Lack of a pharmacokinetic drug-drug interaction between lithium and valproate when co-administered with aripiprazole.

WHAT IS KNOWN AND OBJECTIVE: The antipsychotic, aripiprazole, plus lithium or valproate demonstrates rapid and significant improvement in manic symptoms that is sustained over the long term. A previous report showed that therapeutic doses of either lithium or valproate had no clinically significant effects on the pharmacokinetics of aripiprazole. We aimed to determine the effects of co-administration of aripiprazole on the steady-state pharmacokinetics of lithium or valproate in healthy subjects. MATERIALS AND METHODS: Two similarly designed, open-label, single-sequence studies were conducted. Healthy subjects received daily oral doses of either lithium (450 mg every 12 h) or valproate (500 mg every 12 h) on Days 1-7. Following Day 7 was a 2-day washout period, and on Day 10, subjects began receiving oral doses of aripiprazole (10 mg once daily) for 2 days. Aripiprazole was then titrated from 10 to 20 mg once daily to establish tolerance of aripiprazole. On Day 14, the dose was escalated and subjects received aripiprazole 30 mg once daily for 13 days. Beginning on Day 20, subjects received lithium (450 mg every 12 h) or valproate (500 mg every 12 h) concomitantly with aripiprazole 30 mg once daily through Day 26. Serial blood samples for serum lithium or valproate concentration determination were collected for up to 12 h post-lithium or valproate administration on Days 7 and 26. RESULTS: The lithium study enrolled 32 healthy subjects (72% completed the study), and the valproate study enrolled 48 healthy subjects (58% completed the study). In both studies, the 90% confidence intervals for the ratios of population geometric means, with and without aripiprazole, were contained within 80% and 125% for both the C(max) and AUC(τ) , respectively. Furthermore, the addition of aripiprazole did not change the median T(max) of lithium or valproate (4 h). Thus, the addition of aripiprazole did not affect the steady-state pharmacokinetics of lithium or valproate. The majority of subjects (76·9% for aripiprazole plus lithium and 68·4% for aripiprazole plus valproate) reported adverse events, but this adverse event profile is consistent with what has been observed in other studies. WHAT IS NEW AND CONCLUSION: The addition of aripiprazole to either lithium or valproate had no clinically meaningful effects on the pharmacokinetics of either drug. In addition, co-administration of aripiprazole with lithium or valproate demonstrated no unexpected safety signals in healthy subjects.

Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of three oral antidiabetic drugs (metformin, glyburide or pioglitazone) in healthy subjects.

AIM: To evaluate the pharmacokinetic interactions of the potent, selective, dipeptidyl peptidase-4 inhibitor, saxagliptin, in combination with metformin, glyburide or pioglitazone. METHODS: To assess the effect of co-administration of saxagliptin with oral antidiabetic drugs (OADs) on the pharmacokinetics and tolerability of saxagliptin, 5-hydroxy saxagliptin, metformin, glyburide, pioglitazone and hydroxy-pioglitazone, analyses of variance were performed on maximum (peak) plasma drug concentration (C(max)), area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) [saxagliptin + metformin (study 1) and saxagliptin + glyburide (study 2)] and area under the concentration-time curve from time 0 to time t (AUC) [saxagliptin + pioglitazone (study 3)] for each analyte in the respective studies. Studies 1 and 2 were open-label, randomized, three-period, three-treatment, crossover studies, and study 3 was an open-label, non-randomized, sequential study in healthy subjects. RESULTS: Co-administration of saxagliptin with metformin, glyburide or pioglitazone did not result in clinically meaningful alterations in the pharmacokinetics of saxagliptin or its metabolite, 5-hydroxy saxagliptin. Following co-administration of saxagliptin, there were no clinically meaningful alterations in the pharmacokinetics of metformin, glyburide, pioglitazone or hydroxy-pioglitazone. Saxagliptin was generally safe and well tolerated when administered alone or in combination with metformin, glyburide or pioglitazone. CONCLUSIONS: Saxagliptin can be co-administered with metformin, glyburide or pioglitazone without a need for dose adjustment of either saxagliptin or these OADs.

Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects.

Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter-2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single-ascending-dose (SAD; 2.5-500 mg) and multiple-ascending-dose (MAD; 2.5-100 mg daily for 14 days) studies in healthy subjects. Dapagliflozin exhibited dose-proportional plasma concentrations with a half-life of approximately 17 h. The amount of glucosuria was also dose-dependent. Cumulative amounts of glucose excreted on day 1, relating to doses from 2.5-100 mg (MAD), ranged from 18 to 62 g; day 14 values were comparable to day 1 values, with no apparent changes in glycemic parameters. Doses of approximately 20-50 mg provided close-to-maximal SGLT2 inhibition for at least 24 h. Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose-dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once-daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.

Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus.

Dapagliflozin, administered to patients in once-daily oral doses, is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that blocks the reabsorption of glucose from urine into the blood. This 14-day study randomized patients with type 2 diabetes mellitus (T2DM) to four treatment groups receiving daily oral doses of 5-, 25-, or 100-mg doses of dapagliflozin or placebo, in order to evaluate glucosuria and glycemic parameters. Significant reductions in fasting serum glucose (FSG) were observed on day 2 with 100 mg dapagliflozin (-9.3%, P < 0.001), and dose-dependent reductions were observed on day 13 with the 5-mg (-11.7%; P < 0.05), 25-mg (-13.3%; P < 0.05), and 100-mg (-21.8%; P < 0.0001) doses as compared with placebo. Significant improvements in oral glucose tolerance test (OGTT) were observed with all doses on days 2 and 13 (P < 0.001 as compared with placebo). On day 14, urine glucose values were 36.6, 70.1, and 69.9 g/day for the 5-, 25-, and 100-mg doses (as compared with no change for placebo), which were slightly lower than those on day 1. This was attributed to the decrease in filtered glucose load following improved glycemic control. Dapagliflozin produced dose-dependent increases in glucosuria and clinically meaningful changes in glycemic parameters in T2DM patients.

Anticoagulant pharmacodynamics of tinzaparin following 175 iu/kg subcutaneous administration to healthy volunteers.

Tinzaparin, a sodium salt of a low-molecular-weight heparin (LMWH) produced via heparinase digestion, is used for the treatment of deep vein thrombosis (DVT) and pulmonary embolism in conjunction with warfarin for the prevention of DVT in patients undergoing hip or knee replacement surgery, and as an anticoagulant in hemodialysis circuits. Its average molecular weight ranges between 5500 and 7500 daltons (Da); the percentage of chains with molecular weight lower than 2000 Da is not more than 10% in the marketed tinzaparin formulation. While this fraction is generally considered pharmacologically inactive, this has never been evaluated in vivo. The importance of the < 2000 Da fraction on the anticoagulant pharmacodynamics of tinzaparin assessed by anti-Xa and anti-IIa activity was studied in a two-way crossover trial. In this trial, 30 healthy volunteers received a single 175 IU/kg subcutaneous administration of tinzaparin containing approximately 3.5% of the < 2000 Da fraction and a tinzaparin-like LMWH containing 18.3% of the < 2000 Da fraction. The anti-Xa/anti-IIa ratios of the drug substances were comparable at 1.5 and 1.7 for tinzaparin and the tinzaparin-like LMWH, respectively. Both formulations were safe and well tolerated. Mean maximum plasma anti-Xa activity (A(max)) was approximately 0.818 IU/ml at 4 h following tinzaparin injection. Mean maximum plasma anti-IIa activity was 0.308 IU/ml at 5 h postdose. Intersubject variation was lower (< 18% for both anti-Xa and anti-IIa metrics) than in previous fixed-dose administration studies. There was no correlation between anti-Xa or anti-IIa AUC or A(max) and bodyweight in the present study supporting the weight-adjusted dosing regimen. Individual anti-Xa and anti-IIa profiles following the single 175 IU/kg subcutaneous administration of the tinzaparin-like LMWH were similar to that obtained with tinzaparin. Based on average equivalence criteria, the two LMWH preparations were determined to be bioequivalent using either anti-Xa or anti-IIa activity as biomarkers. The calculated intrasubject variabilities were low (< 14% for anti-Xa activity and < 18% for anti-IIa activity) yielding little evidence for a significant Subject x Formulation interaction. In summary, anti-Xa and anti-IIa activity following a single subcutaneous administration of tinzaparin 175 IU/kg to healthy volunteers yielded activity consistent with targeted therapeutic levels derived from previous trials in adult DVT patients. Weight-based dosing for the treatment of DVT appears rational based on the reduction in anti-Xa and anti-IIa variability consistent with the recommendation derived from earlier fixed-dose pharmacokinetic studies. Furthermore, differences in the percentage of molecules in the < 2000 Da molecular weight fraction of tinzaparin do not translate into differences in anti-Xa and anti-IIa activity in vivo.

Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team.

BACKGROUND: Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors. METHODS: The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations. RESULTS: At base line, the 57 HIV-1-infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment. CONCLUSIONS: In HIV-1-infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect.

The effect of increasing gastric pH upon the bioavailability of orally-administered foscarnet.

For systemic use, the anti-cytomegalovirus (CMV) agent foscarnet must be given intravenously because oral administration results in unmeasurable or barely measurable plasma levels. At low pH, foscarnet decomposes via an acid-catalyzed decarboxylation; therefore, poor oral bioavailability might be due to decomposition of foscarnet in gastric acid. We evaluated whether increasing gastric pH with ranitidine would enhance the absorption of oral foscarnet in six asymptomatic HIV-infected individuals. Each volunteer received two oral 4000-mg (60 mg/kg) doses of foscarnet, preceded intravenously by a 20-min infusion of either ranitidine 50 mg in D5W or D5W alone in a randomized, double-blind, cross-over study. Intragastric pH monitoring revealed that subjects had evidence of gastric acid production (pH < 2.0) prior to administration of ranitidine and increased gastric pH (pH > 6.0) following ranitidine administration. Most foscarnet plasma levels were below the assay limit of detection (33 microM) with only 4/30 levels detectable after D5W and 8/30 after ranitidine. Urinary recovery of foscarnet increased after ranitidine pretreatment. A mean recovery of 9.9% of the drug was realized in the urine in 24 h following ranitidine pretreatment compared to 6.2% of the dose after D5W pretreatment (P < 0.03). We estimate that 9.9% recovery in the urine in 24 h is equivalent to absorption of 17.1% of the oral dose. In spite of the enhanced bioavailability associated with ranitidine pretreatment, the degree of absorption is still insufficient to achieve effective plasma concentrations for the treatment of CMV or acyclovir-resistant herpes viruses. We conclude that gastric acidity is a determinant of foscarnet absorption, albeit not a major one. Oral foscarnet is unlikely to be clinically useful even if administered in the setting of increased gastric pH.

Pharmacodynamics and pharmacokinetics of DMP 728, a platelet GPIIb/IIIa antagonist, in healthy subjects.

DMP 728 showed a dose-dependent inhibition of platelet aggregation at doses of 0.05 to 0.9 mg per subject, with a maximal inhibition (> 90%) of platelet aggregation at doses of 0.9 mg per subject and higher. Minimal changes in bleeding time from baseline were observed at doses up to 0.6 mg per subject. At the 0.9 mg/subject dose level, bleeding time was prolonged by approximately twofold to threefold above the baseline. At higher doses (1.5 mg/subject to 3.9 mg/subject), bleeding time prolongation was > 30 minutes during the infusion. In all dose groups, bleeding times returned to the control value within 8 hours after cessation of the infusion. Maximum plasma concentration and area under the curve of DMP 728 increased linearly and proportionally to the dose. No clinical changes in vital signs, 12-lead electrocardiograms, physical examinations, coagulation tests, or stool hemoccult tests were observed at any of the doses. In conclusion, DMP 728 is a potent antiplatelet agent and well tolerated at doses ranging from 0.05 to 3.0 mg/subject.

