Chemical Properties
Crystalline Solid
Uses
antiprotozoal, inhibits nucleic acid & protein synthesis
Uses
Has been widely used as a drug to treat protozoal diseases, such as malaria, amoebic dysentery and trypanosomiasis. It has also been shown to be effective for both prophylaxis of pneumocystic carinii pneumonia (PCC)
Description
Pentamidine is an aromatic diamine that is effective against protozoal diseases, such as amoebic dysentery, malaria, trypanosomiasis, and leishmaniasis.
1,2,3 In clinical studies, it has also been shown to be an effective prophylaxis against pneumocystis pneumonia.
4
Originator
Nebupent,Fujisawa Healthcare Inc ,USA
Definition
ChEBI: Pentamidine is a diether consisting of pentane-1,5-diol in which both hydroxyl hydrogens have been replaced by 4-amidinophenyl groups. A trypanocidal drug that is used for treatment of cutaneous leishmaniasis and Chagas disease. It has a role as a trypanocidal drug, an antifungal agent, a NMDA receptor antagonist, an anti-inflammatory agent, a chemokine receptor 5 antagonist, an EC 2.3.1.48 (histone acetyltransferase) inhibitor, a calmodulin antagonist, a S100 calcium-binding protein B inhibitor and a xenobiotic. It is a carboxamidine, a diether and an aromatic ether. It is a conjugate base of a pentamidinium(2+).
Manufacturing Process
2.5 g of p,p'-dicyano-1,5-diphenoxy-pentane (obtained by the interaction of phydroxybenzonitrile and pentamethylene-dibromide in aqueous alkaline solution, melting point 114°C) are dissolved in 15 cc of nitrobenzene and 2.5 cc of absolute ethyl alcohol added. The solution is saturated with dry hydrochloric acid gas at 0°C and allowed to stand for 48 h. It is then diluted with dry ether and the precipitated 1,5-diphenoxypentane, 4,4'di(ethoxycarbonimidoyl) dihydrochlorid is filtered and washed with ether.
4 g of 1,5-diphenoxypentane, 4,4'-di(ethoxycarbonimidoyl) dihydrochloride are mixed with 30 cc. of 6 % ethyl alcoholic ammonia and heated in a closed vessel at 50°C for 5 h. The alcohol is removed and the residual 1,5diphenoxypentane, 4,4'-diamidino dihydrochloride is twice recrystallised fromdilute hydrochloric acid and finally purifled by dissolving in water and precipitating with acetone. Its melts at 236°C, dec.
Pentamidine isetionate salt may be produced by the reaction pentamidine base with isethionic acid.
Brand name
Nebupent [as isethionate]
(Fujisawa); Pentacarinat [as isethionate] (Rhone-Poulenc
Rorer); Pentam 300 [as isethionate] (Fujisawa).
Therapeutic Function
Antiprotozoal
Antimicrobial activity
Pentamidine has broad activity in experimental models against
P. falciparum, Toxoplasma gondii, Leishmania spp., Trypanosoma
spp. and Babesia spp. It also has activity against Pn. jirovecii.
Acquired resistance
Relapse rates of 7–16% have been reported in the treatment
of human African trypanosomiasis in West Africa. Patients
usually respond to a subsequent course of treatment with
melarsoprol. A membrane transporter is involved in crossresistance
of arsenic-resistant T. brucei to diamidines, affecting
diminazene and stilbamidine more than pentamidine.
Pharmaceutical Applications
A synthetic diamidine, available as the isethionate
(2-hydroxymethane sulfonate) salt for parenteral use. It is also
administered by instillation of a nebulized solution directly
into the lungs.
Mechanism of action
Pentamidine is not well absorbed from the intestinal
tract after oral administration and generally is given by
intramuscular injection. The drug binds to tissues, particularly
the kidney, and is slowly excreted, mostly as the
unmodified drug. It does not enter the central nervous
system (CNS). Its sequestration in tissues accounts for
its prophylactic use in trypanosomiasis.
Pharmacokinetics
Oral absorption: Negligible
Cmax 4 mg/kg intramuscular: c. 0.5 mg/L after 1 h
Plasma half-life: c. 6.5 h
Volume of distribution: 3 L/kg
Plasma protein binding: c. 70%
Pentamidine is rapidly and extensively metabolized by rat liver,
and high concentrations are retained in renal and hepatic tissue
for up to 6 months after administration. In humans distribution
is mainly in the liver, kidney, adrenal glands and spleen,
with lower accumulation in the lung. This tissue retention is
the basis for its prophylactic use. Although transport across
the blood–brain barrier has been demonstrated in experimental
models, it is probably unable to cross the blood–brain
barrier in sufficient quantity to be trypanocidal: <1% of the
plasma concentration has been measured in the CSF of sleeping
sickness patients. About 15–20% of the dose is excreted
in the urine but because of retention in tissues there is an
extremely long terminal half-life (>12 days).
Clinical Use
Human African trypanosomiasis (early stages before CNS involvement)
Prophylaxis and therapy of Pn. jirovecii pneumonia
Visceral leishmaniasis unresponsive to pentavalent antimonials and
cutaneous leishmaniasis caused by L. guyanensis
There is limited evidence for its use in the treatment of
babesiosis.
Clinical Use
Pentamidine is active against Pneumocystis carinii,
trypanosomes, and leishmaniasis unresponsive to pentavalent
antimonials. It is an alternative agent for the
treatment of P. carinii pneumonia. Although it is more
toxic than trimethoprim–sulfamethoxazole, it has been
widely used in patients with acquired immunodeficiency
syndrome (AIDS), in whom P. carinii infection is
common.
Pentamidine is an alternative drug for visceral leishmaniasis,
especially when sodium stibogluconate has
failed or is contraindicated. Pentamidine is also a reserve
agent for the treatment of trypanosomiasis before
the CNS is invaded. This characteristic largely restricts
its use to Gambian trypanosomiasis.
Synthesis
Pentamidine, 4-4??-(pentamethylendioxy)dibenzamidine (37.4.2), is made by
reacting 4-hydroxybenzonitrile with 1,5-dibromopentane in the presence of sodium hydroxide to make 1,5-bis-(4-cyanophenoxy)pentane (37.4.1). Subsequent reaction of this with an
ethanol solution of hydrogen chloride with the intermediate formation of an iminoester, and
then with an ethanol solution of ammonia gives the desired pentamidine.
