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M R Blum

Publications and source records attributed to M R Blum.

At least 19 recordsLinked to original sources
PubMed2000

Single-shot fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging of the bladder.

The purpose of this study was to reduce artifacts and increase imaging speed in fluid-attenuated inversion recovery (FLAIR) imaging of the urinary bladder. An existing half-Fourier, single-shot fast spin-echo imaging sequence was modified to allow presaturation with a non-slice-selective inversion recovery pulse (NSI SSFLAIR). Four independent, blinded readers rated severity of bladder artifacts and image quality in six normal male volunteers. NSI SSFLAIR effectively suppressed bladder urine signal in all six cases using a TI of 2900-3100 msec. Although NSI SSFLAIR images were noisier than standard fast spin-echo images, imaging time was only 10 seconds per slice location. Furthermore, perceived image sharpness was only minimally reduced, and conspicuity of the seminal vesicles and peripheral zone of the prostate were nearly equivalent. NSI SSFLAIR provides rapid T2-weighted imaging of the bladder wall and perivesicular tissues with nearly complete negation of signal from urine in the bladder.

Artifacts↗
PubMed2000

Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1.

Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [(14)C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.

Animals↗
PubMed1996

In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents.

141W94 (VX-478) is a novel HIV-1 protease inhibitor with an IC50 of 0.08 microM against HIV-1 (strain IIIB) and a mean IC50 of 0.012 microM against six HIV clinical isolates. 141W94 was synergistic on the basis of isobologram analysis with each of the following reverse transcriptase inhibitors: AZT, 935U83, 524W91, 1592U89 and ddl, 141W94 was also synergistic with saquinavir and additive with either indinavir or ritonavir. Resistance to 141W94 has been reported in vitro passage experiments. The binding of 141W94 to human alpha 1-acid glycoprotein was relatively weak (Kd = 4 microM) and the off-rate for the drug is very fast (> or = 100 s-1). Only a 2-fold reduction of in vitro antiviral activity was observed in the presence of 45% human plasma. No serious drug associated adverse experiences were reported in a Phase I placebo-controlled, single-dose escalation, pharmacokinetic and safety study. The average concentration of 141W94 at 8 and 12 h after single doses of 900 and 1200 mg, respectively, was in excess of 10 times the IC50. As 141W94 is synergistic with a variety of anti-HIV-1 agents and exhibits a unique cross resistance profile compared to other protease inhibitors, 141W94 is considered a good candidate for combination therapy.

Carbamates↗
PubMed1996

Pharmacokinetics and safety of multiple-dose valaciclovir in geriatric volunteers with and without concomitant diuretic therapy.

A randomized, double-blind study was conducted to evaluate the safety and pharmacokinetics of acyclovir following multiple-dose oral administration of valaciclovir (three times a day for 8 days) in geriatric volunteers (65 to 83 years of age). Pharmacokinetic evaluation was performed for three groups: normotensive subjects given 500-mg doses of valaciclovir (n = 11), normotensive subjects given, 1,000-mg doses of valaciclovir (n = 9), and thiazide diuretic-treated hypertensive subjects given 500-mg doses of valaciclovir (n = 9). Valaciclovir, the l-valyl ester of acylclovir, was rapidly absorbed and converted to acyclovir, with plasma valaciclovir concentrations generally undetectable or < or = 0.4 microgram/ml. The peak concentration of drug in plasma (Cmax) for acyclovir occurred at 1 to 2 h, and the half-life of acyclovir was 3 to 4 h in all three elderly groups. The Cmax and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) values of acyclovir obtained on days 1 and 8 indicated no unexpected accumulation at steady state. The steady-state acyclovir Cmax (4.30 and 5.98 micrograms/ml) and daily AUC0-infinity (44 and 74 h.micrograms/ml) following dosing of valaciclovir (500 and 1,000 mg) three times a day were two to three times greater than those expected after high-dose oral acyclovir treatment (800 mg, five times daily). There were no valaciclovir-related changes or abnormalities in safety parameters and no reports of serious adverse experiences in these elderly volunteers. The plasma acyclovir concentration-time curves for the hypertensive and normotensive (500-mg valaciclovir treatment) elderly groups were almost superimposable, and acyclovir pharmacokinetic parameters for the two groups were not significantly different, indicating that concomitant thiazide diuretics do not alter acyclovir pharmacokinetics following valaciclovir dosing in the elderly. Compared with historical data for younger volunteers (creatinine clearance [CLCR] > 75 ml/min/1.73 m2), the elderly subjects (CLCR = 40 to 65 ml/min/1.73 m2) showed higher (approximately 15 to 20%) mean Cmaxs and higher (approximately 30 to 50%) mean AUC(0-infinity)s of acyclovir (P < 0.01), which were consistent with age-related decreases in CLCR. The increased acyclovir exposure from valaciclovir dosing will permit reduced dosing frequency and may result in improved efficacy in the management of herpesvirus diseases.

