Diabetic ketoacidosis (DKA) and the hyperglycemic hyperosmolar state (HHS) are potentially fatal hyperglycemic crises that occur as acute complications of uncontrolled diabetes mellitus. The authors provide a review of the current epidemiology, precipitating factors, pathogenesis, clinical presentation, evaluation, and treatment of DKA and HHS. The discovery of insulin in 1921 changed the life expectancy of patients with diabetes mellitus dramatically. Today, almost a century later, DKA and HHS remain significant causes of morbidity and mortality across different countries, ages, races, and socioeconomic groups and a significant economic burden for society.

The antiprotozoal agent pentamidine, used for the treatment of Pneumocystis jirovecii pneumonia (PCP), is known to cause abnormalities in blood glucose homeostasis, such as hypoglycemia and hyperglycemia. Pentamidine has been reported to be a substrate of organic cation transporter 1 (OCT1). We investigated the combination effects of cimetidine, an OCT1 inhibitor, on the pharmacokinetics of pentamidine and on pentamidine-induced hyperglycemia. Pentamidine was infused intravenously to rats for 20 min at a dose of 7.5 or 15 mg/kg and serum samples were obtained periodically. The serum concentration of glucose did not change significantly after pentamidine infusion at 7.5mg/kg, while it increased with pentamidine at 15 mg/kg, and the maximal concentration of glucose was 167 ± 36 mg/dl, 30 min after the start of pentamidine infusion. Cimetidine (50mg/kg) enhanced the pentamidine-induced elevation of glucose concentration and the maximal concentration of glucose was 208 ± 33 mg/dl in the pentamidine 15 mg/kg treated group. Cimetidine combination significantly reduced total body clearance of pentamidine and increased pentamidine concentrations in the liver, kidneys, and lungs. A significant correlation was found between changes in serum glucose concentrations and serum concentrations of pentamidine 30 min after the start of pentamidine infusion. These results suggest that the hyperglycemic effect of pentamidine is dependent on the concentration of pentamidine and can be enhanced by cimetidine combination.

We determined the frequency and clinical nature of severe hyperglycemia in a university clinic for HIV-1-infected patients. The medical records of 1392 adult HIV-infected patients were reviewed for cases of severe hyperglycemia, defined as two or more serum glucose values >250 mg/dl or diabetes treatment during clinic care. Demographic information, family histories of diabetes mellitus, body weights, CD4+ lymphocyte counts, and use of corticosteroids, megestrol acetate, pentamidine, or didanosine were recorded for subjects meeting the case definition. Comparisons were made between preexisting diabetic (group 1) and incident hyperglycemic cases (group 2). Less than 2% of the total clinic population experienced severe hyperglycemia: 12 in group 1 and 13 in group 2. Group 2 had lower body weights (mean, 70.6 kg versus 90.0 kg; p < 0.05) and more advanced HIV disease (mean CD4 count, 79/mm3 versus 550/mm3; p < 0.05) than group 1. Group 2 cases had evidence of drug-associated hyperglycemia; four cases demonstrated hyperglycemia coinciding with large fluctuations in weight during megestrol therapy. Among megestrol recipients, cases did not differ from noncases in demographics, weight, or CD4 count. Severe hyperglycemia is uncommon in adult HIV-infected patients. Approximately one half of these patients have preexisting diabetic conditions; many of the remainder may have drug-induced hyperglycemia, especially as a result of corticosteroids or megestrol acetate.

Although autopsy studies reveal significant pancreatic lesions in about 10% of AIDS patients, pancreatic lesions infrequently produce symptoms and are rarely recognized premortem. Patients with AIDS can develop pancreatic disease from causes not related to AIDS or AIDS-specific lesions. AIDS-specific causes include opportunistic infection, AIDS-associated neoplasia, and medications used to treat complications of AIDS. Pancreatic involvement is usually part of a widely disseminated tumor and rarely produces clinical symptoms.

Improved understanding of Pneumocystis carinii, in particular the widespread use of chemoprophylaxis, has resulted in a declining incidence of infection in patients infected with HIV since the late 1980s. Despite these advances, P. carinii pneumonia continues to represent an important cause of pulmonary disease in HIV-seropositive individuals who do not receive chemoprophylaxis or when breakthrough episodes occur. This article reviews the history, biology, clinical manifestations, prognostic markers, therapy, and chemoprophylaxis of P. carinii pneumonia in HIV-seropositive patients.

Pentamidine is known to cause severe dysglycaemia by damaging beta-cell function of the pancreas. The exact mechanism still remains unclear. We report the case of a 53-year-old man infected with the human immunodeficiency virus who developed insulin-dependent permanent diabetes mellitus 3 days after starting intravenous treatment with pentamidine for pneumocystis carinii pneumonia. Discharged from hospital the daily need of insulin increased continuously over one year now requiring an average dose of 80 units per day. So far, a number of cases of insulin-dependent diabetes mellitus following pentamidine therapy has been reported, but long-term observations are rare.

In summary, patients with HIV infection may develop a bewildering variety of electrolyte and acid-base disturbances. Hyponatremia from many causes is common and associated with an increased mortality. Potassium disorders are frequent, with hyperkalemia, even to life-threatening levels, more common than hypokalemia. Disturbances in calcium and uric acid homeostasis are less frequent. Acid-base disorders also complicate the clinical course of AIDS and, as with the electrolyte perturbations, may result from HIV infection itself, the illnesses associated with AIDS, or medications.

This report describes the analysis of pentamidine by isocratic reversed-phase high-performance liquid chromatography (HPLC) using a commercially available compound (melphalan) as the external standard. Previously described assays use ion-pairing HPLC, an internal standard (hexamidine) that is not readily available, and require a relatively large sample size. In the present assay, pentamidine was extracted from plasma using solid-phase extraction and was analyzed using a C18 column and a mobile phase containing 18% acetonitrile, 2% methanol, 0.2 M ammonium acetate and 0.5% triethylamine. The identity of the eluting peaks was verified using a diode array detector. The extraction yield of pentamidine was 82%. The limit of detection was 8.6 ng/ml with a sample size of 100 microliters. The inter-day and intra-day coefficients of variation ranged between 0.3% and 10% with an average of 5%. This method was applied to study the pharmacokinetics of pentamidine in rodents.

Pentamidine concentrations in plasma, whole blood and cerebrospinal fluid (CSF) were determined in 11 patients with Trypanosoma gambiense infection without involvement of the central nervous system in Côte d'Ivoire. Blood samples were drawn during a 48 h period after the first and last dose of pentamidine dimesylate given as 10 intramuscular injections on alternate days. Maximum plasma concentrations were generally attained within one hour after injection but varied extensively (420-13420 nmol/litre). The median plasma concentration 48 h after the last dose was approximately 5 times higher than that after the first dose. The ratio between whole blood and plasma concentration was approximately 2. Small amounts of the drug were found in the CSF after the last dose. The findings showed inter-individual differences in the pharmacokinetics of pentamidine. The currently recommended daily dose regimen could be questioned, as drug accumulation was pronounced. All patients were cured and the concentrations attained should be considered as parasiticidal. Further studies on the kinetics and distribution after single and multiple doses of pentamidine as well as studies on the possible relationship between adverse effects and plasma concentrations are, however, needed.