didanosine and amprenavir

Deaths related to the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome and the incidence of opportunistic infections have been drastically decreased in the industrialized world. These reductions are mainly due to recent advances in the management of HIV infection, including the availability of new therapies. Until November 1995, the antiretroviral drugs available and approved by the Food and Drug Administration for clinical use in the United States consisted of only four nucleoside analogue reverse transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine. Since then, 2 new classes of agents and 10 new agents have been approved; thus, the number of available antiretroviral drugs has more than tripled. Additional drugs and newer classes of antiretrovirals are in various stages of development. Because of the availability of more drugs, the complexity of HIV treatment has increased. Selecting an appropriate antiretroviral therapeutic regimen involves addressing multiple interdependent issues, including patient adherence, pharmacokinetic properties of the drugs (including food effects and drug-drug interactions), drug resistance, and overlapping adverse effects.

Topics: Adolescent; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Carbamates; Cyclopropanes; Delavirdine; Didanosine; Dideoxynucleosides; Female; Furans; HIV Infections; Humans; Indinavir; Lamivudine; Nelfinavir; Nevirapine; Oxazines; Pregnancy; Pregnancy Complications, Infectious; Protease Inhibitors; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Stavudine; Sulfonamides; Zalcitabine; Zidovudine

To determine the effects of concurrent, single doses of didanosine (both buffered and encapsulated enteric-coated bead formulations) on amprenavir steady-state pharmacokinetics, and to determine the effect of staggered dosing of the buffered formulation.. Two-period, single-sequence, prospective, open-label drug interaction study with a 10-day washout interval.. Clinical research unit.. Sixteen healthy volunteers without human immunodeficiency virus infection.. Amprenavir 600 mg twice/day was given for the first 4 days of each treatment period, with 12-hour pharmacokinetic evaluations conducted on the last 2 days of each period. Amprenavir was administered according to the following sequential treatments (all fasting): amprenavir alone, concurrent with buffered didanosine, 1 hour before buffered didanosine, and concurrent with the encapsulated enteric-coated bead formulation of didanosine.. Plasma was collected 0, 1, 2, 3, 4, 6, 8, and 12 hours after dosing and assayed for amprenavir by using high-performance liquid chromatography. Noncompartmental pharmacokinetic parameters were determined. Geometric mean ratios for each treatment relative to amprenavir alone were determined and reported with 90% confidence intervals (CIs). No significant trends were noted in predose concentrations measured during either period. Area under the concentration-time curve during one 12-hour dosing interval (AUC12) was found to be bioequivalent for all treatments. Peak drug concentration (Cmax) was reduced by 15% on average with concurrent administration of buffered didanosine, and bioequivalence was not demonstrated for this parameter. For concurrent enteric-coated didanosine, geometric mean ratios for Cmax and AUC12 were 0.93 and 0.94, respectively. For buffered didanosine given 1 hour after amprenavir, geometric mean ratios were 1.06 and 1.10 for the same parameters, respectively. No differences were observed in 12-hour concentration (C12) with concurrent administration of buffered or enteric-coated didanosine.. Amprenavir AUC12 and C12 are not significantly affected by concurrent administration of the buffered or enteric-coated formulations of didanosine. Therefore, amprenavir may be administered concurrently with either the buffered or the encapsulated enteric-coated bead formulation of didanosine in the fasting state.

Topics: Administration, Oral; Adult; Anti-HIV Agents; Area Under Curve; Capsules; Carbamates; Cross-Over Studies; Didanosine; Drug Interactions; Drug Therapy, Combination; Female; Furans; Humans; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Sulfonamides; Tablets, Enteric-Coated; Time Factors

The interest in therapeutic drug monitoring (TDM) of antiretroviral drugs has grown significantly since highly active antiretroviral therapy (HAART) became a standard of care in clinical practice. TDM is useful to determine the best dosage regimen adapted to each patient. Here, we apply MALDI-TOF/TOF technology to quantify abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine in the plasma of HIV-infected patients, by standard additions analysis. Regression of standard additions was linear over the whole anti-HIV concentration range explored (1.00 x 10(-2)-1.00 pmol/microL). The absolute recovery ranged between 80% and 110%. Values of the drug concentration determined by MALDI-TOF/TOF were in the range of 1.00 x 10(-2)-1.00 pmol/microL. The limit of quantification value was 1.00 x 10(-2)pmol/microL for abacavir, amprenavir, didanosine, efavirenz, nevirapine, and stavudine.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Carbamates; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Monitoring; Feasibility Studies; Furans; Humans; Molecular Structure; Nevirapine; Reverse Transcriptase Inhibitors; Sensitivity and Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spectrophotometry, Ultraviolet; Stavudine; Sulfonamides

