Basic experiments with clotrimazole administered orally

Seo, Mizuna; Iida, Haruzo; Miura, Yusho

doi:10.1185/03007997709110160

Cited by 35 publications

(16 citation statements)

References 4 publications

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“…As shown in Fig. 1, oral administration of CLT in subjects A, B, and C was associated with random plasma levels of CLT varying between 0.03 and 0.44 M. These values are in accordance with published data on blood levels of CLT following oral administration in normal controls or patients with systemic mycoses (26)(27)(28)(29). In two subjects (D and E) higher levels of plasma CLT were achieved at dosages of 30 mg CLT/kg/d (0.74 and 0.41 M, respectively; Fig.…”

Section: Resultssupporting

confidence: 80%

Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease.

Brugnara¹,

Gee²,

Armsby³

et al. 1996

J. Clin. Invest.

222

150

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Pathologic water loss from sickle erythrocytes concentrates the abnormal hemoglobin and promotes sickling. The Ca 2 ϩ -activated K ϩ channel (Gardos channel) contributes to this deleterious dehydration in vitro, and blockade of K ϩ and water loss via this channel could be a potential therapy in vivo. We treated five subjects who have sickle cell anemia with oral clotrimazole, a specific Gardos channel inhibitor. Patients were started on a dose of 10 mg clotrimazole/kg/d for one week. Protocol design allowed the daily dose to be escalated by 10 mg/kg each week until significant changes in erythrocyte density and K ϩ transport were achieved. Blood was sampled three times a week for hematological and chemical assays, erythrocyte density, cation content, and K ϩ transport. At dosages of 20 mg clotrimazole/kg/d, all subjects showed Gardos channel inhibition, reduced erythrocyte dehydration, increased cell K ϩ content, and somewhat increased hemoglobin levels. Adverse effects were limited to mild/moderate dysuria in all subjects, and a reversible increase in plasma alanine transaminase and aspartic transaminase levels in two subjects treated with 30 mg clotrimazole/kg/d. This is the first in vivo evidence that the Gardos channel causes dehydration of sickle erythrocytes, and that its pharmacologic inhibition provides a realistic antisickling strategy. ( J. Clin. Invest. 1996. 97:1227-1234.)

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Section: Resultssupporting

confidence: 80%

Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease.

Brugnara¹,

Gee²,

Armsby³

et al. 1996

J. Clin. Invest.

222

150

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“…Pharmacokinetic information on CLT in humans indicates that, in healthy subjects after a single oral dose of 1 g CLT (Ϸ15 mg͞kg body weight), plasma levels reach mean peak concentrations of about 2 M within 2-4 hr of administration (15,16). Similar and even higher CLT levels have been found by others after oral administration of comparable doses (12,17). Most of CLT in plasma is bound to lipoproteins, 4% is bound to albumin, and less than 1% appears to be free (15).…”

Section: Discussionsupporting

confidence: 60%

“…Absorption is more efficient when given in oil solution than in tablets (12). Infants and children have shown good absorption and delayed excretion, compared with adults (13).…”

