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At least 19 recordsLinked to original sources
PubMed1997

Effects of pentamidine on polyamine level and biosynthesis in wild-type, pentamidine-treated, and pentamidine-resistant Leishmania.

Polyamine biosynthesis was studied in wild-type promastigotes of Leishmania donovani and Leishmania amazonensis treated with pentamidine and in the parasites resistant to this drug. Treatment of wild-type clones with low pentamidine concentrations for 24 hr provoked a strong decrease in arginine, ornithine, and putrescine pools, while the level of intracellular spermidine remained unchanged. In these cells, the activity of the enzyme ornithine decarboxylase was found to be decreased. Compared to wild-type cells, resistant clones had a lower level of putrescine, higher pools of arginine and ornithine, and a similar spermidine content. Analysis by Western blot and DFMO-binding showed reduced amount of ornithine decarboxylase. Furthermore, in the resistant cells, the kinetic parameters of the enzyme spermidine synthase were markedly changed, showing increased affinity to putrescine and decreased affinity to pentamidine. Thus, it seems that polyamine biosynthesis pathway is a target of pentamidine in Leishmania and is altered in resistant clones.

Animals↗
PubMed1994

Lobar pentamidine levels and Pneumocystis carinii pneumonia following aerosolized pentamidine.

Recent studies have suggested that failure of pentamidine prophylaxis against Pneumocystis carinii pneumonia (PCP) may be due to reduced deposition of pentamidine in the upper lobes. In this study, we performed bronchoalveolar lavage from the apical segment of the upper lobe and the middle lobe in 51 HIV-positive patients, all of whom were receiving prophylaxis with aerosolized pentamidine, who had presented with acute respiratory symptoms. Lavage fluid from each lobe was assayed for pentamidine using high-performance liquid chromatography (HPLC). The number of clusters of P carinii were counted after staining with a Wright-Giemsa stain. The patients were subclassified as PCP-positive (32 patients) and PCP-negative (19 patients) on the basis of the presence/absence of P carinii clusters in their BAL fluid. The concentration of pentamidine in the upper lobe compared with the middle lobe was no different (using paired Student's t tests) for either PCP-positive patients or PCP-negative patients. In comparing the positive with the negative subjects, using unpaired Student's t test, there was no difference in the concentration of pentamidine in the upper lobe or the middle lobe. For PCP-positive patients, the numbers of P carinii clusters were on average higher in the upper lobes (mean +/- SD: upper = 14.9 +/- 16.6, middle 7.5 +/- 10.8, p = 0.013, paired Student's t test), but there was no correlation between lobar P carinii cluster counts and pentamidine levels. We conclude that the absence of a relationship between cluster count and pentamidine level, the similarity in regional pentamidine levels between upper and middle lobes, as well as the similarity in pentamidine levels between the PCP-positive and PCP-negative groups indicate that the regional dose of pentamidine is not the determining factor as to whether aerosolized pentamidine prophylaxis will succeed or fail.

Adult↗
PubMed1991

Urine pentamidine as an indicator of lung pentamidine in patients receiving aerosol therapy.

To determine if urine pentamidine was reflective of lung pentamidine, we compared levels of the drug in bronchoalveolar lavage fluid and simultaneously obtained urine. Thirty-one patients who were receiving aerosolized pentamidine either as treatment or as prophylaxis underwent BAL and submitted urine samples for pentamidine analysis. Pentamidine was analyzed in both phases of BAL fluid (supernatant and cell pellet) and in urine using high performance liquid chromatography. Urine results were normalized for creatinine. Patients were categorized as prophylaxis failures (active Pneumocystis carinii pneumonia on prophylaxis), electives (free from PCP on prophylaxis), treatment (daily AP in treatment doses for active PCP, or miscellaneous (single dose of AP). Levels in BAL fluid and urine varied widely over several orders of magnitude. However, for all patients, we found a highly significant relationship between BAL supernatant and urine (r = 0.97, p less than 0.0001). No statistical differences were found when comparing levels of pentamidine between failures and electives; however, the number of failures was small. We conclude that urine pentamidine is related to lung pentamidine and can be used as a clinical indicator in patients receiving aerosolized therapy.

Administration, Inhalation↗
PubMedDate not supplied

Aerosolized pentamidine versus i.v. pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia.

