Hyperglycemia toxic effects

Tacrolimus can be administered orally or intravenously. The half-life of the intravenous form is approximately 9-12 hours. Like cyclosporine, tacrolimus is metabolized primarily by P450 enzymes in the liver, and there is potential for drug interactions. The dosage is determined by trough blood level at steady state. Its toxic effects are similar to those of cyclosporine and include nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, and gastrointestinal complaints. 

Modified-release formulations of nicotinic acid do not appear to be better tolerated than regular formulations, flushing and itching being the most common adverse effects (SEDA-19, 206). There have also been several reports of hepatotoxicity with this form of the drug (SEDA-16,438). Other adverse effects are hepatotoxicity (apparently a dose-related direct toxic effect), hyperglycemia, and hyperuricemia. It has been questioned whether the modified-release formulation, which is available over the counter in some countries, ought to continue to be available for self-medication in view of its serious adverse effects (2,3). 

Chronic toxic effects are dose related and typically involve cerebellar and vestibular functions (nystagmus and ataxia). Nausea, dizziness, diplopia, behavioral changes, gingival hyperplasia, hirsutism, hyperglycemia, osteomalacia, pancytopenia, and skin eruptions are reported complications of chronic therapy. Hypersensitivity (idiosyncratic) reactions, including hepatic necrosis and Stevens-Johnson syndrome, can occur and are potentially fatal. 

Some investigators suggested that the toxic effects observed during urea infusion experiments were due to products formed from urea (G17) (Fig. 1). Dimhuber and Schultz had shown earlier that cyanate, formed in urea solutions, could cause drowsiness and hyperglycemia (D16, S15). Gilboe and Javid had likewise con-... 

Toxicity. Toxic effects of nicotinamide Include (Table 9) flushing, pruritus, skin rash, heartburn, nausea, vomiting, diarrhea, ulcer activation, abnormal liver function, hypertension, and hyperglycemia (Ban, 1974 Berge, 1961 Berge et al, 1961 DlPalma and Ritchie, 1977). The doses used are often greater In excess of... 

Caffeine is a CNS stimulant, which may account for such adverse effects as cardiac stimulation, palpitations, irritability, insomnia, delirium, tremor, and hyperglycemia. Toxic dose for adults is 1 g (25 tablets). 

According to inpatient records from St. Luke s Hospital, the most common laboratory finding related to sarin toxicity was a decrease in plasma cholinesterase (ChE) levels in 74% of patients. In patients with more severe toxicity, plasma ChE levels tended to be lower, but a more accurate indication of ChE inhibition is the measurement of erythrocyte ChE, as erythrocyte acetylcholinesterase (AChE) is considered "true ChE" and plasma ChE is "pseudo-ChE." However, erythrocyte ChE is not routinely measured, whereas plasma ChE is included in many clinical chemistry panels thus, it can be used as a simple index for ChE activity. In both the Matsumoto and Tokyo subway sarin attacks, plasma ChE served as a useful index of sarin exposure. In 92% of hospitalized patients, plasma ChE levels returned to normal on the following day. In addition, inpatient records from St. Luke s Hospital showed an elevated creatine phosphokinase and leukocytosis in 11% and 60% of patients, respectively. In severe cases such as the Matsumoto attack, hyperglycemia, ketonuria, and low serum triglycerides due to tire toxic effects of sarin on the adrenal medulla were observed (Yanagisawa et al, 2006). 

Cyclosporine reduces production of cytokines involved in T-cell activation and has direct effects on B cells, macrophages, bone, and cartilage cells. Its onset appears to be 1 to 3 months. Important toxicities at doses of 1 to 10 mg/kg/day include hypertension, hyperglycemia, nephrotoxicity, tremor, GI intolerance, hirsutism, and gingival hyperplasia. Cyclosporine should be reserved for patients refractory to or intolerant of other DMARDs. It should be avoided in patients with current or past malignancy, uncontrolled hypertension, renal dysfunction, immunodeficiency, low white blood cell or platelet counts, or elevated Ever function tests. 

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. 

Clinical trials of ARIs have yielded encouraging results in alleviating painful symptoms of diabetic complications. However, unacceptable side effects related to toxicity or inadequate pharmocokinetic profiles have rendered most of the drug candidates undesirable. Nevertheless, several ARIs are commercially available in some countries and more appear to be in the pipeline. The therapeutic rationale for treatment of human diabetics with ARIs to delay or prevent onset of diabetic complications is compelling. Animal models with experimentally induced hyperglycemia develop complications that are morphologically and functionally similar to that seen in the human diabetic patient. Many structurally... 

Patients with poorly controlled diabetes are at risk of greater or more severe fluorouracil toxicity, causing hyperglycemia, which has been fatal. This effect seems to be independent of previous diabetic control and or fluorouracil dosage schedules (414)... 

Adverse Effects. Common side effects of tacrolimus include gastrointestinal disturbances (cramps, nausea, diarrhea, constipation), weakness, fever, and skin rashes and itching. More serious problems include renal and central nervous system (CNS) toxicity (headache, anxiety, nervousness, seizures).41 Tacrolimus is also associated with problems with glucose metabolism (hyperglycemia, glucose intolerance), and can cause diabetes mellitus in certain individuals.73... 

Pancreatic toxicity is common. Hypoglycemia due to inappropriate insulin release often appears 5-7 days after onset of treatment, can persist for days to several weeks, and may be followed by hyperglycemia. Reversible renal insufficiency is also common. Other adverse effects include rash, metallic taste, fever, gastrointestinal symptoms, abnormal liver function tests, acute pancreatitis, hypocalcemia, thrombocytopenia, hallucinations, and cardiac arrhythmias. Inhaled pentamidine is generally well-tolerated but may cause cough, dyspnea, and bronchospasm. 

In addition to sinus tachycardia and tremor, vomiting is common after overdose. Hypotension, tachycardia, hypokalemia, and hyperglycemia may occur, probably due to -adrenergic activation. The cause of this activation is not fully understood, but the effects can be ameliorated by the use of B-blockers (see below). Cardiac arrhythmias include atrial tachycardias, premature ventricular contractions, and ventricular tachycardia. In severe poisoning (eg, acute overdose with serum level > 100 mg/L), seizures often occur and are usually resistant to common anticonvulsants. Toxicity may be delayed in onset for many hours after ingestion of sustained-release tablet formulations. 

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