RESUMO
Tenofovir DF is an antiviral nucleotide with activity against human immunodeficiency virus type 1 (HIV-1). The pharmacokinetics, safety, and activity of oral tenofovir DF in HIV-1-infected adults were evaluated in a randomized, double-blind, placebo-controlled, escalating-dose study of four doses (75, 150, 300, and 600 mg given once daily). Subjects received a single dose of tenofovir DF or a placebo, followed by a 7-day washout period. Thereafter, subjects received their assigned study drug once daily for 28 days. Pharmacokinetic parameters were dose proportional and demonstrated no change with repeated dosing. Reductions in plasma HIV-1 RNA were dose related at tenofovir DF doses of 75 to 300 mg, but there was no increase in virus suppression between the 300- and 600-mg dose cohorts, despite dose-proportional increases in drug exposure. Grade III or IV adverse events were limited to laboratory abnormalities, including elevated creatine phosphokinase and liver function tests, which resolved with or without drug discontinuation and without sequelae. No patients developed detectable sequence changes in the reverse transcriptase gene.
Assuntos
Adenina/análogos & derivados , Adenina/farmacocinética , Fármacos Anti-HIV/farmacocinética , Infecções por HIV/metabolismo , Organofosfonatos , Compostos Organofosforados/farmacocinética , Adenina/efeitos adversos , Adulto , Fármacos Anti-HIV/efeitos adversos , Método Duplo-Cego , Tolerância a Medicamentos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/efeitos adversos , RNA Viral/sangue , RNA Viral/efeitos dos fármacos , TenofovirAssuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Retinite por Citomegalovirus/tratamento farmacológico , Citosina/análogos & derivados , Organofosfonatos , Compostos Organofosforados/uso terapêutico , Infecções Oportunistas Relacionadas com a AIDS/virologia , Animais , Antivirais/farmacologia , Cidofovir , Ensaios Clínicos como Assunto , Citomegalovirus/efeitos dos fármacos , Citosina/farmacologia , Citosina/uso terapêutico , Humanos , Compostos Organofosforados/farmacologiaRESUMO
Ganciclovir and cidofovir, two antiviral agents used in the treatment of cytomegalovirus (CMV) retinitis, have a synergistic effect inhibiting CMV replication in vitro. In a phase I study, seven patients with AIDS-related CMV retinitis were treated with cidofovir (5 mg/kg intravenously every 2 weeks) combined with ganciclovir (1 g orally three times a day). During a median of 5.5 months (range, 1-12 months) of combined therapy, only one patient had retinitis progression, and only two of 28 blood cultures (specimens of which were obtained on a monthly basis) yielded CMV. Dose-limiting adverse ocular effects (anterior uveitis [two patients] and hypotony [two patients]) occurred in three of seven patients. The results suggest that combination therapy with intravenous cidofovir and oral ganciclovir (a regimen that does not require indwelling central venous catheter access) might enhance clinical efficacy. Less frequent administration of cidofovir in combination with oral ganciclovir should be prospectively studied to determine if the incidence of treatment-associated toxicity might be reduced.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antivirais/uso terapêutico , Retinite por Citomegalovirus/tratamento farmacológico , Citosina/análogos & derivados , Ganciclovir/uso terapêutico , Organofosfonatos , Compostos Organofosforados/uso terapêutico , Adulto , Antivirais/efeitos adversos , Cidofovir , Citosina/efeitos adversos , Citosina/uso terapêutico , Quimioterapia Combinada , Feminino , Ganciclovir/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/efeitos adversos , Resultado do TratamentoAssuntos
Gorduras/metabolismo , Infecções por HIV/metabolismo , Peso Corporal/efeitos dos fármacos , Glucose/metabolismo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/uso terapêutico , Humanos , Metabolismo dos Lipídeos , Lipodistrofia/etiologia , Lipodistrofia/metabolismo , SíndromeRESUMO
A randomized, double-blind, clinic-initiated, sequential dose-escalation pilot study was performed to compare the safety and efficacy of single applications of 1, 3, and 5% cidofovir gel with placebo in the treatment of early, lesional, recurrent genital herpes at five Canadian outpatient sites. Ninety-six patients began treatment within 12 h of lesion appearance and were evaluated twice daily until healing of the lesion occurred. Cidofovir gel at all strengths significantly decreased the median time to negative virus culture in a dose-dependent fashion (3.0 days in the placebo group versus 2.2, 1.3, and 1.1 days in the 1, 3, and 5% cidofovir gel treatment groups, respectively; P = 0.02, 0.0001, and 0.0003, respectively). A trend toward a reduction in the median time to complete healing in association with treatment was present, but the differences were not statistically significant (5.0 days in the placebo group versus 4.3, 4.1, and 4.6 days in the 1, 3, and 5% cidofovir gel treatment groups, respectively). Application site reactions occurred in 3, 5, 19, and 22% of the patients in these four groups, respectively. Treatment-associated lesion recrudescence with delayed healing, which is suggestive of local toxicity, was observed in three patients treated with 5% cidofovir gel and one patient treated with 3% cidofovir gel. In summary, single-dose application of cidofovir gel confers a significant antiviral effect on lesions of recurrent genital herpes. Additional studies are warranted to further identify the optimal efficacious dose of cidofovir in association with the maximum gel strength that can be tolerated.