The efficacy and toxicity of aerosolized pentamidine was evaluated in 78 AIDS patients given 60 mg biweekly as secondary prophylaxis against Pneumocystis carinii pneumonia (PCP). Patients were monitored for clinical progression and mortality and were compared to 42 historical controls given 200-300 mg i.v. pentamidine biweekly. The relapse rates did not differ markedly between the two groups, and the PCP-free rates in survivors were at 12 months 0.83 and 0.77, respectively. Seventy-one new AIDS-defining events and 25 deaths were recorded in patients on aerosolized pentamidine compared to 29 AIDS events and two deaths in patients on intravenous pentamidine. Recurrent PCP contributed to death in only one case of the aerosolized pentamidine group. PCP is not a serious clinical problem in immunodeficient patients taking pentamidine prophylaxis by either route compared to the progression of clinical HIV disease and death.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Metabolism is an important route of pentamidine elimination in the rat: disposition of 14C-pentamidine and identification of metabolites in urine using liquid chromatography-tandem mass spectrometry.

This study assesses the contribution of metabolism for the disposition of pentamidine in the rat. With the use of 14C-labelled compound, the excretion of radioactivity in urine and faeces has been studied in four rats during 44 days after a single intravenous injection of the drug. The urinary and faecal excretion of the radioactivity were of equal importance; 22 +/- 2% (mean +/- S.D.) and 25 +/- 4% being detected in urine and faeces, respectively. The activity in organs and tissues at 44 days after drug administration was also measured and amounted to 21 +/- 5% of the administered dose. Using HPLC the proportion of metabolites in urine in relation to unchanged pentamidine increased with time after dose, being 76 +/- 15% (mean +/- S.D.) of the total excreted radioactivity on day 1 and 97 +/- 1% on day 6. HPLC--tandem mass spectometry was used for identification of metabolites in urine obtained from four rats given unlabelled pentamidine. Using synthetic reference compounds and the selective MS/MS mode four oxidized metabolites of pentamidine were identified either by direct injection into the system or by analyses of extracted urine. Thus, a substantial part of pentamidine is excreted as metabolites in urine.

Animals↗
PubMed1991

Activity of pentamidine and pentamidine analogs against Toxoplasma gondii in cell cultures.

The capabilities of pentamidine and nine pentamidine analogs to inhibit the development of Toxoplasma gondii were examined in vitro. Treatment of infected cultures with pentamidine and five of its analogs caused a significant (P less than 0.05) reduction in the numbers of tachyzoites produced. Analogs of pentamidine may be useful agents in the treatment of toxoplasmosis.

Animals↗
PubMedDate not supplied

Pentamidine sensitivity and resistance in Saccharomyces cerevisiae as a model for pentamidine effects on Pneumocystis carinii.

Pentamidine isethionate inhibits growth of Saccharomyces cerevisiae. Inhibition requires lower drug concentrations under respiratory than fermentative growth conditions. Pentamidine-resistant strains bear heritable resistance mutations. Tested mutations are dominant to wild type sensitivity. These mutations may identify cellular targets of pentamidine and potential mechanisms of fungal pentamidine resistance.

Cations, Divalent↗
PubMed1992

Bilateral pneumothoraces hasten mortality in AIDS patients receiving secondary prophylaxis with aerosolized pentamidine. Association with a lower Dco prior to receiving aerosolized pentamidine.

We have administered aerosolized pentamidine (AP) to 48 AIDS patients for secondary prophylaxis of Pneumocystis carinii pneumonia (PCP). Pentamidine 60 mg was administered by ultrasonic nebulization (Fisoneb) five times during the first two weeks and then every two weeks. The mean follow-up was 343 +/- 22 days. PCP recurred in ten patients, 297 +/- 33 days after starting AP therapy. All responded to anti-Pneumocystis therapy but two patients died of unrelated reasons (20 percent mortality). Five patients developed bilateral pneumothoraces 260 +/- 35 days after starting AP therapy. Recurrence of PCP could be documented in only one patient. All died 66 +/- 27 days after the onset of the first pneumothorax. Only 5 of 33 patients without recurrence of pneumonia or pneumothorax died during the study period (15 percent mortality). No association was found between the development of pneumothorax and age, smoking, previous respiratory or infectious problems, time from last PCP and the initiation of AP therapy, and treatment duration of last PCP. Patients with pneumothoraces had a significantly lower Dco (58.6 +/- 2.6 percent predicted) prior to AP therapy than patients with recurrence of PCP without pneumothoraces (81.1 +/- 2.1 percent predicted) or patients with no recurrence of PCP (67 +/- 2.5 percent predicted) (p less than 0.05, ANOVA). In conclusion, bilateral pneumothoraces are associated with a hastened mortality in patients receiving AP for secondary prophylaxis of PCP. Low Dco before AP therapy is associated with an increased risk of bilateral pneumothoraces in patients treated with AP for secondary prophylaxis of PCP.

