High pentamidine levels associated with hypoglycemia and azotemia in a patient with Pneumocystis carinii pneumonia

Comtois, Ronald; Pouliot, Joël; Gervais, André; Vinet, Bernard; Lemieux, Claude

doi:10.1016/0732-8893(92)90102-y

Cited by 7 publications

(7 citation statements)

References 12 publications

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“…Importantly, the effective concentrations of test compounds were physiologically appropriate. For example, the maximum concentrations in the plasma of patients treated with pentamidine parenterally have been reported to range from 164 to 1,360 ng/ml (16,24,35), while for patients receiving aerosolized pentamidine, levels of pentamidine in bronchoalveolar lavage specimens varied widely (26 to 1,200 ng/ml) depending on the length of treatment (41). The ϳ300 ng/ml required to reduce the ATP pool of rat P. carinii by 50% is well within these ranges.…”

Section: Discussionmentioning

confidence: 99%

A cytotoxicity assay for evaluation of candidate anti-Pneumocystis carinii agents

Cushion

Chen

Kloepfer

1997

Antimicrob Agents Chemother

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A series of over 60 agents representing several different classes of compounds were evaluated for their effects on the ATP pools of Pneumocystis carinii populations derived from immunosuppressed rats. A cytotoxicity assay based on an ATP-driven bioluminescent reaction was used to determine the concentration of agent which decreased the P. carinii ATP pools by 50% versus untreated controls (IC50). A ranking system based on the IC50 value was devised for comparison of relative responses among the compounds evaluated in the cytotoxic assay and for comparison to in vivo efficacy. With few exceptions, there was a strong correlation between results from the ATP assay and the performance of the compound in vivo. Antibiotics, with the exception of trimethoprim-sulfamethoxazole (TMP-SMX), were ineffective at reducing the ATP pools and were not active clinically or in the rat model of P. carinii pneumonia. Likewise, other agents not expected to be effective, e.g., antiviral compounds, did not show activity. Standard anti-P. carinii compounds, e.g., TMP-SMX, pentamidine, and dapsone, dramatically reduced ATP levels. Analogs of the quinone and topoisomerase inhibitor groups were shown to reduce ATP concentrations and hold promise for further in vivo investigation. The cytotoxicity assay provides a rapid assessment of response, does not rely on replicating organisms, and should be useful for assessment of structure-function relationships.

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Section: Discussionmentioning

confidence: 99%

A cytotoxicity assay for evaluation of candidate anti-Pneumocystis carinii agents

Cushion

Chen

Kloepfer

1997

Antimicrob Agents Chemother

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“…infusion of pentamidine was not associated with significant untoward effects. However, its lack of major adverse reactions is not surprising as the development of side effects, especially renal toxicity, occurs on repeated dosing [15,16]. Haematuria might have been related to the use of pentamidine in two of our patients but seems to be a rare manifestation of pentamidine toxicity as there are few reports in the literature [17,18].…”

Section: Adverse Reactionsmentioning

confidence: 92%

“…[12], in blood samples obtained at 1, 2, 4, 7, 14 and 29-34 days after pen-tamidine administration, showed that only three patients (2, 3 and 10) had uniformly detectable concentrations. The plasma phenobarbitone concentrations varied between 20 and 86 gmol l-1, except in patient 10 whose levels were in the range [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] ,umol 1-1 (the therapeutic range for treatment of convulsive disorders is 40-135 gmol l-l). A majority of the subjects were also given a single intramuscular injection of betamethasone (Diprostene®, ScheringPlough, Levallois-Perret, France).…”

Section: Concomitant Medicationmentioning

confidence: 99%

Pharmacokinetics and adverse reactions after a single dose of pentamidine in patients with Trypanosoma gambiense sleeping sickness.

Bronner

Gustafsson

Doua

et al. 1995

Brit J Clinical Pharma

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1 Plasma concentrations of pentamidine were measured up to 1-8 months after a single 2 h i.v. infusion of 3.0 to 4.8 mg kg-1 pentamidine isethionate in 11 patients with late stage Trypanosoma gambiense sleeping sickness. 2 Maximum plasma drug concentrations varied between 713 and 2461 nmol 1-1.After termination of infusion, a rapid distribution phase over 10 min was followed by a slower distribution phase and an elimination phase prolonged over weeks to months. 3 The 'terminal'"elimination rate constant could be determined in six patients and subsequent kinetic calculations showed a three to fourfold variation in plasma clearance and 'terminal' half-life (median 1126 (range 553-2036) ml min-1 and 265 (107-446) h, respectively). The median apparent volume of distribution (Vss) was 11 850 1. Renal clearance accounted for a median of 11% of total plasma clearance, indicating that metabolism is a major route of pentamidine elimination in man. 4 Side effects were few and mild and a slight or moderate decrease in blood pressure was the most common registered adverse reaction observed in four subjects. 5 The prolonged elimination of pentamidine seems inconsistent with the present recommended dosage regimen of pentamidine for treatment of trypanosomiasis of 7 to 10 parenteral doses given once daily or every second day.

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“…Pentamidine, when given intravenously or as an aerosol, has been reported to induce hypoglycemia because of elevated endogenous insulin levels (Fitzgerald and Young, 1984;Karboski and Godley, 1988). There is a dose-response relationship, as in one prospective study all patients with serum pentamidine levels greater than 100 ng/ml developed hypoglycemia (Comtois et al, 1992). In their case study Fitzgerald and Young demonstrated a reversal of this hypoglycemia by treating with oral diazoxide (Fitzgerald and Young, 1984).…”

Section: G Diamidinesmentioning

confidence: 97%

Pharmacological Agents That Directly Modulate Insulin Secretion

2003

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High pentamidine levels associated with hypoglycemia and azotemia in a patient with Pneumocystis carinii pneumonia

Cited by 7 publications

References 12 publications

A cytotoxicity assay for evaluation of candidate anti-Pneumocystis carinii agents

A cytotoxicity assay for evaluation of candidate anti-Pneumocystis carinii agents

Pharmacokinetics and adverse reactions after a single dose of pentamidine in patients with Trypanosoma gambiense sleeping sickness.

Pharmacological Agents That Directly Modulate Insulin Secretion

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