Phase I safety and pharmacokinetic studies of brequinar sodium after single ascending oral doses in stable renal, hepatic, and cardiac allograft recipients.

Brequinar sodium (BQR), a substituted 4-quinoline carboxylic acid, was in clinical development in combination with cyclosporine (CsA) as a potentially effective therapy for the treatment and prophylaxis of rejection in organ transplant patients. This phase I study was performed in stable renal, hepatic, and cardiac transplant patients receiving CsA and prednisone maintenance therapy for immunosuppression. The pharmacokinetic objectives of this study were to characterize the pharmacokinetics of (a) single oral 0.5- to 4-mg/kg doses of BQR when given in combination with CsA and prednisone to stable renal, hepatic, and cardiac transplant patients and (b) steady-state oral doses of CsA, with and without single oral doses of BQR. In all three patient populations, the pharmacokinetics of BQR were characterized by a lower oral clearance (12-19 mL/min) than that seen in previous studies in patients with cancer (approximately 30 mL/min at similar doses) and a long terminal half life (13-18 hrs). This slower oral clearance for BQR could be due either to a drug interaction between BQR and CsA or to altered clearance or metabolic processes in patients with transplants. Steady-state CsA trough levels and the oral clearance of CsA were not affected by BQR coadministration. Among the three transplant populations, the cardiac transplant patients had lower oral clearance values of BQR and of CsA. The cause of this lower clearance is not known. Safety results indicate that BQR was well tolerated by this patient population.

Cyclic HIV protease inhibitors: synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas.

High-resolution X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure-activity relationships of C2-symmetric diol inhibitors, computed-aided drug design tools, and first principles, we designed and synthesized a novel class of cyclic ureas that incorporates this structural water and preorganizes the side chain residues into optimum binding conformations. Conformational analysis suggested a preference for pseudodiaxial benzylic and pseudodiequatorial hydroxyl substituents and an enantiomeric preference for the RSSR stereochemistry. The X-ray and solution NMR structure of the complex of HIV-1PR and one such cyclic urea, DMP323, confirmed the displacement of the structural water. Additionally, the bound and "unbound" (small-molecule X-ray) ligands have similar conformations. The high degree of preorganization, the complementarity, and the entropic gain of water displacement are proposed to explain the high affinity of these small molecules for the enzyme. The small size probably contributes to the observed good oral bioavailability in animals. Extensive structure-based optimization of the side chains that fill the S2 and S2' pockets of the enzyme resulted in DMP323, which was studied in phase I clinical trials but found to suffer from variable pharmacokinetics in man. This report details the synthesis, conformational analysis, structure-activity relationships, and molecular recognition of this series of C2-symmetry HIV-1PR inhibitors. An initial series of cyclic ureas containing nonsymmetric P2/P2' is also discussed.

Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers.

Data describing the pharmacokinetics and pharmacodynamics of low dose aspirin (acetylsalicylic acid; ASA) are limited. This single-center study was designed to determine the rate and extent of oral absorption of 80-mg ASA tablets in healthy, young male subjects and to assess the intra- and inter-subject variability of ASA pharmacokinetics and platelet aggregation effects. Ten subjects each received a single, open-label, oral 80-mg ASA dose on three separate days. Each dose was separated by a 2-week washout interval. Blood samples for pharmacokinetic determinations of ASA and its metabolite, salicylic acid (SA) and platelet aggregation studies were obtained at scheduled timepoints before and up to 24 hours after each dose. Peak plasma ASA levels of 1 microgram/mL were achieved within 30 minutes. Peak plasma SA levels of approximately 4 micrograms/mL were attained in 1 hour. The terminal half-lives (t1/2) of ASA and SA were 0.4 and 2.1 hours, respectively. Both ASA and SA pharmacokinetics and the platelet aggregation response to ASA exhibited considerable intra- and inter-subject variability. Inhibition of platelet aggregation was found to relate with ASA area under the plasma concentration versus time curve (AUC).

