on long-term lidocaine infusion. Urinary excretion of lidocaine and its metabolites is in agreement with previous work. These data suggest that much information still remains to be learned about the active metabolites of lidocaine as well as of lidocaine.

Bretylium kinetics in renal insufficiency.

Bretylium kinetics were examined in patients with varying degrees of renal impairment after a single intravenous dose of bretylium tosylate. Maximum plasma concentrations achieved at the end of the infusion, when normalized to the dose, correlated strongly with creatinine clearance. Drug disposition from plasma was biexponential, with a short distributive phase, but drug elimination was reduced, especially in patients with creatinine clearance below 30 ml/min X 1.73 m2. There was reduction in renal and total clearance and prolongation of t 1/2, with deteriorating renal function. In one patient who was reevaluated after a year, there was 76% reduction in the total clearance, corresponding to 43% deterioration of renal function. The difference of 33% between these values is due to a reduction of nearly 36% in volume of distribution, caused by the further deterioration of the renal function. Six-hour hemodialysis procedure on two anephric patients, resulted in an apparent one- to threefold increase in the computed bretylium clearance during dialysis, but the fraction of the total body load eliminated during the same period was not proportionally significant. The strong linear relationships between renal and total clearance, beta, and the creatinine clearance, may be helpful in adjusting dosage regimens for bretylium in patients with renal dysfunction.

Quinidine saliva concentrations: absence of correlation with serum concentrations at steady state.

Serum and saliva quinidine concentrations were measured in eight subjects with cardiac arrhythmias on various dosage regimens. There was good correlation between serum and saliva quinidine concentration after a single dose, but there was no such relationship after repeated dosing. Comparison of the area under a hysteresis loop, obtained by plotting the saliva/serum quinidine concentration ratio as a function of serum quinidine concentration over a dosing interval, indicated an exponential increase with increasing mean serum quinidine concentration. Salivary quinidine concentration predictions based on the Henderson-Hasselbalch equation did not correlate with the serum quinidine concentration under the steady-state conditions. These data suggest that quinidine concentration in saliva is not a direct reflection of its serum concentration in cardiac patients on maintenance (steady-state) therapy and hence not useful for therapeutic drug monitoring.

Evaluation of zimeldine in Alzheimer's disease. Cognitive and biochemical measures.

Neuropsychological and neurochemical effects of zimeldine, a relatively specific serotonin reuptake blocker, were examined in four patients with clinically diagnosed Alzheimer's disease, in a double-blind, placebo-controlled, crossover study. Individualized doses of zimeldine were administered to achieve target plasma zimeldine concentrations of approximately 50 (low) to 100 (high) ng/mL. Overall, there was no significant effect of zimeldine on memory or reaction time measures as compared with placebo. The drug significantly reduced (by up to 38%) 5-hydroxyindoleacetic acid concentrations in the cereobrospinal fluid and almost abolished (90% reduction) platelet serotonin uptake. Cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol, a major metabolite of norepinephrine, and homovanillic acid, the major metabolite of dopamine, were not altered. Our findings indicate that alterations in central and peripheral serotoninergic function by a serotonin reuptake blocker (zimeldine) are unaccompanied by measurable changes in memory and/or reaction time in patients presumed to have Alzheimer's disease.

Neuroendocrine, physiologic, and behavioral responses following intravenous nicotine in nonsmoking healthy volunteers and in patients with Alzheimer's disease.

In separate studies, nonsmoking nicotine-naive subjects (11 young and middle-aged normal volunteers and 11 nonsmoking patients with Alzheimer's disease) received up to three doses of intravenous nicotine bitartrate (0.125, 0.25, and 0.5 micrograms/kg/min) and placebo for 60 min. Measurement of plasma ACTH, cortisol, and prolactin showed that nicotine produced in both groups a dose-dependent increase in cortisol, with ACTH in both groups and prolactin in the Alzheimer's group significantly elevated only by the 0.5 micrograms dose. Physiologic measures showed dose-dependent increases that were consistent with previous reports of nicotinic cholinergic stimulation. Behavioral effects included increases in anxiety and decreases in mood, especially following the 0.5 micrograms dose. Physical side effects were modest. The results indicate that nicotinic cholinergic stimulation can activate pituitary hormonal secretion in the human and suggest that nicotinic cholinergic stimulation may constitute an important part of cholinesterase inhibitor-induced endocrine stimulation and behavioral activation.