Acquired Immunodeficiency Syndrome↗
PubMed1996

An effectiveness community-based clinical trial of Respirgard II and Fisoneb nebulizers for Pneumocystis carinii prophylaxis with aerosol pentamidine in HIV-infected individuals. Toronto Aerosol Pentamidine Study (TAPS) Group.

STUDY OBJECTIVE: To compare the effectiveness of a standard jet nebulizer, Respirgard II, and a standard ultrasonic nebulizer, Fisoneb, for the administration of aerosolized pentamidine (AP) as primary and secondary prophylaxis against Pneumocystis carinii pneumonia (PCP) in HIV-infected individuals. DESIGN: A retrospective, nonrandomized, parallel group comparative study. SETTING: Patients were enrolled in a community-based AP program (APP) between May 1989 and April 1992 in Ontario, Canada. They received AP in either (1) a centralized treatment facility ("clinic") or (2) their attending physician's office or regionalized centers ("nonclinic"). Clinic administration of pentamidine was via Fisomeb; nonclinic via Respirgard II. PATIENTS: The study group comprised of 1,762 HIV-infected individuals requiring AP for either primary (CD4 < 200/mm3) or secondary PCP prophylaxis. Of these, 1,151 used Fisoneb (clinic) and 611 used Respirgard II (nonclinic). RESULTS: In the primary prophylaxis group, 41 of the 892 patients using Fisoneb (4.6%; mean follow-up, 18 months) compared with 16 of 435 patients using Respirgard II (3.7%; mean follow-up, 14.6 months) developed PCP (p = 0.44). A total of 28 of 259 (10.8%; mean follow-up, 15.3 months) patients using Fisoneb for secondary prophylaxis compared with 11 of 176 (6.3%; mean follow-up, 14.4 months) patients using Respirgard II for secondary prophylaxis developed PCP (p = 0.1). CONCLUSIONS: Despite the difference in dosage (120 mg/mo vs 300 mg/mo), type of nebulizer (ultrasonic vs jet), and frequency of administration (twice vs once monthly), the results of this study indicate that both regimens of AP provide comparable protection against PCP. This study further supports the effectiveness of AP as a solid second-line prophylaxis for HIV-infected individuals who are intolerant to trimethoprim/sulfamethoxazole or dapsone.

AIDS-Related Opportunistic Infections↗
PubMedDate not supplied

A novel HPLC assay for pentamidine: comparative effects of creatinine and inulin on GFR estimation and pentamidine renal excretion in the isolated perfused rat kidney.

PURPOSE: 1. To develop and validate an analytical method for pentamidine (PTM) by reversed-phase HPLC. 2. To compare the effects of creatinine and inulin on PTM excretion in the isolated perfused rat kidney. METHODS: The HPLC method utilized a base deactivated, 5 micro, C18 column and a mobile phase containing acetonitrile (24%) and 0.025 M monobasic phosphate buffer, pH 3.2 (76%). Mobile phase flow rate and UV detection wavelength were 1 mL/min and 270 nm, respectively. Sulfadiazine (SDZ) was used as the internal standard. The method was used to measure pentamidine in perfusate and urine samples generated from studies with the isolated perfused rat kidney (IPK) model. Perfusion experiments were conducted in the presence of two different GFR markers: creatinine and inulin (PTM dose 800 micro g). Both creatinine and inulin were assayed using colorimetric methods. RESULTS: The HPLC assay is rapid, sensitive and reproducible. The method was validated over two standard concentration ranges: 0.1 to 1 micro g/mL, and 1 to 10 micro g/mL. In control (drug-naïve) IPK perfusions, creatinine clearance was approximately 15% greater than inulin clearance (0.80+/- 0.21 mL/min vs. 0.69+/-0.17 mL/min, p > 0.05). In the presence of PTM, however, creatinine clearance was reduced to 0.56+/-0.27 (p < 0.05 compared to control). Inulin clearance was not altered by PTM administration (0.76+/-0.26 mL/min). Cumulative urinary excretion of PTM (% dose) was 3.0+/-0.47% and 9.6+/-4.2% in the presence of creatinine and inulin, respectively. PTM clearance was significantly reduced (0.06+/-0.01 mL/min vs. 0.13+/-0.01 mL/min, p < 0.05) and % kidney accumulation significantly enhanced (66+/-4.7% vs. 37+/-9.7%, p < 0.05) by creatinine. CONCLUSIONS: Creatinine overestimated GFR in the IPK. The altered renal excretion of PTM by creatinine is consistent with inhibition of PTM tubular secretion. Because of increased kidney accumulation, detrimental effects of PTM on renal function were observed. Based on these findings, creatinine should be used cautiously as an indicator of GFR in IPK experimentation.

