RESUMEN
Kaposi sarcoma is a rare angioproliferative disease associated with human herpes virus-8 (HHV-8) infection. Kaposi sarcoma is frequent and aggressive in HIV-infected people, whereas the classic form (CKS) generally has an indolent course. Notably, all conventional therapies against Kaposi sarcoma have only temporary efficacy. We have previously shown that indinavir, a HIV protease-inhibitor with direct antiangiogenic and antitumor activity, is safe and effective in patients with early CKS, whereas effects are less prominent in advanced disease, probably due to the larger tumor mass. Therefore, the clinical response to indinavir was assessed in patients with advanced CKS after debulking chemotherapy. This was a monocentric phase 2 trial in elderly with progressive/advanced CKS treated with debulking chemotherapy and indinavir combined, followed by a maintenance phase with indinavir alone. Secondary endpoints included safety and Kaposi sarcoma biomarker evaluation.All evaluable patients (22) responded to debulking therapy. Out of these, 16 entered the indinavir maintenance phase. The overall response rate at end of maintenance was 75% (estimated median response-duration 43 months). Moreover, most responders showed further clinical improvements (lesion number/nodularity) during maintenance and post-treatment follow-up. Notably, after relapse, progressors did not require systemic Kaposi sarcoma therapy and showed clinical improvements (including disease stabilization) remaining on study. Responders also showed immune status amelioration with a consistent B-cell increase and positive changes of other biomarkers, including anti-HHV-8 natural killer activity. In advanced CKS a strategy combining indinavir and chemotherapy is safe and associated with high and durable response rates and it could be rapidly adopted for the clinical management of these patients. SIGNIFICANCE: This phase-2 trial showed that the HIV protease inhibitor indinavir may boost and extend the duration of the effects of chemotherapy in elderly with advanced progressive classic Kaposi sarcoma, without additional toxicity. Further, the amelioration of the immune status seen in responders suggests a better control of HHV-8 infection and tumor-cell killing. Thus, indinavir combined with chemotherapy may represent an important tool for the clinical management of classic Kaposi sarcoma in elderly patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Inhibidores de la Proteasa del VIH , Indinavir , Sarcoma de Kaposi , Humanos , Sarcoma de Kaposi/tratamiento farmacológico , Indinavir/uso terapéutico , Indinavir/administración & dosificación , Indinavir/efectos adversos , Masculino , Femenino , Anciano , Inhibidores de la Proteasa del VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Resultado del Tratamiento , Herpesvirus Humano 8RESUMEN
BACKGROUND: The COVID-19 has now been declared a global pandemic by the World Health Organization. There is an emergent need to search for possible medications. METHOD: Utilization of the available sequence information, homology modeling, and in slico docking a number of available medications might prove to be effective in inhibiting the SARS-CoV-2 two main drug targets, the spike glycoprotein, and the 3CL protease. RESULTS: Several compounds were determined from the in silico docking models that might prove to be effective inhibitors for SARS-CoV-2. Several antiviral medications: Zanamivir, Indinavir, Saquinavir, and Remdesivir show potential as and 3CLPRO main proteinase inhibitors and as a treatment for COVID-19. CONCLUSION: Zanamivir, Indinavir, Saquinavir, and Remdesivir are among the exciting hits on the 3CLPRO main proteinase. It is also exciting to uncover that Flavin Adenine Dinucleotide (FAD) Adeflavin, B2 deficiency medicine, and Coenzyme A, a coenzyme, may also be potentially used for the treatment of SARS-CoV-2 infections. The use of these off-label medications may be beneficial in the treatment of the COVID-19.