Assuntos
Antivirais/uso terapêutico , Citosina/análogos & derivados , Herpes Genital/tratamento farmacológico , Organofosfonatos , Compostos Organofosforados/uso terapêutico , Adulto , Idoso , Cidofovir , Citosina/administração & dosagem , Citosina/efeitos adversos , Citosina/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Géis , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , RecidivaRESUMO
9-[2-(R)-(Phosphonomethoxy)propyl]adenine (PMPA) is a nucleotide analogue with potent antiretroviral activity in vitro and in simian models. A randomized, double-blind, placebo-controlled, dose-escalation clinical trial of intravenous PMPA monotherapy was conducted in 20 human immunodeficiency virus (HIV)-infected adults with CD4 cell counts of >/=200 cells/mm3 and plasma HIV RNA levels of >/=10,000 copies/ml. Two dose levels were evaluated (1 and 3 mg/kg of body weight/day). Ten subjects were enrolled at each dose level (eight randomized to receive PMPA and two randomized to receive placebo). On day 1, a single dose of PMPA or placebo was administered by intravenous infusion. Beginning on study day 8, PMPA or placebo was administered once daily for an additional 7 consecutive days. All subjects tolerated dosing without significant adverse events. Mean peak serum PMPA concentrations were 2.7 +/- 0.9 and 9.1 +/- 2.1 microgram/ml in the 1- and 3-mg/kg cohorts, respectively. Serum concentrations declined in a biexponential fashion, with a terminal half-life of 4 to 8 h. At 3 mg/kg/day, a single infusion of PMPA resulted in a 0.4 log10 median decline in plasma HIV RNA by study day 8. Following 7 consecutive days of study drug administration thereafter, the median changes in plasma HIV RNA from baseline were -1.1, -0.6, and 0.1 log10 in the 3-mg/kg/day, 1-mg/kg/day, and placebo dose groups, respectively. Following the final dose in the 3-mg/kg/day cohort, the reduction in HIV RNA was sustained for 7 days before returning toward baseline. Further studies evaluating an oral prodrug of PMPA are under way.
Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Organofosfonatos , Compostos Organofosforados/uso terapêutico , Adenina/efeitos adversos , Adenina/farmacocinética , Adenina/uso terapêutico , Adolescente , Adulto , Método Duplo-Cego , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/efeitos adversos , Compostos Organofosforados/farmacocinética , RNA Viral/sangue , Linfócitos T/imunologia , TenofovirRESUMO
A 34-year-old healthy woman presented with a 15-month history of persistent, nonhealing vulvar ulcerations due to herpes simplex virus (HSV) type 2. Extensive dermatologic workup and serial skin biopsies failed to reveal an underlying vulvar dermatosis or autoimmune bullous disorder. Virologic studies revealed resistance to acyclovir in vitro due to deficiency in thymidine kinase activity. Serum antibody to human immunodeficiency virus was negative on two occasions, separated by 1 year. Immunologic evaluation showed normal HSV-specific proliferative and CD8 cytotoxic T lymphocyte responses as well as normal NK cell function. Vulvar lesions failed to heal in association with trials of topical trifluorothymidine and oral valacyclovir but resolved completely with the application of 1% foscarnet cream. No recurrence of HSV has been observed in 24 months of follow-up to date.