Acyclovir↗
PubMed1996

Safety and pharmacokinetics of 5-chloro-2',3'-dideoxy-3'-fluorouridine (935U83) following oral administration of escalating single doses in human immunodeficiency virus-infected adults.

5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a nucleoside analog reverse transcriptase inhibitor that has demonstrated selective anti-human immunodeficiency virus (HIV) activity in vitro and favorable safety profiles in monkeys and mice. A phase I study was conducted to evaluate the safety and pharmacokinetics of six escalating single oral doses of 935U83 in 12 HIV-infected adults. The effect of a high-fat meal on the oral bioavailability of 935U83 was also assessed. The volunteers enrolled had CD4+ cell counts ranging from < 50 to 753 cells per mm3 (median, 198). In the dose range of 100 to 1,500 mg 935U83 was well tolerated by all subjects with no drug-related adverse events reported. No significant clinical or laboratory abnormalities were observed throughout the study. 935U83 was rapidly and well absorbed following oral administration with peak plasma concentrations (Cmax) occurring at 0.8 to 1.3 h postdosing. Mean Cmax and AUC0-infinity values of 935U83 were nearly dose proportional in the 100- to 1,500-mg dose range (from 2.4 to 30 micrograms/ml and from 3.4 to 59 h.micrograms/ml, respectively). Elimination of 935U83 from the plasma was rapid, with an apparent half-life of 1.3 to 1.7 h which was independent of the dose level. Administration of 935U83 with a high-fat meal decreased the rate of 935U83 absorption (mean Cmax decreased by approximately 50% and mean time to Cmax increased by approximately 1 h) but did not affect the extent of oral bioavailability (AUC0-infinity) of 935U83. The 5'-O-glucuronide conjugate was the principal metabolite of 935U83 and was present in the plasma of all volunteers at concentrations lower than 935U83. The molar AUC0-infinity ratio (935U83 glucuronide to the parent compound) was similar across all dose levels (mean, 21 to 27%). At least 60% of the 935U83 dose was absorbed, and approximately an equal percentage of the dose (approximately 30%) was excreted as unchanged 935U83 and as 935U83 glucuronide. Systemic exposure to 935U83 at levels exceeding its average in vitro antiretroviral 50% inhibitory concentration (approximately 0.5 microgram/ml or 1.8 microM) can be achieved after a single oral dose.

Administration, Oral↗
PubMed1994

An unusual vascular hamartoma on the gingiva of an 11-year-old boy.

A case is reported of an unusual vascular lesion on the gingiva of an 11-year-old boy which clinically and histopathologically did not fit well into any current classification of vascular lesions. The lesion presented as a firm nodular swelling of the buccal and lingual gingiva which had been present for 9 years. The term endovascular papillary haemangioma is suggested. Histopathologically it had features in common with a number of benign vascular lesions, as well as with some more sinister locally-aggressive vascular tumours and angiosarcomas. It is stressed that, although some of these lesions may display features suggestive of malignancy, care should be exercised when making this diagnosis, as in recent years there has been an increase in the recognition and characterization of benign vascular lesions which exhibit unusual features.

