Toxicity lactic acidosis

Before an antiviral agent becomes a drug, advanced toxicity testing, pharmacological combination, and drug-interaction studies are needed. The use of new cell-based assays that can predict mitochondrial toxicity, lactic acidosis, peripheral neuropathy, anemia, hypersensitivity, lipodystrophy, and other potential side effects can alleviate these issues (Stuyver et al. 2002). 

Lactic acidosis/severe hepatomegaly with steatosis/hepatic toxicity Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination, including zalcitabine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Exercise particular caution when... 

Toxicity. Lactic acidosis is associated with plasma concentrations greater than 1 pg/ml. 

Several other biochemical changes may occur with moderate to marked muscle toxicity. Lactic acidosis occurs if there is compromised mitochondrial activity, such as with NRTIs. If muscle injury is severe enough to cause serum CK to increase to several thousand, then serum calcium may decrease due to dystrophic calcification. Serum potassium increases (peracutely) with acidosis, rhabdomyolysis, and myo-globinuric nephrosis. Hemoconcentration occurs with hypermetabolic states (Guis et al. 2005). Whereas creatinine does not significantly increase with rhabdomyolysis due to release of cellular contents, it may increase dramatically with urea due to myoglobinuric nephrosis. 

The use of ribavirin with the NRTIs may result in increased toxicity (lactic acidosis, blood dyscrasias and hepatotoxicity), which may be more frequent with didanosine than other NRTIs. These effects may also be exacerbated by the additional use of interferon for hepatitis C. Early in vitro data su ested that ribavirin may reduce the antiretroviral effects of some NRTIs but this does not appear to have been demonstrated in practice. 

Antiretroviral toxic neuropathy Any stage Subacute rarely acute with lactic acidosis Distal sensory loss and neuropathic pain Toxic neuropathy mitochondrial damage... 

NRTls are structural analogues of the natural nucleotides that form the building blocks of RNA and DNA in human cells. Their use as part of HAART has dramatically modified the natural history of HIV infection. They, however, cause a range of drag- or tissue-specific toxicides zidovudine (AZT) causes myopathy zalcitabine (ddC), didanosine (ddl), and lamivudine (3TC) cause neuropathy stavudine (d4T) causes neuropathy or myopathy and lactic acidosis (Dalakas 2001). During phase 1 and 11 trials, the dose-limiting toxicity of didanosine, zalcitabine, and stavudine was identified as peripheral neuropathy (Dalakas 2001). 

Zalcitabine (ddC) Hivid (anticipated discontinuation of distribution in 2006) 0.375-, 0.75-mg tab 0.75 mg tid CrCI Dose (mL/minute) 10-40 0.75 mg bid less than 10 0.75 mg qday No data on hemodialysis None Peripheral neuropathy stomatitis, lactic acidosis with hepatic steatosis (rare but potentially life-threatening toxicity with use of NRTIs) pancreatitis Renal excretion... 

The following factors have been suggested as alternatives to consider when presented with a potential case of exposure to carbon monoxide diabetic ketoacidosis, hypothyroidism and myxedema coma, labyrinthitis, and lactic acidosis toxic exposures resulting in methemoglobinemia ingestion of alcohols or narcotics and diseases that cause gastroenteritis, encephalitis, meningitis, and acute respiratory distress syndrome. 

In addition to pulmonary toxicity, nausea/vomiting, lactic acidosis and transaminitis, UCN-01 induced insulin resistance during Phase I clinical trials. As shown recently with rat adipose cells, this effect may be due to UCN-01 inhibition of PKB Thr-308 phosphorylation—no effect on Ser-473 was observed in this study—and subsequent blockade of GLUT4 translocation in response to insulin [104]. If this mode of action is confirmed in the ongoing clinical trials and contrary to what was observed in the PDKl hypomorphic mice (vide supra) [100], insulin resistance may represent an important hurdle in the development of PDKl inhibitors and, in general, of any agent that blocks the PI3K/PKB pathway in adipose and muscle cells. 

If patients require treatment with amprenavir oral solution, monitor them closely for propylene glycol-associated adverse reactions, including seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis. Switch patients from amprenavir oral solution to capsules as soon as they are able to take the capsule formulation. 

A serious toxicity of didanosine is pancreatitis, which may be fatal (see Warnings). Other important toxicities include lactic acidosis/severe hepatomegaly with steatosis retinal changes and optic neuritis and peripheral neuropathy (see Warnings and Precautions). 

The drug metformin is useful in the treatment of patients with type 2 diabetes mellitus who are obese and whose hyperglycemia cannot be controlled by other agents. There are reports that some patients are predisposed to the toxic side effects of this drug, which include potentially fatal lactic acidosis. 

Tenofovir should not be given to patients with renal insufficiency. Its coadministration with didanosine results in increased plasma levels of didanosine that can produce toxicity. Because lactic acidosis and severe hepatomegaly with steatosis have been reported with NRTIs, it is important to monitor patients with known risk factors during treatment with tenofovir. 