Concentration-dependent protein binding of a novel oral thromboxane synthase inhibitor--FCE 22,178.

The protein binding of FCE 22,178 in humans was determined ex vivo by equilibrium dialysis using plasma samples obtained from a dose-ranging study in normal male volunteers. These data suggested that FCE 22,178 may exhibit concentration-dependent protein binding over an in vivo concentration range of .8 to 64 micrograms/mL. Increase in free fraction at higher plasma drug concentrations corresponded directly to the dose-dependent increase in renal drug clearance. Nonlinear parameter estimation showed that FCE 22,178 binds tightly to plasma proteins with an apparent equilibrium association constant of 1.44 x 10(5) mol/L. Predicted change in the free fraction is consistent with the observed changes in renal clearance.

Effects of rifabutin and rifampicin on the pharmacokinetics of ethinylestradiol and norethindrone.

This open-label, randomized, three-way crossover study of 28 healthy premenopausal women was conducted to compare the impact of concomitant rifabutin and rifampicin on the safety, pharmacokinetics, and pharmacodynamics of the oral contraceptives ethinylestradiol and norethindrone (Ortho-Novum 1/35; Ortho Pharmaceutical, Raritan, NJ). Each participant received oral contraceptives daily for 21 days for the first control cycle, then was randomized to one of two sequences to receive oral contraceptives with concomitant rifampicin and rifabutin at equal doses of 300 mg/day for 10 days. Ethinylestradiol, norethindrone, follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, rifampicin, and rifabutin (and metabolite) were measured in plasma over the same time frames in all three cycles. Safety was assessed from before the beginning to the end of each cycle. Twenty-two subjects completed all three cycles. Compared with the control cycle, rifabutin and rifampicin significantly altered the disposition of the oral contraceptive. Area under the concentration-time curve from 0 to 24 hours (AUC0-24) and maximum plasma concentration (Cmax) of ethinylestradiol decreased by 64% and 42%, respectively, after coadministration with rifampicin and by 35% and 20%, respectively, after coadministration with rifabutin. The AUC0-24 of norethindrone decreased by 60% and 20% after coadministration with rifampicin and rifabutin, respectively. Unlike progesterone levels, FSH and LH levels increased during coadministration with rifampicin and rifabutin. The incidence of spotting was significantly higher after coadministration with rifampicin (36.4%) and rifabutin (21.7%) than during the control cycle (3.7%). Although both rifampicin and rifabutin affected the pharmacokinetics of ethinylestradiol and norethindrone, the magnitude of this effect was more pronounced with rifampicin. Likewise, the fact that the highest incidence of spotting occurred with rifampicin was consistent with higher metabolic induction by rifampicin. Despite the fact that there was no change in progesterone levels, it is recommended that patients be advised to use additional contraceptive methods while receiving rifabutin or rifampicin with oral contraceptives to prevent inadvertent pregnancy.

A phase I dose-ranging safety and pharmacokinetics study of a novel oral thromboxane synthase inhibitor, FCE 22, 178.

A 100- to 3200-mg dose range of FCE 22,178 was studied in this phase I single-dose escalation safety/kinetics study. After oral administration, a rapid drug absorptive phase and a biexponential disposition profile were observed. Mean estimates of the terminal elimination half-life of FCE 22,178, over the doses studied, ranged from 7.6 to 14.4 hours. A disproportionate increase in both maximum peak plasma concentration (Cmax) and area under the curve (AUC0-infinity) was noticed for doses higher than 400 mg. Mean estimates of systemic clearance (CLs/F) over the 100- to 400-mg doses were 0.053 to 0.064 L/hour/kg, and were significantly higher for the three higher dose levels. This nonlinearity appears to be related to the changes in oral bioavailability. Estimates of distribution volume (Vd, lambda z/F) for FCE 22,178 increased from 0.75 L/kg at the 100-mg dose to 3.00 L/kg at the 3200-mg dose, and renal clearance (CLr) also increased with dose. Both observations may be related to an increase in free fraction of FCE 22,178 at higher doses. Urinary excretion of unchanged drug averaged < 10% for all dose levels. The urinary excretion of the glucuronide metabolite (M1) averaged 41 to 70% for doses up to 400 mg, but diminished to 13% at the 3200-mg dose. The disposition of M1 appeared to be formation-rate limited. In addition, the ratio of the formation to the disposition clearance for M1 was relatively stable and apparently dose independent. No drug-related adverse experiences were observed over the studied dose range after single doses at FCE 22,178.