Child↗
PubMed1994

Phase I trial of valaciclovir, the L-valyl ester of acyclovir, in patients with advanced human immunodeficiency virus disease.

Valaciclovir, the L-valyl ester of acyclovir, is rapidly and extensively converted in humans to acyclovir after oral administration by first-pass metabolism. A phase I study was conducted in two cohorts of volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count of < 150 cells per microliters) who received oral valaciclovir at dosages of 1,000 or 2,000 mg four times daily for 30 days. All patients were clinically stable without any changes in underlying HIV-related medications for > or = 6 weeks prior to entry in study; these medications were continued throughout the study. Multiple-dose administration of valaciclovir showed a generally favorable safety profile. Nausea, vomiting, diarrhea, and abdominal pain each were reported in < or = 31% of the patients; of these symptoms, only one episode of diarrhea was considered causally related to valaciclovir exposure. Four patients developed neutropenia (two at each dose level) which was not clinically significant. There were no renal or neurologic adverse events. Valaciclovir was rapidly absorbed and converted to acyclovir, with plasma valaciclovir levels generally undetectable or levels of < or = 0.4 microgram/ml. After 3 h postdosing, valaciclovir was not detectable in plasma. Acyclovir was measurable in plasma as early as 15 min following valaciclovir dosing, and plasma concentrations of acyclovir greatly exceeded those of valaciclovir. The mean values for the maximum concentration of drug in plasma, time to maximum concentration of drug in plasma, area under the concentration-time curve from 0 h to infinity, and apparent half-life of acyclovir obtained after single- and multiple-dose valaciclovir administration in HIV-infected patients were similar to those reported in normal healthy volunteers. The time to maximum concentration in serum and half-life of acyclovir after valaciclovir administration were approximately 2 and 3 h, respectively, which were similar to those reported after oral administration of acyclovir itself. The mean trough and peak acyclovir concentrations and the daily area under the concentration-time curve acyclovir values at steady state were 2.5 and 8.4 micrograms/ml and 120 h micrograms/ml, respectively, after a dosage of 2,000 mg of valaciclovir four times daily. These values were approximately fivefold greater than those achieved with high dosages of oral acyclovir (800 mg, five times daily) and were not affected by continued use of medications necessary for management of advanced HIV disease. Thus, 2,000 mg of valaciclovir given orally four times daily should be evaluated for its potential efficacy in suppressing cytomegalovirus and other herpes group virus infections not optimally managed with current oral acyclovir therapy.

Acyclovir↗
PubMed1993

The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Zidovudine Collaborative Working Group.

OBJECTIVES: We measured the pharmacokinetics and safety of zidovudine in pregnant women infected with human immunodeficiency virus and their offspring. STUDY DESIGN: Asymptomatic human immunodeficiency virus-infected women with uncomplicated singleton gestations (28 to 36 weeks) underwent parenteral and oral zidovudine treatment during pregnancy and labor. Maternal and neonatal drug levels were measured at delivery and sequentially for 48 hours. Infants were followed up for 18 months. RESULTS: The total body clearance (26.3 +/- 10.1 ml/min/kg), mean terminal elimination phase zidovudine half-life (1.3 +/- 0.2 hours), and urinary zidovudine recovery were similar to values in nonpregnant adults. Essentially equivalent zidovudine levels in the mother and neonate at delivery implied little, if any, fetal zidovudine metabolism. The half-life of zidovudine in the neonates was tenfold that of the mother. No significant adverse effects were noted in the infant at birth or on follow-up. CONCLUSIONS: In both mothers and infants the drug appeared safe and well tolerated with no significant hematologic abnormalities.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers.