The most common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), which occur in up to 20% of patients. They are dose-related, tend to occur at the onset of therapy, and are often transient. However, metformin may have to be discontinued in 3-5% of patients because of persistent diarrhea. Absorption of vitamin B12 appears to be reduced during long-term metformin therapy, and annual screening of serum vitamin B12 levels and red blood cell parameters has been encouraged by the manufacturer to determine the need for vitamin B12 injections. In the absence of hypoxia or renal or hepatic insufficiency, lactic acidosis is less common with metformin therapy than with phenformin therapy. 

Metformin Obscure Reduced hepatic and renal gluconeogenesis Decreased endogenous glucose production Type 2 diabetes Oral maximal plasma concentration in 2-3 h Toxicity Gastrointestinal symptoms, lactic acidosis (rare) cannot use if impaired renal/hepatic function congestive heart failure (CHF), hypoxic/acidotic states, alcoholism... 

The principal toxicity of linezolid is hematologic—reversible and generally mild. Thrombocytopenia is the most common manifestation (seen in approximately 3% of treatment courses), particularly when the drug is administered for longer than 2 weeks. Anemia and neutropenia may also occur, most commonly in patients with a predisposition to or underlying bone marrow suppression. Cases of optic and peripheral neuropathy and lactic acidosis have been reported with prolonged courses of linezolid. These side effects are thought to be related to linezolid-induced inhibition of mitochondrial protein synthesis. 

All NRTIs may be associated with mitochondrial toxicity, probably owing to inhibition of mitochondrial DNA polymerase gamma. Less commonly, lactic acidosis with hepatic steatosis may occur, which can be fatal. NRTI treatment should be suspended in the setting of rapidly rising aminotransferase levels, progressive hepatomegaly, or metabolic acidosis of unknown cause. The thymidine analogues zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance. Also,... 

The mechanism of toxicity of ethylene glycol involves metabolism, but unlike previous examples, this does not involve metabolic activation to a reactive metabolite. Thus, ethylene glycol is metabolized by several oxidation steps eventually to yield oxalic acid (Fig. 7.84). The first step is catalyzed by the enzyme alcohol dehydrogenase, and herein lies the key to treatment of poisoning. The result of each of the metabolic steps is the production of NADH. The imbalance in the level of this in the body is adjusted by oxidation to NAD coupled to the production of lactate. There is thus an increase in the level of lactate, and lactic acidosis may result. Also, the intermediate metabolites of ethylene glycol have metabolic effects such as the inhibition of oxidative phosphorylation, glucose metabolism, Krebs cycle, protein synthesis, RNA synthesis, and DNA replication. 

In combination with other antiretroviral agents, stavudine has caused fatal lactic acidosis in some patients. It is also associated with motor weakness in which case it should be discontinued. Peripheral neuropathy is the most common toxicity associated with stavudine, which is more prevalent at high doses (4mg/kg per day). Neuropathy in these patients generally is associated with numbness, tingling or pain in feet or hands. Patients treated with the combination of stavudine and didanosine may also exhibit liver function abnormalities (hepatic steatosis) and pancreatitis. It may also be associated with the etiology of HIV lipodystrophy syndrome. 

A 68-year-old man was treated for a subcutaneous infection of the thigh by subcutaneous irrigation with povidone iodine (71). Toxic plasma and urinary iodine concentrations were associated with abnormalities of cardiac conduction, lactic acidosis, acute renal insufficiency, hypocalcemia, and thyroid dysfunction. 

Adverse effect Lactic acidosis due to biguanides Dose-relation toxic effect Time-course time-independent Susceptibility factors genetic (slow phenformin metabolizers) age disease (impaired liver, kidney, or cardiac function, alcoholism)... 

An apparent interaction between nicotinic acid and alcohol caused toxic delirium and lactic acidosis (45). 

Lactic acidosis in this patient supports the view that interference with the mitochondrial respiratory chain may play a role in the toxicity of the statins. 

Lactic acidosis is a severe and potentially fatal form of mitochondrial toxicity. Metabolic stress or vitamin deficiencies (riboflavin, carnitine) might provoke it. There is suggestive evidence of clinical benefit with riboflavin therapy (846). 

Valik D, Yeh KH, Cheng AL. Encephalopathy, lactic acidosis, hyperammonaemia and 5-fluorouracil toxicity. Br J Cancer 1998 77(10) 1710-2. 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS RIBAVIRIN 1. t side-effects, risk of lactic acidosis, peripheral neuropathy, pancreatitis, hepatic decompensation, mitochondrial toxicity and anaemia with didanosine and stavudine 2.1 efficacy of lamivudine 1. Additive side-effects t intracellular activation of didanosine and stavudine 2. J intracellular activation of lamivudine 1. Not recommended. Use with extreme caution monitor lactate, LFTs and amylase closely. Stop co-administration if peripheral neuropathy occurs. Stavudine and didanosine carry a higher risk 2. Monitor HIV RNA levels if they T, review treatment combination... 

Jeevaratnam, K., Vijayraghavan, R., Kaushik, M.P., Vaidyanathan, C.S. (1992c). Acute toxicity of methyl isocyanate in mammals. II. Induction of hyperglycemia, lactic acidosis, uraemia and hypothermia in rats. Arch. Environ. Contam. Toxicol. 19 314-18. 

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