Effects of ritonavir-boosted lopinavir on the pharmacokinetics of quinine.

The centuries-old antimalarial drug, quinine, continues to play a critical role in the treatment of severe falciparum malaria and uncomplicated malaria in pregnant women. It shares cytochrome P450 (CYP )-mediated metabolic pathways with several commonly used antiretroviral drugs, raising the potential for clinically important drug­drug interactions. A phase I pharmacokinetic study was conducted to assess the impact of long-term use of ritonavir-boosted lopinavir (LPV/r) on quinine pharmacokinetics in healthy volunteers. LP V/r significantly decreased the exposure of quinine and its major active metabolite, 3-hydroxyquinine, in both total and free (unbound) forms. These findings highlight the complex nature of the influence exerted by LPV/r on several of the drug-metabolizing enzymes involved in quinine disposition,including CYP 3A4, UDP-glucuronosyltransferase (UG T), and P-glycoprotein (P-gp). A decline in quinine exposure may compromise clinical efficacy. Further studies are warranted to assess changes in quinine pharmacokinetics and treatment outcomes in patients with acute malaria receiving antiretroviral therapy that includes LPV/r.

Factors influencing nerve regeneration in a trial of timcodar dimesylate.

The authors assessed the ability of the neurophilin compound, timcodar dimesylate, to accelerate the return of epidermal nerve fiber density (ENFD) after a standardized nerve injury in a randomized double blind, placebo controlled trial. While there was no difference in the regeneration rate between the treatment and placebo arms, the baseline ENFD (p = 0.006), height (p = 0.02), and race (p = 0.03) were associated with the regeneration rate.

Adverse intraoperative medical events and their association with anesthesia management strategies in cataract surgery.

OBJECTIVE: To compare adverse medical events by different anesthesia strategies for cataract surgery. DESIGN: Prospective cohort study. PARTICIPANTS: Patients 50 years of age and older undergoing 19,250 cataract surgeries at nine centers in the United States and Canada between June 1995 and June 1997. INTERVENTION: Local anesthesia applied topically or by injection, with or without oral and intravenous sedatives, opioid analgesia, hypnotics, and diphenhydramine (Benadryl). MAIN OUTCOME MEASURES: Intraoperative and postoperative adverse medical events. RESULTS: Twenty-six percent of surgeries were performed with topical anesthesia and the remainder with injection anesthesia. There was no increase in deaths and hospitalizations associated with any specific anesthesia strategy. No statistically significant difference was observed in the prevalence of intraoperative events between topical and injection anesthesia without intravenous sedatives (0.13% and 0.78%, respectively). The use of intravenous sedatives was associated with a significant increase in adverse events for topical (1.20%) and injection anesthesia (1.18%), relative to topical anesthesia without intravenous sedation. The use of short-acting hypnotic agents with injection anesthesia was also associated with a significant increase in adverse events when used alone (1.40%) or in combination with opiates (1.75%), sedatives (2.65%), and with the combination of opiates and sedatives (4.04%). These differences remained after adjusting for age, gender, duration of surgery, and American Society of Anesthesiologists risk class. CONCLUSIONS: Adjuvant intravenous anesthetic agents used to decrease pain and alleviate anxiety are associated with increases in medical events. However, cataract surgery is a safe procedure with a low absolute risk of medical complications with either topical or injection anesthesia. Clinicians should weigh the risks and benefits of their use for individual patients.

Injectable versus topical anesthesia for cataract surgery: patient perceptions of pain and side effects. The Study of Medical Testing for Cataract Surgery study team.