The pharmacokinetics and safety of the L-valyl ester pro-drug of acyclovir, valaciclovir (256U87), were investigated in two phase I, placebo-controlled trials in normal volunteers. These included a single-dose study with doses from 100 to 1000 mg (single cohort) and a multiple-dose investigation with doses from 250 to 2000 mg (five separate cohorts). In each cohort, eight subjects received valaciclovir and four subjects received placebo. Pharmacokinetic findings for valaciclovir and acyclovir were consistent in the two studies. Valaciclovir was rapidly and extensively converted to acyclovir, resulting in significantly greater acyclovir bioavailability (approximately threefold to fivefold) compared with that historically observed with high-dose (800 mg) oral acyclovir. At the higher valaciclovir doses, acyclovir maximum concentration and daily area under the concentration-time curve approximated those obtained with intravenous acyclovir. The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administration has prompted additional clinical evaluations for zoster and herpes simplex virus treatment, as well as cytomegalovirus suppression in immunocompromised patients.

Acyclovir↗
PubMed1993

Soft tissue chondroma of the cheek.

Soft tissue chondromas are rare benign tumours unrelated to bone that arise primarily in the distal extremities. Lesions in the soft tissues of the oral cavity are extremely rare although several chondromatous lesions have been reported in the tongue. A case is presented of a chondroma arising in the buccal mucosa. It was composed of a lobulated mass of myxoid tissue showing central areas of chondroid differentiation. Immunocytochemistry confirmed the lesion to be mesenchymal and not epithelial in origin. In the differential diagnosis it is important to exclude chondromatous change in a pleomorphic adenoma and also the possibility of a metastasis from an osseous chondrosarcoma.

Cheek↗
PubMed1992

Hyperthermia-induced enhancement of melphalan activity against a melphalan-resistant human rhabdomyosarcoma xenograft.

The effects of regional hyperthermia (42 degrees C for 70 min) on the antitumor activity of melphalan were examined in athymic mice bearing melphalan-resistant human rhabdomyosarcoma (TE-671 MR) xenografts growing in the right hind limb, and results were compared with similar studies of melphalan-sensitive (TE-671) parent xenografts. Melphalan alone at a dose of 36 mg/m2 (0.5 of the 10% lethal dose) produced growth delays of 4.1 to 10.2 days in TE-671 MR xenografts and 21.8 to 28.7 days in TE-671, respectively. Hyperthermia alone produced growth delays of 0.9 days in TE-671 MR xenografts and 0.8 days in TE-671. Combination therapy with melphalan and hyperthermia produced growth delays of 7.2 to 13.3 days in TE-671 MR xenografts and 34.3 to 42.8 days in TE-671, respectively, representing a mean thermal enhancement ratio of 1.7 in TE-671 MR and 1.5 in TE-671. Measurement of glutathione levels in TE-671 MR xenografts following treatment with melphalan, hyperthermia, or melphalan plus hyperthermia revealed significant reductions in glutathione content with the nadir (60% of control values) seen 6 h following treatment. Glutathione levels in TE-671 xenografts following identical therapy revealed no differences from control values. Hyperthermia plus melphalan did not result in a higher tumor-to-plasma melphalan ratio compared with treatment with melphalan alone in either TE-671 MR or TE-671 xenografts. These studies suggest that heat-induced alterations in tumor glutathione or melphalan levels are not responsible for the increase in melphalan activity produced by hyperthermia. Combination therapy with melphalan plus regional hyperthermia offers promise for treatment of melphalan-resistant neoplasms.

Animals↗
PubMed1991

Therapeutic analysis of melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR.

