RESUMEN
Neuropathic pain sometimes occurs during chemotherapy with paclitaxel or HIV/AIDS antiretroviral therapy with nucleoside reverse transcriptase inhibitors (NRTIs). We previously reported that coadministration of indomethacin plus minocycline (IPM) was antihyperalgesic in a cannabinoid type 1 (CB1) receptor-dependent manner in a mouse model of paclitaxel-induced neuropathic pain. We evaluated if IPM combination has antihyperalgesic and antiallodynic activities in animal models of paclitaxel or NRTI (ddC, zalcitabine)-induced neuropathic pain, and whether antagonists of CB1, CB2 receptors or G protein-coupled receptor 55 (GPR55) can inhibit these activities of IPM. IPM produced antihyperalgesic and antiallodynic effects against paclitaxel and ddC-induced thermal hyperalgesia and mechanical allodynia. WIN 55,212-2, a cannabinoid receptor agonist, also had antihyperalgesic activity. The antihyperalgesic and antiallodynic activities of IPM were antagonized by a CB1 receptor antagonist AM251 and a CB2 receptor antagonist AM630, but not a GPR55 antagonist ML193. IPM had no effects on the mean time spent on the rotarod, whereas WIN 55,212-2 reduced it in a dose-dependent manner. These results show that IPM at a fixed ratio produces antihyperalgesic and antiallodynic effects in mice models of both paclitaxel and NRTI-induced neuropathic pain which is dependent on both CB1 and CB2 receptors, without causing the typical cannabinoid receptor agonist-induced motor impairment.
Asunto(s)
Antibacterianos/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Antirretrovirales/efectos adversos , Antineoplásicos Fitogénicos/efectos adversos , Indometacina/administración & dosificación , Minociclina/administración & dosificación , Neuralgia/inducido químicamente , Neuralgia/tratamiento farmacológico , Paclitaxel/efectos adversos , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Zalcitabina/efectos adversos , Animales , Antibacterianos/farmacología , Modelos Animales de Enfermedad , Femenino , Indometacina/farmacología , Ratones Endogámicos BALB C , Minociclina/farmacologíaRESUMEN
Neuropathic pain associated with nucleoside reverse transcriptase inhibitors (NRTIs), therapeutic agents for human immunodeficiency virus (HIV), responds poorly to available drugs. Smoked cannabis was reported to relieve HIV-associated neuropathic pain in clinical trials. Some constituents of cannabis (Cannabis sativa) activate cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors. However, activation of the CB1 receptor is associated with side effects such as psychosis and physical dependence. Therefore, we investigated the effect of ß-caryophyllene (BCP), a CB2-selective phytocannabinoid, in a model of NRTI-induced neuropathic pain. Female BALB/c mice treated with 2'-3'-dideoxycytidine (ddC, zalcitabine), a NRTI, for 5 days developed mechanical allodynia, which was prevented by cotreatment with BCP, minocycline or pentoxifylline. A CB2 receptor antagonist (AM 630), but not a CB1 receptor antagonist (AM 251), antagonized BCP attenuation of established ddC-induced mechanical allodynia. ß-Caryophyllene prevented the ddC-induced increase in cytokine (interleukin 1 beta, tumor necrosis factor alpha and interferon gamma) transcripts in the paw skin and brain, as well as the phosphorylation level of Erk1/2 in the brain. In conclusion, BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation. Therefore, BCP could be useful for prevention and treatment of antiretroviral-induced neuropathic pain.
