antifungals kill everything?

[Guest guest]

This was posted on another list.

FIrst we've got Schardt saying diflucan is anti borrelial.

Now we've got antifungals as antibabesia.

Admittedly its in vitro.

Still I wish somebody would study this.

Clotrimazole, ketoconazole, and clodinafop-propargyl as potent growth

inhibitors of equine Babesia parasites during in vitro culture.

Bork S, Yokoyama N, Matsuo T, Claveria FG, Fujisaki K, Igarashi I.

National Research Center for Protozoan Diseases, Obihiro University

of Agriculture and Veterinary Medicine, Inada-cho, Obihiro, Hokkaido

080-8555, Japan.

The antifungal agents clotrimazole (CLT) and ketoconazole (KC) and

the herbicide clodinafop-propargyl (CP) inhibit growth of Plasmodium

sp., Toxoplasma sp., and Trypanosoma sp. In the present study, we

evaluated these drugs against the in vitro growth of the equine

protozoan parasites Babesia equi and B. caballi. Clotrimazole (IC50:

2 and 17 microM), KC (IC50: 6 and 22 microM), and CP (IC50: 450 and

354 microM) were effective growth inhibitors. Interestingly,

intraerythrocytic KC-treated Babesia sp. were observed to be in

immediate contact with the plasma fraction of the blood in electron

microscopy. These results demonstrate the babesiacidial activities of

these compounds and suggest their chemotherapeutic potential for the

treatment of equine babesioses.

[Guest guest]

I was doing a pubmed search and inadvertantly ended up here. This

drug caught my attention, its effect on lipids etc.

DRUG REVIEW

Year : 2003 | Volume : 49 | Issue : 1 | Page : 101-3

Miltefosine: great expectations against visceral leishmaniasis.

More B, Bhatt H, Kukreja V, Ainapure SS

Department of Clinical Pharmacology, Seth G. S. Medical College and

K. E. M. Hospital, Parel, Mumbai, India.

Correspondence Address:

Department of Clinical Pharmacology, Seth G. S. Medical College and

K. E. M. Hospital, Parel, Mumbai, India.

How to cite this article:

More B, Bhatt H, Kukreja V, Ainapure SS. Miltefosine: great

expectations against visceral leishmaniasis. J Postgrad Med

2003;49:101-3

How to cite this URL:

More B, Bhatt H, Kukreja V, Ainapure SS. Miltefosine: great

expectations against visceral leishmaniasis. J Postgrad Med [serial

online] 2003 [cited 2005 Jul 22];49:101-3. Available from:

http://www.jpgmonline.com/article.asp?issn=0022-

3859;year=2003;volume=49;issue=1;spage=101;epage=3;aulast=More

Visceral leishmaniasis is a disease endemic in 47 countries and

continues to be a difficult therapeutic challenge.[1] There are an

estimated 500 000 cases per year in Asia (primarily India), South

America and South Africa. Up to half of the world's cases of visceral

leishmaniasis (Kala azar) occur in India, and about 90% of patients

live in the Indian state of Bihar.[2]

Hexadecylphosphocholine (Miltefosine) is a phosphorylcholine ester of

hexadecanol, a membrane-active, alkylphospholipid. It is the first

effective oral agent for visceral leishmaniasis, an intracellular

protozoal infection of tissue macrophages.[3],[4] The emergence of

leishmaniasis strains resistant to pentavalent antimonials and the

growing incidence of visceral leishmaniasis among AIDS patients have

made the availability of an oral agent extremely important for

management of this disease.[1]

:: Mechanism of action

a) Anti-leishmaniasis Action

Leishmania have high levels of ether-lipids and these are mainly

found in the glycosylphosphophatidylinositol anchored glycoprotein

and glycolipids present on the surface of the parasites. Miltefosine

acts on key enzymes involved in the metabolism of ether lipids. These

enzymes include diethylacetonephosphate acetyltransferase, sn-l-acyl-

2-lyso-glycero-phosphocholine and sn-l-alkyl-2-lyso-glycero-3-

phosphocholine acyltransferase. The initating steps in the ether –

lipid metabolism occur in glycosomes. Miltefosine does not act on the

enzymes involved in the initial steps in ether lipid metabolism in

leishmania. However, the metabolism of the latter phosphatidylcholine

base intermediates, which are involved in the synthesis of acyl- and

alkyl-glycerophospholipids are associated with glycosomes.