Investigations with the melphalan-resistant human rhabdomyosarcoma xenograft TE-671 MR were carried out to identify patterns of cross-resistance and collateral sensitivity and to define the mechanism(s) mediating melphalan resistance. TE-671 MR was cross-resistant to thio-TEPA, mitomycin, vincristine, and cisplatin, and partially resistant to chlorambucil and cyclophosphamide. TE-671 MR and the parent line TE-671 were both resistant to 1,3-bis(2-chloroethyl)-nitrosourea and expressed similar levels of O6-alkylguanine-DNA alkyltransferase. TE-671 MR retained full sensitivity to actinomycin D and demonstrated enhanced sensitivity to VP-16 compared to TE-671. Treatment of TE-671 MR with melphalan plus VP-16 resulted in greater than additive growth delays. The frequency of hypoxic regions was similar in TE-671 MR and TE-671, respectively. Measurement of tumor-to-plasma levels at 180 min following i.p. administration of melphalan at 0.5 of the 10% lethal dosage showed mean tumor-to-plasma ratios of 3.81 in TE-671 MR and 7.38 in TE-671, respectively. The lower drug levels in TE-671 MR may be contributing to the resistance to melphalan and thus indicate the need for further studies to define the reasons for these differences in tumor drug level.

Animals↗
PubMed1989

A phase I clinical and pharmacological study of weekly intravenous infusions of piritrexim (BW301U).

Thirty-eight patients with advanced resistant cancers were enrolled on this study of piritrexim (PTX; BW 301U) administered intravenously weekly for 4 weeks. Of 50 courses of treatment begun, 39 evaluable 4-week courses of the drug were completed by this group of patients. Dosages ranged from 44 to 530 mg/m2/week. One patient at each dosage level received an initial weekly dose of PTX in oral form accompanied by pharmacokinetic blood sampling after the oral dose and also after a subsequent intravenous dose. Toxicities included mild nausea and vomiting, and moderate to severe peripheral vein phlebitis. Anemia and thrombocytopenia were the dominant hematological toxicities. One patient with pulmonary metastases from malignant fibrous histiocytoma experienced a 12-week partial response to PTX treatment at a dosage of 400 mg/m2/week. Pharmacokinetic analysis of plasma for PTX concentrations was accomplished utilizing a competitive protein binding assay. The estimated total body clearance ranged from 136 to 173 ml/min/1.73 m2. Mean terminal half-life after intravenous administration was 5.61 +/- 2.38 h (S.D.), and after oral administration was 5.72 +/- 2.04 h. Mean systemic bioavailability after oral administration was 75 +/- 56%.

Adult↗
PubMed1989

Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS-related complex.

The anti-human immunodeficiency virus drug zidovudine is metabolized extensively in human beings to the 5'-glucuronide (GAZT) and is cleared rapidly, resulting in a short half-life and the need for frequent dosing. This study explores whether probenecid, which is also metabolized by glucuronidation, reduces zidovudine clearance when zidovudine is administered orally to patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The mean zidovudine plasma levels were significantly higher after concurrent administration of probenecid than in its absence, resulting in a twofold increase in the mean AUC, a corresponding decline in the apparent total clearance, and a prolongation in the mean half-life. Similar alterations were observed in GAZT disposition. There was a marked reduction in the urinary excretion ratio of GAZT to zidovudine and a decline in the renal clearance of GAZT after probenecid coadministration. Probenecid inhibits zidovudine glucuronidation and renal excretion of GAZT.

AIDS-Related Complex↗
PubMed1989

Bioequivalence assessment of zidovudine (Retrovir) syrup, solution, and capsule formulations in patients infected with human immunodeficiency virus.

The objectives of this open-labeled, multiple-dose, three-way-crossover trial were to evaluate the safety and tolerance of zidovudine (Retrovir) oral syrup and to assess the bioequivalence of this formulation relative to zidovudine solution and capsule formulations in human immunodeficiency virus-infected patients. Over the 7-day study, 12 adult male subjects received 12 administrations each of the capsule, solution, and syrup formulations every 4 h (six times daily) in a randomized sequence. Frequent blood samples were collected over the 4-h period after dose 12 was administered. Zidovudine concentrations in plasma were determined by a specific and sensitive radioimmunoassay. Results from statistical analyses indicated that all three formulations were bioequivalent with respect to systemic availability (area under the time-concentration curve) and that the syrup was also equivalent to the solution with respect to the maximum peak concentration in serum. The lower relative maximum peak concentration in serum (approximately 81%) and small delays in time to peak concentration (less than 30 min) of the capsule formulation as compared with the liquid formulations are thought to be due to the additional processes of disintegration and dissolution associated with capsule administration. All three preparations were well tolerated during the 7-day study.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma.

