Monitoring antimalarial drug resistance in India via sentinel sites: outcomes and risk factors for treatment failure, 2009–2010

Objective

To describe India’s National Antimalarial Drug Resistance Monitoring System, measure the efficacy of first-line malaria treatments, and determine risk factors for treatment failure.

Methods

In 2009–2010, prospective studies with 28 days of follow-up were conducted at 25 sentinel sites. Patients infected with Plasmodium falciparum were given artesunate plus sulfadoxine-pyrimethamine (AS+SP); those infected with P. vivax were given chloroquine. Polymerase chain reaction was used to distinguish post-treatment reinfection from treatment failure. Isolates of P. falciparum were checked for dhfr and dhps mutations.

Findings

Overall, 1664 patients were enrolled. Kaplan–Meier survival analysis showed an efficacy of 98.8% for AS+SP. Most patients with P. falciparum parasitaemia cleared their parasitaemias within 24 hours of treatment initiation, but six, including four with treatment failure, remained parasitaemic after 72 hours. Double mutants in dhfr were found in 68.4% of the genotyped isolates. Triple or quadruple mutants in dhfr and mutations in dhps were rare. A daily dose of artesunate of < 3 mg per kg of body weight, age of less than 5 years, and fever at enrolment were associated with an increased risk of treatment failure. Chloroquine remained 100% efficacious and generally cleared P. vivax parasitaemias within 48 hours. Vomiting (seen in 47 patients) was the most common adverse event.

Conclusion

India’s National Antimalarial Drug Resistance Monitoring System provides wide coverage. The first-line antimalarials used in the country remain safe and efficacious. The treatment of malaria in young children and the relative benefits of age- and weight-based dosing need further exploration.     

Mononuclear cell modulation of connective tissue function: suppression of fibroblast growth by stimulation of endogenous prostaglandin production.

The role of immune cell products in modulating connective tissue metabolism was investigated. Supernates of both unstimulated and phytohemagglutinin-stimulated human mononuclear cell cultures suppressed fibroblast proliferation (up to 90%) and concomintantly stimulated fibroblast prostaglandin E(PGE) synthesis (20- to 70-fold). The growth suppression was, at least in part, a secondary result of the increased fibroblast PGE synthesis; growth suppression (a) paralled the increased fibroblast PGE synthesis, (b) was reversed by addition of inhibitors of prostaglandin synthesis (indomethacin, meclofenamate, and eicostaetraynoic acid), and (c) was reproduced by addition of exogenous PGE2 to fibroblast cultures. The prostaglandin-stimulatory, growth-suppressive activity was a product of non-T-lymphocyte, adherent cells and was present within 6 h of mononuclear cell culture. The activity was heat (56 degrees C) and trypsin sensitive, nondialyzable, and appeared in the 12,000-20,000 mol wt fractions by Sephadex G-100 chromatography. The activity in supernates of mononuclear cell cultures was removed by incubation with fibroblasts but not by similar incubation with peripheral blood mononuclear cells. Mononuclear cells release a factor(s) which modulates fibroblast proliferation by altering prostaglandin metabolism.     

Homologous desensitization of human platelet thromboxane A2/prostaglandin H2 receptors.

Desensitization of platelet thromboxane (TX)A2/prostaglandin (PG)H2 receptors was induced by incubating platelet-rich plasma with the stable PGH2 analog 11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619) (1 microM). Iloprost, a stable prostacyclin analog, was included in the incubation to prevent platelet activation. The TXA2 mimetic, [1S-1 alpha,2 beta(5Z), 3 alpha(1E,3S*), 4 alpha)]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo - [2.2.1]heptan-2-yl]-5-heptenoic acid (I-BOP), was used to induce platelet aggregation, shape change and increases in intracellular free calcium. The EC50 values for I-BOP-induced rise in intracellular free calcium (control = 10.2 +/- 1.5 nM; desensitized = 79.4 +/- 22.4 nM, n = 6, P less than .05), aggregation (control = 15.8 +/- 2.4 nM; desensitized = 51.7 +/- 11.9 nM; P less than .05, n = 5) and shape change (control = 172 +/- 37 pM; desensitized = 350 +/- 60 pM; P less than .05, n = 7) were increased by the preincubation with U46619. Aggregation responses to thrombin and the calcium ionophore, ionomycin, were unaltered by the preincubation with U46619. Equilibrium binding studies at pH 7.4 revealed a decrease in the number of binding sites for the receptor antagonist 9,11-dimethylmethano-11,12- methano-16(3-iodo-4-hydroxyphenyl)-13,14-dihydro-13-aza-15 alpha beta-omega- tetranor-TXA2 [125I]PTA-OH) (control = 3246 +/- 509 sites/platelet, desensitized = 2198 +/- 324 sites/platelet, n = 6, P less than .05) without a change in affinity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Desensitization of platelet thromboxane A2/prostaglandin H2 receptors by the mimetic U46619

Thromboxane A2 (TXA2) and prostaglandin H2 (PGH2) activate platelets through membrane receptors. This study sought to determine if changes occur in the TXA2/PGH2 receptor during its desensitization induced by exposure to its agonist 11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619). Washed human platelets were incubated for 30 min with U46619 in the presence of an antiaggregatory agent, Iloprost. The platelets were washed and the aggregation response to U46619 was determined. The EC50 increased from 372 +/- 94 nM in the control group to 826 +/- 143 nM for the U46619-pretreated group (n = 7). This desensitization was specific inasmuch as the aggregation responses to thrombin and the calcium ionophore A23187 were not affected by U46619 pretreatment. Desensitization was accompanied by a decrease in the number of binding sites for [3H]U46619 from 789 +/- 189 in the control to 386 +/- 120 sites per platelet in the U46619-treated group (n = 5) and a decrease in the number of binding sites for the TXA2/PGH2 receptor antagonist, [125I]9,11-dimethylmethano-11,12-methano-16(3-iodo-4-hydroxyphenyl )-13,14- dihydro-13-aza-15-alpha beta-omega-tetranor-TXA2 from 3988 +/- 957 to 2443 +/- 553 (n = 8). The Kd for U46619 was 37 +/- 10 nM in the control group and 23 +/- 11 nM for the U46619-treated group (n = 5). The Kd for I-9,11-dimethylmethano-11,12-methano-16(3-iodo-4-hydroxyphenyl)-13 ,14-dihydro- 13-aza-15-alpha beta-omega-tetranor-TXA2 changed from 58 +/- 12 nM in the control to 44 +/- 9 nM in the U46619-treated group (n = 8).(ABSTRACT TRUNCATED AT 250 WORDS)     

国产尼莫地平片和尼莫通片的生物利用度比较

国产尼莫地平片和尼莫通片的生物利用度比较施孝金王宏图韦阳张静华张莉莉钟明康（上海医科大学华山医院临床药学研究室，上海２０００４０）钙离子通道拮抗剂尼莫地平（ｎｉｍｏｄｉｐｉｎｅ，ＮＭ），临床上主要用于治疗有明显症状的老年性脑功能损伤和由于蛛网膜下腔出...