Animals↗
PubMed1996

Long-term administration of aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia in infants and children with symptomatic human immunodeficiency virus infection. The Italian Pediatric Collaborative Study Group on Pentamidine.

SUMMARY: We assessed the long-term feasibility, safety, and tolerability of two regimens of aerosolized pentamidine (AP) as primary prophylaxis of Pneumocystis carinii pneumonia (PCP) in a large sample of infants and children with symptomatic HIV infection in 21 pediatric departments. One hundred forty children were assigned to receive 60 mg every 2 weeks (n = 60) or 120 mg every 4 weeks (n = 80) of AP, delivered by the ultrasonic nebulizer Fisoneb under the supervision of trained personnel. Children underwent monthly clinical and laboratory controls for toxicity and/or development of PCP for an 18-month period. Baseline characteristics were similar in the two treatment groups. The median age was 5 years. The feasibility of administering AP was excellent in 84 (60 percent) and good in 38 (27 percent) children. All children aged <2 years showed excellent or good feasibility. Long-term compliance was good with both regimens. No child had severe adverse reactions requiring discontinuation of the treatment. Cough, sneezing, and bronchospasm were the most frequent side effects occurring, respectively, in 12, 3.7, and 0.7 percent of the 60-mg treatments and in 19.1, 6. 1, and 2.8 percent of 120-mg treatments (p < 0.05). Their incidence was not different in children younger or older than 5 years. Two episodes of PCP were observed in the group receiving 120 mg monthly, whereas none of the 60 children in the biweekly schedule had PCP (p = 0.20). AP can be safely administered to very young children with few adverse side effects.

AIDS-Related Opportunistic Infections↗
PubMed1992

The long-term effects of aerosol pentamidine on pulmonary function. The Toronto Aerosolized Pentamidine Study (TAPS) Group.

Aerosolized pentamidine (AP) has been widely used for prophylaxis of pneumocystis carinii pneumonia (PCP) since 1988. The objective of this study was to evaluate the long-term effects of AP on pulmonary function. Of 36 patients with AIDS who were receiving AP for secondary prophylaxis of PCP, 13 patients had been using AP continuously for more than 52 weeks. AP was given using a Fisoneb ultrasonic nebulizer with five loading doses of 60 mg over two weeks, followed by one dose of 60 mg every two weeks. Baseline PFT were TLC 92 +/- 14% pred, FVC 90 +/- 11% pred, FEV1 91 +/- 11% pred, FEF25-75 95 +/- 17% pred, and DLCO (corrected for hemoglobin) 70 +/- 22% pred. No significant change in TLC, FVC, FEV1, or DLCO was seen after 56 weeks of AP. There was a 20% fall in FEF25-75 seen after 56 weeks, which was statistically significant. However, the clinical significance of a fall of this magnitude in the FEF25-75 is uncertain. Similar results were seen in a smaller subset of patients who received AP for at least 76 weeks. Although the small sample size must be considered, this data suggests that there is no clinically significant change in pulmonary function associated with the use of AP for up to 76 weeks.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Acute pulmonary effects of aerosolized pentamidine. A randomized controlled study. Toronto Aerosolized Pentamidine Study (TAPS) Group.

From June 1988 to February 1989, we enrolled 36 patients with human immunodeficiency virus into a randomized double-blind placebo-controlled trial assessing the efficacy and toxicity of aerosolized pentamidine (AP) as secondary prophylaxis for Pneumocystis carinii pneumonia. Each patient underwent spirometric evaluations before and after aerosolized treatment. There was no significant difference in the results of baseline pulmonary function tests between the two groups. Eleven patients (65 percent) in the AP group developed cough but only four demonstrated significant reduction in the forced expiratory flow rates after AP; four patients (21 percent) in the placebo group developed cough, but no significant change in the expiratory flow rates was noted. All bronchospastic episodes were self-limited and symptomatically responded to remedial inhaled albuterol (salbutamol) treatment. We conclude that AP treatment is frequently associated with coughing attacks (65 percent), but the actual incidence of bronchospasm on spirometry is much lower (24 percent) and is generally quite mild.

