Pentamidine isethionate

Used as a drug to treat protozoal diseases, such as amoebic dysentery, malaria and trypanosomiasis. Also has been shown to be effective for both prophylaxis of pneumocystic carinii pneumonia (PCC).

Monitoring the response of patients with cutaneous leishmaniasis to treatment with pentamidine isethionate by quantitative real-time PCR, and identification of Leishmania parasites not responding to therapy.[Pubmed:26648589]

Clin Exp Dermatol. 2016 Aug;41(6):610-5.

BACKGROUND: Leishmania (Viannia) guyanensis is believed to be the principal cause of cutaneous leishmaniasis (CL) in Suriname. This disease is treated with Pentamidine isethionate (PI), but treatment failure has increasingly been reported. AIM: To evaluate PI for its clinical efficacy, to compare parasite load, and to assess the possibility of treatment failure due to other infecting Leishmania species. METHODS: Parasite load of patients with CL was determined in skin biopsies using real-time quantitative PCR before treatment and 6 and 12 weeks after treatment. Clinical responses were evaluated at week 12 and compared with parasite load. In parallel, molecular species differentiation was performed. RESULTS: L. (V.) guyanensis was the main infecting species in 129 of 143 patients (about 90%). PI treatment led to a significant decrease (P < 0.001) in parasite counts, and cured about 75% of these patients. Treatment failure was attributable to infections with Leishmania (Viannia) braziliensis, Leishmania (Leishmania) amazonensis and L. (V.) guyanensis (1/92, 1/92 and 22/92 evaluable cases, respectively). There was substantial agreement beyond chance between the parasite load at week 6 and the clinical outcome at week 12, as indicated by the kappa value of 0.61. CONCLUSIONS: L. (V.) guyanensis is the main infecting species of CL in Suriname, followed by L. (V.) braziliensis and L. (L.) amazonensis. Furthermore, patient response to PI can be better anticipated based on the parasite load 6 weeks after the treatment rather than on parasite load before treatment.

Physical characterization of pentamidine isethionate during freeze-drying-relevance to development of stable lyophilized product.[Pubmed:22271285]

J Pharm Sci. 2012 May;101(5):1732-43.

The purpose of this study was to perform physical characterization of Pentamidine isethionate (PI) in frozen and freeze-dried systems and to monitor the phase behavior during all the stages of freeze-drying. Frozen aqueous PI solutions as well as the final lyophiles were characterized by differential scanning calorimetry and X-ray diffractometry. The effect of cosolutes, cosolvents, and processing conditions on the PI crystallization behavior during freeze-drying was evaluated. In frozen aqueous solutions, irrespective of the cooling rate and the initial solute concentration, PI readily crystallized as a trihydrate (C(19) H(24) N(4) O(2) .3H(2) O). It dehydrated to a poorly crystalline anhydrate upon drying at 100 mTorr. The presence of a readily crystallizing cosolute or an organic cosolvent did not influence the physical form of PI in the final lyophile. On the contrary, even in the absence of cosolutes and cosolvents, the crystalline trihydrate was retained when the chamber pressure was increased to 500 mTorr. By altering the drying conditions, it was possible to obtain either a crystalline trihydrate or a poorly crystalline anhydrate. The stability of PI is dependent on its physical form and only the amorphous PI undergoes discoloration. The PI stability can be enhanced by retaining it in a crystalline state in the lyophile.

Randomized single-blinded non-inferiority trial of 7 mg/kg pentamidine isethionate versus 4 mg/kg pentamidine isethionate for cutaneous leishmaniaisis in Suriname.[Pubmed:25793773]

PLoS Negl Trop Dis. 2015 Mar 20;9(3):e0003592.