OBJECTIVE: To compare patient reports of intraoperative pain and postoperative side effects by different anesthesia strategies for cataract surgery. DESIGN: Prospective cohort study. PARTICIPANTS: Men and women 50 years of age and older undergoing 19,250 cataract surgeries at nine centers in the United States and Canada from June 1995 through June 1997. INTERVENTION: Topical anesthesia or anesthesia with injection, with or without sedatives, opioid analgesia, hypnotics, and diphenhydramine (Benadryl). MAIN OUTCOME MEASURES: Patient ratings of intraoperative pain, satisfaction with pain management, and early postoperative side effects (drowsiness, nausea, vomiting, or a combination thereof). RESULTS: Twenty-six percent of surgeries were performed using topical anesthesia alone, and the remainder were performed with peribulbar, retrobulbar, or facial nerve block, or a combination thereof. Local anesthesia by injection with sedatives and diphenhydramine resulted in the lowest reporting of any intraoperative pain (1.3%), with postoperative drowsiness (9.6%) and nausea, vomiting, or both (1.5%) comparable with those administered topical anesthesia alone. Among those receiving topical anesthesia, use of sedatives and opioids reduced reports of any pain during surgery by 56% (95% confidence interval [CI], 34%, 70%), but increased nausea and vomiting (odds ratio, 2.27; 95% CI, 1.26, 4.09) compared with those administered topical anesthesia alone, after adjusting for age, gender, race, American Society of Anesthesiologists risk class, self-reported health status, and duration of surgery. Among those receiving local injections, use of opioids reduced reports of any pain among those receiving sedatives by 37% (95% CI, 15%, 54%), but did not increase postoperative side effects. The use of diphenhydramine among those receiving sedatives decreased reports of any pain by 59% (95% CI, 33%, 75%) and also reduced drowsiness and nausea and vomiting by 57% (95% CI, 48%, 65%) and by 60% (95% CI, 36%, 75%), respectively. Use of hypnotics with sedatives was associated with increased reports of any pain during surgery and increased nausea and vomiting after surgery. CONCLUSIONS: Patient reports of any pain during cataract surgery (5%) and postoperative side effects (16% drowsiness and 4% nausea and vomiting) were low, but varied by anesthesia strategy. Patient perceptions of pain and side effects can be helpful in guiding the appropriate choice of anesthesia strategy.

The value of routine preoperative medical testing before cataract surgery. Study of Medical Testing for Cataract Surgery.

BACKGROUND: Routine preoperative medical testing is commonly performed in patients scheduled to undergo cataract surgery, although the value of such testing is uncertain. We performed a study to determine whether routine testing helps reduce the incidence of intraoperative and postoperative medical complications. METHODS: We randomly assigned 19,557 elective cataract operations in 18,189 patients at nine centers to be preceded or not preceded by a standard battery of medical tests (electrocardiography, complete blood count, and measurement of serum levels of electrolytes, urea nitrogen, creatinine, and glucose), in addition to a history taking and physical examination. Adverse medical events and interventions on the day of surgery and during the seven days after surgery were recorded. RESULTS: Medical outcomes were assessed in 9408 patients who underwent 9626 cataract operations that were not preceded by routine testing and in 9411 patients who underwent 9624 operations that were preceded by routine testing. The most frequent medical events in both groups were treatment for hypertension and arrhythmia (principally bradycardia). The overall rate of complications (intraoperative and postoperative events combined) was the same in the two groups (31.3 events per 1000 operations). There were also no significant differences between the no-testing group and the testing group in the rates of intraoperative events (19.2 and 19.7, respectively, per 1000 operations) and postoperative events (12.6 and 12.1 per 1000 operations). Analyses stratified according to age, sex, race, physical status (according to the American Society of Anesthesiologists classification), and medical history revealed no benefit of routine testing. CONCLUSIONS: Routine medical testing before cataract surgery does not measurably increase the safety of the surgery.

Tolerability of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy subjects.

This phase I, double-blind, randomized, placebo-controlled study evaluated the safety of single and multiple (daily for 7 days) subcutaneous administrations of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy human volunteers at seven doses, ranging from 3 to 500 microg/kg/day. No serious or life-threatening adverse events occurred. The most frequently recorded adverse effects were mild injection-site pain, diarrhea, and elevation of liver function tests. No change in neurologic function was noted with these dosing regimens. We conclude that r-metHuNT3 is safe and well tolerated in the dosages used in this study.

Escalating multiple-dose safety and tolerance study of oral WR 6026 in HIV-infected subjects: AIDS clinical trials group 173.

WR 6026 is an 8-aminoquinoline with activity against Pneumocystis carinii in vitro and in an animal model of P. carinii pneumonia that has predicted the clinical utility of related compounds. This study was conducted to assess the safety and tolerance of WR 6026 given once daily for 21 days to HIV-infected subjects with CD4 counts <500 cells/microl. This double-blind, placebo-controlled study employed WR 6026 doses starting at 30 mg once daily and increasing to 60, 90, 120, or 150 mg once daily. Weekly visits for clinical and laboratory monitoring were conducted. Forty-nine study subjects, including 25 subjects with CD4 counts <200 cells/microl and 12 subjects with CD4 counts <100 cells/microl, entered the study. The maximum tolerated dose was 120 mg/day. Dose-limiting methemoglobinemia (>20%) was seen in 3 of 6 study subjects who received 150 mg/day for > or =19 days. Methemoglobin level was correlated with peak plasma WR 6026 concentrations. Three other study subjects developed skin rashes that may have been drug-related, and two developed asymptomatic serum triglyceride levels >1000 mg/dl. We conclude that WR 6026 is well tolerated at doses up to 120 mg/day for 21 days in HIV-infected volunteers including those with CD4 counts <200 cells/microl. Methemoglobinemia appears to be the primary dose-limiting toxicity.