Miltefosine inhibits this glycosomal alkyl specific alkyl-specific-

acyl CoA acyltransferase in a dose dependent manner.[5]

In vitro studies demonstrate that miltefosine stimulates T cells and

macrophages to secrete activating cytokines, including interferon

(IFN)- gamma and enhances macrophage production of microcidal

reactive nitrogen and oxygen intermediates. To determine these

effects in vivo genetically deficient mice were infected with

Leishmania donovani. Intracellular killing was retained in T cell

deficient mice suggesting that miltefosine induced visceral

leishmanicidal effect does not require host T cell-dependent or

activated macrophage- mediated mechanisms.[6]

Anticancer Action

Miltefosine was originally discovered and synthesized as an anti

cancer agent. Its action is exerted at the plasma membrane level,

where it interferes with mitogenic signal transduction pathways.

Malignant cells are highly sensitive to the lethal action of

miltefosine; while normal cells remain relatively unaffected,

illustrating the potential anti-tumour properties of the drug.

Moreover, miltefosine induce apoptosis in various tumour cell lines

and in combination with other anticancer regimens cause additive

cytotoxic effects.[7] Miltefosine also interacts with its molecular

targets in myeloid cells to induce molecular and cellular effects

associated with introduction of differentiation, distinct from its

cytotoxic activity.[8] The mode of action is mediated via the cell

membrane by inducing apoptosis. There is an increase in intracellular

free calcium via calcium channels in the cell membrane.[9]

:: Pharmacokinetics

Miltefosine is well absorbed after oral administration and is widely

distributed. It has a long half-life of about 8 days.[10] However

little pharmacokinetic data is available in human beings. In rat,

miltefosine is rapidly taken up and accumulates in several internal

organs, such as kidney, liver, lung, spleen and adrenal glands. On

oral administration of miltefosine 30 mg/kg of body weight twice per

day, concentrations of 155 to 189 nmol/g of tissue are achieved.[11]

Miltefosine is degraded slowly in vivo, with half-life of 96 hours in

mice.[12] It is slowly metabolized by phospholipase to form products

such as choline and long chain alcohols that are physiological

metabolites and can be recycled into phospholipids.[12],[13]

:: Therapeutic indications

1. Visceral Leishmaniasis

Orally administered miltefosine is an effective modality of treatment

of Indian visceral leishmaniasis including antimony resistant cases.

[11],[14],[15] A case has been reported of visceral leishmaniasis

with HIV co-infection, which responded to treatment with miltefosine.

[16] Topical treatment with miltefosine has been shown to efficiently

reduce parasite load in experimental cutaneous leishmaniasis. The

clinical application of miltefosine for the treatment cutaneous

leishmaniasis represent a potential future use for the drug.[17]

Intracellular visceral infection is suppressed by once or twice

weekly orally administered miltefosine in T cell- deficient nude mice

infected with Leishmania donovani. This supports the usefulness of

miltefosine as oral maintenance therapy for T cell deficient patients

with visceral leishmaniasis.[10]

2. As an Anticancer Agent

Skin metastasis of breast cancer has been treated with 6% miltefosine

applied locally once daily in the first week and twice daily

following week, with significant reductions in the lesions.[18]

3. Other Potential Uses

Miltefosine has significant amoebicidal activity in vitro. Entameoba

histolytica, could be a possible new target for it.[12] Miltefosine

is also effective against Trypanosoma cruzi and Trypanosoma brucei,

however further studies are needed.[5]

Miltefosine is potent inducer of apoptosis and displays increased

antileukemic efficacy against BCR-ABL-positive blasts.[19] Human

urinary bladder carcinoma cells line responds to treatment with

miltefosine, which could prove to be of benefit for patients with

urinary bladder neoplasia.[20] Its use has been evaluated in squamous

cell head and neck cancer[21] and number of metastatic solid tumors.

[22] However, more studies are required to prove its efficacy.