Assuntos
Aciclovir/farmacologia , Simplexvirus/enzimologia , Timidina Quinase/deficiência , Úlcera/virologia , Doenças da Vulva/virologia , Aciclovir/análogos & derivados , Aciclovir/uso terapêutico , Antivirais/farmacologia , Doença Crônica , Resistência Microbiana a Medicamentos , Feminino , Foscarnet/uso terapêutico , Humanos , Imunocompetência , Simplexvirus/efeitos dos fármacos , Úlcera/tratamento farmacológico , Valaciclovir , Valina/análogos & derivados , Valina/uso terapêutico , Doenças da Vulva/tratamento farmacológicoRESUMO
Cryptosporidium causes a debilitating illness in immunocompromised individuals, yet the source of sporadic Cryptosporidium infections is unknown. Because early cases of cryptosporidiosis were associated with animals, and pets are a source of companionship to individuals with AIDS, determination of the risk of cryptosporidiosis associated with pets is important. To assess this risk, we conducted a case-control study of HIV-infected individuals with and without cryptosporidiosis. No statistically significant difference in the rate of overall pet ownership, cat ownership, or bird ownership was found between the two groups. Dog ownership reached borderline statistical significance; 15 of 48 (31%) cases owned a dog, compared with 17 of 99 (17%) controls (odds ratio [OR] = 2.19; p = .05; 95% confidence interval [CI], 0.9-5.3). No statistically significant differences between cases and controls were found in the frequency of surface water ingestion, rural exposure, travel history, or contact with diarrheic individuals. Our findings indicate that pets do not represent a major risk factor for acquisition of Cryptosporidium for HIV-infected individuals. Whether dog ownership presents a minimal risk for cryptosporidiosis needs further investigation.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Animais Domésticos , Criptosporidiose/transmissão , Infecções por HIV/complicações , Animais , Aves , Estudos de Casos e Controles , Gatos , Cães , Humanos , Fatores de Risco , São FranciscoRESUMO
The safety and efficacy of cidofovir gel for treatment of acyclovir-unresponsive herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days. Ten of 20 cidofovir-treated and none of 10 placebo-treated patients had complete healing or >50% decreased area (P = .008); 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (P = .031). Viral shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 placebo-treated patients (P = .00004). For cidofovir-treated patients, median time to complete or good response was 21 days, and median time to negative viral culture was 2 days (P = .025, P = .0001, respectively). Median lesion area decreases were 58% for cidofovir-treated versus 0 for placebo-treated patients (P = .005), and mean pain score changes were -1.84 versus -0.34 (P = .042). Application site reactions occurred in 25% of cidofovir-treated and 20% of placebo-treated patients; none was dose-limiting. Cidofovir therapy provided significant benefits in lesion healing, virologic effect, and pain reduction.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Citosina/análogos & derivados , Herpes Simples/tratamento farmacológico , Organofosfonatos , Compostos Organofosforados/uso terapêutico , Aciclovir/administração & dosagem , Aciclovir/farmacologia , Adulto , Animais , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Células Cultivadas , Chlorocebus aethiops , Cidofovir , Citosina/administração & dosagem , Citosina/efeitos adversos , Citosina/uso terapêutico , Método Duplo-Cego , Resistência Microbiana a Medicamentos , Feminino , Foscarnet/farmacologia , Géis , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mucosa Bucal/virologia , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/efeitos adversos , Simplexvirus/crescimento & desenvolvimento , Células VeroRESUMO
In the majority of cases, the mechanism underlying the resistance to acyclovir (ACV) of herpes simplex viruses (HSVs) is thymidine kinase (TK) deficiency. Plaque isolates from eight ACV-resistant (ACVr) clinical isolates from AIDS patients, of which five reactivated, were sequenced to determine the genetic lesion within the tk gene conferring resistance and whether this may have correlated with reactivation potential. Mutations were clustered within two homopolymer nucleotide stretches. Three plaque isolates (1737-14, 90-150-3, and 89-650-5) had insertion mutations within a stretch of 7 guanosines, while two isolates (89-063-1 and 89-353-1) had frameshift mutations within a stretch of 6 cytosines (a deletion and an insertion, respectively). Mutations resulted in premature termination codons, and the predicted 28- and 32-kDa truncated TK products were detected by Western blot analysis of virus-infected cell extracts. The repair of one homopolymer frameshift mutation (in isolate 1737-14) restored TK activity, demonstrating that this mutation is the basis of TK deficiency. Of the five reactivated isolates, four were TK deficient and contained frameshift mutations while the fifth retained TK activity because of its altered-TK or Pol- phenotype. These data demonstrate that the majority of ACVr clinical isolates contain frameshift mutations within two long homopolymer nucleotide stretches which function as hot spots within the HSV tk gene and produce nonfunctional, truncated TK proteins.