Asunto(s)
Betacoronavirus/química , Infecciones por Coronavirus/virología , Cisteína Endopeptidasas/química , Descubrimiento de Drogas/métodos , Neumonía Viral/virología , Glicoproteína de la Espiga del Coronavirus/química , Proteínas no Estructurales Virales/química , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/química , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/química , Alanina/uso terapéutico , Sitios de Unión , COVID-19 , Proteasas 3C de Coronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/química , Indinavir/uso terapéutico , Simulación del Acoplamiento Molecular , Uso Fuera de lo Indicado , Pandemias , Neumonía Viral/tratamiento farmacológico , SARS-CoV-2 , Saquinavir/química , Saquinavir/uso terapéutico , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Homología Estructural de Proteína , Proteínas no Estructurales Virales/antagonistas & inhibidores , Zanamivir/química , Zanamivir/uso terapéutico , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Kidney injury is a serious comorbidity among HIV-infected patients. Intravenous drug use is listed as one of the risk factors for impaired renal function; however, this group is rarely assessed for specific renal-related risks. METHODS: Patients attending methadone program from 1994 to 2015 were included in the study. Data collected included demographic data, laboratory tests, antiretroviral treatment history, methadone dosing and drug abstinence. Patients' drug abstinence was checked monthly on personnel demand. We have evaluated two study outcomes: (1) having at least one or (2) three eGFR < 60 ml/min (MDRD formula). RESULTS: In total, 267 persons, with 2593 person-years of follow-up were included into analyses. At the time of analyses, 251 (94%) were on antiretroviral therapy (ARV). Fifty-two (19.5%) patients had 1eGFR and 20 (7.5%) 3eGFR < 60. In univariate analysis, factors significantly increasing the odds of impaired renal function were: female gender, detectable HIV RNA on ART, age at registration per 5 years older, atazanavir use and time on antiretroviral treatment per 1 year longer. In the multivariate model, only female gender (OR 4.7; p = 0.002), time on cART (OR 1.11; p = 0.01) and baseline eGFR (OR 0.71; p = 0.001) were statistically significant. CONCLUSIONS: We have demonstrated a high rate of kidney function impairment among HIV-1 positive patients in the methadone program. All risk factors for decreased eGFR in this subpopulation of patients were similar to those described for general HIV population with very high prevalence in women. These findings imply the need for more frequent kidney function monitoring in this subgroup of patients.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Enfermedades Renales/epidemiología , Enfermedades Renales/fisiopatología , Metadona/uso terapéutico , Narcóticos/uso terapéutico , Trastornos Relacionados con Opioides/rehabilitación , Adulto , Fármacos Anti-VIH/uso terapéutico , Sulfato de Atazanavir/uso terapéutico , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular , Infecciones por VIH/complicaciones , Humanos , Indinavir/uso terapéutico , Masculino , Tratamiento de Sustitución de Opiáceos , Trastornos Relacionados con Opioides/complicaciones , Polonia/epidemiología , Factores de Riesgo , Factores Sexuales , Tenofovir/uso terapéutico , Factores de TiempoRESUMEN
BACKGROUND: An abnormal HMGB1 activation plays a key role in the pathogenesis of ALI. METHODS: In this study, the effects of Indinavir plus methylprednisolone on the LPS-mediated activation in human pulmonary microvascular endothelial cells (HPMECs), on the injury of AT I in vitro, and on rats with LPS-induced two-hit model with or without methylprednisolone were investigated. RESULTS: Indinavir treatment resulted in a reduction of HMGB1, its receptor TLR-4, and HMGB1's downstream p-NF-κB, attenuating a decrease of VE-cadherin in LPS-stimulated HPMECs. Apoptosis of AT I was attenuated with an increase of RAGE and aquaporin 5. Compared to methylprednisolone alone, methylprednisolone plus Indinavir attenuated the decrease of GRα and IκB-α in cytoplasm and avoid GRα deficiency in LPS-stimulated HPMECs for 96âh, attenuated the increase of p-NF-κB in nucleus. Indinavir ameliorated histopathological changes of two-hit ALI model of rats with reductions in microvascular permeability, lower HMGB1, TLR4, p-NF-κB, and MPO expression, whereas higher RAGE, aquaporin 5, and VE-cadherin in LPS-instilled lungs. Compared to methylprednisolone alone, methylprednisolone plus Indinavir attenuated the decrease of GRα and IκB-α in cytoplasm, decreased p-NF-κB in nucleus of lung tissue of two-hit ALI rats, and enhanced the anti-inflammatory effect of methylprednisolone for avoiding GRα deficiency. CONCLUSION: It demonstrated that Indinavir prevented experimental ALI model of rats by modulating the HMGB1/TLR-4 pathway to resolve systemic inflammation response in a greater degree with methylprednisolone, reduced the use time and dose of methylprednisolone, and avoided GRα deficiency in ALI and ARDS.