To examine the effect of antiretroviral agents and clinical factors on the development of tenofovir-associated kidney dysfunction.. Observational cohort study of HIV-infected patients receiving tenofovir in an HIV clinic population. Patients' kidney function prior to initiating and while receiving tenofovir was evaluated in relation to other antiretroviral medications and demographic and clinical characteristics. Decline in kidney function was assessed by the glomerular filtration rate (GFR) as estimated by the Cockcroft-Gault (CG) equation, which incorporates weight. Logistic regression analysis was used to examine factors associated with GFR of > 90, 60-90, 30-60, and < 30 ml/min per 1.73 m(2) while on tenofovir. Secondary analyses used the simplified Modification of Diet in Renal Disease (MDRD) equation.. Among the 445 patients initiating tenofovir, 51 (11%) developed a decline in kidney function. In multivariate analysis, there was a significant association between decline in kidney function and concurrent use of amprenavir [odds ratio (OR) 3.6; P = 0.045] and didanosine (OR, 3.1; P = 0.006), age over 50 years (OR, 4.4; P = 0.03), and lower baseline weight (OR, 0.95/kg; P < 0.001). Patients identified with kidney dysfunction by the MDRD equation did not fully overlap with those identified by the CG equation.. Didanosine and amprenavir use, increased age, and lower baseline weight were significantly associated with risk for kidney dysfunction among patients receiving tenofovir. GFR results using the MDRD equation were inconsistent with those using CG, which highlights the impact of including weight in the estimation of GFR among HIV-infected patients.

Topics: Adenine; Adult; Age Factors; Analysis of Variance; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Body Weight; Carbamates; Creatinine; Didanosine; Drug Interactions; Female; Furans; Glomerular Filtration Rate; HIV Infections; HIV-1; Humans; Kidney; Linear Models; Male; Middle Aged; Organophosphonates; Sulfonamides; Tenofovir; Time Factors

We report a case of small cell lung cancer in a patient with human immunodeficiency virus (HIV) infection. The patient was a 51-year-old man diagnosed 8 years previously as seropositive for HIV, who was admitted to our hospital for re-evaluation of antiretroviral medications due to multidrug resistance. Chest radiograph revealed an abnormal hilar shadow subsequently confirmed to be small cell lung cancer. He received chemotherapy concurrently with highly active antiretroviral therapy (HAART), and lived for 14 months after the diagnosis. The prognosis of lung cancer in HIV-seropositive patients is very poor, and adverse effects of chemotherapy occur more frequently than in other patients. However, the simultaneous antiretroviral agents and combination chemotherapy was successful. Such treatment may be effective despite an otherwise poor prognosis, including HIV infection.

Topics: Alkynes; Anti-HIV Agents; Antineoplastic Combined Chemotherapy Protocols; Antiretroviral Therapy, Highly Active; Benzoxazines; Camptothecin; Carbamates; Carboplatin; Carcinoma, Small Cell; Cisplatin; Cyclopropanes; Didanosine; Dideoxynucleosides; Drug Administration Schedule; Furans; HIV Infections; HIV Long-Term Survivors; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Oxazines; Ritonavir; Sulfonamides; Tomography, X-Ray Computed

We report a case of antiretroviral therapy-related fatal lactic acidosis occurring in a vertically infected HIV-positive 17-year-old patient. While receiving antiretroviral therapy with stavudine, didanosine, tenofovir and amprenavir, the patient developed severe acidosis and rapid neuromuscular and respiratory failure mimicking Guillain-Barré syndrome.

Topics: Acidosis, Lactic; Adenine; Adolescent; Antiretroviral Therapy, Highly Active; Carbamates; Diagnosis, Differential; Didanosine; Disease Progression; Drug Therapy, Combination; Fatal Outcome; Female; Furans; Guillain-Barre Syndrome; HIV Infections; Humans; Infectious Disease Transmission, Vertical; Organophosphonates; Organophosphorus Compounds; Risk Assessment; Severity of Illness Index; Stavudine; Sulfonamides; Tenofovir

To determine the extent to which genotype (GT) or phenotype (PT) methods provide HIV-1 drug resistance information that is overlapping or complementary, both tests were performed on 1378 patient plasma samples. Discordance, defined as determination of reduced susceptibility measured by PT but sensitivity by GT (PT-R/GT-S), or vice versa (PT-S/GT-R), was common: 83, 62, 43, and 28% of samples with evidence of drug resistance had at least 1, 2, 3, or 4 drugs discordant, respectively. Three types of discordance were observed: PT-R/GT-S, and PT-S/GT-R with or without the presence of mixtures at resistance-associated positions (25%, 34%, and 41% of all discordance, respectively). After accounting for mixtures, results for didanosine (30%), zalcitabine (18%), tenofovir (17%), abacavir (14%), lamivudine (12%), and amprenavir (11%) were discordant in >or= 10% of samples. PT-S/GT-R results were most common for didanosine and zalcitabine, whereas PT-R/GT-S results were most common for lamivudine and amprenavir. PT provided quantitative assessment of the degree of reduced susceptibility and identified reduced susceptibility (PT-R/GT-S) or normal susceptibility (PT-S/GT-R) that was not recognized by the GT interpretation algorithm. GT provided valuable information when mixtures were present and minor populations of drug resistant virus were not detected by phenotyping (PT-S/GT-R results). This demonstrates the complementary nature of information provided by PT and GT tests and suggests that their combined use can provide additional clinically-relevant information.

Topics: Adenine; Anti-HIV Agents; Carbamates; Didanosine; Dideoxynucleosides; Drug Resistance, Viral; Furans; Genotype; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Microbial Sensitivity Tests; Organophosphonates; Organophosphorus Compounds; Phenotype; Reverse Transcriptase Inhibitors; Sulfonamides; Tenofovir; Zalcitabine

Updates are provided for new anti-HIV drugs currently in development. ABT-378, Tipranavir, and DMP-450 are among the new protease inhibitors discussed. Drugs from other classes that are discussed include emivirine (Coactinon, formerly MKC-442), FTC (emtricitabine, Coviracil), adefovir (Preveon), and pentafuside (T-20). A small study has found that women using Ritonavir (Norvir) may be at a greater risk for anemia (a decrease in red blood cells), caused by excessive menstrual bleeding or hypermenorrhea. New formulations of Ritonavir and ddI (Didanosine, Videx) are described.

Topics: Adverse Drug Reaction Reporting Systems; Anti-HIV Agents; Capsules; Carbamates; Chemistry, Pharmaceutical; Didanosine; Drug Synergism; Drug Therapy, Combination; Drugs, Investigational; Female; Furans; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Menorrhagia; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Sulfonamides

A controversy has developed, initiated by a paper in the April 1995 issue of Nature, over the use of protease inhibitors among AIDS patients. The article, written by Jon Condra and Emilio Emini, reported that HIV developed resistance to indinavir (Merck & Co.'s protease inhibitor), and all other protease inhibitors as well. In response to the study on Merck's product, Roche released information suggesting that their protease inhibitor, saquinavir, does not cause resistance nearly as quickly or as much. Merck is currently studying the combination of indinavir and AZT, and Abbott Laboratories is examining the effects of AZT, ddC, and ritonavir. These studies imply that optimal multi-drug combination therapy should delay drug resistance as well as cross-resistance. The implications are promising for patients with HIV and AIDS. Pharmaceutical companies are conducting additional studies to develop new reverse transcriptase inhibitors and to determine the effectiveness of the combination of two or more protease inhibitors. Each drug trial demonstrates the relationship between dosing and resistance; patients are advised to adhere completely to dosing instructions.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Carbamates; Didanosine; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Isoquinolines; Lamivudine; Nelfinavir; Pyridines; Quinolines; Saquinavir; Sulfonamides; Zalcitabine; Zidovudine