RESUMEN
Combination therapy for HIV-1 infection can reduce plasma virus to undetectable levels, indicating that prolonged treatment might eradicate the infection. However, HIV-1 can persist in a latent form in resting CD4+ T cells. We measured the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable. The mean half-life of the latent reservoir was very long (43.9 months). If the latent reservoir consists of only 1 x 10(5) cells, eradication could take as long as 60 years. Thus, latent infection of resting CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , Latencia del Virus , Adulto , Linfocitos T CD4-Positivos/citología , Células Cultivadas , Estudios Transversales , Quimioterapia Combinada , Femenino , Infecciones por VIH/sangre , Semivida , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Carga Viral , Replicación ViralRESUMEN
Human CD4+ T cell clones and cell lines were shown to lyse recombinant vaccinia virus-infected cells that synthesize the HIV-1 envelope glycoprotein gp160. The processing of endogenously synthesized gp160 for recognition by CD4+ T cells required that the protein, after synthesis on the rough endoplasmic reticulum and during subsequent cellular transport, remain attached to the luminal/extracellular membrane face by a hydrophobic anchor sequence.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Productos del Gen env/metabolismo , VIH/metabolismo , Precursores de Proteínas/metabolismo , Secuencia de Aminoácidos , Productos del Gen env/inmunología , Genes env , VIH/genética , Proteínas gp160 de Envoltorio del VIH , Humanos , Precursores de Proteínas/inmunología , Señales de Clasificación de Proteína/metabolismoRESUMEN
To identify pharmacokinetic (PK) drug-drug interactions between tipranavir-ritonavir (TPV/r) and rosuvastatin and atorvastatin, we conducted two prospective, open-label, single-arm, two-period studies. The geometric mean (GM) ratio was 1.37 (90% confidence interval [CI], 1.15 to 1.62) for the area under the concentration-time curve (AUC) for rosuvastatin and 2.23 (90% CI, 1.83 to 2.72) for the maximum concentration of drug in serum (Cmax) for rosuvastatin with TPV/r at steady state versus alone. The GM ratio was 9.36 (90% CI, 8.02 to 10.94) for the AUC of atorvastatin and 8.61 (90% CI, 7.25 to 10.21) for the Cmax of atorvastatin with TPV/r at steady state versus alone. Tipranavir PK parameters were not affected by single-dose rosuvastatin or atorvastatin. Mild gastrointestinal intolerance, headache, and mild reversible liver enzyme elevations (grade 1 and 2) were the most commonly reported adverse drug reactions. Based on these interactions, we recommend low initial doses of rosuvastatin (5 mg) and atorvastatin (10 mg), with careful clinical monitoring of rosuvastatin- or atorvastatin-related adverse events when combined with TPV/r.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Fluorobencenos/farmacocinética , Ácidos Heptanoicos/farmacocinética , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Pironas/farmacocinética , Pirroles/farmacocinética , Ritonavir/farmacocinética , Sulfonamidas/farmacocinética , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/efectos adversos , Atorvastatina , Interacciones Farmacológicas , Femenino , Fluorobencenos/efectos adversos , Ácidos Heptanoicos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Piridinas/efectos adversos , Pirimidinas/efectos adversos , Pironas/efectos adversos , Pirroles/efectos adversos , Ritonavir/efectos adversos , Rosuvastatina Cálcica , Sulfonamidas/efectos adversos , Adulto JovenRESUMEN
Characterization of the host immune response to human immunodeficiency virus type 1 (HIV-1) is critical to the rational design of an effective AIDS vaccine. In this study, cytotoxic T lymphocytes (CTL) specific for HIV-1 reverse transcriptase (RNA-dependent DNA polymerase) were found in blood samples from HIV-1-infected individuals. CTL targets were prepared by immortalizing B cells from ten seropositive and six seronegative individuals, and then infecting these cells with recombinant vaccinia viruses containing HIV-1 genes. CTL directed against autologous B lymphoblasts expressing HIV-1 reverse transcriptase were detected in fresh blood samples from eight HIV-1 seropositive subjects, but in no seronegative controls. The effector cells were identified as major histocompatibility complex-restricted CD3+CD8+ lymphocytes. Because the HIV-1 pol gene is highly conserved among different isolates and generates both humoral and cellular immune responses, it bears consideration for inclusion in a candidate AIDS vaccine.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , VIH/enzimología , ADN Polimerasa Dirigida por ARN/inmunología , Linfocitos T Citotóxicos/inmunología , Antígenos Virales/inmunología , Linfocitos B/inmunología , ADN Recombinante , Genes Virales , VIH/genética , Seropositividad para VIH , Antígenos HLA/inmunología , Humanos , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Vacunas Virales/inmunologíaRESUMEN
SETTING: Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues. OBJECTIVE: niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI). DESIGN: PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval. RESULTS: The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001-0.0025 h-1 and 0.0015-0.0025 h-1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing. CONCLUSION: We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed.
Asunto(s)
Antituberculosos/administración & dosificación , Antituberculosos/farmacocinética , Tuberculosis Latente/tratamiento farmacológico , Adolescente , Adulto , Diarilquinolinas/administración & dosificación , Diarilquinolinas/farmacocinética , Esquema de Medicación , Liberación de Fármacos , Quimioterapia Combinada , Femenino , Humanos , Inyecciones Intramusculares , Isoniazida/administración & dosificación , Isoniazida/farmacocinética , Masculino , Persona de Mediana Edad , Nitroimidazoles/administración & dosificación , Nitroimidazoles/farmacocinética , Oxazoles/administración & dosificación , Oxazoles/farmacocinética , Prueba de Estudio Conceptual , Rifampin/administración & dosificación , Rifampin/análogos & derivados , Rifampin/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
Long-acting/extended-release drug formulations have proved very successful in diverse areas of medicine, including contraception, psychiatry and, most recently, human immunodeficiency virus (HIV) disease. Though challenging, application of this technology to anti-tuberculosis treatment could have substantial impact. The duration of treatment required for all forms of tuberculosis (TB) put existing regimens at risk of failure because of early discontinuations and treatment loss to follow-up. Long-acting injections, for example, administered every month, could improve patient adherence and treatment outcomes. We review the state of the science for potential long-acting formulations of existing tuberculosis drugs, and propose a target product profile for new formulations to treat latent tuberculous infection (LTBI). The physicochemical properties of some anti-tuberculosis drugs make them unsuitable for long-acting formulation, but there are promising candidates that have been identified through modeling and simulation, as well as other novel agents and formulations in preclinical testing. An efficacious long-acting treatment for LTBI, particularly for those co-infected with HIV, and if coupled with a biomarker to target those at highest risk for disease progression, would be an important tool to accelerate progress towards TB elimination.
Asunto(s)
Antituberculosos/uso terapéutico , Preparaciones de Acción Retardada , Tuberculosis Latente/tratamiento farmacológico , Antituberculosos/química , HumanosRESUMEN
In clinical research, ethics review generally first examines whether study risks are reasonable in light of benefits provided. Through informed consent, then, prospective subjects consider whether the risk/benefit balance and procedures are reasonable for them. Unique ethics issues emerge in clinical research with healthy volunteers. Certain types of studies only recruit healthy volunteers as participants. Phase 1 studies, for example, including first time in human studies of investigational drugs and vaccines, generally are conducted in healthy volunteers. Although such research carries inherent and often unknown risks, healthy subjects provide the most efficient target population in which to conduct such research, as these volunteers generally are free of concurrent diseases or medications that could confound interpretation of toxicity. Other studies enrolling healthy volunteers often are simply looking for the most scientifically sound population for the study of normal human physiology.
Asunto(s)
Investigación Biomédica/métodos , Voluntarios Sanos/legislación & jurisprudencia , Autonomía Personal , Justicia Social , Adulto , Anciano , Actitud del Personal de Salud , Actitud Frente a la Salud , Investigación Biomédica/ética , Investigación Biomédica/legislación & jurisprudencia , Conducta Cooperativa , Disentimientos y Disputas , Femenino , Educación en Salud , Humanos , Masculino , Persona de Mediana Edad , Motivación , Educación del Paciente como Asunto , Selección de Paciente , Prisioneros/legislación & jurisprudencia , Reembolso de Incentivo , Relaciones Investigador-SujetoRESUMEN
PURPOSE: This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART. PATIENTS AND METHODS: Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir. RESULTS: The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL. CONCLUSION: Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Infecciones por VIH/complicaciones , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma Relacionado con SIDA/virología , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/virología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Terapia Antirretroviral Altamente Activa , Terapia Combinada , Ciclofosfamida/administración & dosificación , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Indinavir/administración & dosificación , Lamivudine/administración & dosificación , Linfoma Relacionado con SIDA/patología , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Prednisona/administración & dosificación , Estavudina/administración & dosificación , Resultado del Tratamiento , Vincristina/administración & dosificación , Carga ViralRESUMEN
BACKGROUND: Rifampin (INN, rifampicin), a CYP34A inducer, results in significant interactions when coadministered with combination oral contraceptives that contain norethindrone (INN, norethisterone) and ethinyl estradiol (INN, ethinylestradiol). Little is known about the effects of rifabutin, a related rifamycin. OBJECTIVES AND METHODS: The relative effects of rifampin and rifabutin on the pharmacokinetics and pharmacodynamics of ethinyl estradiol and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 microg ethinyl estradiol/1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. RESULTS: Rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] of ethinyl estradiol and the mean AUC(0-24) of norethindrone. Rifabutin significantly decreased the mean AUC(0-24) of ethinyl estradiol and the mean AUC(0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC(0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. CONCLUSION: In this study, rifampin (600 mg daily) was a more significant inducer of ethinyl estradiol and norethindrone clearance than rifabutin (300 mg daily), but neither agent reversed the suppression of ovulation caused by oral contraceptives. The carefully monitored oral contraceptive administration and the limited exposure to rifamycins may restrict the application of this study to clinical situations.
PIP: The relative effects of rifampin and rifabutin (a related rifamycin) on the pharmacokinetics and pharmacodynamics of ethinyl estradiol (EE) and norethindrone were evaluated in a prospective, randomized, double-blinded crossover study in 12 premenopausal women who were on a stable oral contraceptive regimen that contained 35 mcg EE and 1 mg norethindrone. Subjects were randomized to receive 14 days of rifampin or rifabutin from days 7 through 21 of their menstrual cycle. After a 1-month washout period (only the oral contraceptives were taken), subjects were crossed over to the other rifamycin. Findings showed that rifampin significantly decreased the mean area under the plasma concentration-time curve from time 0 to 24 hours [AUC (0-24)] of EE and the mean AUC (0-24) of norethindrone. Rifabutin significantly decreased the mean AUC (0-24) of EE and the mean AUC (0-24) of norethindrone. The effect of rifampin was significantly greater than rifabutin on each AUC (0-24). Despite these changes, subjects did not ovulate (as determined by progesterone concentrations) during the cycle in which either rifamycin was administered. Levels of mean follicle-stimulating hormone increased 69% after rifampin. This study suggests that rifampin (600 mg daily) was a more important inducer of EE and norethindrone clearance than rifabutin, but none of these agents were able to reverse the suppression of ovulation done by oral contraceptives.
Asunto(s)
Antibióticos Antituberculosos/farmacología , Anticonceptivos Hormonales Orales/farmacocinética , Inhibidores Enzimáticos/farmacología , Etinilestradiol/farmacocinética , Noretindrona/farmacocinética , Rifabutina/farmacología , Rifampin/farmacología , Adulto , Estudios Cruzados , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Método Doble Ciego , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Oxigenasas de Función Mixta/metabolismo , Estudios Prospectivos , gamma-Glutamiltransferasa/sangreRESUMEN
Deciding on postexposure prophylaxis for any infection requires that the patient and healthcare provider understand the magnitude of infection risk and the adverse consequences of therapeutic intervention or nonintervention. Principles of epidemiology and microbiology allow us to estimate the risk of infection. Principles of clinical pharmacology allow us to estimate the risk and benefit of therapy. The dose-response-time relationships for antiviral activity and toxicity of a drug can be used to develop regimens that maximize benefit and minimize risk. Other important pharmacologic considerations include the role of active and toxic drug metabolites, combination chemotherapy, drug interactions, and medication compliance.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/prevención & control , Personal de Salud , Exposición Profesional/efectos adversos , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Quimioterapia Combinada , Interacciones Alimento-Droga , Infecciones por VIH/sangre , Infecciones por VIH/etiología , Humanos , Cooperación del PacienteRESUMEN
Repeated hospital admission is a serious problem for both the patient and the health care system. The life story of a patient repeatedly admitted for treatment of exacerbations of a chronic disease, such as diabetic ketoacidosis, can often be compared to Faulkner's family Sartoris. The Sartoris characters were wholly occupied in the pursuit of their painful decline and eventual demise. At the Johns Hopkins Hospital, 45 persons were identified who were repeatedly admitted to the medical service for diabetic ketoacidosis. Forty-two charts of "recidivist" patients and "non-recidivist" control patients matched for age and severity of disease were reviewed to determine factors that, if corrected, would prevent repeated admission. Case reports of three patients who were admitted an average of 11 times annually for several years are presented. Implications of the "Game of Sartoris" for the American teaching hospital are discussed.
Asunto(s)
Cetoacidosis Diabética/psicología , Cooperación del Paciente , Readmisión del Paciente/economía , Adulto , Femenino , Humanos , Masculino , Estados UnidosRESUMEN
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.
Asunto(s)
Antiinfecciosos/administración & dosificación , Endocarditis Bacteriana/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Abuso de Sustancias por Vía Intravenosa/complicaciones , Administración Oral , Adulto , Antibacterianos/administración & dosificación , Antibióticos Antituberculosos/administración & dosificación , Ciprofloxacina/administración & dosificación , Endocarditis Bacteriana/etiología , Endocarditis Bacteriana/mortalidad , Femenino , Gentamicinas/administración & dosificación , Humanos , Infusiones Intravenosas , Tiempo de Internación , Masculino , Oxacilina/administración & dosificación , Penicilinas/administración & dosificación , Estudios Prospectivos , Rifampin/administración & dosificación , Infecciones Estafilocócicas/etiología , Infecciones Estafilocócicas/mortalidad , Resultado del Tratamiento , Vancomicina/administración & dosificaciónRESUMEN
AIDS: The benefits and toxicity of any drug are a function of the drug's concentration in the patient. Therapeutic drug monitoring (TDM), or drug concentration analysis, implies that a patient's drug concentration must fall within a certain range in order for the drug to be therapeutic. TDM requirements are described in a table. Researchers are looking at the relationship between antiretroviral drug concentrations and clinical outcome. There is no consensus regarding TDM use for antiretroviral drugs. An appendix includes text from the AIDS Clinical Trials Group Pharmacology Committee Position Paper on Therapeutic Drug Monitoring for Antiretroviral Drugs. The committee does not recommend using drug concentrations to change antiretroviral therapy in individual patients.^ieng
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Monitoreo de Drogas , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Guías como Asunto , Humanos , Replicación Viral/efectos de los fármacosRESUMEN
AIDS: The Centers for Disease Control and Prevention (CDC) convened a meeting in 1997 to revisit guidelines for post-exposure prophylaxis (PEP) for occupationally acquired HIV infection. Recent data show that the health care worker's infection risk is increased with deeper injury, bloodier needles, and source patients with more advanced disease suggesting higher viral load. A CDC study shows that AZT use of any kind was associated with an 81 percent reduction in the risk of seroconversion compared with controls not given AZT. AZT is the only drug for which proof exists of clinical benefits in the prophylaxis setting. However, attempts to assess AZT's efficacy in a randomized, prospective, placebo-controlled trial have failed, making the assessment of PEP's efficacy unlikely in the future. PEP initiation, according to the CDC, is guided by two principles: relative risks of exposure and the risks of the injury balanced with risks of the drug therapy. Future treatment guidelines are likely to pay more attention to the source patient, disease stage, and/or viral load as determinants of risk. Other nucleotides and protease inhibitors could arguably be included in PEP regimens, particularly for treatment of high-risk cases. Studies show no fetal harm from AZT; there is little information on fetal toxicity of other antiretrovirals. New guidelines are due to be published in the MMWR in early 1998.^ieng
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/prevención & control , Lesiones por Pinchazo de Aguja , Exposición Profesional , Zidovudina/uso terapéutico , Fármacos Anti-VIH/administración & dosificación , Centers for Disease Control and Prevention, U.S. , Quimioterapia Combinada , Guías como Asunto , Infecciones por VIH/epidemiología , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Estados Unidos/epidemiología , Zidovudina/administración & dosificaciónRESUMEN
AIDS: Researchers at the 12th World AIDS Conference in Geneva shared information on HIV lipodystrophy syndrome (LDS), addressing the difficulty in defining and understanding the condition. Researchers discussed the prevalence of LDS, its endocrinology, and suggested possible causes. There is uncertainty as to which anti-HIV drugs may cause LDS and whether switching drug regimens once LDS is diagnosed will reverse the condition. Evidence is now suggesting that there is little chance that diabetes is being caused by protease inhibitors, however, hyperlipidemia appears to be more common than expected. Studies investigating if physiological or endocrinological abnormalities may cause LDS have not shown any consistent changes to indicate that a specific mechanism may be the cause.^ieng
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/complicaciones , Inhibidores de la Proteasa del VIH/uso terapéutico , Lipodistrofia/complicaciones , Fármacos Anti-VIH/efectos adversos , Glucemia/análisis , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Humanos , Lípidos/sangre , Lipodistrofia/inducido químicamente , Lipodistrofia/epidemiologíaRESUMEN
AIDS: Several sessions at the 6th Conference on Retroviruses and Opportunistic Infections described the current state of pharmacology. Sessions were devoted to Zidovudine (AZT), Stavudine (d4T), and intracellular phosphorylation; the interactions between antiretrovirals and opiates; and Delavirdine (DLV) and Adefovir (ADV) interactions. Also addressed were the pharmacokinetics in patients with liver disease; the toxicities associated with Adefovir and Amprenavir (APV); and the uses of Hydroxyurea (HU).^ieng
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Fármacos Anti-VIH/farmacología , Interacciones Farmacológicas , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Chicago , Ensayos Clínicos como Asunto , Congresos como Asunto , Quimioterapia Combinada , Drogas en Investigación , HumanosRESUMEN
AIDS: Dr. Charles Flexner, an Associate Professor at Johns Hopkins University, discusses different issues involving drug interactions. Flexner states that some interactions exist between street drugs and HIV medications, including between benzodiazepines and Ritonavir (Norvir) or Nelfinavir (Viracept). He also reports on toxicity and death cases associated with MDMA (ecstasy) and protease inhibitors. Drugs for opportunistic infections are also described; most are not implicated in clinically significant drug interactions, nor are most over-the-counter medications. Dr. Flexner's opinions on protease-sparing regimens and lipodystrophy are also provided.^ieng
Asunto(s)
Consumo de Bebidas Alcohólicas , Fármacos Anti-VIH/efectos adversos , Sistema Enzimático del Citocromo P-450/metabolismo , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Drogas Ilícitas , Inhibidores de la Transcriptasa Inversa/efectos adversos , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Fármacos Anti-VIH/metabolismo , Antituberculosos/efectos adversos , Antituberculosos/metabolismo , Interacciones Farmacológicas , Inhibidores de la Proteasa del VIH/metabolismo , Humanos , Lipodistrofia/inducido químicamente , Medicamentos sin Prescripción/efectos adversos , Medicamentos sin Prescripción/metabolismo , Inhibidores de la Transcriptasa Inversa/metabolismoRESUMEN
Although major advances in drug development and public health are helping to control the HIV/AIDS epidemic, there is a strong rationale for pursuing a more definitive cure. Several bold but unproven strategies for HIV eradication are reviewed in this issue of CPT, including novel drugs, gene therapy, and bone marrow transplantation (BMT). Early results, including one probable case of HIV eradication in a leukemia patient, are intriguing but raise many questions.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa/tendencias , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , HumanosRESUMEN
Although there is much discussion regarding the ethics of making payments to healthy volunteers for participating in clinical research, little data are available from the point of view of the volunteers as to what they would consider to be fair payment. The objectives of this study were to determine healthy volunteers' estimates of appropriate payments for participation in hypothetical clinical trials in order to explore the reasoning behind these estimates and to examine the association between volunteer demographics and payment expectations. Sixty participants with previous experience as healthy volunteers in research studies were presented with four hypothetical studies and interviewed about their impressions of burden and risks involved in the studies. They were also asked to estimate an appropriate payment to the volunteers for each of the studies. For each of the studies, the payment estimates made by the participants varied over a wide range. However, each individual tended to be consistent in estimate placement within this range. No demographic factor was significantly associated with the estimated study payment. Subjects frequently mentioned risk and logistical burden as factors that should determine payment levels. Healthy volunteer subjects appear to have individualized yet consistent methods of arriving at estimates of payments for participating in clinical studies. These estimates are based on each subject's perception of study burden and associated risk.
Asunto(s)
Investigación Biomédica/economía , Voluntarios Sanos , Sujetos de Investigación/economía , Adolescente , Adulto , Investigación Biomédica/métodos , Ensayos Clínicos como Asunto/economía , Ensayos Clínicos como Asunto/métodos , Recolección de Datos/métodos , Femenino , Voluntarios Sanos/legislación & jurisprudencia , Humanos , Masculino , Persona de Mediana Edad , Selección de Paciente , Sujetos de Investigación/psicología , Adulto JovenRESUMEN
Accelerator mass spectrometry (AMS) is an ultrasensitive technique to detect radiolabeled compounds. We administered a microdose (100 µg) of (14)C-labeled zidovudine (ZDV) with or without a standard unlabeled dose (300 mg) to healthy volunteers. Intracellular ZDV-triphosphate (ZDV-TP) concentration was measured using AMS and liquid chromatography-tandem mass spectrometry (LC/MS/MS). AMS analysis yielded excellent concordance with LC/MS/MS and was 30,000-fold more sensitive. The kinetics of intracellular ZDV-TP formation changed several-fold over the dose range studied (100 µg-300 mg). AMS holds promise as a tool for quantifying intracellular drug metabolites and other biomediators in vivo.