Influence of the cardioprotective agent dexrazoxane on doxorubicin pharmacokinetics in the dog.

The influence of dexrazoxane on doxorubicin pharmacokinetics was investigated in four dogs using the two treatment sequences of saline/doxorubicin or dexrazoxane/doxorubicin. Intravenous doses of 1.5 mg/kg doxorubicin and 30 mg/kg (the 20-fold multiple) dexrazoxane were given separately, with doxorubicin being injected within 1 min of the dexrazoxane dose. Both doxorubicin and its 13-dihydro metabolite doxorubicinol were quantified in plasma and urine using a validated high-performance liquid chromatographic (HPLC) fluorescence assay. The doxorubicin plasma concentration versus time data were adequately fit by a three-compartment model. The mean half-lives calculated for the fast and slow distributive and terminal elimination phases in the saline/doxorubicin group were 3.0 +/- 0.5 and 32.2 +/- 12.8 min and 30.0 +/- 4.0 h, respectively. The model-predicted plasma concentrations were virtually identical for the saline and dexrazoxane treatment groups. Analysis of variance of the area under the plasma concentration-time curve (AUCo-infinity), terminal elimination rate (lambda z), systemic clearance (CLs), and renal clearance (CLr) for the parent drug showed no statistically significant difference (P greater than 0.05) between the two treatments. Furthermore, the doxorubicinol plasma AUCo-t value and the doxorubicinol-to-doxorubicin AUCo-t ratio showed no significant difference, demonstrating that dexrazoxane had no effect on the metabolic capacity for formation of the 13-dihydro metabolite. The total urinary excretion measured as parent drug plus doxorubicinol and the metabolite-to-parent ratio in urine were also unaffected by the presence of dexrazoxane. The myelosuppressive effects of doxorubicin as determined by WBC monitoring revealed no apparent difference between the two treatments. In conclusion, these results show that drug exposure was similar for the two treatment arms. No kinetic interaction with dexrazoxane suggests that its coadministration is unlikely to modify the safety and/or efficacy of doxorubicin.

Pharmacotherapy in Alzheimer's disease: basis and rationale.

Alzheimer's disease is a slowly progressive disorder involving deterioration of both intellect and personality. The neuropathological features of Alzheimer's disease include abundant neurocortical senile plaques and neurofibrillary tangles. Drug therapies of Alzheimer's disease have been based on empirical observations of the signs and symptoms of the disease and have included the use of hypnotics to reverse insomnia or inverse sleep rhythms; anxiolytics to relieve anxiety, tension and restlessness antipsychotics to "tranquilize" or control psychotic symptoms, such as delusions and hallucinations; stimulants to overcome withdrawn behavior or lethargy; and lastly, antidepressants to control depression. Our growing knowledge of neuropathological and neurochemical changes associated with normal aging and Alzheimer's disease has made it possible to explore and develop pharmacologically-based therapies in Alzheimer's disease. Recent research has revealed behavioral symptoms associated with underlying biochemical changes in either the cholinergic, dopaminergic/ GABAergic (gama-aminobutyric acid) noradrenergic, serotoninergic, neurochemical and/or neuropeptidergic systems. Pharmacological strategies involving manipulation of these systems as a means of relieving Alzheimer's disease symptoms will be reviewed from several perspectives, e.g., those involving transmitter substitution, enzyme inhibition and direct specific receptor stimulation.

Implications of dosing tricyclic antidepressants and benzodiazepines in geriatrics.