Bromide pharmacokinetics in cystic fibrosis.

OBJECTIVE: Individuals with cystic fibrosis (CF) have altered kinetics for a number of drugs, most often an increased volume of distribution (Vd) per body weight and increased clearance per body weight. To further evaluate those differences, we studied bromide kinetics (Vd, elimination rate constant, and clearance) and body mass index in eight adults with mild-to-moderate forms of CF, 21 obligate carriers of the CF gene, and 21 healthy controls. Bromide distribution approximates the extracellular fluid volume and bromide is excreted unchanged by the kidney. DESIGN: Individuals were given a single oral dose of bromide (50 mg/kg), and serum bromide concentrations were measured over 4 weeks. Bromide pharmacokinetics (Vd, elimination rate constant, and clearance) were determined using a one-compartment model with first-order kinetics. Body mass index was determined for each individual. RESULTS: Individuals with CF had a significantly greater lean body mass per kilogram as estimated by body mass index compared with individuals in the obligate carrier and control groups. The mean (+/- SD) Vd per kilogram for the CF group (311 +/- 29 mL/kg) was significantly greater than that of the obligate carrier group (261 +/- 26 mL/kg) and the control group (274 +/- 30 mL/kg). However, the mean (+/- SD) Vd per square meter for the three groups was similar. The mean elimination rate constant for the CF group (3.55 +/- 0.98 x 10(-3)/h) was significantly greater compared with the mean elimination rate constant for the obligate carrier group (2.55 +/- 0.36 x 10(-3)/h) and the control group (2.58 +/- 0.49 x 10(-3)/h). The mean (+/- SD) clearance per kilogram was also significantly greater for the CF group (1095 +/- 283 microL/kg per hour) compared with the obligate carrier group (664 +/- 100 microL/kg per hour) and the control group (700 +/- 115 microL/kg per hour). CONCLUSIONS: These findings indicate that individuals with CF have a greater Vd per kilogram for bromide and drugs that distribute in the extracellular fluid volume because of their greater lean body mass per kilogram. The findings also suggest that individuals with CF have a greater renal clearance of bromide and presumably of other anionic drugs excreted by the kidney. The results emphasize the importance of body composition in drug disposition.

Drug prescribing for patients with changing renal function.

The prevalence and course of renal dysfunction in hospitalized patients and the prescribing of renally eliminated drugs in these patients were studied. All adult inpatients at a large teaching hospital who had a serum creatinine concentration assay performed were screened for renal dysfunction (an estimated creatinine clearance of < 40 mL/min). Renally compromised patients were monitored for changes in renal function. The regimens of selected renally eliminated drugs prescribed for these patients were compared with the manufacturers' recommended dosages for patients with renal compromise. Of the 3800 patients screened, 195 (5%) had renal dysfunction; most of these patients were older than 65 years. Although improvements in renal function were noted in 49 (30%) of the 169 patients with renal dysfunction who were not receiving hemodialysis, elderly patients were less likely to show an improvement in renal function. Of the 60 patients with renal dysfunction for whom a renally eliminated drug was prescribed, 27 (45%) were receiving dosages in excess of the manufacturers' recommendations. Changes in creatinine clearance estimates are common in hospitalized patients with renal impairment. Programs designed to alert physicians to potentially excessive dosages of renally eliminated drugs need to be sensitive to these changes.

Intracellular zidovudine (ZDV) and ZDV phosphates as measured by a validated combined high-pressure liquid chromatography-radioimmunoassay procedure.