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Indinavir/uso terapéutico , Metilprednisolona/uso terapéutico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Animales , Acuaporina 5/metabolismo , Western Blotting , Línea Celular , Proteína HMGB1/metabolismo , Humanos , Inmunohistoquímica , Lipopolisacáridos/toxicidad , Masculino , Ratas , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Transcripción ReIA/metabolismoRESUMEN
In the present day antiretroviral therapy, Ctrough is a key tool for efficacy assessment. The present work explored the feasibility of using Ctrough or Cmax in the area under the concentration-time curve (AUC) prediction of indinavir. A simple unweighted linear regression model was developed to describe the relationship between Cmax versus AUC (r = 0.8101, P < 0.001) and Ctrough versus AUC (r = 0.8127, P < 0.001) for indinavir. The regression lines were used to predict the AUC values from literature Cmax or Ctrough data of indinavir in HIV and healthy subjects. The fold difference, defined as the quotient of the observed and predicted AUC values, was evaluated along with statistical comparison, including root mean square error (RMSE) prediction for the 2 models. The correlation between Cmax versus AUC and Ctrough versus AUC was established. Majority of the predicted values for Cmax versus AUC were within 0.75- to 1.5-fold differences. However, the Ctrough versus AUC model showed larger variability with approximately one-third of the predictions within 0.75- to 1.5-fold differences. The r value and %RMSE for observed versus predicted AUC for Ctrough (r = 0.5925, n = 65, P < 0.001, and RMSE: 67%) were inferior to the Cmax (r = 0.8773, n = 86, P < 0.001, and RMSE: 46%). In conclusion, Cmax versus AUC and Ctrough versus AUC relationships were established for indinavir showing the utility of a single concentration time point for therapeutic drug monitoring purpose. The Cmax model for indinavir may be more relevant for AUC prediction as determined by the statistical criteria.
Asunto(s)
Área Bajo la Curva , Monitoreo de Drogas/métodos , Inhibidores de la Proteasa del VIH/farmacocinética , Indinavir/farmacocinética , Infecciones por Retroviridae/tratamiento farmacológico , Estudios de Factibilidad , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/uso terapéutico , Modelos LinealesRESUMEN
To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L,L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150-5000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy.
Asunto(s)
Cromatografía Capilar Electrocinética Micelar/métodos , Succinato de Desvenlafaxina/aislamiento & purificación , Infecciones por VIH/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodos , Clorhidrato de Venlafaxina/aislamiento & purificación , Calibración , Succinato de Desvenlafaxina/sangre , Interacciones Farmacológicas , Electroforesis Capilar/métodos , VIH/fisiología , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/uso terapéutico , Límite de Detección , Polímeros/química , Estereoisomerismo , Clorhidrato de Venlafaxina/sangreRESUMEN
HIV patients on combination oral drug therapy experience insufficient drug levels in lymph nodes, which is linked to viral persistence. Following success in enhancing lymph node drug levels and extending plasma residence time of indinavir formulated in lipid nanoparticles, we developed multidrug anti-HIV lipid nanoparticles (anti-HIV LNPs) containing lopinavir (LPV), ritonavir (RTV), and tenofovir (PMPA). These anti-HIV LNPs were prepared, characterized, scaled up, and evaluated in primates with a focus on plasma time course and intracellular drug exposure in blood and lymph nodes. Four macaques were subcutaneously administered anti-HIV LNPs and free drug suspension in a crossover study. The time course of the plasma drug concentration as well as intracellular drug concentrations in blood and inguinal lymph nodes were analyzed to compare the effects of LNP formulation. Anti-HIV LNPs incorporated LPV and RTV with high efficiency and entrapped a reproducible fraction of hydrophilic PMPA. In primates, anti-HIV LNPs produced over 50-fold higher intracellular concentrations of LPV and RTV in lymph nodes compared to free drug. Plasma and intracellular drug levels in blood were enhanced and sustained up to 7 days, beyond that achievable by their free drug counterpart. Thus, multiple antiretroviral agents can be simultaneously incorporated into anti-HIV lipid nanoparticles to enhance intracellular drug concentrations in blood and lymph nodes, where viral replication persists. As these anti-HIV lipid nanoparticles also prolonged plasma drug exposure, they hold promise as a long-acting dosage form for HIV patients in addressing residual virus in cells and tissue.