Clinical pharmacokinetics of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine in human immunodeficiency virus-infected patients.

The pharmacokinetics and bioavailability of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosi ne (cyclic HPMPC) were examined at four doses in 22 patients with human immunodeficiency virus infection. Two groups of six patients received a single dose of cyclic HPMPC at 1.5 or 3.0 mg/kg of body weight by each of the oral and intravenous routes in a random order with a 2-week washout period between administrations. Additional patients received single intravenous doses of cyclic HPMPC at 5.0 mg/kg (n = 6) or 7.5 mg/kg (n = 4). Serial serum and urine samples were collected at intervals over 24 h after dosing. The concentrations of cyclic HPMPC and cidofovir in serum and urine samples were determined by validated reverse-phase ion-pairing high-performance liquid chromatography methods with derivatization and fluorescence detection. After intravenous administration of cyclic HPMPC, concentrations of cyclic HPMPC declined in a biexponential manner, with a mean +/- standard deviation half-life of 1.09 +/- 0.12 h (n = 22). The pharmacokinetics of cyclic HPMPC were independent of dose over the dose range of 1.5 to 7.5 mg/kg. The total clearance of cyclic HPMPC from serum and the volume of distribution of intravenous cyclic HPMPC were 198 +/- 39.6 ml/h/kg and 338 +/- 65.1 ml/kg, respectively (n = 22). The renal clearance of cyclic HPMPC (132 +/- 27.3 ml/h/kg; n = 22) exceeded the creatinine clearance (86.2 +/- 16.3 ml/h/kg), indicating active tubular secretion. The cyclic HPMPC excreted in urine in 24 h accounted for 71.3% +/- 16.0% of the administered dose. Cidofovir was formed from cyclic HPMPC in vivo with a time to the maximum concentration in serum of 1.64 +/- 0.23 h (n = 22). Cidofovir levels declined in an apparent monoexponential manner, with a mean terminal half-life of 3.98 +/- 1.26 h (n = 22). The cidofovir excreted in urine in 24 h accounted for 9.40% +/- 2.33% of the administered cyclic HPMPC dose. Exposure to cidofovir after intravenous administration of cyclic HPMPC was dose proportional and was 14.9% of that from an equivalent dose of cidofovir. The present study suggests that intravenous cyclic HPMPC also has a lower potential for nephrotoxicity in humans compared to that of intravenous cidofovir. The oral bioavailabilities of cyclic HPMPC were 1.76% +/- 1.48% and 3.10% +/- 1.16% with the administration of doses of 1.5 and 3.0 mg/kg, respectively (n = 6 per dose). The maximum concentrations of cyclic HPMPC in serum were 0.036 +/- 0.021 and 0.082 +/- 0.038 microgram/ml after the oral administration of doses of 1.5 and 3.0 mg/kg, respectively. Cidofovir reached quantifiable levels in the serum of only one patient for each of the 1.5- and 3.0-mg/kg oral cyclic HPMPC doses.

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.

Effects of randomizing second eyes in a trial to evaluate preoperative medical testing for cataract surgery.

The statistical and practical implications of including second eye surgeries were examined in a clinical trial designed to evaluate the impact of routine preoperative testing prior to cataract surgery on major medical events occurring within seven days following surgery. In order to detect a 0.8% difference in the rates of rare major medical events between the tested and untested groups, 20,000 surgeries must be randomized. About 30% of cataract operations were estimated to be done on second eyes of patients already included in the cohort. Different options for dealing with second eye surgeries were: (1) exclusion of all second eye surgeries, (2) inclusion of second eye surgeries only if the first eye is not enrolled, (3) inclusion of first and second eyes but randomization of patients rather than eyes, and (4) inclusion of first and second eyes but randomization of surgeries rather than patients. The final decision was to exclude second eye surgeries done within 28 days of first eye surgeries, but to rerandomize all other second eye surgeries. Differences in event rates between treatment groups can be estimated using Generalized Estimating Equations, and the association between outcomes of first and second eye operations estimated with pairwise odds ratios. An anticipated small positive correlation is likely to have minimal impact on statistical power and effective sample size.

Pharmacokinetics and safety of a single dose of stavudine (d4T) in patients with severe hepatic impairment.

This open-label study enrolled five subjects with biopsy-proven cirrhosis and moderate to severe hepatic impairment (Child-Pugh classification grade B or C) and five age- and gender-matched controls. All subjects received a single 40-mg oral dose of stavudine (d4T). Stavudine pharmacokinetics in subjects with hepatic impairment were similar to those in age- and gender-matched control subjects and were not substantially different from those previously observed in human immunodeficiency virus-infected patients. Based on these findings, stavudine use does not require modification of the dose or dosing interval for patients with liver disease.