In vitro studies of zidovudine (ZDV) phosphorylation may not accurately reflect the in vivo dose-response relationship, which is crucial to determining the relationship between ZDV exposure, efficacy, and toxicity. However, measurement of ZDV phosphorylated anabolites in peripheral blood mononuclear cells (PBMCs) from ZDV-treated human immunodeficiency virus (HIV)-infected patients would be extremely useful in the more appropriate utilization of ZDV in the treatment of HIV infection. We developed a specific and sensitive combined high-pressure liquid chromatography (HPLC)-radioimmunoassay (RIA) procedure for the determination of ZDV, ZDV-monophosphate, ZDV-diphosphate, and ZDV-triphosphate in PBMCs taken from ZDV-treated HIV-infected patients. ZDV and its anabolites were extracted from washed, Ficoll-Paque-isolated PBMCs and then separated by HPLC using a strong anion-exchange column. The anabolites were then hydrolyzed to ZDV with acid phosphatase. ZDV was then measured by using a modified commercially available RIA protocol. Our method was validated by measuring [3H]ZDV anabolites generated in Molt-4 cells radioisotopically and simultaneously by the combined HPLC-RIA procedure. The ZDV determinations correlated well (r2 = 0.97) over the range of 0.037 to 5.2 pmol (10 to 1,400 pg) per assay tube. Furthermore, we defined the stability of ZDV anabolites during ficoll isolation and the recovery after extraction and cleanup. We then measured intracellular parent ZDV and its phosphorylated anabolites in PBMCs from six ZDV-treated HIV-infected patients (PBMCs were taken 2 h after a 300-mg oral dose). The mean concentrations ( +/- standard deviations) of parent and of mono-, di-, and triphosphates were 0.15 +/- 0.08, 1.4 +/-, 0.082 +/- 0.02, and 0.081 +/- 0.03 pmol/10(6) PBMC, respectively (one pmol/10(6) PBMC represents a concentration of approximately 1 microm). Concurrent serum ZDV concentrations were between 1.3 and 7.1 microm. This method should provide a useful tool for evaluating in vivo pharmacokinetics of ZDV anabolites in PBMCs and possibly other cell types, even at the low doses of ZDV currently administered therapeutically.

Thermospray liquid chromatographic-mass spectrometric analysis of anti-AIDS nucleosides: quantification of 2',3'-dideoxycytidine in plasma samples.

Thermospray liquid chromatography-mass spectrometry was investigated as a method for quantification of 2',3'-dideoxycytidine (DDC) from human plasma. A stable isotope analog of DDC ([15N2,2H2]DDC) was used as an internal standard. Selected ion monitoring of the protonated molecular ions for DDC and the internal standard was used to record mass chromatograms. The areas of the peaks in the mass chromatograms were used for quantification. The detection limit of DDC in this assay was 50 pg on-column. The calibration curve was linear over the desired range, 0.25-20 ng/ml. The major advantages of this assay over others are: no derivatization, high sensitivity, high specificity and short assay time.

Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection.

Polysulfated polysaccharides are attractive candidates for antiviral drug development because of their potent in vitro activities against human immunodeficiency virus (HIV), herpesviruses, and other enveloped viruses. To determine the potential anti-HIV activity of a prototypical polysulfated polysaccharide, we administered the maximally tolerated dose of dextran sulfate by continuous intravenous infusion to 10 subjects with symptomatic HIV infection for up to 14 days. Since parenteral dextran sulfate is an anticoagulant, the infusion was adjusted to produce the greatest acceptable increase in activated partial thromboplastin time. Drug concentrations in plasma achieved with this protocol were up to 200-fold greater than the 50% inhibitory concentration for free HIV infectivity in vitro. Despite this, circulating HIV antigen (p24) levels increased in all eight subjects who received the drug for more than 3 days (median proportional increase, 73.5%; range, 32 to 130%); this increase was highly significant when it was compared with that in a large cohort of untreated historical controls (Fisher's exact test, P less than 0.001). Frequent decreases in infusion rate were required in all subjects to maintain a constant activated partial thromboplastin time; plasma dextran sulfate levels did not fall as the infusion rate decreased, suggesting a decline in estimated drug clearance over time. Continuous intravenous dextran sulfate was toxic, producing profound but reversible thrombocytopenia in all eight subjects who received drug for more than 3 days and extensive but reversible alopecia in five of these subjects. Because of its toxicity and lack of beneficial effect on surrogate markers, dextran sulfate is unlikely to have a practical role in the treatment of symptomatic HIV infection.

