Pancreatic toxicity

A 29-year-old man presented with acute pancreatitis after a period of heavy cannabis smoking. Other causes of the disease were ruled out. The pancreatitis resolved itself after the cannabis was stopped and this was confirmed by urinary cannabinoid metabolite monitoring in the community. There were no previous reports of acute pancreatitis associated with cannabis use in the general population. Drugs of all types are related to the etiology of pancreatitis in approximately 1.4-2% of cases k Pancreatic toxicity. The dried leaf, smoked by a 19-year-old woman, was active. The subject was hospitalized with pancrea-titis . 

Pancreatic toxicity is common. Flypoglycemia due to inappropriate insulin release often appears 5-7 days after onset of... 

Symptoms of acute toxicity- are sunilar to those in humans, including hyperpyrexia and neurological and respiratory- dysfunction (WHO, 1987). Furthermore, pahnitoylpenta-chlorophenol, which has been isolated from human fat (Ansari et al., 1985), causes selective pancreatic toxicity in rats after single oral doses of 100 mg/kg bw (Ansari et al., 1987). 

Ansari, G.A.S., Kaphalia, B.S. Boor, P.J. (1987) Selective pancreatic toxicity of palmitoylpenta-chlorophenol. Toxicology, 46, 57-63... 

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. 

Gastrointestinal Abdominal discomfort, nausea and vomiting, pancreatitis, toxic megacolon... 

Stuecklin-Utsch A, Hasan C, Bode U, Fleischhack G. Pancreatic toxicity after hposomal amphotericin B. Mycoses 2002 45(5-6) 170-3. 

Ethionine-induced teratogenesis has been reported in rats and chicks. Both mice and rats demonstrate significant strain difference to the carcinogenic effects that are caused by ethionine. In addition to cancer, the ethionine-induced abnormal methylation may also have pathological effects leading to birth defects, neurological disorder, and liver and pancreatic toxicities. 

Pancreatic toxicity has been observed following excess selenium exposure. Cytoplasmic flocculation was observed in lambs treated with a single oral dose of selenite, and pancreatic damage, which was not further described, was noted in rats following chronic oral treatment with selenate or selenite. Pancreatic toxicity associated with excessive selenium exposure is likely related to the unique ability of that organ to accumulate the element. 

Several urinary enzymes are useful in the assessment of nephrotoxicity, and these are discussed separately in Chapter 4. Although there is some application of cholinesterases in studying hepatotoxicity, these enzymes are important markers in pesticide-induced toxicities and are discussed in Chapter 11. Creatine kinase (CK) remains a useful marker for myotoxicity, but it is rapidly losing its place to troponins in the detection of cardiotoxicity (see Chapter 7). Amylase and lipase remain the enzyme markers of pancreatic toxicity. 

Adverse gastrointestinal events are not uncommon in early clinical trials because one objective of these studies is to assess tolerability however, these effects are not always related to the pharmacology of the compound. Of the top 100 most frequently prescribed medications, 44 have been implicated in episodes of acute pancreatitis (Trivedi and Pitchumoni 2005). There is an objective to improve assessment of gastrointestinal toxicities by biochemical analyses in addition to enhancing safety pharmacology studies. Many of the mechanisms that cause gastrointestinal and pancreatic toxicity are poorly understood. 

Although several enzyme measurements are available for assessing gastrointestinal function, these assays are not frequently used amylase and/or lipase are perhaps measured more often than other enzymes in order to evaluate pancreatic toxicity. Some enzyme measurements require the invasive collection of gastric, pancreatic, and intestinal fluids, or tissues and therefore are not suitable for many toxicological studies. 

The pancreatic secretion of chloride varies inversely to the bicarbonate concentration, which in turn varies directly with the flow rate the sum of these two anions tends to remain constant under physiological conditions, with the electrolyte concentrations of the pancreatic secretions tending to parallel blood pH and electrolytes. Excessive losses of pancreatic fluid can be monitored by plasma chloride measurements. Hypocalcemia may also accompany severe pancreatic toxicity, probably due to the formation of insoluble salts with fatty acids. 

In cases when gastrointestinal or pancreatic toxicity is present, plasma lipids will be affected. The nephrotic syndrome is characterized by hyperlipidemia, hypopro-teinemia, and hyperproteinuria in several species, and lipid changes may also be observed with chronic renal damage (Moestrup and Nielsen 2005). 

Additive pancreatic toxicity has been described with zalcitabine and intravenous pentamidine, and is expected when didanosine or stavudine are given with other drugs that can cause pancreatitis. An isolated case describes pancreatitis with lamivudine and aza-thioprine. 

PRECLINICAL SAFETY ASSESSMENT OF DRUG CANDIDATE-INDUCED PANCREATIC TOXICITY FROM AN APPLIED PERSPECTIVE... 

The initial hazard identification of pancreatic toxicity in a prechnical study is always concerning because of the potentially serious human health risks, which may include fulminant, hfe-threatening cases of DIAP or a lifelong iUness, such as CP, type 1 diabetes, or pancreatic neoplasia. Because both the exocrine and the endocrine pancreas have enormous reserve capacities and there are limited sensitive and specific biomarkers to detect pancreatic injury in both animals and humans, there is always the concern that subclinical DIAP may initially go undetected in humans. Further, AP may progress until a threshold of severity is evident in minimally or asymptomatic healthy human volunteers exposed to drug candidates with unknown risks and/or in previously healthy patients that receive standard-of-care agents with marked... 

The potential for clinical translatabUity of preclinical findings of pancreatic toxicity needs to be determined on a case-by-case basis. Since pancreatic toxicity is a known risk factor for many approved drugs, it is clear that, if first identified early on in a drug development program, the risk does not necessarily preclude the further development of the drug candidate. However, such risk would need to be fuUy understood mechanistically, so that its potential for extrapolation to humans could be determined, successfully monitored and managed in the chnic, and balanced relative to the desired benefit of the proposed drug candidate for the patient population. 

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