Melphalan transport, glutathione levels, and glutathione-S-transferase activity were measured in two continuous human medulloblastoma cell lines and transplantable xenografts in athymic nude mice, TE-671 and Daoy. In vitro mean glutathione levels were 10.06 nmol/10(6) cells in TE-671 and 2.96 nmol/10(6) cells in Daoy. In vitro mean glutathione-S-transferase values were 91.52 nmol/min/mg protein in TE-671 and 50.31 nmol/min/mg protein in Daoy. Transport studies revealed kinetic parameters of Km = 108.3 microM, Vmax = 363.1 pmol/10(6) cells/min in TE-671 and Km = 111.7 microM, Vmax = 180.6 pmol/10(6) cells/min in Daoy. Melphalan transport was inhibited by both DL-alpha-2-aminobicyclo[2.2.1]heptane-2- carboxylic acid and sodium ion depletion in TE-671 and Daoy cells in vitro, indicating that both systems of amino acid transport are functional in these medulloblastoma lines. In vivo s.c. xenograft glutathione values were lower (7.79 nmol/mg protein) in TE-671 than in Daoy (13.68 nmol/mg protein). The mean plasma concentration in mice given a 10% lethal dose (71.3 mg/m2) of melphalan i.p. was 50.3 microM at 10 min, with the half-life of 29.9 min. At this dose, s.c. xenograft levels were 2- to 3-fold higher in TE-671 than in Daoy tumors for the 3-h period measured. These studies demonstrate transport parameters confirming facilitated transport of melphalan in human medulloblastoma, a mean murine plasma melphalan concentration (following treatment with melphalan) above the in vitro drug dose at which there is a 90% reduction in the number of colonies in comparison to controls for TE-671 and Daoy for 2 h, and glutathione and glutathione-S-transferase levels in the same range previously reported in other melphalan-sensitive and melphalan-resistant human tumors. Future work with spontaneous and acquired melphalan-resistant human medulloblastoma cell lines and xenografts will define the role of these mechanisms in mediating drug resistance.

Animals↗
PubMed1988

Pharmacokinetics and bioavailability of zidovudine in humans.

The basic pharmacokinetic and bioavailability information on zidovudine was obtained during the initial phase I study. Following intravenous doses of 1.0 mg/kg every eight hours to 7.5 mg/kg every four hours, zidovudine plasma levels decay in a biexponential manner, indicating two-compartment pharmacokinetics. The mean half-life was 1.1 hours over this dose range and the total body clearance was approximately 1,900 ml/minute/70 kg, up to doses of 5 mg/kg. At 7.5 mg/kg, total body clearance decreased by 35 percent. The 5'-O-glucuronide was identified as a major metabolite of zidovudine in plasma and urine. This inactive metabolite is rapidly formed and cleared from plasma, with a half-life of one hour. No other metabolites have been found in humans. Renal clearance of zidovudine was estimated at 350 ml/minute/70 kg. Zidovudine penetrated the blood brain barrier as indicated by a cerebrospinal fluid:plasma ratio averaging 0.5, determined two to four hours after dosing. Following oral administration of zidovudine at doses from 2.0 mg/kg every eight hours to 10 mg/kg every four hours, peak plasma levels increased proportionately with dose; the average bioavailability was 65 percent. Since 90 percent of the drug was recovered in the urine as zidovudine or the 5'-O-glucuronide, the incomplete bioavailability is assumed to be the result of first-pass metabolism rather than incomplete absorption. Pharmacokinetic questions related to optimal use of the drug are currently being addressed.

AIDS-Related Complex↗