Pentamidine
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Pentamidine was originally developed because of its antitrypanosomal activity (King et al., 1937; Lourie and Warrington, 1939). Pentamidine is active against Pneumocystis jirovecii as third-line treatment, and as second-line prophylaxis for P. jirovecii pneumonia (PJP). Pentamidine is also active against Trypanosoma brucei gambiense stage I (hemolymphatic) human African trypanosomiasis (HAT). Pentamidine is a third-line treatment for Leishmania donovani infection (Old World leishmaniasis; kala-azar) and may have a role in secondary prophylaxis in AIDS patients. Pentamidine is active against American tegumentary (cutaneous and mucocutaneous) leishmaniasis (Tuon et al., 2008). Drug repositioning studies that investigate possible new uses for licensed drugs have found that pentamidine has in vitro anticancer effects against renal cell cancer, melanoma, and glioma (Smith et al., 2010; Jung et al., 2011; Qiu et al., 2012; Zerbini et al., 2014; Capoccia et al., 2015). In a Drosophila model, pentamidine reverses splicing defects of myotonic dystrophy and rescues contractility and rhythmicity of myotonic dystrophy heart dysfunction (Warf et al., 2009; Chakraborty et al., 2015).
Host Defense and Parasite Evasion
Eric S. Loker, Bruce V. Hofkin in Parasitology, 2023
In 1979 Sandy Ford joined the CDC in Atlanta. Her job as a drug technician included responding to requests for drugs that were unavailable in the United States, except through the CDC’s parasitic diseases drug service. One such drug was pentamidine, used to treat pneumonia caused by Pneumocystis jirovecii (then called P. carinii). At the time, P. jirovecii was considered to be a protozoan. It has since been recognized as a fungus (see Chapter 2). In 1979 pneumonia caused by this organism was rare and seen almost exclusively in infants or those with compromised immune defenses, such as those undergoing cancer chemotherapy. So when Ford noticed a spike in requests for pentamidine in 1981 and that the patients were all adult male homosexuals, she knew that something was very wrong. She reported the cluster of cases to her supervisor, the first alarm that a new disease, later recognized as AIDS, had reared its head. At about the same time, clinicians were first noticing patients with unusual opportunistic diseases, including pneumocystis pneumonia, and on June 5, 1981, this worrisome new situation was first reported in the CDC’s Morbidity and Mortality Weekly Report (Figure 4.1). This historic publication marked the initial awareness of a new, fearsome immunosuppressive virus, later named HIV, thanks in large measure to Ford’s alertness and attention to detail.
Diagnostics and therapeutics
Lois N. Magner, Oliver J. Kim in A History of Medicine, 2017
HIV/AIDS has made it clear that the most powerful chemotherapeutic agents are ultimately powerless against the onslaught of germs if the body's own immunological defenses cannot participate in the battle. When Sandy Lee Ford, a public health worker and drug technician, began working in the Parasitic Diseases Division of the CDC in 1979 her primary assignment was to respond to requests for drugs that the CDC provided through the Parasitic Diseases Drug Service (PDDS). One of these drugs, pentamidine isethionate, was used to treat rare, imported cases of African trypanosomiasis, but it also proved useful in treating Pneumocystis carinii pneumonia (PCP, Pneumocystis jiroveci pneumonia or Pneumocystis pneumonia). At the time, the CDC was the only repository for the drug in the United States. Typically, the PDDS received less than 90 requests for the drug annually from physicians treating patients with seriously compromised immune systems who contracted an unusual form of pneumonia. In 1981 Ford realized that the number of requests for pentamidine had surged and the patients needing this rare drug were previously healthy homosexual men with Pneumocystis pneumonia and an unidentified form of immune suppression. Ford sent a memo to her supervisor, the deputy director of parasitic diseases, calling attention to this unusual pattern of requests. Her memo has been called the first documented warning about the looming epidemic of HIV/AIDS.