Protein binding of vancomycin in a patient with immunoglobulin A myeloma.

Atypical vancomycin pharmacokinetics were observed in an immunoglobulin A myeloma patient. Drug concentrations in serum were extremely elevated, the elimination half-life was prolonged despite normal renal function, and the vancomycin therapy was ineffective. Extensive binding of vancomycin, presumably by high concentrations of an aberrant immunoglobulin A protein, may have accounted for these observations.

Dextran sulfate is poorly absorbed after oral administration.

STUDY OBJECTIVE: To determine whether dextran sulfate (molecular weight, 7000 to 8000 daltons; 17% to 20% sulfur), a synthetic heparin analogue with anti-human immunodeficiency virus (HIV) activity in vitro, is absorbed after oral administration. DESIGN: Open-label, single-center study in two parts. The first part was a bioavailability study in which six subjects received a single 1800-mg oral dose and a single 225- or 300-mg intravenous dose. The second part was a study of the dose-response relation between dextran sulfate and total plasma lipolytic activity in which twelve subjects were given a single infusion of either 0.05, 0.5, 5, or 50 mg of dextran sulfate. SUBJECTS: Eighteen healthy volunteers. MEASUREMENTS AND MAIN RESULTS: In the bioavailability study, plasma and urine dextran-sulfate concentrations were measured by a competitive binding assay after each dose. In addition, two bioassays were used to assess plasma concentrations: plasma lipolytic activity and activated partial thromboplastin time (APTT). After the oral dose, plasma concentrations were not measurable with the competitive binding assay (lower limit of sensitivity, 1 microgram/mL); less than 0.5% of the dose was recovered in the urine, the APTT did not increase, and the median increase in the plasma lipolytic activity was only twofold (maximum increase, 11-fold). In contrast, after the intravenous dose of 225 mg, peak plasma concentrations by competitive binding assay were 26 to 35 micrograms/mL (median, 28 micrograms/mL); 25% to 29% (median, 25%) of the dose was recovered in the urine; the APTT increased to 3.5 to 9.2 times the baseline value (median increase, 6.9 times), and the plasma lipolytic activity increased by 185 to 548 times the baseline value (median increase, 438 times). In the dose-response study, intravenous doses as low as 0.5 mg produced significant increases in the plasma lipolytic activity. There was a steep dose-response curve between 0.5 and 50 mg. CONCLUSION: Dextran sulfate is very poorly absorbed after oral administration.

Probenecid and zidovudine metabolism.

The effects of probenecid, a known inhibitor of glucuronidation, on the pharmacokinetics of zidovudine were assessed in eight subjects receiving zidovudine as treatment for human immunodeficiency virus infection. Zidovudine plasma concentrations were measured while subjects were receiving zidovudine alone, after 3 days of zidovudine plus 500 mg probenecid every 8 h, and after 3 days of zidovudine plus 500 mg probenecid plus 260 mg quinine sulphate every 8 h. A median increase of 80% in the area under the zidovudine plasma concentration/time curve occurred with the addition of probenecid. Quinine sulphate prevented the probenecid effect but had no effect on zidovudine kinetics when taken without probenecid by four other subjects. All of the effects were secondary to changes in zidovudine metabolism, since neither probenecid nor quinine changed the renal elimination of zidovudine. Probenecid could be used in combination with zidovudine to extend the interval between doses and reduce the daily requirement for zidovudine, thus enhancing convenience and reducing costs.