BACKGROUND: Standard treatment of cutaneous leishmaniasis (CL) in Suriname entails three injections of Pentamidine isethionate (PI) 4 mg/kg per injection in 7 days (7 day regimen). Compliance to treatment is low and may contribute to increasing therapy failure. A 3 day regimen, including 2 injections of 7 mg/kg in 3 days may increase compliance. METHODS: In a randomized, single-blinded non-inferiority trial conducted in Suriname, 84 CL patients received the 7 day regimen and 79 CL patients received the 3 day regimen. Primary objective was the proportion of patients clinically cured at 6 weeks follow-up. Secondary objectives were clinical cure at 12 weeks follow-up; parasitological cure at 6 and 12 weeks; adverse and drug related toxicity events recorded one week after the end of treatment and health related quality of life. The non-inferiority margin was set at 15%, 1 sided test, alpha = 0.1. RESULTS: At 6 weeks follow-up 31 (39%) patients in the 3 day regimen and 41 (49%) patients in the 7 day regimen were clinically cured. Intention to treat (ITT) analyses showed that the difference in proportion clinically cured was -9.6% (90% Confidence Interval (CI): -22.3% to 3.2%). Per protocol (PP) analysis showed that the difference in proportion clinically cured was 0.2% (90% CI: -14.6% to 15.2%). ITT analysis showed that the difference in proportion parasitological cured at 6 weeks was -15.2% (90% CI:-28.0% to -2.5%). PP analyses showed similar results. Non-inferiority could not be concluded for all adverse and toxicological events. CONCLUSION: We cannot conclude that the 3 day regimen is non-inferior to the 7 day regimen regarding proportion clinically and parasitological cured. Therefore there is no evidence to change the current standard practice of the 7 day regimen for the treatment of CL in Suriname.

Efficacy and tolerability of intravenous pentamidine isethionate for Pneumocystis jiroveci prophylaxis in a pediatric oncology population.[Pubmed:24030353]

Pediatr Infect Dis J. 2014 Mar;33(3):319-21.

Cancer therapy routinely requires Pneumocystis jiroveci prophylaxis. In those intolerant of trimethoprim/sulfamethoxazole, aerosolized pentamidine is convenient and effective. Intravenous pentamidine is often substituted in young children but its efficacy remains controversial. In this retrospective study of a large pediatric oncology cohort, we confirm intravenous pentamidine to be effective and well-tolerated as second-line prophylaxis across all ages.

Inhibition of constitutive nitric oxide synthase in the brain by pentamidine, a calmodulin antagonist.[Pubmed:7542607]

Eur J Pharmacol. 1995 Apr 28;289(2):299-304.

Nitric oxide (NO) which is produced by activation of Ca2+/calmodulin-dependent NO synthase is known to induce neuronal damage. We examined the effects of 3'-azido-2',3'-dideoxythymidine (AZT, a reverse transcriptase inhibitor), pentamidine (a therapeutic drug for Pneumocystis carinii pneumonia) and calmodulin antagonists such as trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on NO synthase activation. Although AZT had no effect on the activity of constitutive neuronal NO synthase, pentamidine inhibited the activation of neuronal NO synthase as did trifluoperazine and W-7. The inhibition by pentamidine was prevented by the addition of purified calmodulin. In addition, pentamidine inhibited calmodulin-dependent activation of neuronal NO synthase purified from rat cerebellum. From these results, it is suggested that pentamidine inhibits the neuronal NO synthase activation by probably acting as a calmodulin antagonist.

Pentamidine is an N-methyl-D-aspartate receptor antagonist and is neuroprotective in vitro.[Pubmed:1532027]

J Neurosci. 1992 Mar;12(3):970-5.

Acquired immunodeficiency syndrome (AIDS) is frequently associated with dementia. The wide spectrum of neurological abnormalities associated with this dementia may involve a neurotoxin that activates the NMDA subtype of glutamate receptor in neurons. We have found that the antimicrobial agent pentamidine, which is prescribed for AIDS patients for the prophylaxis and treatment of Pneumocystis carinii pneumonia, is an effective NMDA receptor antagonist. Pentamidine inhibited 3H-dizocilpine binding to the NMDA receptor in rat brain membranes at a site separate from glutamate, glycine, and spermidine, with an affinity near 2 microM. Similar concentrations of pentamidine block NMDA-induced increases in intracellular Ca2+ and NMDA-induced currents in cultured forebrain and cortical neurons, apparently without use dependence or voltage dependence, suggesting that pentamidine may represent a novel chemical class of NMDA receptor antagonist. Finally, pentamidine protects neurons from the lethal effects of acute NMDA exposure in vitro. AS pentamidine may accumulate in the brain at relevant concentrations following repeated high-dose parenteral administration, these findings suggest that the drug may be neuroprotective in vivo.

Pentamidine isethionate (MP-601205 isethionate) is an antimicrobial agent and interferes with DNA biosynthetics. Pentamidine isethionate inhibits parasite Leishmania infantum with an IC50 of 2.5 μM. Pentamidine isethionate is a potent and selective protein tyrosine phosphatases (PTPases) and phosphatase of regenerating liver (PRL) inhibitor. Pentamidine isethionate has the potential for Gambian trypanosomiasis, antimony-resistant leishmaniasis, and Pneumocystis carinii pneumonia treatment. Antitumor and antibacterial activities.

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