Adult↗
PubMed1990

Intravenous or inhaled pentamidine for treating Pneumocystis carinii pneumonia in AIDS. A randomized trial.

OBJECTIVE: To evaluate the efficacy and toxicity of aerosolized pentamidine and of reduced-dose intravenous pentamidine for the treatment of mild to moderate Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Randomized open study with serial pulmonary function testing and measurement of pentamidine concentrations in plasma and bronchoalveolar lavage fluid. PATIENTS: Of 44 men and 1 woman with a mild to moderate first episode of P. carinii pneumonia (Pao2 greater than or equal to 7.3 kPa [55 mm Hg]), 23 received aerosolized pentamidine and 22, intravenous pentamidine. INTERVENTIONS: Pentamidine isethionate, 600 mg by inhalation using a Respirgard II nebulizer (Marquest Medical Products, Inc., Englewood, Colorado) or 3 mg/kg body weight intravenously, administered once daily for 2 to 3 weeks. MEASUREMENTS AND MAIN RESULTS: The planned 60-patient study was stopped after 45 patients had been enrolled. The rates (aerosolized compared with intravenous pentamidine) of initial failure, early recrudescence of symptoms, and relapse were 12% and 19% (difference, 7%; 99% confidence interval [CI], - 23% to 37%; P = 0.67), 35% and 0% (difference, 35%; CI, 13% to 58%; P = 0.02), and 24% and 0% (difference, 24%; CI, 4% to 49%; P = 0.03). The rates (aerosolized compared with intravenous pentamidine) of major toxicity were 0% (0 of 17 patients) and 10% (2 of 21 patients) (difference 10%; CI, -1% to 29%; P = 0.24). The mean (+/- SD) pentamidine concentration in bronchoalveolar lavage fluid for patients receiving aerosolized pentamidine was 96.6 +/- 65.1 ng/mL compared with 14.4 +/- 17.7 ng/mL for patients receiving intravenous treatment. Trough concentrations of pentamidine in plasma increased from 0 to 25.4 +/- 16.4, 56.5 +/- 26.1, and 61.1 +/- 56.0 ng/mL at the end of weeks 1, 2, and 3 of intravenous therapy, respectively. CONCLUSIONS: The data suggest that reduced-dose intravenous pentamidine was more effective than aerosolized pentamidine for treating mild to moderate P. carinii pneumonia. Systemic absorption during aerosolized therapy was minimal; daily doses of intravenous pentamidine resulted in increased accumulation of pentamidine in plasma.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Characterization of pentamidine excretion in the isolated perfused rat kidney.

OBJECTIVE: To study the renal excretion and kidney accumulation of pentamidine, a potentially nephrotoxic compound, in the isolated perfused rat kidney (IPK). MATERIALS AND METHODS: IPK experiments (3-4 per treatment group) were conducted using male Sprague-Dawley rats (250-350 g). Dose proportionality studies were carried out over a pentamidine dosing range of 80-4000 microg, designed to target initial perfusate concentrations from 1 to 50 microg/mL. Separate interaction experiments were conducted between pentamidine (800 microg) and tetraethylammonium (dose 8000 microg) or dideoxyinosine (dose 80 microg). Inulin was used as a glomerular filtration rate (GFR) marker. Control (drug-naive) perfusions were also carried out. Pentamidine was analysed in perfusate, kidney and urine samples by HPLC. Inulin was measured by a colorimetric method. RESULTS: Pentamidine CLR (1.1 +/- 0.6 to 0.05 +/- 0.03 mL/min) and excretion ratio (3.6 +/- 1.5 to 0.56 +/- 0.15) significantly decreased over the range of doses studied. Significant reductions in viability parameters (GFR, Na reabsorption) were noted in kidneys perfused with high dose pentamidine (4000 microg). Tetraethylammonium co-administration reduced pentamidine renal excretion, resulting in significantly greater kidney accumulation of pentamidine and reduced kidney function. Dideoxyinosine administration had minimal effects on pentamidine disposition. CONCLUSIONS: Pentamidine renal transport involves a combination of mechanisms (filtration, secretion and passive reabsorption). Dose proportionality studies demonstrated non-linear excretion of pentamidine. Inhibition of pentamidine renal clearance by tetraethylammonium was consistent with decreased luminal transport. The detrimental effects of pentamidine on kidney function were the result of significant kidney accumulation of drug. The potential exists for drug-drug interactions between pentamidine and organic cations, increasing the risk of drug-induced nephrotoxicity.

Algorithms↗