Section: Discussionmentioning

confidence: 99%

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Tiffert

Ginsburg

Krugliak

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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The increasing resistance of the malaria parasite Plasmodium falciparum to currently available drugs demands a continuous effort to develop new antimalarial agents. In this quest, the identification of antimalarial effects of drugs already in use for other therapies represents an attractive approach with potentially rapid clinical application. We have found that the extensively used antimycotic drug clotrimazole (CLT) effectively and rapidly inhibited parasite growth in five different strains of P. falciparum, in vitro, irrespective of their chloroquine sensitivity. The concentrations for 50% inhibition (IC50), assessed by parasite incorporation of [ 3 H]hypoxanthine, were between 0.2 and 1.1 M. CLT concentrations of 2 M and above caused a sharp decline in parasitemia, complete inhibition of parasite replication, and destruction of parasites and host cells within a single intraerythrocytic asexual cycle (Ϸ48 hr). These concentrations are within the plasma levels known to be attained in humans after oral administration of the drug. The effects were associated with distinct morphological changes. Transient exposure of ring-stage parasites to 2.5 M CLT for a period of 12 hr caused a delay in development in a fraction of parasites that reverted to normal after drug removal; 24-hr exposure to the same concentration caused total destruction of parasites and parasitized cells. Chloroquine antagonized the effects of CLT whereas mefloquine was synergistic. The present study suggests that CLT holds much promise as an antimalarial agent and that it is suitable for a clinical study in P. falciparum malaria. In the course of an investigation on the homeostasis of human red cells infected in vitro with the human malaria parasite Plasmodium falciparum, we found that clotrimazole (CLT), an imidazole derivative used as an antifungal agent (1), had a powerful growth-inhibiting effect on the parasite. The vast clinical experience, proven tolerance, and unique lack of acquired fungal resistance to CLT prompted a detailed investigation of its antimalarial effects in cultures of P. falciparum to assess its clinical potential. In this study, we report the in vitro effects of CLT on P. falciparum cultures by assessing the timeand concentration-dependent changes in parasite growth, parasite morphology, stage-specific development, and parasite replication. Materials and MethodsCultures. Five different laboratory strains of P. falciparum [A4 (2), W2, NF54, HB3, and FCR] were cultured in human erythrocytes by standard methods (3) under a low oxygen atmosphere. The culture medium was RPMI 1640, supplemented with 40 mM Hepes, 25 mg͞liter gentamicin sulfate, 10 mM D-glucose, 2 mM glutamine, and either 8.5% (vol͞vol) pooled human serum (A4 clone), or 10% heat-inactivated plasma (strains W2, NF54, HB3, and FCR). Culture media, with or without CLT, were changed daily, unless otherwise indicated. Parasites were synchronized at the ring stage with D-sorbitol (4) for all experiments. Initial parasitemias varied between 2% and 7% for the different e...

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“…The latter, however, have been attributed to release ofendotoxins from lysed fungi (26). Plasma levels ofthe drug in patients receiving two oral doses of I g spaced 4 h apart varied between 1.2 and 4 ,g/ml at 9-12 h after the second dose (27). These levels correspond to plasma concentrations of 3.5-11.6 ueM.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Ca(2+)-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives.

Brugnara

Franceschi²,

Alper³

1993

J. Clin. Invest.

348

279

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We have investigated the interaction of clotrimazole (CLT) and related compounds with the erythroid Ca2"-activated K+ channel, a mediator of sickle cell dehydration. We measured K+ transport, membrane potential, and cell volume upon activation of this pathway in sickle erythrocytes. CLT blocked almost completely Ca2"-activated K+ transport in homozygous hemoglobin S cells, with IC5o values of 29±15 nM in isotonic 20 mM salt solution and 51±15 nM in normal saline (n = 3). The inhibition of K+ transport by CLT was caused by a specific interaction with the Ca2"-activated K+ channel of human red cells, since it displaced bound 125I-Charybdotoxin, a specific ligand of the Gardos channel, with an IC50 (12±4 nM in isotonic 20 mM) similar to the IC50 values for flux inhibition. When homozygous hemoglobin S cells were dehydrated by incubation in the presence of 100 ,gM CaCI2 and the ionophore A23187, or by exposure to cycles of oxygenation and deoxygenation, CLT effectively inhibited cell dehydration and K+ loss. The IC50 of CLT for inhibition of Ca2+-activated K+ transport in sickle cells is significantly lower than plasma concentrations of CLT achievable after nontoxic oral doses. We therefore propose that oral administration of CLT may prevent red cell dehydration in patients with sickle cell anemia. (J. Clin. Invest. 1993. 92:520-526.)

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Basic experiments with clotrimazole administered orally

Cited by 35 publications

References 4 publications

Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease.

Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease.

Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum

Inhibition of Ca(2+)-dependent K+ transport and cell dehydration in sickle erythrocytes by clotrimazole and other imidazole derivatives.

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