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Portadores de Fármacos/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Lípidos/farmacocinética , Carga Viral/efectos de los fármacos , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/uso terapéutico , Animales , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Portadores de Fármacos/uso terapéutico , Combinación de Medicamentos , Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1/efectos de los fármacos , Indinavir/sangre , Indinavir/farmacocinética , Indinavir/uso terapéutico , Lípidos/uso terapéutico , Lopinavir/farmacocinética , Lopinavir/uso terapéutico , Ganglios Linfáticos/efectos de los fármacos , Macaca , Nanopartículas/uso terapéutico , Organofosfonatos/farmacocinética , Organofosfonatos/uso terapéutico , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Tenofovir , Latencia del Virus/efectos de los fármacosRESUMEN
BACKGROUND: Few data are available on antiretroviral therapy (ART) response among HIV-2 infected patients. We conducted a systematic review on treatment outcomes among HIV-2 infected patients on ART, focusing on the immunological and virological responses in adults. METHODS: Data were extracted from articles that were selected after screening of PubMed/MEDLINE up to November 2012 and abstracts of the 1996-2012 international conferences. Observational cohorts, clinical trials and program reports were eligible as long as they reported data on ART response (clinical, immunological or virological) among HIV-2 infected patients. The determinants investigated included patients' demographic characteristics, CD4 cell count at baseline and ART received. RESULTS: Seventeen reports (involving 976 HIV-2 only and 454 HIV1&2 dually reactive patients) were included in the final review, and the analysis presented in this report are related to HIV-2 infected patients only. There was no randomized controlled trial and only two cohorts had enrolled more than 100 HIV-2 only infected patients. The median CD4 count at ART initiation was 165 cells/mm3, [IQR; 137-201] and the median age at ART initiation was 44 years (IQR: 42-48 years). Ten studies included 103 patients treated with three nucleoside reverse transcriptase inhibitors (NRTI). Protease inhibitor (PI) based regimens were reported by 16 studies. Before 2009, the most frequent PIs used were Nelfinavir and Indinavir, whereas it was Lopinavir/ritonavir thereafter. The immunological response at month-12 was reported in six studies and the mean CD4 cell count increase was +118 cells/µL (min-max: 45-200 cells/µL). CONCLUSION: Overall, clinical and immuno-virologic outcomes in HIV-2 infected individuals treated with ART are suboptimal. There is a need of randomized controlled trials to improve the management and outcomes of people living with HIV-2 infection.
Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-2 , Síndrome de Inmunodeficiencia Adquirida/diagnóstico , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida/virología , Adulto , Recuento de Linfocito CD4 , Ensayos Clínicos como Asunto , Femenino , Humanos , Indinavir/uso terapéutico , Lopinavir/uso terapéutico , Masculino , Persona de Mediana Edad , Nelfinavir/uso terapéutico , Ritonavir/uso terapéutico , Resultado del TratamientoRESUMEN
Molecular mechanisms behind the defects in insulin production and secretion associated with antihuman immunodeficiency virus (anti-HIV) therapy and the development of HIV-associated lipodystrophy syndrome (HALS) are discussed in this article. Data suggesting insulin resistance on the beta cell and defects in first-phase insulin release of HALS patients are presented. Hepatic extraction of insulin, nonglucose insulin secretagogues and insulin-like growth factor release may exert influence on the demand of circulating insulin and on insulin secretion in HIV-infected patients. Finally, the paucity in understanding the incretin effects in HIV and HIV therapy in relation to insulin secretion is highlighted.
