didanosine and Disease-Models--Animal

Topics: Acyclovir; Animals; Antiviral Agents; Carcinogens; Didanosine; Disease Models, Animal; Evidence-Based Medicine; Humans; Intestinal Absorption; Neoplasms; Risk Factors; Tissue Distribution; Zalcitabine; Zidovudine

Peripheral nerve disorders are among the most common neurological complications of HIV disease. Distal sensory polyneuropathy (DSP) is the most common form of neuropathy in patients with AIDS and can be caused by diverse mechanisms, including infectious, metabolic, inflammatory, nutritional, and toxic factors. Antiretroviral agents may cause or contribute to HIV-related DSP. Recognition of peripheral neuropathy has become increasingly important as more patients receive nucleoside analogue agents for the treatment of HIV disease. It is crucial to correctly distinguish between the neuropathies caused by toxic effects of nucleoside analogues and those that are primarily related to underlying HIV disease, because timely diagnosis and proper treatment of peripheral neuropathies may allow the continuation of antiretroviral therapy as well as improve the quality of life. The identification and treatment of peripheral neuropathies associated with use of the nucleoside drugs zalcitabine (ddC), didanosine (ddI), and stavudine (d4T) are reviewed.

Topics: Animals; Didanosine; Dideoxynucleosides; Disease Models, Animal; HIV Infections; Humans; Peripheral Nervous System Diseases; Stavudine; Zalcitabine

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4⁺-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIV(mac251) and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan (D-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART.

Topics: AIDS Vaccines; Animals; Anti-HIV Agents; CTLA-4 Antigen; Didanosine; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Macaca mulatta; Pancreatitis; Simian Immunodeficiency Virus; Stavudine; Tryptophan

The primary aim of this study was to investigate intranasal (i.n.) administration as a potential route to enhance systemic and brain delivery of didanosine (ddI). A further aim was to investigate the potential use of chitosan nanoparticles as a delivery system to enhance the systemic and brain targeting efficiency of ddI following i.n. administration. Didanosine-loaded chitosan nanoparticles, were prepared through ionotropic gelation of chitosan with tripolyphosphonate anions, and characterized in terms of their size, drug loading, and in vitro release. The nanoparticles were administered i.n. to rats, compared to i.n. and intravenous (i.v.) administration of ddI in solution. The concentrations of ddI in blood, CSF, and brain tissues were analyzed by ultra performance liquid chromatography mass spectroscopy (UPLC/MS). The brain/plasma, olfactory bulb/plasma and CSF/plasma concentration ratios were significantly higher (P < 0.05) after i.n. administration of ddI nanoparticles or solution than those after i.v. administration of didanosine aqueous solution. The ratio of ddI concentration values of the nanoparticles to the solution at 180 min post-i.n. dosing was 2.1 and 1.9 in CSF and brain, respectively. Thus, both the i.n. route of administration and formulation of ddI in chitosan nanoparticles increased delivery of ddI to CSF and brain.

Topics: Administration, Intranasal; Animals; Brain; Chitosan; Chromatography, Liquid; Didanosine; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; HIV Infections; Male; Mass Spectrometry; Microscopy, Electron, Transmission; Nanoparticles; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Inhibitors

Mitochondrial compromise has been documented in infants born to women infected with the human immunodeficiency virus (HIV-1) who received nucleoside reverse transcriptase inhibitor (NRTI) therapy during pregnancy. To model these human exposures, we examined mitochondrial integrity at birth and 1 year in brain cortex and liver from offspring of retroviral-free Erythrocebus patas dams-administered human-equivalent NRTI doses for the last half (10 weeks) of gestation. Additional infants, followed for 1 year, were given the same drugs as their mothers for the first 6 weeks of life. Exposures included: no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/Didanosine (ddI), and Stavudine (d4T)/3TC. In brain and liver, oxidative phosphorylation (OXPHOS) enzyme activities (complexes I, II, and IV) showed minimal differences between unexposed and NRTI-exposed offspring at both times. Brain and liver mitochondria from most NRTI-exposed patas, both at birth and 1 year of age, contained significant (p < 0.05) morphological damage observed by electron microscopy (EM), based on scoring of coded photomicrographs. Brain and liver mitochondrial DNA (mtDNA) levels in NRTI-exposed patas were depleted significantly in the 3TC and d4T/3TC groups at birth and were depleted significantly (p < 0.05) at 1 year in all NRTI-exposed groups. In 1-year-old infants exposed in utero to NRTIs, mtDNA depletion was 28.8-51.8% in brain and 37.4-56.5% in liver. These investigations suggest that some NRTI-exposed human infants may sustain similar mitochondrial compromise in brain and liver and should be followed long term for cognitive integrity and liver function.