Assuntos
Aciclovir/farmacologia , Antivirais/farmacologia , Simplexvirus/efeitos dos fármacos , Timidina Quinase/genética , Western Blotting , Resistência a Medicamentos , Humanos , Mutação , Simplexvirus/genéticaRESUMO
BACKGROUND AND OBJECTIVES: The diagnosis of mucocutaneous herpes simplex virus (HSV) is hampered by suboptimal sensitivity of virus culture and atypical clinical morphology. GOALS: To compare the diagnostic usefulness of the polymerase chain reaction (PCR) and virus culture. STUDY DESIGN: Consecutive samples from 246 patients at an urban sexually transmitted diseases clinic were tested for HSV by both PCR and virus culture. RESULTS: Only 59% of HSV-positive samples were correctly diagnosed by the clinician; 11% had an atypical appearance. HSV-positive lesions were more often vesiculoulcerative or crusted than HSV-negative lesions, and of shorter median duration. Thirty-one samples were PCR positive and virus culture negative; these were often from crusted or older lesions. However, PCR was negative in 27 instances in which HSV was diagnosed clinically, of which 2 were vesicular and 15 ulcerative. CONCLUSIONS: HSV PCR is more rapid and sensitive than virus culture for diagnosis of mucocutaneous lesions. The data suggesting that PCR may be suboptimally sensitive need to be further investigated.
Assuntos
Herpes Simples/diagnóstico , Dermatopatias Infecciosas/diagnóstico , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase , Simplexvirus/isolamento & purificaçãoRESUMO
Cidofovir is a cytidine nucleotide analogue recently licensed as an intravenous treatment for CMV retinitis in AIDS patients. Three controlled clinical trials have demonstrated efficacy of cidofovir for this indication, and have generated data useful as a guideline to prevent potential toxicity. Although de novo emergence of resistance to cidofovir has not been observed clinically in patients receiving cidofovir, cross-resistance to cidofovir in ganciclovir-resistant clinical DNA polymerase mutants has been identified. Cross-resistance of cidofovir and foscarnet has not been identified to date. A broad spectrum agent with in vitro activity against human herpesviruses, adenovirus, HPV, polyomaviruses and human poxviruses, cidofovir is under clinical investigation for a variety of potential applications. Examples include intravenous administration of cidofovir for treatment of progressive multifocal leukoencephalopathy and Kaposi's sarcoma, intraocular injection for treatment of CMV retinitis, intralesional injection for treatment of respiratory papillomatosis, topical application for treatment of molluscum contagiosum, anogenital condyloma acuminata, and recurrent genital herpes, and ophthalmic instillation for treatment of viral keratoconjunctivitis. Copyright 1997 John Wiley & Sons, Ltd.
RESUMO
In a clinical trial involving asymptomatic, HIV-seropositive subjects treated with either the HIV-1 immunogen (an inactivated, gp120-depleted HIV-1 virus in incomplete Freund's adjuvant) or an adjuvant control, we examined the relationship between changes in the percentage of CD4 cells over time and early clinical markers of HIV disease progression. Subjects who had an early clinical event were more likely to have a greater decline in the percentage of CD4 cells than those subjects who did not have a clinical event (p = 0.054). The greatest decline in CD4 percentage occurred within 10 weeks prior to a clinical event (mean 11% decrease from baseline). Subjects from the quartile with the greatest decline in CD4 percentage had a fivefold greater risk of having a clinical event than subjects from the quartile with the second largest decline (p = 0.045). These results demonstrate a relationship between changes in the percentage of CD4 cells and early clinical events. Further validation of this association may be useful in clinical monitoring and in evaluating therapies to treat HIV infection.
