Counterpoint: let's expand the formulary system and renew its vigor.
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Evaluation Studies as Topic↗
Biomedical subjects
C V Fletcher
Publications and source records attributed to C V Fletcher.
The influence of biperiden, benztropine, physostigmine and diazepam on the convulsive effects of Cicuta douglasii.
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Animals↗
Treatment of herpesvirus infections in HIV-infected individuals.
OBJECTIVE: To discuss strategies available for the treatment of herpesvirus infections in individuals infected with HIV. DATA SOURCES: Information was obtained from controlled and uncontrolled clinical trials, abstracts, conference proceedings, and review articles. STUDY SELECTION: Emphasis was placed on controlled investigations in subjects infected with HIV. DATA EXTRACTION: Data from human studies were extracted by the author and evaluated according to the patient population studied, sample size, dosage regimen, and therapeutic response. DATA SYNTHESIS: Herpes group viruses are common opportunistic pathogens in HIV-infected individuals. Zoster, caused by varicella-zoster virus (VZV), is an early indication of the loss of cell-mediated immunity and HIV disease progression. Anorectal mucocutaneous disease is the most common manifestation caused by herpes simplex virus (HSV). Acyclovir is the drug of choice for treatment of both VZV and HSV infections. Cytomegalovirus (CMV) is the most common life-threatening viral infection in patients with AIDS; retinitis is the most frequent clinical manifestation. The response rate of CMV retinitis to initial treatment with either ganciclovir or foscarnet is equivalent, approximately 60-90 percent. Recent data suggest that the survival benefit may be greater with foscarnet. CONCLUSIONS: Advances in the development and application of antiviral drugs for herpes group viruses have made treatment and, in some cases, prevention of infections possible. Future efforts, aimed at earlier intervention and suppression of latent virus, may offer additional improvement in quality of life for the HIV-infected individual.
Acquired Immunodeficiency Syndrome↗
Treatment of resistant herpes simplex virus with continuous-infusion acyclovir.
Two patients with acquired immunodeficiency syndrome who developed severe ulcerative proctitis caused by herpes simplex virus type 2 that was resistant to acyclovir were successfully treated with 6 weeks of high-dose, continuous-infusion acyclovir sodium (1.5 to 2.0 mg/kg per hour). Viruses cultured from the lesions were resistant to acyclovir in vitro after the patients had received prolonged therapy with oral and intravenous acyclovir in traditional divided doses. Investigation into the mechanism of the acyclovir resistance revealed changes in the thymidine-kinase activity of both isolates. This viral enzyme phosphorylates acyclovir and is necessary for drug activation. The first patient's isolate was deficient of all thymidine-kinase activity, while the second patient's isolate had a thymidine kinase with altered substrate specificity for acyclovir. The continuous infusion was safe, well tolerated, and done in an outpatient setting with weekly clinic visits and monitoring of creatinine and acyclovir levels.
Acquired Immunodeficiency Syndrome↗
Current perspectives on antiretroviral therapy.
Current estimates suggest that at least 1 million persons in the United States are infected with the human immunodeficiency virus (HIV), the cause of the acquired immunodeficiency syndrome. Knowledge of the life cycle of HIV has provided the fundamental information necessary to initiate programs that will identify drugs to treat the infection. Inhibition of reverse transcriptase represents the only strategy of proved clinical value. Three such drugs are available: zidovudine, didanosine, and zalcitabine. Zidovudine is the only proved agent for therapy of asymptomatic HIV infection; and for symptomatic disease, monotherapy with zidovudine must also be regarded as the first-line approach. For patients who are intolerant, are failing clinically, or have received prior long-term treatment with zidovudine, monotherapy with didanosine or zalcitabine, or a combination of zidovudine and zalcitabine are alternatives. Progress is being made in the treatment of HIV infection, but the considerable challenge to affect the inexorable progressive nature of HIV disease remains daunting.
Didanosine↗
Effects of long-term drugs on alfentanil clearance in patients undergoing renal transplantation.