Topics: Animals; Animals, Newborn; Cerebral Cortex; Didanosine; Disease Models, Animal; DNA, Mitochondrial; Drug Therapy, Combination; Erythrocebus patas; Female; Lamivudine; Maternal Exposure; Mitochondria, Liver; Oxidative Phosphorylation; Pregnancy; Reverse Transcriptase Inhibitors; Stavudine; Zidovudine

Antiretroviral toxic neuropathy (ATN) has become a common peripheral neuropathy among HIV/AIDS patients, for which the underlying pathogenesis is uncertain. Indeed, no models exist for ATN that assess the interaction between retroviral infection and antiretroviral therapy. Herein, we developed ex vivo and in vivo models of ATN induced by didanosine (ddI) following infection by the lentivirus, feline immunodeficiency virus (FIV), permitting us to address the working hypothesis that ddI mediates ATN through mitochondrial injury in neurons. We investigated neuronal morphology, neurobehavioural testing, viral load, mitochondrial and neurotrophic factor gene expression after ddI treatment of FIV-infected and uninfected animals or dorsal root ganglia (DRG) cultures. ddI caused concentration-dependent neuronal injury in cultured feline DRGs (P < 0.05), together with reduced viral replication and diminished expression of mitochondrial cytochrome C oxidase subunit I gene (mtCOX I) and the neurotrophin, brain-derived neurotrophic factor (BDNF). Indeed, BDNF treatment reversed neuronal injury caused by FIV infection in the presence or absence of ddI exposure (P < 0.05). In vivo FIV infection revealed delays in withdrawal latency to a noxious stimulus, which were exacerbated by ddI treatment. Epidermal density of nerve endings was reduced after FIV infection (P < 0.05), especially with ddI treatment. Although viral replication in blood was suppressed in ddI-treated animals (P < 0.05), ddI had a limited effect on viral abundance in DRGs of the same animals. ddI decreased mtCOX I expression in DRG neurons of FIV-infected animals (P < 0.05). BDNF expression was downregulated by ddI in DRG Schwann cells following FIV infection. Thus, ddI treatment during FIV infection resulted in additive pathogenic effects contributing to the development of ATN, which was associated with mitochondrial injury on neurons and reduced BDNF production by Schwann cells in DRGs, highlighting the convergent pathogenic effects that antiretroviral drugs might have in patients with HIV infection.

Topics: Animals; Anti-HIV Agents; Blotting, Western; Brain-Derived Neurotrophic Factor; Cats; Cells, Cultured; Didanosine; Disease Models, Animal; Feline Acquired Immunodeficiency Syndrome; Ganglia, Spinal; Mitochondria; Peripheral Nervous System Diseases; Polymerase Chain Reaction; Viral Load

Human immunodeficiency virus (HIV)-associated sensory neuropathy (SN) is the most common neurological complication of HIV infection in the current highly active antiretroviral therapy era. The painful sensory neuropathy is associated with the use of dideoxynucleoside antiretrovirals, and its development limits the choice of antiretroviral drugs in affected patients. There are presently no effective therapies for HIV-SN, and moreover there has been no robust animal model of HIV-SN in which candidate therapeutic agents can be tested. In this paper, we show that we have established a rodent model of HIV-SN by oral administration of a dideoxynucleoside drug, didanosine, to transgenic mice expressing the HIV coat protein gp120 under a GFAP promoter. The neuropathy in these rodents is characterized by distal degeneration of unmyelinated sensory axons, similar to the "dying back" pattern of C-fiber loss seen in patients with HIV-SN. This model will be useful in examining mechanisms of distal axonal degeneration and testing potential neuroprotective compounds that may prevent development of the sensory neuropathy.