Asunto(s)
Inhibidores de la Proteasa del VIH/efectos adversos , Síndrome de Lipodistrofia Asociada a VIH/inducido químicamente , Resistencia a la Insulina , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Carbamatos/efectos adversos , Carbamatos/uso terapéutico , Furanos , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/efectos adversos , Indinavir/uso terapéutico , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Nelfinavir/efectos adversos , Nelfinavir/uso terapéutico , Ritonavir/efectos adversos , Ritonavir/uso terapéutico , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéuticoRESUMEN
We previously modeled the in vivo evolution of human immunodeficiency virus-1 (HIV-1) under drug selective pressure from cross-sectional viral sequences. These fitness landscapes (FLs) were made by using first a Bayesian network (BN) to map epistatic substitutions, followed by scaling the fitness landscape based on an HIV evolution simulator trying to evolve the sequences from treatment naïve patients into sequences from patients failing treatment. In this study, we compared four FLs trained with different sequence populations. Epistatic interactions were learned from three different cross-sectional BNs, trained with sequence from patients experienced with indinavir (BNT), all protease inhibitors (PIs) (BNP) or all PI except indinavir (BND). Scaling the fitness landscape was done using cross-sectional data from drug naïve and indinavir experienced patients (Fcross using BNT) and using longitudinal sequences from patients failing indinavir (FlongT using BNT, FlongP using BNP, FlongD using BND). Evaluation to predict the failing sequence and therapy outcome was performed on independent sequences of patients on indinavir. Parameters included estimated fitness (LogF), the number of generations (GF) or mutations (MF) to reach the fitness threshold (average fitness when a major resistance mutation appeared), the number of generations (GR) or mutations (MR) to reach a major resistance mutation and compared to genotypic susceptibility score (GSS) from Rega and HIVdb algorithms. In pairwise FL comparisons we found significant correlation between fitness values for individual sequences, and this correlation improved after correcting for the subtype. Furthermore, FLs could predict the failing sequence under indinavir-containing combinations. At 12 and 48 weeks, all parameters from all FLs and indinavir GSS (both for Rega and HIVdb) were predictive of therapy outcome, except MR for FlongT and FlongP. The fitness landscapes have similar predictive power for treatment response under indinavir-containing regimen as standard rules-based algorithms, and additionally allow predicting genetic evolution under indinavir selective pressure.
Asunto(s)
Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/genética , Indinavir/farmacología , Teorema de Bayes , Biología Computacional , Farmacorresistencia Viral/efectos de los fármacos , Farmacorresistencia Viral/genética , Evolución Molecular , Aptitud Genética , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/uso terapéutico , Estimación de Kaplan-Meier , Modelos Estadísticos , Insuficiencia del Tratamiento , Carga ViralRESUMEN
AIM: To describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period. METHODS: IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10(th) percentile IDV AUC (12.9 µg ml(-1)h) in non-pregnant historical Thai adults and a trough concentration of 0.1 µg ml(-1), the suggested minimum target. RESULTS: Twenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12 h) and Cmax during the second trimester and post-partum (ante : post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12 h) and Cmax ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml(-1) at delivery. All 26 infants were confirmed HIV negative. CONCLUSION: Indinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and â¼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations.
Asunto(s)
Infecciones por VIH/metabolismo , Inhibidores de la Proteasa del VIH/farmacocinética , Indinavir/farmacocinética , Complicaciones Infecciosas del Embarazo/metabolismo , Ritonavir/farmacocinética , Adolescente , Adulto , Terapia Antirretroviral Altamente Activa , Relación Dosis-Respuesta a Droga , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/transmisión , Inhibidores de la Proteasa del VIH/administración & dosificación , Inhibidores de la Proteasa del VIH/sangre , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/administración & dosificación , Indinavir/sangre , Indinavir/uso terapéutico , Lactante , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Periodo Posparto , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/virología , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Estudios Prospectivos , Ritonavir/administración & dosificación , Ritonavir/sangre , Ritonavir/uso terapéutico , Adulto JovenRESUMEN
The present study evaluated the efficacy of garlic plant and Indinavir on cryptosporidiosis in experimentally immunosuppressed infected rats. One hundred forty five Wister rats aging 3 weeks were divided into five groups: GI: normal control, GII: Indinavir treated control, GIII: immunosuppressed infected, GIV: immunosuppressed infected and treated with garlic and GV: immunosuppressed infected and treated with Indinavir. All were subjected to clinical, parasitological and histopathological examination at different days post infection (P.I.). The results showed that in GIII, all rats had diarrhea, loss of appetite, weakness and limited movement, with 51.4% death rate. In both treated groups, some rats regained activities, with death rate of 33.3% (GV) and non GIV. There was significant decrease in the number of excreted oocysts at 5th and 10th day post treatment (P.T.) in treated groups. One week P.T., in GIV, the number of excreted oocysts had continued in decreasing while in GV, it was insignificantly increased. No cure rate was detected in both treated groups as oocysts still excreted till the end of experiment. The histopathological changes improved in treated groups in spite of the presence of some parasites on the epithelial surfaces of ileum.