Although patients in renal failure frequently take several drugs on a long-term basis, drug-induced alterations in alfentanil metabolism have not been examined as a possible source of variability in alfentanil clearance in this population. We compared the pharmacokinetics of alfentanil during renal transplantation in seven patients receiving and six not receiving long-term drug therapy. After the rapid intravenous injection of alfentanil 100 micrograms/kg during isoflurane anesthesia, plasma concentrations were measured at intervals up to 6 hours by radioimmunoassay. The terminal elimination half-life, steady-state volume of distribution (Vdss), and total body clearance were determined by noncompartmental methods. There was no statistical difference in the Vdss between the two patient groups. However, clearance was significantly higher and elimination half-life lower in the group taking long-term drugs: clearance 6.94 +/- 4.64 versus 3.47 +/- 0.16 ml.kg-1.min-1, and elimination half-life 50.6 +/- 13.9 versus 90.7 +/- 22.4 minutes, respectively (p < 0.05). The higher clearance occurred even though five of the seven patients were taking agents known to be metabolized by the same cytochrome P-450 hepatic isozyme that metabolizes alfentanil and therefore potential competitive inhibitors of alfentanil metabolism. Drugs taken by the three patients with the highest alfentanil clearances included known inducers of hepatic drug metabolism. Thus, in the presence of several long-term drugs, the clearance of alfentanil appears to be noticeably increased by inducers of hepatic drug metabolism but unaffected by potential competitive inhibitors.
Adult↗
The effect of cimetidine and ranitidine administration with zidovudine.
STUDY OBJECTIVE: To evaluate the possibility of a drug interaction with zidovudine and histamine2-receptor antagonists in individuals infected with the human immunodeficiency virus. DESIGN: Randomized crossover study. SETTING: University-affiliated research center. PATIENTS: Six HIV-infected individuals. INTERVENTIONS: The subjects received 7-day regimens of zidovudine 600 mg/day alone, zidovudine with cimetidine 1200 mg/day, and zidovudine with ranitidine 300 mg/day. MEASUREMENTS AND MAIN RESULTS: The renal clearance of zidovudine when given alone was 0.41 L/kg/hour, and was reduced to 0.18 L/kg/hour (p = 0.002) when given with cimetidine. In the presence of cimetidine the urinary excretion of zidovudine decreased from 89.5 to 53.7 microM (p = 0.01), the urinary ratio of metabolite to parent increased from 5.16 to 9.96 (p = 0.0001), and the fraction of zidovudine converted to metabolite increased from 0.86 to 0.92 (p = 0.0025). CONCLUSION: Cimetidine presumably inhibits the renal clearance of zidovudine by competing for tubular secretion. Based on the observation that neither cimetidine nor ranitidine had a significant effect on serum concentrations of zidovudine or zidovudine glucuronide, a change in the dosage of zidovudine is not warranted.
Adolescent↗
Variability in zidovudine serum concentrations.
This study explored the variability of zidovudine concentrations with computer simulations and measured concentrations. A one-compartment oral absorption model was selected to characterize zidovudine disposition. Mean (+/-standard deviation) values for the pharmacokinetic parameters were taken from the literature. Five different Monte Carlo simulations (50 each) were performed of zidovudine concentrations following repetitive administration of 100-mg oral doses 6 times/day in patients weighing 45-85 kg. A sixth simulation considered a weight-adjusted regimen. Predicted concentrations were compared with those measured in 30 HIV-infected persons receiving 100 mg/dose. Predicted concentrations 1 hour after 100 mg was administered fell in the range of 0.52-5.18 microM; measured values in 30 patients were 0.54-3.07 microM. This study confirms substantial variability in zidovudine serum concentrations. The simulation study of a weight-adjusted regimen suggests one possibility to reduce this variability. These observations provide a basis to explore dosing strategies that control for pharmacokinetic and perhaps pharmacodynamic sources of interpatient variability.
Adult↗
Pharmacokinetics and safety of concentration-controlled oral zidovudine therapy.
STUDY OBJECTIVE: To evaluate the pharmacokinetics, safety, and feasibility of concentration-controlled oral zidovudine therapy. DESIGN: Randomized, crossover, open-label study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight individuals infected with the human immunodeficiency virus with CD4+ lymphocyte counts of 100 cells/microliter or greater. INTERVENTION: During the 24-week study, patients received oral zidovudine regimens that consisted of a standard fixed dose of 500 mg/day and a concentration-controlled regimen designed to maintain a steady-state plasma concentration (Css) of 0.187 +/- 0.04 mg/L (0.7 +/- 0.14 microM). MEASUREMENTS AND MAIN RESULTS: The mean Css during standard therapy was 0.170 +/- 0.024 mg/L versus 0.205 +/- 0.021 mg/L with the concentration-controlled regimen (p = 0.025). Respective mean changes in hemoglobin were -0.02 g/dl (range -0.9-0.9 g/dl) and -0.30 g/dl (range -1.5-0.4 g/dl, p = 0.67). The absolute neutrophil count decreased 0.90 x 10(9)/L during standard therapy and increased 0.40 x 10(9)/L during concentration-controlled therapy (p = 0.07). The regimens did not differ in toxicity. CONCLUSION: Concentration-controlled oral antiretroviral therapy with zidovudine is feasible and safe, and provides pharmacologic data to determine the regimen's virologic and immunologic benefits.
Administration, Oral↗