Asunto(s)
Hiperalgesia/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neuralgia/metabolismo , Sesquiterpenos Policíclicos/farmacología , Receptor Cannabinoide CB2/agonistas , Inhibidores de la Transcriptasa Inversa/efectos adversos , Zalcitabina/efectos adversos , Animales , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Hiperalgesia/patología , Ratones , Ratones Endogámicos BALB C , Neuralgia/inducido químicamente , Neuralgia/patología , Sesquiterpenos Policíclicos/química , Receptor Cannabinoide CB2/metabolismo , Inhibidores de la Transcriptasa Inversa/farmacología , Piel/metabolismo , Piel/patología , Zalcitabina/farmacologíaRESUMEN
The etiology and pathogenesis of Alzheimer's disease (AD) are not fully understood. Thus, there are no drugs available that can provide a cure for it. We and others found that DNA polymerase-ß (DNA pol-ß) is required for neuronal death in several neurodegenerative models. In the present study, we tested the effect of a DNA pol-ß inhibitor 2',3'- Dideoxycytidine (DDC) in AD models both in vitro and in vivo. DDC protected primary neurons from amyloid-ß (Aß)-induced toxicity by inhibiting aberrant DNA replication mediated by DNA pol- ß. Chronic oral administration of DDC alleviated Aß deposition and memory deficits in the Tg2576 mouse model of AD. Moreover, DDC reversed synaptic loss in Tg2576 mice. These results suggest that DDC represents a novel therapeutic agent for the treatment of AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , ADN Polimerasa beta/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Zalcitabina/uso terapéutico , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/toxicidad , Animales , ADN Polimerasa beta/metabolismo , Replicación del ADN/efectos de los fármacos , Inhibidores Enzimáticos/efectos adversos , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/etiología , Trastornos de la Memoria/psicología , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/efectos adversos , Cultivo Primario de Células , Sinapsis/efectos de los fármacos , Sinapsis/patología , Zalcitabina/efectos adversosRESUMEN
UNLABELLED: Although antiretroviral agents have been used successfully in suppressing viral production, they have also been associated with a number of side effects. The antiretroviral toxic neuropathy induces debilitating and extremely difficult to treat pain syndromes that often lead to discontinuation of antiretroviral therapy. Due to the critical need for the identification of novel therapeutic targets to improve antiretroviral neuropathic pain management, we investigated the role of the JNK signalling pathway in the mechanism of antiretroviral painful neuropathy. Mice were exposed to zalcitabine (2',3'-dideoxycytidine, ddC) and stavudine (2',3'-didehydro-3'-deoxythymidine, d4T) that induced a persistent mechanical allodynia and a transient cold allodynia. Treatment with the JNK blocker SP600125 before antiretroviral administration abolished mechanical hypersensitivity with no effect on thermal response. A robust spinal JNK overphosphorylation was observed on post-injection day 1 and 3, along with a JNK-dependent increase in p-c-Jun and ATF3 protein levels. Co-immunoprecipitation experiments showed the presence of a heterodimeric complex between ATF3 and c-Jun indicating that these transcription factors can act together to regulate transcription through heterodimerization. A rise in BDNF and caspase-3 protein levels was detected on day 1 and BDNF sequestration prevented both caspase-3 and p-JNK increase. These data suggest that BDNF plays a role in the early stages of ddC-induced allodynia by promoting apoptotic events and the activation of a hypernociceptive JNK-mediated pathway. We illustrated the activation of a BDNF-mediated JNK pathway involved in the early events responsible for the promotion of neuropathic pain, leading to a better knowledge of the mechanisms involved in the antiretroviral neuropathy. SUMMARY: JNK blockade prevents antiretroviral-induced pain hypersensitivity. This may represent a potential prophylactic treatment of neuropathic pain to improve antiretroviral tolerability.
Asunto(s)
Antirretrovirales/efectos adversos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hiperalgesia/prevención & control , MAP Quinasa Quinasa 4/antagonistas & inhibidores , Neuralgia/prevención & control , Médula Espinal/efectos de los fármacos , Animales , Antracenos/farmacología , Caspasa 3/metabolismo , Frío , Hiperalgesia/inducido químicamente , Hiperalgesia/enzimología , MAP Quinasa Quinasa 4/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones , Modelos Animales , Neuralgia/inducido químicamente , Neuralgia/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Distribución Aleatoria , Médula Espinal/enzimología , Estavudina/efectos adversos , Tacto , Zalcitabina/efectos adversosRESUMEN
Patients treated with nucleoside reverse transcriptase inhibitors (NRTIs) develop painful neuropathies that lead to discontinuation of antiretroviral therapy thus limiting viral suppression strategies. The mechanisms by which NRTIs contribute to the development of neuropathy are not known. In order to elucidate the mechanisms underlying this drug-induced neuropathy, we have characterized cellular events in the central nervous system following antiretroviral treatment. Systemic administration of the antiretroviral agent, 2',3'-dideoxycytidine (ddC) considerably increased the expression and phosphorylation of protein kinase C (PKC) γ and É, enzymes highly involved in pain processes, within periaqueductal grey matter (PAG), and, to a lesser extent, within thalamus and prefrontal cortex. These events appeared in coincidence with thermal and mechanical allodynia, but PKC blockade did not prevent the antiretroviral-induced pain hypersensitivity, ruling out a major involvement of PKC in the ddC-induced nociceptive behaviour. An increased expression of GAP43, a marker of neuroregeneration, and decreased levels of ATF3, a marker of neuroregeneration, were detected in all brain areas. ddC treatment also increased the expression of HuD, a RNA-binding protein target of PKC known to stabilize GAP43 mRNA. Pharmacological blockade of PKC prevented HuD and GAP43 overexpression. Silencing of both PKCγ and HuD reduced GAP43 levels in control mice and prevented the ddC-induced GAP43 enhanced expression. Present findings illustrate the presence of a supraspinal PKC-mediated HuD-GAP43 pathway activated by ddC. Based on our results, we speculate that antiretroviral drugs may recruit the HuD-GAP43 pathway, potentially contributing to a response to the antiretroviral neuronal toxicity.