Asunto(s)
Antiprotozoarios/uso terapéutico , Criptosporidiosis/tratamiento farmacológico , Ajo/química , Indinavir/uso terapéutico , Fitoterapia/normas , Extractos Vegetales/uso terapéutico , Animales , Criptosporidiosis/inmunología , Ciclofosfamida/administración & dosificación , Modelos Animales de Enfermedad , Terapia de Inmunosupresión , Inmunosupresores/administración & dosificación , Masculino , Ratas , Ratas WistarRESUMEN
OBJECTIVE: In a nationwide, population-based cohort study we assessed the risk of diabetes mellitus (DM) in HIV-infected individuals compared with the general population, and evaluated the impact of risk factors for DM in HIV-infected individuals. METHODS: We identified 4,984 Danish-born HIV-infected individuals from the Danish HIV Cohort Study and a Danish born population-based age- and gender-matched comparison cohort of 19,936 individuals (study period: 1996-2009). Data on DM was obtained from the Danish National Hospital Registry and the Danish National Prescription Registry. Incidence rate ratios (IRR) and impact of risk factors including exposure to Highly Active Antiretroviral Therapy (HAART) and antiretroviral drugs were estimated by Poisson regression analyses. RESULTS: In the period 1996-1999 risk of DM was higher in HIV-infected individuals compared to the comparison cohort (adjusted IRR: 2.83; 95%CI: 1.57-5.09), both before (adjusted IRR: 2.40; 95%CI: 1.03-5.62) and after HAART initiation (adjusted IRR: 3.24; 95% CI: 1.42-7.39). In the period 1999-2010 the risk of DM in HIV-infected individuals did not differ from that of the comparison cohort (adjusted IRR: 0.90; 95% CI: 0.72-1.13), although the risk was decreased before HAART-initiation (adjusted IRR: 0.45; 95%CI: 0.21-0.96). Increasing age, BMI and the presence of lipoatrophy increased the risk of DM, as did exposure to indinavir, saquinavir, stavudine and didanosine. CONCLUSION: Native HIV-infected individuals do not have an increased risk of developing DM compared to a native background population after year 1998. Some antiretroviral drugs, not used in modern antiretroviral treatment, seem to increase the risk of DM.
Asunto(s)
Diabetes Mellitus/diagnóstico , Infecciones por VIH/complicaciones , Adulto , Antirretrovirales/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Índice de Masa Corporal , Estudios de Cohortes , Dinamarca , Complicaciones de la Diabetes/diagnóstico , Didanosina/uso terapéutico , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/terapia , Humanos , Incidencia , Indinavir/uso terapéutico , Masculino , Persona de Mediana Edad , Análisis de Regresión , Factores de Riesgo , Saquinavir/uso terapéutico , Estavudina/uso terapéutico , Resultado del TratamientoRESUMEN
The incidence of HIV/Leishmania co-infection decreases after antiretroviral drug therapy; therefore, the in vitro and in vivo activity of three antiretroviral drugs against Leishmania (Viannia) braziliensis and L. (L.) amazonensis was evaluated. Different concentrations of indinavir (IDV), atazanavir (ATV), and ritonavir (RTV) were added to promastigote cultures, and the 50% inhibitory concentration (IC50) was determined. IDV and RTV were also evaluated against intracellular amastigotes, and the Infection Index determined. BALB/c mice, infected with L. (L.) amazonensis in the left footpad, were treated orally with IDV and RTV for 30 days, and monitored by measuring the footpad thickness and parasite load of regional lymph nodes and spleen. For promastigotes, IDV exhibited an IC50 value of 100 µM against L.(L.) amazonensis. The RTV IC50 for L. (L.) amazonensis and L. (V.) braziliensis were 40 and 2.3 µM, respectively, and the ATV IC50 for L. (V.) braziliensis was 266 µM. For intracellular amastigotes, IDV (25, 50, and 100 µM) significantly decreased the Infection Index of L. (L.) amazonensis (56.8%, 47.9%, and 65.0%) and L. (V.) braziliensis (37.8%, 48.7%, and 43.2%). RTV (12.5, 25, and 50 µM) decreased the infection index of L. (L.) amazonensis by 26.3%, 42.4%, and 44.0%, and that of L. (V.) braziliensis by 27.6%, 37.3%, and 39.2%. Antiretroviral-treated mice had a significant reduction in footpad thickness after the third week of IDV and after the fifth week of RTV treatment. However, there was no reduction in parasite load. These results suggest that IDV and RTV have anti-Leishmania activity, but only in higher concentrations.