Oral antibiotic treatment of right-sided staphylococcal endocarditis in injection drug users: prospective randomized comparison with parenteral therapy.

PURPOSE: To compare the efficacy and safety of inpatient oral antibiotic treatment (oral) versus standard parenteral antibiotic treatment (intravenous) for right-sided staphylococcal endocarditis in injection drug users. PATIENTS AND METHODS: In a prospective, randomized, non-blinded trial, febrile injection drug users were assigned to begin oral or intravenous (IV) treatment on admission, before blood culture results were available. Oral therapy consisted of ciprofloxacin and rifampin. Parenteral therapy was oxacillin or vancomycin, plus gentamicin for the first 5 days. Antibiotic dosing was adjusted for renal dysfunction. Administration of other antibacterial drugs was not permitted during the treatment or follow-up periods. Bacteremic subjects having right-sided staphylococcal endocarditis received 28 days of inpatient therapy with the assigned antibiotics. Test-of-cure blood cultures were obtained during inpatient observation 6 and 7 days after the completion of antibiotic therapy, and again at outpatient follow-up 1 month later. Criteria for treatment failure and for drug toxicity were prospectively defined. RESULTS: Of 573 injection drug users who were hospitalized because of a febrile illness and suspected right-sided staphylococcal endocarditis, 93 subjects (16.2%) had two or more sets of blood cultures positive for staphylococci; 85 of these bacteremic subjects (14.8%) satisfied diagnostic criteria for at least possible right-sided staphylococcal endocarditis (no other source of bacteremia was apparent) and entered the trial. Forty-four (oral, 19; IV, 25) of these 85 subjects completed inpatient treatment and evaluation including test-of-cure blood cultures. There were four treatment failures (oral, 1 [5.2%]; IV, 3 [12.0%]; not significant, Fisher's exact test). Drug toxicity was significantly more common in the parenterally treated group (oral, 3%; IV, 62%; P < 0.0001), consisting largely of oxacillin-associated increases in liver enzymes. CONCLUSIONS: For selected patients with right-sided staphylococcal endocarditis, oral ciprofloxacin plus rifampin is effective and is associated with less drug toxicity than is intravenous therapy.

Pharmacokinetics, safety and bioavailability of HPMPC (cidofovir) in human immunodeficiency virus-infected subjects.

We conducted a single-center, double-blind, placebo-controlled phase I study in HIV-positive subjects to ascertain the safety, tolerance, bioavailability, pharmacokinetics, and maximum tolerated dose of HPMPC (cidofovir). Five subjects were randomized to receive drug and two to receive placebo at each of three dosage tier (1, 3, and 10 mg/kg) with a 2-week washout period doses. Subjects at 1 and 3 mg/kg received single doses of HPMPC by subcutaneous (s.c.) intravenous (i.v.), and oral (p.o.) routes, while subjects at 10 mg/kg received only i.v. and p.o. doses. For subjects already taking zidovudine, zidovudine AUC values are determined before and then with HPMPC administration for each route. The AUC values of HPMPC were dose-proportional. Subcutaneous bioavailability was essentially equivalent to that of the intravenous route, but the development of transient local fibrosis ad the volumes needed for subcutaneous dosing precluded higher subcutaneous dosing than 3 mg/kg. Oral bioavailability was poor, estimated to be less than 5%. Drug elimination was predominantly renal. Nephrotoxicity in one subject was the only serious adverse event observed. This subject had a significant lag period prior to oral absorption and also had the highest AUC values for both HPMPC and zidovudine. We found no consistent effect on zidovudine AUC concomitant HPMPC.

Modulation of alpha-interferon's antiviral and clinical effects by aspirin, acetaminophen, and prednisone in healthy volunteers.

The magnitude and duration of the antiviral and clinical effect of alpha-interferon was measured in healthy volunteers. A single 3 million unit intramuscular dose of interferon was given either alone (controls) or after 72 h of concomitant medications. These medications included either aspirin (650 mg every 4 h), acetaminophen (650 mg every 4 h), or prednisone (40 mg per day). Peripheral blood mononuclear cells were assayed for resistance to vesicular stomatitis virus infection and induction of 2'-5'-oligoadenylate synthetase activity as evidence of interferon's antiviral effect. Co-administration of acetaminophen increased both antiviral parameters by more than 70% (P < 0.05) and reduced symptoms after interferon dosing, compared to controls. Aspirin and prednisone did not demonstrate any significant differences from controls in antiviral effect. As a group, acetaminophen, aspirin, and prednisone reduced the clinical symptoms by 47% compared to controls (P = 0.03) after interferon dosing, although individual drug comparisons failed to reach statistical significance. Independent of treatment group, the changes in antiviral markers after interferon dosing correlated closely with each other (r = 0.72, P < 0.001), but neither correlated with symptoms or fever (r < 0.30, P > 0.05). Acetaminophen enhances the antiviral effects of a single intramuscular dose of alpha-interferon, considering the parameters measured in these healthy volunteers.