Limited activity is demonstrated against in advanced colorectal

carcinoma[23] Oral miltefosine in a dose 50mg thrice daily has no

activity in soft tissue sarcoma.[24]

:: Dosage and contraindications

The recommended dose of miltefosine for the treatment of visceral

leishmaniasis is 100mg/day (approximately 2.5 mg/kg per day) for 28

days. The dose should be adjusted based on patients weight so that a

dose of 4mg/kg per day is not exceeded. Miltefosine is available as

50mg oral tablet (Asta Medica, frut, Germany). The drug is

registered and expected to be soon available in India. It is

contraindicated in women with child bearing potential because of its

teratogenic effects in animal studies.[11],[16]

:: Adverse effects

Miltefosine is well tolerated with considerably fewer adverse effects

as compared to antimonials and amphotericin. The most commonly seen

adverse effects are nausea and vomiting.[25] There is an increase in

aspartate aminotransferase and creatinine and/or blood urea nitrogen

level, which is mild. Grade III hepatotoxicity and renal damage, has

also been reported in some cases. However, these changes are

reversible in the face of continued treatment or after

discontinuation of treatment.[4],[8],[25] Diarrhoea and hepatotoxicity

[4] is reported and is common during first 2 weeks treatment.

Miltefosine though used as an antineoplastic agent is devoid of

hematological toxicity.

:: Clinical studies

Visceral Leishmaniasis

Sunder et al demonstrated that 100mg/day miltefosine for 28 days is a

promising oral treatment regimen for visceral leishmaniasis cases,

including those with antimony unresponsive infection.[4],[11],[15]

The results of various studies that have evaluated the efficacy of

miltefosine by different researchers are summarised in [Table - 1].

Skin Metastasized Breast Cancer

In a phase, II trial, 6 % miltefosine solution was topically applied

in patients with skin metastasized breast cancer. A mixture of

alkylated glycerols of various chain lengths and water was used as

the pharmaceutical vehicle to dissolve and further facilitate tissue

penetration of miltefosine. It is found to be an effective treatment

modality, and to reduce the skin lesion.[5],[18]

In another trial, miltefosine was applied to the skin at a dose of 2

drops/10cm2 skin area. Twenty-five patients were treated; most of

them had been heavily pre-treated with chemotherapy for a median

period of 14 weeks. In 7 patients grade I skin toxicity was seen and

in 4 patients grade III local toxicities necessitated dose

adjustment. The responses were seen in 9 patients (1 complete

response, 2 partial responses, 6 minor responses) giving a total

response rate of 36%, with stable disease in 11 patients 44%) and

progressive disease in 5 (20%). Those lesions which were superficial

or < 2cm in diameter were most likely to respond.[26]

:: Conclusions

It is evident from studies in Indian visceral leishmaniasis that oral

miltefosine is a highly effective and a well tolerated drug. In

immunocompromised patients with conventional treatment with anti-

leishmanial drugs, cured visceral leishmaniasis or cutaneous lesion

may relapse. By rapid reduction of parasite load the duration of

treatment can be reduced[17] and subsequent relapses prevented.

Nevertheless, larger controlled phase III studies miltefosine are

required to support these findings. It is hoped that miltefosine

becomes an approved antileishmanial drug available at reasonable cost

for the majority of patients. In view of the fact that the only known

reservoir of the leishmania parasite is man, it can be expected that

miltefosine will play a key role in eradication of visceral

leishmaniasis.

:: References

1. Gangneux JP. Treatment of visceral leishmaniasis: recent

modalities. Presse Med 1999;28:2057-66. [PUBMED]

2. Sundar S, Agarwal G, Ria M, Murray HW. Treatment of Indian

visceral leishmaniasis with single dose or daily infusion of low dose

liposomal amphotericin B, a randomized trial. BMJ 2002:25;323:419-

22.

3. Hansjorg E. Miltefosine for visceral leishmaniasis. New Engl J Med

2000;342:894-5.

4. Sundar S, Gupta B, Makharia MK, Singh MK, Voss A, Rosenkiamer F,

Engel J, Murray HW. Oral treatment of visceral leishmaniasis with

miltefosine. Ann Trop Med Parasitol 1999:93;589-97

5. Lux H, Heise N, Klenner T, Hart D, Opperdoes FR. Ether –lipid

((alkyl- phospholipid) matabolism and the mechanism of action of

ether –lipid analogues in visceral leishmania. Mol Biochem Parasitol

2000;111:1-14. [PUBMED] [FULLTEXT]