Asunto(s)
Antiprotozoarios/uso terapéutico , Inhibidores de la Proteasa del VIH/uso terapéutico , Leishmania/efectos de los fármacos , Leishmaniasis Cutánea/tratamiento farmacológico , Anfotericina B/administración & dosificación , Anfotericina B/uso terapéutico , Animales , Antiprotozoarios/administración & dosificación , Sulfato de Atazanavir , Relación Dosis-Respuesta a Droga , Inhibidores de la Proteasa del VIH/administración & dosificación , Indinavir/administración & dosificación , Indinavir/uso terapéutico , Ratones , Oligopéptidos/administración & dosificación , Oligopéptidos/uso terapéutico , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Ritonavir/administración & dosificación , Ritonavir/uso terapéuticoRESUMEN
Medical studies often involve semi-competing risks data, which consist of two types of events, namely terminal event and non-terminal event. Because the non-terminal event may be dependently censored by the terminal event, it is not possible to make inference on the non-terminal event without extra assumptions. Therefore, this study assumes that the dependence structure on the non-terminal event and the terminal event follows a copula model, and lets the marginal regression models of the non-terminal event and the terminal event both follow time-varying effect models. This study uses a conditional likelihood approach to estimate the time-varying coefficient of the non-terminal event, and proves the large sample properties of the proposed estimator. Simulation studies show that the proposed estimator performs well. This study also uses the proposed method to analyze AIDS Clinical Trial Group (ACTG 320).
Asunto(s)
Funciones de Verosimilitud , Análisis de Regresión , Riesgo , Síndrome de Inmunodeficiencia Adquirida/diagnóstico , Síndrome de Inmunodeficiencia Adquirida/inmunología , Simulación por Computador , VIH/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Indinavir/uso terapéuticoRESUMEN
There is much evidence to indicate the ability of Indinavir (IND) to reduce Cryptosporidium parvum infection in both in vitro and in vivo models. However, there are limitations to the administration of IND as such, due to its renal toxicity and the high rate of metabolism and degradation. We aimed to encapsulate IND in biodegradable poly (D,L-lactide-co-glycolide) nanoparticles (Np) and to engineer their surface by conjugation with an anti-Cryptosporidium IgG polyclonal antibody (Ab). Tetramethylrhodamine-labelled Np were loaded with IND and modified by conjugation with an Ab. The IND-loaded modified Np (Ab-TMR-IND-Np) did not show any change, as demonstrated by chemical analysis studies. Simultaneous addition of 50µM Ab-TMR-IND-Np and excysted oocysts to the cell culture resulted in complete inhibition of the infection. In C. parvum-infected cells, the extent to which the infection decreased depended on the duration of treatment with the Ab-TMR-IND-Np. The antibody-engineered Np loaded with IND were able to target C. parvum in infected cells and therefore might represent a novel therapeutic strategy against Cryptosporidium sp. infection. Moreover, the use of Np as an IND delivery device, allows the development of a more appropriate dose formulation thereby reducing the IND side effects.