Do ophthalmologists, anesthesiologists, and internists agree about preoperative testing in healthy patients undergoing cataract surgery?

To assess variation in reported use of preoperative medical tests in patients undergoing cataract surgery and to identify factors that influence test use by different physician groups we performed a national survey of ophthalmologists, anesthesiologists, and internists. Participants included randomly selected members of American professional societies who provided care to one or more patients undergoing cataract surgery in 1991. Responses were obtained from 538 (82%) of 655 eligible ophthalmologists, 109 (76%) of 143 anesthesiologists, and 54 (44%) of 122 internists. Fifty percent of ophthalmologists, 40% of internists, and 33% of anesthesiologists frequently or always obtained a chest x-ray film, while 20% of ophthalmologists, 27% of internists, and 37% of anesthesiologists never obtained a chest x-ray film for patients being considered for cataract surgery who had no history of major medical problems (P < .01 for differences between ophthalmologists and the other groups). Similarly, 70% to 90% of ophthalmologists, 73% to 79% of internists, and 41% to 79% of anesthesiologists frequently or always obtained a complete blood cell count, electrolyte panel, and electrocardiogram, while 4% to 11% of ophthalmologists, 13% to 17% of internists, and 9% to 28% of anesthesiologists never obtained these tests for such patients. Many respondents (32% to 80%) believed tests were unnecessary but cited multiple reasons for obtaining tests (eg, medicolegal concerns and institutional requirements). Many physicians in each group viewed preoperative evaluations as screening opportunities or believed that one of the other two types of physicians "required" tests. We conclude that marked variation exists within and across physician specialties in the use and rationale for use of medical tests in patients undergoing cataract surgery.

Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients.

The pharmacokinetics of cidofovir (HPMPC; (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine) were examined at five dose levels in three phase I/II studies in a total of 42 human immunodeficiency virus-infected patients (with or without asymptomatic cytomegalovirus infection). Levels of cidofovir in serum following intravenous infusion were dose proportional over the dose range of 1.0 to 10.0 mg/kg of body weight and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 h (n = 25). Approximately 90% of the intravenous dose was recovered unchanged in the urine in 24 h. The overall mean +/- standard deviation total clearance of the drug from serum (148 +/- 25 ml/h/kg; n = 25) approximated renal clearance (129 +/- 42 ml/h/kg; n = 25), which was significantly higher (P < 0.001) than the baseline creatinine clearance in the same patients (83 +/- 21 ml/h/kg; n = 12). These data indicate that active tubular secretion played a significant role in the clearance of cidofovir. The steady-state volume of distribution of cidofovir was approximately 500 ml/kg, suggesting that the drug was distributed in total body water. Repeated dosing with cidofovir at 3.0 and 10.0 mg/kg/week did not alter the pharmacokinetics of the drug. Concomitant administration of intravenous cidofovir and oral probenecid to hydrated patients had no significant effect on the pharmacokinetics of cidofovir at a 3.0-mg/kg dose. At higher cidofovir doses, probenecid appeared to block tubular secretion of cidofovir and reduce its renal clearance to a level approaching glomerular filtration.

Relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and antiretroviral activity in two concentration-controlled trials.

Two concentration-controlled trials (CCTs) defined the relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and changes in surrogate markers of antiretroviral activity. In an initial open-label CCT involving 14 subjects infected with human immunodeficiency virus (HIV), unacceptable hematologic toxicity occurred when the area under the concentration-time curve during a 12-h dosing interval (AUC12) was > or = 300 ng*h/mL. Consequently, 46 subjects were assigned to AUC12s of 50, 100, or 200 ng*h/mL for up to 16 weeks in a prospective, randomized, double-blind CCT. Alovudine caused a concentration-dependent reduction in p24 antigen and peripheral blood mononuclear cell HIV titers within 4 weeks of start of treatment. The AUC12 producing a 50% reduction in p24 (108 ng*h/mL) had a trough concentration identical to the reported IC50 of alovudine in HIV-infected H9 cells. It may be possible to predict the antiretroviral activity of certain nucleoside analogues as a function of plasma drug concentration.