Asunto(s)
Proteínas ELAV/metabolismo , Proteína GAP-43/metabolismo , Dolor/metabolismo , Enfermedades del Sistema Nervioso Periférico/metabolismo , Proteína Quinasa C/metabolismo , Inhibidores de la Transcriptasa Inversa/efectos adversos , Zalcitabina/efectos adversos , Animales , Fármacos Anti-VIH/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Proteína 4 Similar a ELAV , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Masculino , Ratones , Dolor/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamenteRESUMEN
OBJECTIVE: Previous studies of cardiomyopathy among children perinatally infected with HIV were conducted before the routine use of HAART. Nucleoside analogs [nucleoside reverse transcriptase inhibitors (NRTIs)], the backbone of HAART, have been associated with mitochondrial toxicity, which can lead to cardiomyopathy. We evaluated the association of HAART and specific NRTIs associated with mitochondrial toxicity, on development of cardiomyopathy among perinatally HIV-infected children. DESIGN: Three thousand and thirty-five perinatally HIV-infected children enrolled in a US-based multicenter prospective cohort study were followed for cardiomyopathy, defined as a clinical diagnosis or initiation of digoxin, from 1993 to 2007. METHODS: Cox models were used to estimate the effects of HAART and NRTIs on cardiomyopathy, identify predictors of cardiomyopathy among HAART users, and estimate the association between development of cardiomyopathy and mortality. RESULTS: Ninety-nine cases of cardiomyopathy were identified over follow-up (incidence rate: 5.6 cases per 1000 person-years) at a median age of 9.4 years. HAART was associated with a 50% lower incidence of cardiomyopathy compared with no HAART use (95% confidence interval: 20%, 70%). Zalcitabine (ddC) use, however, was associated with an 80% higher incidence of cardiomyopathy. Among HAART users, older age at HAART initiation, ddC use before HAART initiation, initiating a HAART regimen containing zidovudine (ZDV), and a nadir CD4 percentage less than 15% were independently associated with a higher rate of cardiomyopathy. Cardiomyopathy was associated with a six-fold higher mortality rate. CONCLUSION: HAART has dramatically decreased the incidence of cardiomyopathy among perinatally HIV-infected children. However, they remain at increased risk for cardiomyopathy and ongoing ZDV exposure may increase this risk.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Terapia Antirretroviral Altamente Activa/efectos adversos , Cardiomiopatías/inducido químicamente , Seropositividad para VIH/tratamiento farmacológico , Transmisión Vertical de Enfermedad Infecciosa/estadística & datos numéricos , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Zalcitabina/efectos adversos , Zidovudina/efectos adversos , Adolescente , Recuento de Linfocito CD4 , Cardiomiopatías/epidemiología , Cardiomiopatías/prevención & control , Cardiotónicos/administración & dosificación , Niño , Preescolar , Estudios de Cohortes , Digoxina/administración & dosificación , Femenino , Estudios de Seguimiento , Seropositividad para VIH/complicaciones , Seropositividad para VIH/epidemiología , Humanos , Lactante , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/epidemiología , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Peripheral nerve injury is associated with a spinal microglial response that has been correlated with the development of behaviours reflective of neuropathic pain. METHODS: To examine whether this phenomenon is generalizable to neuropathic pain of non-traumatic aetiology, this study investigated the association between spinal microgliosis and behavioural measures of neuropathic hypersensitivity and pain-related anxiety behaviour in four distinct rat models of peripheral neuropathic pain. These were traumatic neuropathy [L5 spinal nerve transection (SNT)], HIV-related neuropathies (either treatment with the antiretroviral drug Zalcitabine (ddC) or combination of perineural exposure to the HIV-gp120 protein and ddC treatment) and varicella zoster virus (VZV) infection. RESULTS AND CONCLUSION: Persistent mechanical hypersensitivity developed in all 'neuropathic' rats. However, spinal microgliosis, as measured by increased CD11b/c immunohistochemical staining and increased numbers of cells expressing CD11b measured by flow cytometry, was evident in the SNT and to a lesser extent in the HIV neuropathy models but not the VZV model. These results suggest that behavioural hypersensitivity and thigmotaxis can only be linked to a microglial response in certain models of neuropathy.
Asunto(s)
Conducta Animal , Gliosis/patología , Microglía/patología , Enfermedades del Sistema Nervioso Periférico/patología , Médula Espinal/patología , Animales , Fármacos Anti-VIH/efectos adversos , Modelos Animales de Enfermedad , Citometría de Flujo , Proteína gp120 de Envoltorio del VIH/efectos adversos , Infecciones por VIH/complicaciones , Infecciones por VIH/patología , Herpes Zóster/complicaciones , Herpes Zóster/patología , Herpesvirus Humano 3 , Hiperalgesia/patología , Inmunohistoquímica , Masculino , Traumatismos de los Nervios Periféricos/complicaciones , Traumatismos de los Nervios Periféricos/patología , Enfermedades del Sistema Nervioso Periférico/etiología , Ratas , Ratas Wistar , Nervios Espinales/lesiones , Zalcitabina/efectos adversosRESUMEN
A major dose-limiting side effect of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) chemotherapies, such as the nucleoside reverse transcriptase inhibitors (NRTIs), is a small-fiber painful peripheral neuropathy, mediated by its mitochondrial toxicity. Co-morbid conditions may also contribute to this dose-limiting effect of HIV/AIDS treatment. Alcohol abuse, which alone also produces painful neuropathy, is one of the most important co-morbid risk factors for peripheral neuropathy in patients with HIV/AIDS. Despite the prevalence of this problem and its serious impact on the quality of life and continued therapy in HIV/AIDS patients, the mechanisms by which alcohol abuse exacerbates highly active antiretroviral therapy (HAART)-induced neuropathic pain has not been demonstrated. In this study, performed in rats, we investigated the cellular mechanism by which consumed alcohol impacts antiretroviral-induced neuropathic pain. NRTI 2',3'-dideoxycytidine (ddC; 50 mg/kg) neuropathy was mitochondrial-dependent and PKCε-independent, and alcohol-induced painful neuropathy was PKCε-dependent and mitochondrial-independent. At low doses, ddC (5 mg/kg) and alcohol (6.5% ethanol diet for 1 week), which alone do not affect nociception, together produce profound mechanical hyperalgesia. This hyperalgesia is mitochondrial-dependent but PKCε-independent. These experiments, which provide the first model for studying the impact of co-morbidity in painful neuropathy, support the clinical impression that alcohol consumption enhances HIV/AIDS therapy neuropathy, and provide evidence for a role of mitochondrial mechanisms underlying this interaction.
Asunto(s)
Neuropatía Alcohólica/metabolismo , Fármacos Anti-VIH/efectos adversos , Etanol/farmacología , Mitocondrias/metabolismo , Zalcitabina/efectos adversos , Neuropatía Alcohólica/complicaciones , Neuropatía Alcohólica/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Proteínas del Complejo de Cadena de Transporte de Electrón/antagonistas & inhibidores , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Masculino , Oligodesoxirribonucleótidos Antisentido/farmacología , Oligodesoxirribonucleótidos Antisentido/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/complicaciones , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/metabolismo , Proteína Quinasa C-epsilon/metabolismo , Ratas , Ratas Sprague-DawleyAsunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Zalcitabina/análogos & derivados , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/análogos & derivados , Adenina/farmacología , Adenina/uso terapéutico , Alquinos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacología , Benzoxazinas/administración & dosificación , Benzoxazinas/efectos adversos , Benzoxazinas/farmacología , Benzoxazinas/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Ciclopropanos , Infecciones por VIH/virología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Humanos , Lamivudine/administración & dosificación , Lamivudine/efectos adversos , Lamivudine/farmacología , Lamivudine/uso terapéutico , Organofosfonatos/administración & dosificación , Organofosfonatos/efectos adversos , Organofosfonatos/farmacología , Organofosfonatos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/farmacología , Tenofovir , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Zalcitabina/administración & dosificación , Zalcitabina/efectos adversos , Zalcitabina/farmacología , Zalcitabina/uso terapéuticoRESUMEN
OBJECTIVE: Peripheral neuropathy and central nervous system neurodegeneration may result from the mitochondrial toxicity of some antiretroviral nucleoside analogues. We investigated whether this neuropathology may be antagonized by uridine supplementation in vivo. DESIGN: Because of the obvious difficulties in obtaining human neural tissues, the mitochondrial neurotoxicity of the nucleoside analogues was studied in mice. METHODS: BALB/C mice (7 weeks of age) were fed for 9 weeks with zalcitabine (13 mg/kg per day) or zidovudine (100 mg/kg per day) with or without mitocnol (340 mg/kg per day), a dietary supplement with high uridine bioavailability. Hippocampal and sciatic nerve mitochondria were analyzed. RESULTS: Zalcitabine and to a lesser extent zidovudine induced a significant peripheral neuropathy and encephalopathy with disrupted mitochondrial ultrastructure, depleted mitochondrial DNA, reduced levels of cytochrome c oxidase activity and diminished expression of mitochondrial DNA-encoded cytochrome c oxidase subunit I. Mitocnol had no intrinsic effects but attenuated or fully normalized all measured disorder of the peripheral and central nervous system. CONCLUSION: Zidovudine and zalcitabine induce a mitochondrial disorder in the peripheral and central nervous system, both of which are antagonized by uridine supplementation.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Miopatías Mitocondriales/prevención & control , Uridina/farmacología , Zalcitabina/efectos adversos , Zidovudina/efectos adversos , Administración Oral , Animales , ADN Mitocondrial/análisis , ADN Mitocondrial/efectos de los fármacos , Interacciones Farmacológicas , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Encefalomiopatías Mitocondriales/inducido químicamente , Encefalomiopatías Mitocondriales/prevención & control , Miopatías Mitocondriales/inducido químicamente , Miopatías Mitocondriales/genética , Uridina/administración & dosificaciónRESUMEN
La introducción del tratamiento antirretroviral de gran actividad (TARGA) en 1996 supuso un cambio radical en la historia natural de la infección por el virus de la inmunodeficiencia humana (VIH) al lograr reducir drásticamente la mortalidad en estos pacientes. No obstante, estos tratamientos no están exentos de limitaciones que incluyen efectos adversos, fracaso del tratamiento, interacciones farmacocinéticas, aparición de resistencias y respuestas inmunes anómalas. En este artículo se revisa la situación actual de las reacciones cutáneas adversas a fármacos en los pacientes con infección por el VIH (AU)
The introduction of highly active antiretroviral treatment (HAART) in 1996 radically changed the clinical course of human immunodeficiency virus (HIV) infection as it led to a dramatic reduction in mortality in these patients. However, these treatments have their limitations, including adverse effects, therapeutic failure, pharmacokinetic interactions, the development of resistance, and abnormal immune responses. In this article we review the current situation of cutaneous drug reactions in HIV-infected patients (AU)
Asunto(s)
Humanos , Masculino , Femenino , Preparaciones Farmacéuticas/efectos adversos , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico , Enfermedades Cutáneas Infecciosas/complicaciones , Exantema/complicaciones , Indinavir/efectos adversos , Antirretrovirales/efectos adversos , Enfermedades de la Piel/complicaciones , Enfermedades Cutáneas Vesiculoampollosas/complicaciones , Inhibidores de la Transcriptasa Inversa/efectos adversos , Zidovudina/análogos & derivados , Zidovudina/efectos adversos , Didanosina/análogos & derivados , Didanosina/efectos adversos , Zalcitabina/análogos & derivados , Zalcitabina/efectos adversos , Hiperpigmentación/complicacionesRESUMEN
BACKGROUND: Peripheral neuropathy (PN) in HIV-infected individuals is thought be due to a toxic effect on mitochondria induced by some nucleoside reverse transcriptase inhibitors (NRTI). METHODS: A time-to-event analysis was performed using data from the Delta trial to study the incidence of PN in HIV-infected individuals receiving zidovudine (AZT) alone or in combination with didanosine (ddl) or zalcitabine (ddC). In an on-treatment analysis, changes in the incidence of PN by duration of treatment were directly estimated using a flexible parametric survival model. RESULTS: A total of 3,195 patients (total follow-up 4,593 person-years) were included in the analysis. AZT+ddC was associated with a higher incidence of PN (6.2 cases/100 person-years) compared with AZT monotherapy (3.0 cases/100 person-years) and AZT+ddl (2.2 cases/100 person-years). The risk of PN peaked around day 90 following randomization (at 8.9 events/100 person-years in the AZT+ddC arm). PN was also associated with age at entry (hazard ratio (HR)=2.35 for those aged 35-44 years compared with <30) and current CD4+ T-cell count (HR=2.27 for CD4+ T-cell counts <150 cell/mm3 compared with >350). CONCLUSION: Our findings challenge the common supposition that PN arises from cumulative exposure to NRTIs. We found that patients who developed PN tended to do so shortly after exposure to antiretroviral therapy. Therefore, our results support the hypothesis of a susceptibility in a subgroup of patients. These results will be of direct interest to those working in resource-limited countries where potentially neurotoxic dideoxynucleosides are still widely used.
Asunto(s)
Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/epidemiología , Inhibidores de la Transcriptasa Inversa/efectos adversos , Adulto , Fármacos Anti-VIH/uso terapéutico , Didanosina/efectos adversos , Didanosina/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/virología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Factores de Riesgo , Factores de Tiempo , Zalcitabina/efectos adversos , Zalcitabina/uso terapéutico , Zidovudina/efectos adversos , Zidovudina/uso terapéuticoRESUMEN
While altered activities in sensory neurons were noticed in neuropathic pain, caused by highly diverse insults to the peripheral nervous system, such as diabetes, alcohol ingestion, cancer chemotherapy and drugs used to treat AIDS, other infections and autoimmune diseases, as well as trauma, our understanding of how these various peripheral neuropathies manifest as altered neuronal activity is still rudimentary. The recent development of models of several of those neuropathies has, however, now made it possible to address their impact on primary afferent nociceptor function. We compared changes in mechanically-evoked C-fiber activity, in models of painful peripheral neuropathy induced by drinking ethanol (alcohol) or administering 2',3'-dideoxycytidine (ddC), a nucleoside reverse transcriptase inhibitor for AIDS therapy, two co-morbid conditions in which pain is thought to be mediated by different second messenger signaling pathways. In C-fiber afferents, ddC decreased conduction velocity. In contrast, alcohol but not ddC caused enhanced response to mechanical stimulation (i.e., decrease in threshold and increase in response to sustained threshold and supra-threshold stimulation) and changes in pattern of evoked activity (interspike interval and action potential variability analyses). These marked differences in primary afferent nociceptor function, in two different forms of neuropathy that produce mechanical hyperalgesia of similar magnitude, suggest that optimal treatment of neuropathic pain may differ depending on the nature of the causative insult to the peripheral nervous system, and emphasize the value of studying co-morbid conditions that produce painful peripheral neuropathy by different mechanisms.
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Síndrome de Inmunodeficiencia Adquirida/complicaciones , Neuropatía Alcohólica/fisiopatología , Fibras Nerviosas Amielínicas/efectos de los fármacos , Dolor/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Zalcitabina/efectos adversos , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Animales , Comorbilidad , Modelos Animales de Enfermedad , Etanol/efectos adversos , Mecánica , Mecanotransducción Celular , Dolor/etiología , Dolor/fisiopatología , RatasRESUMEN
Nucleoside reverse transcriptase inhibitors (NRTIs) are known to produce painful neuropathies and to enhance states of pain hypersensitivity produced by HIV-1 infection. It has also been observed that in some neuropathic pain models, chemokines and their receptors are upregulated, perhaps contributing to the pain state. In order to understand if chemokines are involved in NRTI-mediated sensory neuropathies, we treated rats with the anti-retroviral drug, 2',3'-dideoxycytidine (ddC), which is known to produce an extended period of hyperalgesia and allodynia. Using in situ hybridization, we observed that under normal conditions, CXCR4 chemokine receptors were widely expressed by satellite glia in the dorsal root ganglia (DRG) and Schwann cells in the sciatic nerve. A limited number of DRG neurons also expressed CXCR4 receptors. The chemokine SDF-1/CXCL12 was similarly expressed in glial cells in the DRG and peripheral nerve. Following a single administration of ddC, expression levels of CXCR4 mRNA in glia and neurons and SDF-1 mRNA in glia increased considerably. The functional nature of increased CXCR4 mRNA expression was confirmed by measuring SDF-1 induced [Ca2+]i increases in acutely isolated DRG neurons and glia. In contrast, the expression of the chemokine receptors CCR2 and CCR5 did not change following ddC treatment. Pain hypersensitivity produced by ddC could be inhibited by treatment with the CXCR4 antagonist, AMD3100. Hence, we postulate that NRTIs produce pain hypersensitivity through the upregulation of CXCR4 signaling in the DRG. Increased numbers of CXCR4 receptors would also explain the synergism observed between NRTI treatment and the proalgesic effects of HIV-1 infection.
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Quimiocinas CXC/metabolismo , Neuralgia/inducido químicamente , Umbral del Dolor/efectos de los fármacos , Receptores CXCR4/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/inmunología , Zalcitabina/inmunología , Análisis de Varianza , Animales , Quimiocina CXCL12 , Quimiocinas CXC/genética , Quimiocinas CXC/inmunología , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Ganglios Espinales/ultraestructura , Regulación de la Expresión Génica/efectos de los fármacos , Neuralgia/inmunología , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Neuroglía/patología , Neuroglía/ultraestructura , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Neuronas/ultraestructura , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Inhibidores de la Transcriptasa Inversa/efectos adversos , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Células de Schwann/patología , Células de Schwann/ultraestructura , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Nervio Ciático/patología , Nervio Ciático/ultraestructura , Estadísticas no Paramétricas , Zalcitabina/efectos adversosRESUMEN
UNLABELLED: Zalcitabine is an antiretroviral nucleoside analogue that exhibits long-term toxicity to hepatocytes by interfering with the replication of mitochondrial DNA (mtDNA). Uridine antagonizes this effect in vitro. In the present study we investigate the mechanisms of zalcitabine-induced hepatotoxicity in mice and explore therapeutic outcomes with oral uridine supplementation. BalbC mice (7 weeks of age, 9 mice in each group) were fed 0.36 mg/kg/d of zalcitabine (corresponding to human dosing adapted for body surface), or 13 mg/kg/d of zalcitabine. Both zalcitabine groups were treated with or without Mitocnol (0.34 g/kg/d), a dietary supplement with high bioavailability of uridine. Liver histology and mitochondrial functions were assessed after 15 weeks. One mouse exposed to high dose zalcitabine died at 19 weeks of age. Zalcitabine induced a dose dependent microvesicular steatohepatitis with abundant mitochondria. The organelles were enlarged and contained disrupted cristae. Terminal transferase dUTP nick end labeling (TUNEL) assays showed frequent hepatocyte apoptosis. mtDNA was depleted in liver tissue, cytochrome c-oxidase but not succinate dehydrogenase activities were decreased, superoxide and malondialdehyde were elevated. The expression of COX I, an mtDNA-encoded respiratory chain subunit was reduced, whereas COX IV, a nucleus-encoded subunit was preserved. Uridine supplementation normalized or attenuated all toxic abnormalities in both zalcitabine groups, but had no effects when given without zalcitabine. Uridine supplementation was without apparent side effects. CONCLUSION: Zalcitabine induces mtDNA-depletion in murine liver with consequent respiratory chain dysfunction, up-regulated synthesis of reactive oxygen species and microvesicular steatohepatitis. Uridine supplementation attenuates this mitochondrial hepatotoxicity without apparent intrinsic effects.
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Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado Graso/inducido químicamente , Hígado Graso/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa/efectos adversos , Uridina/farmacología , Zalcitabina/efectos adversos , Animales , Replicación del ADN/efectos de los fármacos , ADN Mitocondrial/genética , Suplementos Dietéticos , Hígado Graso/patología , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Mitocondrias Hepáticas/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Succinato Deshidrogenasa/genética , Succinato Deshidrogenasa/metabolismo , Uridina/administración & dosificaciónRESUMEN
The aim of this study was to determine the prevalence of distal sensory polyneuropathy (DSP) in our HIV-positive patients under highly active antiretroviral therapy (HAART) and to investigate correlations with clinical, laboratory and demographic factors. One hundred consecutive HIV-positive patients underwent clinical and electrophysiological evaluation for DSP. Correlations with HIV stage, CD4 count, nadir CD4 count, viral load (VL), disease duration, age, sex and type of antiretrovirals were examined. Thirty-six percent of the patients had DSP (13% clinical, 23% subclinical diagnosed by electrophysiology). The prevalence of DSP was affected in a statistically significant manner by the diagnosis of AIDS (P = 0.00033), age (P = 0.0102), nadir CD4 count (P = 0.0087) and exposure to two neurotoxic antiretrovirals (P = 0.0189). Advanced HIV stage, sex, time from diagnosis, current CD4 count and VL did not seem to affect the prevalence of DSP. Clinical examination plus electrophysiology reveals that DSP affects 36% of patients under HAART, although subclinical in 2/3 of cases. Age, severe prior immunosuppression and the combined use of zalcitabine (ddC), stavudine (d4T) and didanosine (ddI) are important risk factors.
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Terapia Antirretroviral Altamente Activa/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Polineuropatías/epidemiología , Adulto , Anciano , Fármacos Anti-VIH/efectos adversos , Didanosina/efectos adversos , Electrofisiología , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , Humanos , Masculino , Persona de Mediana Edad , Polineuropatías/diagnóstico , Polineuropatías/patología , Prevalencia , Inhibidores de la Transcriptasa Inversa/efectos adversos , Factores de Riesgo , Estavudina/efectos adversos , Zalcitabina/efectos adversosRESUMEN
Racivir [RCV; (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine], a 50:50 racemic mixture of the two beta nucleoside enantiomers, is currently in development for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. RCV was administered once a day orally for 14 days at doses of 200, 400, or 600 mg in combination with stavudine and efavirenz to HIV-1-infected treatment-naïve male volunteers in a phase Ib/IIa study. Six volunteers at each dose were monitored for a total of 35 days for tolerance, pharmacokinetics, and plasma HIV RNA levels. RCV in combination with stavudine and efavirenz was well tolerated at all doses tested. Pharmacokinetic parameters were dose proportional, and the maximum concentration of drug in serum at all doses exceeded the 90% effective concentration for wild-type HIV-1. Viral loads dropped as expected in all dosage groups, with mean reductions from 1.13 to 1.42 log10 by day 4 and 2.02 to 2.43 log10 by day 14. HIV RNA levels remained suppressed for more than 2 weeks in the absence of any additional therapy, with mean viral loads ranging from 2.1 to 2.6 log10 below baseline through day 28. By day 35, HIV RNA levels began to increase but still remained >1 log10 below baseline levels.
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Fármacos Anti-VIH , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Transcriptasa Inversa , Zalcitabina , Zalcitabina/análogos & derivados , Administración Oral , Adulto , Alquinos , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas , Ciclopropanos , Quimioterapia Combinada , Emtricitabina/análogos & derivados , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Humanos , Persona de Mediana Edad , Oxazinas/uso terapéutico , Plasma/metabolismo , ARN Viral/sangre , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/farmacocinética , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Estavudina/uso terapéutico , Orina/química , Zalcitabina/administración & dosificación , Zalcitabina/efectos adversos , Zalcitabina/farmacocinética , Zalcitabina/uso terapéuticoAsunto(s)
Infecciones por VIH/complicaciones , Enfermedades Neuromusculares/etiología , Enfermedades del Sistema Nervioso Periférico/etiología , Fármacos Anti-VIH/efectos adversos , Infecciones por Citomegalovirus/etiología , Infecciones por VIH/tratamiento farmacológico , Humanos , Neuritis/etiología , Enfermedades Neuromusculares/inducido químicamente , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/etiología , Zalcitabina/efectos adversos , Zidovudina/efectos adversosRESUMEN
Nucleoside reverse transcriptase inhibitors (NRTIs) have been a mainstay in the treatment of human immunodeficiency virus since the introduction of azidothymidine (AZT) in 1987. However, none of the current therapies can completely eradicate the virus, necessitating long-term use of anti-retroviral drugs to prevent viral re-growth. One of the side effects associated with long-term use of NRTIs is mitochondrial toxicity stemming from inhibition of the mitochondrial DNA (mtDNA) polymerase gamma, which leads to mtDNA depletion and consequently to mitochondrial dysfunction. Here we report the use of fluorescence in situ hybridization (FISH) and immunocytochemistry (ICC) to monitor mtDNA depletion in cultured fibroblasts treated with the NRTI 2',3'-dideoxycytidine (ddC). These techniques are amenable to both microscopy and flow cytometry, allowing analysis of populations of cells on a single-cell basis. We show that, as mtDNA depletion progresses, a mosaic population develops, with some cells being depleted of and others retaining mtDNA. These techniques could be useful as potential therapeutic monitors to indicate when NRTI therapy should be interrupted to prevent mitochondrial toxicity and could aid in the development of less toxic NRTIs by providing an assay suitable for pharmacodynamic evaluation of candidate molecules.
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ADN Mitocondrial/biosíntesis , Inhibidores de la Transcriptasa Inversa/efectos adversos , Zalcitabina/efectos adversos , Línea Celular , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Reacción en Cadena de la PolimerasaRESUMEN
The "D drug" HIV reverse-transcriptase inhibitors zalcitabine, didanosine, and stavudine are relatively strong inhibitors of polymerase-gamma compared with the "non-D drugs" zidovudine, lamivudine, and abacavir. D drugs deplete mitochondrial DNA (mtDNA) in cultured hepatocytes. This mtDNA depletion is associated with an increased in vitro production of lactate. To investigate the origin of hyperlactatemia in HIV-infected patients and the effects of antiretroviral therapy on liver mtDNA, we biopsied liver tissue from 94 individuals with chronic hepatitis C virus (HCV) infection. Eighty subjects were coinfected with HIV. Serum lactate was measured at the time of biopsy. Hepatic mtDNA and liver histology were centrally assessed. Liver mtDNA content of HIV-infected patients receiving D drugs at the time of biopsy (n = 34) was decreased by 47% (P<.0001) compared with those without D drugs (n = 35). Aside from a possible association between HCV genotype I status and mtDNA depletion in multivariate analysis, there were no other virologic, immunologic, histologic, demographic or treatment-related variables that could explain the mtDNA depletion. Lactate was above the upper limit of normal in only three patients, all of whom were treated with D drugs. The mtDNA in each of them was lower than in any non-D drug patient and significantly (P =.017) depleted compared with D drug patients with normal lactate. In conclusion, D drug treatment is associated with decreased hepatic mtDNA in HIV-infected patients with chronic HCV infection. Moderate mtDNA depletion in liver does not necessarily lead to hyperlactatemia, but more pronounced decreases in hepatic mtDNA may be an important contributor to lactate elevation.