The management of Babesia, amoeba and other zoonotic diseases provoked by protozoa
Published in Expert Opinion on Therapeutic Patents, 2023
Clemente Capasso, Claudiu T. Supuran
Miltefosine (hexadecylphosphocholine) 26, readily dissolvable in water and self-administerable, possesses intense anti-leishmanial activity against human visceral Leishmaniasis [131]. It seems that miltefosine has the potential to alter the parasite membrane composition and fluidity by interfering with the glycosylphosphatidylinositol anchor production and the ether-lipid metabolism, as well as with signal transmission and Ca2+ homeostasis [131,132]. Generally, miltefosine is combined with paromomycin 15 (Figure 1), an off-patent aminoglycoside antibiotic isolated from the actinomycete Streptomyces krestomuceticus [133]. This drug suppresses the protein synthesis in the parasite by targeting numerous ribosomal proteins as well as is involved in the depolarization of the mitochondrial membrane [133]. Another drug used with an anti-leishmanial activity is pentamidine 28, a cationic diamidine used in the 1980s to treat pneumonia caused by Pneumocystis carinii in HIV patients [134].
Comparative in vitro transportation of pentamidine across the blood-brain barrier using polycaprolactone nanoparticles and phosphatidylcholine liposomes
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Geofrey Omarch, Yunus Kippie, Shireen Mentor, Naushaad Ebrahim, David Fisher, Grace Murilla, Hulda Swai, Admire Dube
The major problems and challenges in treatment of HAT are the level of toxicities exhibited by the drugs [1,10]. Pentamidine isethionate (see chemical structure in Figure 1) is an aromatic dicationic diamidine molecule [11,12] which is a white crystalline powder soluble in water and glycerine and insoluble in acetone, ether and chloroform. It is chemically designated as 4, 4′ diamidino-dephenoxypentane di (β hydroxyethanesulfonate) [13]. It is administered daily by deep intramuscular administration at a dose of 4 mg/kg for 7–10 days [8,12,14]. Patients treated with pentamidine are reported to experience undesirable side effects including abdominal pain, diarrhoea, nausea, vomiting [15] cardiac arrhythmias, very high or low blood sugar, pancreas, kidney and liver problems [11,16]. Furthermore, pentamidine treatment is complicated by the mode of drug administration which requires hospitalization of a patient for more than 7 days and therefore, creates significant logistical and societal problems in the remote rural areas of Africa, where HAT is endemic. This makes it difficult to implement with consistency because of poor health facilities and few healthcare personnel [5,12,16,17]. Pentamidine is not well absorbed through gastrointestinal tract (GIT) which leads to poor oral bioavailability and has a very slow rate of diffusion across the biological membranes and thus, making the concentrations not sufficient enough to affect the trypanosomes which advance to the central nervous system (CNS) [11].
The advantages of nanomedicine in the treatment of visceral leishmaniasis: between sound arguments and wishful thinking
Published in Expert Opinion on Drug Delivery, 2021
Kevin Matha, Brice Calvignac, Jean-Pierre Gangneux, Jean-Pierre Benoit
Pentamidine is used in its isethionate salt form under the trade name Pentacarinat®. Pentamidine mechanism is still not well elucidated, it enters the parasite through the polyamine and arginine transporters and inhibits DNA replication [14], by inhibition of mitochondrial topoisomerase II leading to Leishmania death [15]. This drug is used either IV or IM at a dose of 3 to 4 mg/kg, every 48 h for a total of 10 injections. The most serious reactions observed come from gastrointestinal and cardiac toxicity [16], other adverse effects observed are hypoglycemia, hypotension, diabetes, and renal dysfunction. Due to the side effects, the pentamidine is a second-line drug. Moreover a drop in efficacy from 99% to 70% in two decades has been observed in India [17–19]. Pentamidine resistance protein 1 (PRP1) is a member of the ATP-binding cassette (ABC) transporter superfamily that has been discovered in L. major and could be the source of potential resistance [20].
Related Knowledge Centers
- African Trypanosomiasis
- Babesiosis
- Balamuthia Mandrillaris
- Central Nervous System
- Immunosuppression
- Leishmaniasis
- Antimicrobial
- Medication
- Pneumocystis Pneumonia
- Suramin