It is important to understand both the kinetic and the dynamic implications of dosing TCAs and BZs in the elderly, for whom these drugs are frequently prescribed. The TCAs are used to treat responsive signs and symptoms including such somatic complaints as chest pain, dizziness, and arthralgias, as well as the endogenous signs such as loss of appetite with associated weight loss, psychomotor retardation, loss of libido, and insomnia. The pharmacokinetic studies of TCAs such as desipramine and nortriptyline have shown few, if any, age-related changes. The dose required for responsivity is significantly reduced for both TCAs (desipramine and nortriptyline) in the elderly, which may suggest increased end-organ responsiveness. The major recommendations for treatment of depression with nortriptyline in the elderly are (1) to administer small doses in order to avoid side effects, and (2) to expect a longer response time for the antidepressant effect than in young and middle-aged depressed patients. Although the BZs are extensively prescribed in the elderly, primarily for insomnia and anxiety, the physiologic and biochemical changes of aging alter the kinetics and dynamics of these extensively metabolized and slowly eliminated drugs. Based on the kinetic data and information in Tables 1 and 2, the relatively sensitive elderly population should receive a reduced dosage. Careful evaluation of the patient and the kinetic profile of the agent employed will ensure safe use of these drugs. A clear understanding of anxiety and respect for the alterations in the pharmacokinetics and pharmacodynamics of these agents in the elderly will allow the physician to prescribe the BZs wisely. As with the TCAs, remember to administer doses of BZs that are reduced by 50 to 75 per cent of the usual recommended doses for young and middle-aged individuals and to increase dosage in small increments. Ultimately, sound, scientifically based, clinical judgment that considers the needs of the patient is the best guide for the selection of an appropriate BZ.

Lack of a pharmacologic interaction between rifabutin and methadone in HIV-infected former injecting drug users.

Rifampin, an agent known to decrease the half-life of methadone, and rifabutin are two rifamycins that are structurally similar and share mechanisms of action. Hence the possibility of a drug-drug interaction between rifabutin and methadone was evaluated in 24 methadone-maintained, former injecting drug users infected with the human immunodeficiency virus. The study was an open-label, drug-drug interaction and safety trial in which patients were followed for 15 days. Each patient received rifabutin 300 mg as a single dose concomitantly with their individualized methadone dosage. No significant differences in methadone peak plasma concentration, time to peak plasma concentration, area under the plasma concentration-time curve, systemic clearance or renal clearance was observed in the presence of rifabutin. Seventy-five percent of the patients reported at least one symptom of narcotic withdrawal during the study, however, these symptoms were mild. A relationship between the development of narcotic withdrawal and methadone systemic exposure could not be established. Concurrent administration of rifabutin and methadone appeared to be safe in human immunodeficiency virus-infected injecting drug users maintained on stable doses of methadone and is not expected to produce any significant changes in the pharmacokinetics of methadone in these patients.

Dihydroquinidine contamination of quinidine raw materials and dosage forms: rapid estimation by high-performance liquid chromatography.

Dihydroquinidine is a commonly encountered contaminant in quinidine raw materials. The USP allows 0-20% dihydroquinidine in quinidine products, but the assays used to quantitate dihydroquinidine have been lengthy or have required sophisticated equipment. The present method separates dihydroquinidine from quinidine and provides rapid, precise quantitation of both dihydroquinidine and quinidine. The clinical importance of dihydroquinidine contamination of quinidine dosage forms remains unanswered.

Amino acid effect on aspirin stability in propylene glycol.

Temperature stability studies were conducted on 0.36 M (6.5% W/V) aspirin solutions including either 0.02 M L-methionine or 0.02 M histidine in propylene glycol. Aspirin was determined spectrophoto-fluorometrically as salicylic acid content at 412 nm. A 0.36 M aspirin in polyethylene glycol 400 solution was studied concurrently. Aspirin degradation rate constants, k, obtained from semilogarithmic plots of percent drug remaining versus time at 30-70 +/- 0.5 degrees were used for preparing Arrhenius plots. Good correlation was seen between predicted aspirin stability and experimental k25 degrees values. L-Methionine and histidine markedly reduced aspirin stability.

High-performance liquid chromatographic assay for benzocaine and p-aminobenzoic acid including preliminary stability data.

A high-performance liquid chromatographic assay was developed that separates and quantitates benzocaine and its primary degradation product, p-aminobenzoic acid. This method is rapid, sensitive, and specific. Preliminary stability data obtained with this method demonstrate its utility for this purpose.