Topics: Animals; Anti-Retroviral Agents; Didanosine; Disease Models, Animal; HIV Infections; HIV-1; Mice; Mice, Transgenic; Peripheral Nervous System Diseases

Zidovudine (AZT) and didanosine (ddI) are antiretroviral drugs widely used in AIDS patients. Hypokalemia and hypomagnesemia are frequently encountered in AIDS patients using AZT and/or ddI.. To verify the effects of AZT and ddI on rat renal function submitted to normal diet, low potassium diet and magnesium-free diet.. Glomerular filtration rate and renal hemodynamic were measured in Wistar rats submitted to a normal or a potassium-depleted diet. The animals were given AZT, ddI for 15 days. Six groups of rats were studied: normal diet, normal diet + AZT, normal diet + ddI, low K diet, low K diet + AZT and low K diet + ddI. Three additional groups of rats submitted to magnesium depletion for 15 days were also studied: magnesium-free diet, magnesium-free diet + AZT and magnesium-free diet + ddI.. AZT and didanosine did not modify renal function of rats on a normal diet. However, in hypokalemic rats, both drugs produced a decrease in glomerular filtration rate and in renal blood flow consequent to renal vasoconstriction and associated with alterations in tubular function (characterized by an increased fractional excretion of sodium). Hypomagnesemia induced a decrease in glomerular filtration rate and in renal blood flow only in AZT-treated rats.. Our data suggest that hypokalemia predisposes to AZT and ddI nephrotoxicity, while hypomagnesemia predisposes only to AZT nephrotoxicity. Thus, chronic AZT and ddI administration may produce acute renal failure in AIDS patients with hypokalemia and/or hypomagnesemia. Serum K and Mg levels should be carefully monitored in these patients.

Topics: Acute Kidney Injury; Animals; Anti-HIV Agents; Didanosine; Diet; Disease Models, Animal; HIV Infections; Hypokalemia; Magnesium; Male; Rats; Rats, Wistar; Risk Factors; Zidovudine

To compare the efficacy of the nucleoside reverse transcriptase inhibitors (NRTIs) abacavir, zidovudine (AZT), lamivudine (3TC), didanosine (ddI), and stavudine (d4T) to inhibit viral replication in brain macrophages. A severe combined immunodeficiency (SCID) mouse model of HIV-1 encephalitis (HIVE) was used to monitor spreading viral infection in the CNS.. The development of antiretroviral therapies with CNS efficacy against neuroinvasive virus is important if eradication of HIV-1 can be achieved within critical "hidden reservoirs.". HIV-1-infected human monocyte-derived macrophages (MDMs) (after a single round of viral replication) were inoculated into the caudate and putamen of SCID mice. This resulted in the spreading of viral infection with a concomitant multinucleated giant cell encephalitis (astrogliosis, microglial activation, and neuronal injury). NRTIs were administered to animals at the time of intracerebral MDM inoculations and continued until the time of sacrifice. Antiretroviral effects were assessed by viral load and percentages of infected MDMs.. In brains of SCID mice with HIVE, abacavir and lamivudine reduced HIV-1 p24 antigen-positive cells by 80% and 95%, respectively, whereas both decreased viral load by approximately 1 log. Zidovudine, didanosine, and stavudine showed variable effects.. Abacavir and lamivudine showed significant antiretroviral activity in SCID mice with HIVE when compared with other NRTIs. The extrapolation of these results to humans with HIV-1 dementia awaits future investigations.

Topics: AIDS Dementia Complex; Animals; Cells, Cultured; Didanosine; Dideoxynucleosides; Disease Models, Animal; HIV-1; Humans; Lamivudine; Male; Mice; Mice, SCID; Monocytes; Reverse Transcriptase Inhibitors; Stavudine; Virus Replication; Zidovudine

We have utilized combination antiretroviral therapy following human immunodeficiency virus type 1-induced human CD4(+) thymocyte depletion in the SCID-hu mouse to examine the immune competence of reconstituting thymocytes which appear following administration of combination therapy. These cells express a normal distribution of T-cell receptor variable gene families and are responsive to costimulatory signals. These results suggest that normal thymic function may be restored following antiretroviral treatment.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Disease Models, Animal; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Mice; Mice, SCID; Receptors, Antigen, T-Cell, alpha-beta; Reverse Transcriptase Inhibitors; Thymus Gland; Zidovudine

In this study we investigated the effect of the antiretroviral molecule 2',3'-dideoxyinosine (Videx) against cerebral cysts in a murine model of toxoplasmic encephalitis caused by a wild cystic strain of Toxoplasma gondii. The role of the vehicle was also studied. Three doses were used: 50, 100 and 150 mg/kg of body weight/day. The doses of 50 and 150 mg/kg were prepared by dissolving pure 2',3'-dideoxyinosine powder in Maalox suspension before gavaging the mice; the dose of 100 mg/kg was prepared by grinding tablets of Videx that were suspended in water. A decrease in the number of cysts and a morphological modification of them were noted from day 15 with the lowest dose. The most important decrease could be observed with the dose of 100 mg/kg/d. After 30 days of treatment with this dose, 65% of the cysts were destroyed compared to controls. For the doses of 50 and 150 mg/kg/d prepared with Maalox, 36% and 51% of the cysts were destroyed respectively. So ddI has an effect on the cerebral cysts of T. gondii even at a low dose. The galenic formulation influences its action since the doses prepared with Maalox were less efficient than those prepared from ground tablets.

Topics: Animals; Antacids; Buffers; Didanosine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Compounding; Encephalitis; Female; Mice; Toxoplasma; Toxoplasmosis, Cerebral

Human immunodeficiency virus type 1 (HIV-1)-infected SCID-hu thymic implants depleted of CD4(+) cells can support renewed thymopoiesis derived from both endogenous and exogenous T-cell progenitors after combination antiretroviral therapy. However, successful production of new thymocytes occurs transiently. Possible explanations for the temporary nature of this thymic reconstitution include cessation of the thymic stromal support function, exhaustion of T-cell progenitors, and viral resurgence. Distinguishing between these processes is important for the development of therapeutic strategies aimed at reconstituting the CD4(+) T-cell compartment in HIV-1 infection. Using an HIV-1 strain engineered to express the murine HSA heat-stable antigen surface marker, we explored the relationship between HIV-1 expression and CD4(+) cell resurgence kinetics in HIV-1-depleted SCID-hu implants following drug therapy. Antiviral therapy significantly suppressed HIV-1 expression in double-positive (DP) CD4/CD8 thymocytes, and the eventual secondary decline of DP thymocytes following therapy was associated with renewed viral expression in this cell subset. Thymocytes derived from exogenous T-cell progenitors induced to differentiate in HIV-1-depleted, drug-treated thymic implants also became infected. These results indicate that in this model, suppression of viral replication occurs transiently and that, in spite of drug therapy, virus resurgence contributes to the transient nature of the renewed thymic function.

Topics: Animals; Anti-HIV Agents; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Didanosine; Disease Models, Animal; Drug Therapy, Combination; Hematopoietic Stem Cell Transplantation; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Kinetics; Lymphocyte Depletion; Mice; Mice, SCID; Reverse Transcriptase Inhibitors; Thymus Gland; Zidovudine

In the present communication we evaluate the feline leukemia virus (FeLV) infection of cats as a model for antiretroviral chemotherapy studies. Additionally, we report the results of testing the antiviral effect of the compounds, 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine, 2',3'-dideoxyinosine and 2',3'-dideoxyadenosine against FeLV replication in vitro. Cumulative data from experiments in which FeLV-infected cats were treated with AZT at different stages of experimental infection are also evaluated.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antibodies, Viral; Antiviral Agents; Cats; Cell Line; Didanosine; Dideoxyadenosine; Dideoxynucleosides; Disease Models, Animal; Drug Evaluation, Preclinical; Immunologic Deficiency Syndromes; Leukemia Virus, Feline; Leukemia, Experimental; Nucleosides; Specific Pathogen-Free Organisms; Virus Replication; Zalcitabine; Zidovudine