Mitochondrial toxicities of nucleoside analogue reverse transcriptase inhibitors in AIDS cases

Mitochondrial toxicities of nucleoside analogue reverse transcriptase inhibitors in AIDS cases

Acyclovir, 9-(2-hydroxyethoxymethyl)guanine, is an acyclic nucleoside analogue which has a high activity and selectivity for herpes viruses, particularly herpes simplex viruses types 1 and 2 and varicella zoster virus. In particular, the increasing numbers of immunosuppressed people due to AIDS, transplantation, cancer and aging has driven the need for improved antivirals to treat diseases caused by human cytomegalovirus (HCMV). Acyclovir Pharmacology Acyclovir is an antiviral agent highly active in vitro against herpes simplex virus (HSV) types I and II, and varicella zoster virus. The compounds need a long alkyl or alkylaryl side-chain at the base moiety for pronounced biological activity. Several promising highly potent HPI will be described with a particular focus on the identification of drug-resistance mutations. Acyclo-GTP acts as a more potent inhibitor of the viral DNA polymerases than of the cellular polymerases. 10 Aluminum Lake, FD&C Blue No.

The maximum solubility in water at 25°C exceeds 100 mg/mL. Product NDC 63323-325 The labeler code and product code segments of the National Drug Code number, separated by a hyphen. Asterisks are no longer used or included within the product code segment to indicate certain configurations of the NDC. Product Type Name HUMAN PRESCRIPTION DRUG Indicates the type of product, such as Human Prescription Drug or Human OTC Drug. Product Type Name HUMAN PRESCRIPTION DRUG Indicates the type of product, such as Human Prescription Drug or Human OTC Drug. This data element corresponds to the “Document Type” of the SPL submission for the listing. Proprietary Name Valacyclovir Hydrochloride Also known as the trade name.

Transport of nucleoside analogues across the gastrointestinal tract is often mediated by passive diffusion or active transporters (Na+-independent equilibrative transporters and Na+-dependent concentrative transporters) [1]. Non Proprietary Name valacyclovir hydrochloride Sometimes called the generic name, this is usually the active ingredient(s) of the product. Dosage Form Name TABLET, FILM COATED The translation of the DosageForm Code submitted by the firm. The complete list of codes and translations can be found www.fda.gov/edrls under Structured Product Labeling Resources. Similar to the procedure for the penciclovir-treated ducks, three ducks were killed after 12 weeks of treatment, three ducks were killed at 24 weeks of treatment, and two ducks continued with 4 weeks of treatment-free follow-up. We used this assay to measure the antiviral activity of cidofovir ([S]-9-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine; Vistide) (Gilead Sciences, Foster City, CA), and its esters octadecyloxyethyl (ODE)-cidofovir, oleyloxyethyl (OLE)-cidofovir, and hexadecyloxypropyl (HDP)-cidofovir. While the discovery of truly broad spectrum antiviral drugs will be difficult, the development of CMX001 represents a significant advance.
Mitochondrial toxicities of nucleoside analogue reverse transcriptase inhibitors in AIDS cases

The morbidity produced by these acute and recurrent infections as outlined below produce much human suffering for which there remains an unmet need for control by effective immunization or antiviral therapy. Although the EBV and KSHV TKs are able to phosphorylate nucleoside analogs of thymidine, such as BVDU and azidodeoxythymidine, these enzymes appear to be inefficient at catalyzing the phosphorylation of ACV and GCV (17–19). In this study, we determined the sensitivities of alpha-, beta-, and gammaherpesviruses to KAY-2-41 and KAH-39-149. However, in contrast to BVDU, HSV-1 TK does not recognize the BCNA or the BCNA 5′-monophosphates (MPs) as substrates for phosphorylation. Mitochondrial toxicity developed in 26 (30%) cases out of 90 which included 3 (7%) out of 42 cases on AZT + 3TC and 23 (48%) out of 48 cases on d4T + 3TC []. Thus, a valuable system for studying the genotypes and phenotypes of clinical VZV isolates known to be refractory to antiviral treatment was developed, and the causative role of specific VZV sequence variants in phenotypic drug resistance was proven. Kaposi’s Sarcoma is now recognized as one of the most common cancers in many sub-Saharan African countries [3].

Fomivirsen specifically is a complementary anti-sense sequence of mRNA for the CMV. The viral DNA polymerase holoenzyme complex (pUL30 DNA polymerase plus pUL42) catalyzes DNA elongation by a presumed double-stranded rolling-circle mechanism. The three-dimensional structure of VZV TK is not known. Hepatic steatosis was seen in three cases and pancreatitis in one case receiving AZT. Five cases on d4T were shifted to AZT due to toxicities; though tenofovir could have been an ideal switch, but was not available []. Aliquots were carefully frozen and stored at −140°C or in liquid nitrogen. Serum amylase was 1140 IU/L, blood urea – 37 mg, serum creatinine – 0.8, and CT abdomen was suggestive of pancreatic necrosis.

These properties make PVAS, PVS, and their congeners particularly attractive as vaginal microbicides in the prevention of the sexual transmission of HIV, HSV, and other sexually transmitted disease pathogens. Chickenpox: Three randomized, double-blind, placebo-controlled trials were conducted in 993 pediatric patients aged 2 to 18 years with chickenpox. Without such stabilizing interactions, the loop conformation is thus altered in the HSV1TK structure, and it is responsible for different positioning of Tyr66 and Gln95 in the active site. ACV andd-BVDU were obtained from Sigma (St. Ayusawa) as a template. A mutation in TDP1 causes the neurodegenerative disease spinocerebellar ataxia with axonal neuropathy (SCAN1) (20,24,25). Mitochondrial complications are a challenging issue because of potential of morbidity, mortality and distressing morphologic disfigurement.

The most common cause culprit was stavudine, which is still used as part of free ART program in resource restricted setup. Like cytidine and deoxycytidine, araC can undergo deamination either as a free nucleoside or as a monophosphate, and the initial phosphorylation can be undone by the enzyme 5′-nucleotidase. There are many issues remaining to be clarified about the effects of NRTIs on mitochondria and the potential for clinical manifestations of these effects. Some of these issues involve the differing adverse effects among NRTIs, which may be associated with mitochondrial toxicities, different NRTIs have been reported to have varying magnitude of inhibitory effect on gamma polymerase in vitro, there may be differences among NRTIs regarding the ability of gamma polymerase to proofread and excise the NRTI once it has been incorporated into the DNA chain and finally, it is not understood why only some patients appear to have mitochondrial toxicity or clinical manifestations of such toxicities. Regular monitoring and early diagnosis of mitochondrial toxicities with timely switch to safer alternatives (nucleotide reverse transcriptase inhibitor/tenofovir based) is of utmost importance.

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