Assuntos
Vacinas contra a AIDS/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Soropositividade para HIV/imunologia , Complexo AIDS Demência/complicações , Adjuvantes Imunológicos , Biomarcadores , Contagem de Linfócito CD4 , Candidíase Bucal/complicações , Estudos de Coortes , Progressão da Doença , Método Duplo-Cego , Seguimentos , Soropositividade para HIV/complicações , Soropositividade para HIV/terapia , Infecções por Herpesviridae/complicações , Humanos , Leucoplasia Pilosa/complicações , Doenças do Sistema Nervoso Periférico/complicações , Sarcoma de Kaposi/complicações , Vacinas de Produtos Inativados/uso terapêuticoRESUMO
SUMMARY: Twenty-six AIDS patients were enrolled in an open label pilot study to evaluate the efficacy and toxicity of topical 1 percent ophthalmic trifluridine solution for the treatment of chronic mucocutaneous herpes simplex virus disease unresponsive to at least 10 days of acyclovir therapy. Susceptibility testing to acyclovir, trifluridine, and foscarnet was determined by plaque reduction assay. Twenty-four patients were evaluable for efficacy and 25 for toxicity analyses. Seven patients (29 percent) had complete healing of lesions. The overall estimated median time to complete healing was 7.1 weeks. An additional seven patients had > or = 50 percent reduction in lesion area. The overall estimated median time to 50 percent healing was 2.4 weeks. Ten (42 percent) patients discontinued treatment for reasons other than primary treatment failure and seven (29 percent) for failure to respond to therapy. Baseline patient characteristics associated with greater reduction in lesion area included higher Karnofsky score (p = 0.05), fewer lesions (p = 0.07), smaller lesion area (p = 0.11), and trifluridine susceptibility (p = 0.07). Eight (33 percent) patients developed new lesions outside of the treatment area while on study, reflecting the local nature of this therapy. No dose-limiting toxicity attributable to trifluridine was reported. Given the limited options for the treatment of acyclovir-resistant herpes simplex disease, topical trifluridine may be a useful alternative in selected patients.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antivirais/administração & dosagem , Herpes Simples/complicações , Herpes Simples/tratamento farmacológico , Trifluridina/administração & dosagem , Aciclovir/farmacologia , Administração Tópica , Adulto , Antivirais/efeitos adversos , Doença Crônica , Resistência Microbiana a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Segurança , Trifluridina/efeitos adversosRESUMO
OBJECTIVE: To compare the tolerability and efficacy of three oral regimens for the treatment of patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia. DESIGN: A randomized, double-blind study. SETTING: 24 U.S. academic medical centers. PATIENTS: 181 patients with morphologically confirmed P. carinii pneumonia and alveolar-arterial oxygen differences (PAO2-PaO2) of 45 mm Hg or less. INTERVENTION: Patients were randomly assigned to receive trimethoprim-sulfamethoxazole, dapsone-trimethoprim, or clindamycin-primaquine for 21 days. Patients with a PAO2-PaO2 of 35 to 45 mm Hg at study entry also received prednisone. MEASUREMENTS: Serial clinical and laboratory evaluations for therapeutic response and toxicity. Therapeutic failure at day 21 was defined by any of the following: increase in PAO2-PaO2 of greater than 20 mm Hg; no remission of baseline signs and symptoms; and change in antipneumocystis therapy for reasons other than toxicity, intubation, or death. Dose-limiting toxicity was defined as discontinuation of therapy by the primary physician because of one or more adverse reactions. RESULTS: No statistically significant differences were seen among treatment groups in the proportions of patients who had dose-limiting toxicity (P=0.2), therapeutic failure (P>0.2), or a complete course of therapy (P>0.2). Survival during therapy or for 2 months thereafter did not differ among the three groups (P>.02). However, elevation of serum aminotransferase levels to more than five times the baseline levels was more frequent in the trimethoprim-sulfamethoxazole group (P=0.003), and one or more serious hematologic toxicities (neutropenia, anemia, thrombocytopenia, or methemoglobinemia) occurred more frequently in the clindamycin-primaquine group (P=0.01). CONCLUSIONS: The rates of dose-limiting toxicity, therapeutic failure, and survival did not differ among patients with AIDS who were receiving oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, or clindamycin-primaquine for mild to moderate P. carinii pneumonia. However, the limited sample size prevents the unequivocal demonstration of the equality of these three regimens. Differences in expected categories of toxicities associated with each regimen should guide the clinician in choosing first-line therapy, particularly for patients with baseline hepatic insufficiency or myelosuppression.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Anti-Infecciosos/uso terapêutico , Clindamicina/uso terapêutico , Dapsona/uso terapêutico , Pneumonia por Pneumocystis/tratamento farmacológico , Primaquina/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Anti-Infecciosos/efeitos adversos , Clindamicina/efeitos adversos , Dapsona/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Doenças Hematológicas/induzido quimicamente , Humanos , Masculino , Primaquina/efeitos adversos , Estudos Prospectivos , Qualidade de Vida , Falha de Tratamento , Combinação Trimetoprima e Sulfametoxazol/efeitos adversosRESUMO