Asunto(s)
Química Farmacéutica/métodos , Criptosporidiosis/tratamiento farmacológico , Cryptosporidium parvum/efectos de los fármacos , Portadores de Fármacos/química , Inhibidores de la Proteasa del VIH/farmacocinética , Inmunoconjugados/farmacocinética , Indinavir/farmacocinética , Terapia Molecular Dirigida , Nanopartículas/química , Animales , Anticuerpos Antiprotozoarios/química , Anticuerpos Antiprotozoarios/inmunología , Materiales Biocompatibles/química , Bovinos , Línea Celular Tumoral , Criptosporidiosis/inmunología , Criptosporidiosis/parasitología , Composición de Medicamentos , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Inmunoconjugados/química , Inmunoconjugados/inmunología , Indinavir/uso terapéutico , Ácido Láctico/química , Microscopía Fluorescente , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Rodaminas/análisis , Análisis EspectralRESUMEN
The HIV protease inhibitor indinavir presents a wide inter-individual variability related to an intense hepatic metabolism. Published studies were analyzed to establish whether there is evidence that therapeutic drug monitoring of indinavir could improve patient care. It was reported that indinavir virological efficacy in HIV-infected patients with wild-type virus was significantly associated with trough concentrations > 100-150 ng/mL. Concerning the exposure-toxicity relationship, the risk of occurrence of nephrotoxicity was more frequently associated with trough concentrations > 500-1 000 ng/mL. Studies with concentration-controlled indinavir therapy suggest that therapeutic drug monitoring allows to achieve safe and effective concentrations, therefore, the level of evidence of the interest of indinavir therapeutic drug monitoring is highly recommended when indinavir is not associated with ritonavir and recommended when ritonavir is combined with ritonavir.
Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Indinavir/uso terapéutico , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Monitoreo de Drogas , Medicina Basada en la Evidencia , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/economía , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Indinavir/efectos adversos , Indinavir/economía , Indinavir/farmacocinética , Enfermedades Renales/inducido químicamenteRESUMEN
Indinavir, an antiretroviral protease inhibitor used in treatment of HIV infection has limited penetration into brain due to efflux of P-glycoprotein. The aim of this work was to develop transferrin coupled submicron lipid emulsions (SLEs) containing indinavir for delivery to brain. Stearylamine containing SLEs were prepared, characterized, tested for stability and optimized formulation (SLE-4) was developed. Transferrin was coupled to get SLE-6 by water soluble EDC method and purified by gel filtration. The coupled transferrin was quantified by modified Bradford dye assay method. The fluorescent dye (DiD oil) incorporated SLEs were used to check the brain specific delivery of SLEs. The in vivo pharmacokinetic and tissue distribution were conducted in mice. During pharmacokinetic studies, there was no significant difference in the serum levels of indinavir from SLE-1, SLE-4 and SLE-6 formulations at all time points. In tissue distribution studies the therapeutic availability (TA) of indinavir in brain from SLE-6 was 4.69, 3.1 and 1.7 times higher than drug solution, SLE-1 and SLE-4 respectively whereas, the TA of indinavir from SLE-4 was 2.76 and 1.82 times the drug solution and SLE-1. The brain to serum ratios with SLE-6 were above one indicates the brain specific delivery. The brain delivery of indinavir was improved with transferrin ligand attachment to SLEs by receptor mediated transcytosis.
Asunto(s)
Portadores de Fármacos/farmacocinética , Emulsiones/farmacocinética , Inhibidores de la Proteasa del VIH/farmacocinética , Indinavir/farmacocinética , Transferrina/farmacocinética , Aminas/química , Animales , Encéfalo/citología , Encéfalo/metabolismo , Cromatografía en Gel , Portadores de Fármacos/metabolismo , Estabilidad de Medicamentos , Emulsiones/química , Colorantes Fluorescentes/análisis , VIH/fisiología , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Indinavir/uso terapéutico , Lípidos/química , Masculino , Ratones , Microscopía Fluorescente , Microtomía , Tamaño de la Partícula , Receptores de Transferrina/metabolismo , Distribución Tisular , Transferrina/metabolismoAsunto(s)
Farmacorresistencia Viral/fisiología , Evolución Molecular , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , Indinavir/uso terapéutico , Sustitución de Aminoácidos/genética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacología , Terapia Antirretroviral Altamente Activa/métodos , Farmacorresistencia Viral/genética , Estudios de Seguimiento , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , Humanos , Indinavir/administración & dosificación , Masculino , Polimorfismo Genético , Análisis de Secuencia de ADNRESUMEN
Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a nonlinear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics were best described by a one-compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir apparent oral clearance and volume of distribution were 21.3 L/h/70 kg (30%) and 90.7 L/70 kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration greater than 0.1 mg/L was greater than 99% for 600/100 mg and greater than 98% for 400/100 mg, twice daily, in patients weighing 40 to 80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (greater than 10.0 mg/L) increased from 1% to 10% with 600/100 mg compared with less than 1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients less than 50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity.