Geometric Mean IC50 Research Articles

Ferrocene-chloroquine analogues as antimalarial agents: in vitro activity of ferrochloroquine against 103 Gabonese isolates of Plasmodium falciparum.

The in vitro activities of ferrochloroquine, chloroquine, quinine, mefloquine, halofantrine, amodiaquine, primaquine, atovaquone and artesunate were evaluated against Plasmodium falciparum isolates from children with uncomplicated malaria from Libreville (Gabon), using an isotopic, micro, drug susceptibility test. The IC(50) values for ferrochloroquine were in the range 0.43-30.9 nM and the geometric mean IC(50) for the 103 isolates was 10.8 nM (95% CI 8.6-13.5 nM), while the geometric means for chloroquine, quinine, mefloquine, amodiaquine and primaquine were 370 nM, 341 nM, 8.3 nM, 18.1 nM and 7.6 microM, respectively. Ferrochloroquine was active against P. falciparum isolates, 95% of which showed in vitro resistance to chloroquine. Weak positive significant correlations were observed between the responses to ferrochloroquine and that to chloroquine, amodiaquine and quinine, but too low to suggest cross-resistance. There was no significant correlation between the response to ferrochloroquine and those to mefloquine, halofantrine, primaquine, atovaquone or artesunate. Ferrochloroquine may be an important alternative drug for the treatment of chloroquine-resistant malaria.

Resistance of Plasmodium falciparum to antimalarial drugs in a highly endemic area of southern Viet Nam: a study in vivo and in vitro

To assess the antimalarial sensitivity of Plasmodium falciparum in vivo and in vitro in a highly endemic area of southern Viet Nam, a field study was conducted (in 1999) at a rubber plantation in Binh Phuoc Province north of Ho Chi Minh City. Fifty patients were treated with either artesunate (4 mg/kg on day 0, then 2 mg/kg on day 1 to 4) or mefloquine (10 mg/kg at 0 h, then 5 mg/kg at 6 h), and their progress was followed for 28 days under standard WHO protocols. Blood spots were taken at baseline from all patients, as well as from those who redeveloped parasitaemia during follow-up, for polymerase chain reaction (PCR) determination of parasite genotypes to assist differentiation of re-infection from recrudescence. Both treatments cleared parasites within 5 days. Of the 25 mefloquine-treated patients, 2 (8%) re-presented with probable re-infections. For artesunate, 4 patients (16%) had re-infections and 5 (20%) had recrudescences. Sensitivity tests in vitro of pre-treatment P. falciparum isolates showed geometric mean IC 50 values of 29, 38, 209 and 15 nmol/L for chloroquine ( n = 32), mefloquine ( n = 33), quinine ( n = 31) and artemisinin ( n = 31), respectively. There were significant correlations between IC 50s for artemisinin and mefloquine ( r = 0·72, P = 0·004), and chloroquine and quinine ( r = 0·44, P = 0·05). These data show that, although mefloquine has been used for 10 years in Binh Phuoc Province, it remains fully effective, perhaps because an artemisinin derivative is commonly given at the same time. The recrudescence rate for artesunate is similar to those reported in other epidemiological contexts. The present in-vitro data imply that quinine remains effective and that reduced drug pressure has been associated with increased sensitivity of local strains of P. falciparum to chloroquine. Although from one hyperendemic area, these results may have implications for antimalarial prophylaxis and treatment strategies for residents and travellers to southern Viet Nam.

EFFECTS OF SILDENAFIL ON THE RELAXATION OF HUMAN CORPUS CAVERNOSUM TISSUE IN VITRO AND ON THE ACTIVITIES OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE ISOZYMES

Purpose Sildenafil, an inhibitor of cGMP-specific phosphodiesterase 5 (PDE5), is currently undergoing evaluation as an oral therapy for penile erectile dysfunction. The aims of this study were to investigate the mechanism of action of sildenafil on the neurogenic relaxation of human corpus cavernosum (HCC) in vitro and to determine the activity of sildenafil against a full range of PDE isozymes. Materials and Methods Strips of HCC tissue were precontracted with phenylephrine. Relaxation responses resulting from electrical field stimulation (EFS) were then determined in the presence and absence of sildenafil. The effects of sildenafil on PDE1 to 5 prepared from human tissues and PDE6 from bovine retina were determined by measuring the conversion of [( 3) H]-cGMP or [( 3) H]-cAMP to their respective [( 3) H]-5′-mononucleotides. Results Sildenafil (0.001 to 1 micro M) enhanced the EFS-induced, nitric oxide (NO) dependent, relaxation of HCC in a concentration-dependent manner to a maximum of 3 times the pretreatment level at 1 micro M sildenafil. Compared with zaprinast, an early PDE5 inhibitor, sildenafil was approximately 240-fold more potent, inhibiting PDE5 from HCC with a geometric mean IC 50 of 3.5 nM. For sildenafil, IC 50 values for inhibition of PDE1 to 4 were 80 to more than 8500 times greater than that for PDE5 and the IC 50 for PDE6 (33 nM) was approximately 9-fold greater. Conclusions The data support the proposal that enhancement of penile erection by sildenafil in patients with erectile dysfunction involves potentiation of the NO-stimulated cGMP signal mediating relaxation of cavernosal smooth muscle during sexual stimulation. Sildenafil is a potent inhibitor of PDE5 from HCC, with high selectivity for PDE5 relative to other PDE isozymes.

Protein kinase C inhibition enhances platelet-activating factor-induced eicosanoid production in human eosinophils.

Previous investigations have suggested that protein kinase C (PKC) may regulate guinea pig eosinophil responses through a suppressive "negative feedback" mechanism. Using the selective PKC inhibitors bisindolylmaleimide I (Bis I, GF 109203X) and calphostin C, we examined the role of PKC in platelet-activating factor (PAF)-induced respiratory burst and generation of arachidonic acid metabolites in human peripheral blood eosinophils. Bis I inhibited PAF-induced generation of superoxide anion with substantially lower potency (geometric mean IC50 = 1.41 microM, 95% CI 0.94-2.11 microM) than it exhibited against responses to the phorbol esters 4-beta-phorbol 12-myristate 13-acetate (PMA; IC50 = 0.25 microM, 0.09-0.72 microM; P < 0.01) and 4-beta-phorbol 12,13-dibutyrate (IC50 = 0.48 microM, 0.20-1.14 microM; P < 0.05). The production of thromboxane (measured as TxB2) induced by 1 microM PAF was increased significantly by Bis I at concentrations of 1 microM (162 +/- 7.5% of control PAF response; P < 0.01) and 10 microM (194 +/- 17%; P < 0.001); TxB2 release induced by PMA was unaffected by concentrations of Bis I up to 1 microM and inhibited by 10 microM Bis I (48 +/- 11%; P < 0.05). Bis I (1 microM) significantly increased both thromboxane and leukotriene C4 (LTC4) production induced by 2 microM (P < 0.01 and P < 0.05, respectively) or 20 microM PAF (both P < 0.001). The actions of Bis I on PAF-stimulated thromboxane and leukotriene production were mimicked by a second PKC inhibitor, calphostin C, whereas the non-PKC-inhibitory analog, bisindolylmaleimide V, caused no enhancement of TxB2 or LTC4 production. The increase in intracellular free calcium induced by 1 microM PAF was heightened and prolonged in cells pre-treated with 1 microM Bis I or 1 microM calphostin C (peak increase, P < 0.05 for both drugs; level 60 s after addition of PAF, P < 0.001 and P < 0.05 for Bis I and calphostin C, respectively; time to return to 50% of peak, P < 0.05 for Bis I). We conclude that PKC inhibition causes augmentation of thromboxane and LTC4 production in PAF-stimulated human eosinophils despite suppressing respiratory burst activity, indicating that different signaling pathways predominate in these two responses and that PKC mediates a suppression of an early stage in an alternative pathway of activation.

In vitro activity of atovaquone against the African isolates and clones of Plasmodium falciparum.

The in vitro activity of atovaquone (566C80) was evaluated and compared with that of chloroquine, quinine, mefloquine, halofantrine, artemether, pyrimethamine, and cycloguanil against African isolates and clones of Plasmodium falciparum using an isotopic, semimicro, drug susceptibility test. Atovaquone was highly active against the chloroquine-susceptible L-3 (geometric mean 50% inhibitory concentration [IC50] = 0.978 nM) and L-16 clones (mean IC50 = 0.680 nM) and against the multidrug-resistant FCM 29 clone (mean IC50 = 1.76 nM). Similar low IC50 values for atovaquone were observed against the chloroquine-susceptible isolates (n = 35; geometric mean IC50 = 0.889 nM) and the chloroquine-resistant parasites (n = 26; geometric mean IC50 = 0.906 nM). The in vitro responses between atovaquone and the other antimalarial drugs were not correlated, indicating the absence of in vitro cross-resistance. The high in vitro activity of atovaquone without any in vitro evidence for cross-resistance with other antimalarial drugs against the naturally occurring malaria parasites is a factor that favors further development of the drug for clinical use.