Zidovudine is widely prescribed for the treatment of human immunodeficiency virus (HIV) infection. Trimethoprim and dapsone are commonly used in the management of Pneumocystis carinii pneumonia in HIV-infected patients. To examine the pharmacokinetic interactions among these drugs, eight HIV-infected patients (26 to 43 years old) with a mean CD4 count of 524.4 +/- 405.7 cells per mm3 received zidovudine (200 mg), trimethoprim (200 mg), and dapsone (100 mg) as single agents and in two- and three-drug combinations. Blood and urine samples were collected at a specified time and analyzed for zidovudine, zidovudine-glucuronide, trimethoprim, dapsone, and monoacetyl-dapsone concentrations under single-dose and steady-state conditions. Zidovudine did not influence the pharmacokinetic disposition of dapsone or trimethoprim. Dapsone had no effect on the pharmacokinetic disposition of zidovudine. Trimethoprim significantly decreased the renal clearance of zidovudine by 58% (5.0 +/- 1.8 versus 2.1 +/- 0.5 ml/min/kg of body weight [P < 0.05]). There was a concurrent 54% decrease in the mean urinary recovery of zidovudine (11.7 +/- 3.5 versus 5.4 +/- 3.0 [P < 0.05]), and the metabolic ratio was decreased by 78% (0.32 +/- 0.4 versus 0.07 +/- 0.05 [P < 0.05]). The mean area under the concentration-time curve from 0 to 6 h of the zidovudine-glucuronide/ zidovudine ratio was unchanged. We conclude that zidovudine, trimethoprim, and dapsone can be coadministered to patients with AIDS without significant pharmacokinetic interaction. However, in AIDS patients with liver impairment and impaired glucuronidation, doses of zidovudine may need to be decreased.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Dapsona/farmacocinética , Trimetoprima/farmacocinética , Zidovudina/farmacocinética , Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/urina , Adulto , Dapsona/administração & dosagem , Dapsona/uso terapêutico , Combinação de Medicamentos , Humanos , Masculino , Trimetoprima/administração & dosagem , Trimetoprima/uso terapêutico , Zidovudina/administração & dosagem , Zidovudina/uso terapêuticoRESUMO
We tested the antiviral susceptibilities of 30 clinical isolates of herpes simplex virus using the microplate in situ enzyme-linked immunosorbent assay (MISE) and the plaque reduction assay (PRA). There was concordance for 26 of 30 acyclovir results and all 30 foscarnet results. MISE and PRA results each predicted the response to acyclovir in 12 of 14 instances and the response to foscarnet in 8 instances. MISE is more rapid than PRA, has an objective endpoint, and correlates well with the clinical response to therapy.
Assuntos
Aciclovir/farmacologia , Antivirais/farmacologia , Foscarnet/farmacologia , Herpes Simples , Testes de Sensibilidade Microbiana/métodos , Ensaio de Imunoadsorção Enzimática , HumanosAssuntos
Aciclovir/farmacologia , Aciclovir/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Varicela/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 3/efeitos dos fármacos , Simplexvirus/efeitos dos fármacos , Animais , Varicela/virologia , Resistência Microbiana a Medicamentos , Herpes Simples/virologia , HumanosRESUMO
BACKGROUND: Current methods of antiviral susceptibility testing for herpes simplex virus (HSV) are poorly standardized and have rarely been compared critically. OBJECTIVES: To compare the three most commonly utilized HSV susceptibility assays for accuracy of result, method of implementation, and time required. STUDY DESIGN: We compared susceptibility results for acyclovir and foscarnet using the plaque reduction, dye uptake and DNA hybridization assays in 30 patient isolates of HSV, of varying susceptibility pattern. Compared parameters included: values for ID(50) (the concentration of drug required to inhibit virus growth by 50% or more), ratio of ID(90) to ID(50), and correlation of susceptibility result with clinical response to antiviral therapy, when available. In addition, we compared ease of the assay, presence of objective endpoint, time required to generate the susceptibility result, and necessary equipment for implementation. RESULTS: The dye uptake yielded ID(50) results that were approximately two-fold greater than those from the plaque reduction assay, while ID(50) values from the DNA hybridization assay were one-half those from the plaque reduction assay. Comparison of the correlation of susceptibility result with clinical response to acyclovir therapy in 17 instances and to foscarnet therapy in 10 instances suggested the possibility of a somewhat greater discriminative ability of the dye uptake assay, and a somewhat lesser discriminative ability of the DNA hybridization assay, when compared with results from the plaque reduction assay in isolates with borderline acyclovir susceptibility. CONCLUSIONS: Larger comparative studies are necessary to further differences in discriminative ability of the three assays for HSV. All three assays were deemed suboptimal due to an overly long turnaround time, associated expense, and/or level of equipment required for their performance. Continued evaluation of alternative, more rapid assays is therefore warranted.