Medicines for Malaria Venture new developments in antimalarials

Choosing appropriate chemoprophylaxis and stand-by treatment for travelers will remain a problem for the near future because of resistant Plasmodium falciparum. For those who live in the malaria endemic regions of the world it is a matter of life and death, but the future looks bright for control of malaria because of the development of organizations like MMV and their ability to forge suitable partnerships to tackle really big problems. This would not be possible if it were not for the MMV Stakeholders who provide the funding necessary for the discovery and development of new drugs. Malaria is a difficult problem but even if only a few of the potential drugs in the MMV pipeline become drugs, the control of malaria may again become possible.     

Ca-Agonists: a new class of inotropic drugs

Summary The basic pharmacology of dihydropyridine Ca-agonists published so far (BAY k8644, CGP 28–392, H 160/51, YC 170, and 202–791) is described. The importance of the potency of the enantiomeres for the effect of a racemic compound is underlined. The Ca agonist prototype BAY k8644 leads to an increase of the maximal rate of rise of left ventricular pressure (LV(dP/dt)) and an increase of left ventricular stroke work in conscious dogs. When the vascular effects of BAY k8644 are counterbalanced by intravenous injection of sodiumnitroprusside, the left ventricular functions curves show markedly increased stroke work against the same mean arterial blood pressure at the same filling pressure. BAY k8644 stimulates the heart economically: the net efficiency in isolated working guinea-pig hearts is about 20%, identical to a stimulation by calcium or ouabain. Cardiotonic drugs acting via cAMP-dependent mechanisms like isoprenaline, amrinone, or pimobendane however, stimulate the heart about 1/3 less economically. The mechanism of action of Ca-agonists is explained from electrophysiological findings: Ca-agonistic dihydropyridines increase the open probability of the Ca-channels by a shift of the openprobability curve to more negative membrane potentials. As a consequence, the steady-state inactivation curve of the Ca-channel is also shifted in the same direction. While the effect on open-probability is the underlying mechanism for Ca-agonism, the latter effect results in Ca-antagonism. Therefore, depending on drug concentration and on membrane resting potential, a single chemical compound can act either as a Ca-agonist or a Ca-antagonist. A kinetic model of dihydropyridine action on the Ca-channel is described.     

Dofetilide: a new class III antiarrhythmic agent

Dofetilide is a new, pure class III antiarrhythmic agent that prolongs the refractory period and action potential duration without having beta-blocking or calcium channel-blocking properties, making it unique among established class III agents. Dofetilide is effective in converting atrial and ventricular arrhythmias, and in maintaining sinus rhythm after cardioversion. Interestingly, it is more effective in converting atrial flutter than atrial fibrillation. It appears to be safe in patients with left ventricular dysfunction and postmyocardial infarction. In small studies, intravenous dofetilide was superior to flecainide, procainamide and amiodarone in converting atrial fibrillation and flutter. Dofetilide can be administered orally or intravenously with no significant effect on heart rate or blood pressure, but it can prolong QT interval and cause torsade de pointes in 3% to 4% of patients receiving it intravenously and in 0.8% to 1.5% of patients receiving it orally. So far, it is recommended that therapy be initiated in hospital under electrocardiogram monitoring for at least two days, with particular care to avoid torsade de pointes in high risk patients such as women, and those with bradycardia, hypokalemia, hypomagnesia and renal dysfunction. Studies have failed to show any extracardiac side effects.     

Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis

Carcinogenesis is blocked by an extraordinary variety of agents belonging to many different classes--e.g., phenolic antioxidants, azo dyes, polycyclic aromatics, flavonoids, coumarins, cinnamates, indoles, isothiocyanates, 1,2-dithiol-3-thiones, and thiocarbamates. The only known common property of these anticarcinogens is their ability to elevate in animal cells the activities of enzymes that inactivate the reactive electrophilic forms of carcinogens. Structure-activity studies on the induction of quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2] and glutathione S-transferases have revealed that many anti-carcinogenic enzyme inducers contain a distinctive and hitherto unrecognized chemical feature (or acquire this feature after metabolism) that regulates the synthesis of these protective enzymes. The inducers are Michael reaction acceptors characterized by olefinic (or acetylenic) bonds that are rendered electrophilic (positively charged) by conjugation with electron-withdrawing substrates. The potency of inducers parallels their efficiency in Michael reactions. Many inducers are also substrates for glutathione S-transferases, which is further evidence for their electrophilicity. These generalizations have not only provided mechanistic insight into the perplexing question of how such seemingly unrelated anticarcinogens induce chemoprotective enzymes, but also have led to the prediction of the structures of inducers with potential chemoprotective activity.     

Antioxidant action of antimalarials.

The effects of antimalarials, chloroquine and quinacrine, on the generation of reactive oxygen species were examined both in polymorphonuclear leucocytes and in the xanthine-xanthine oxidase system. Antimalarials showed inhibitory effects on the production of reactive oxygen species probably by affecting cell functions, such as membrane phospholipid methylation. It is suggested that antimalarial agents can work as antioxidants at the site of inflammation protecting against auto-oxidative tissue damage with resultant anti-inflammatory effects.     

Identification of RL-TGR,a coreceptor involved in aversive chemical signaling

Chemical signaling plays an important role in predator–prey interactions and feeding dynamics. Like other organisms that are sessile or slow moving, some marine sponges contain aversive compounds that defend these organisms from predation. We sought to identify and characterize a fish chemoreceptor that detects one of these compounds. Using expression cloning in Xenopus oocytes coexpressing the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, the beta-2 adrenergic receptor (β₂AR), and fractions of a zebrafish cDNA library, we isolated a cDNA clone encoding receptor activity–modifying protein (RAMP)-like triterpene glycoside receptor (RL-TGR), a novel coreceptor involved in signaling in response to triterpene glycosides. This coreceptor appears to be structurally and functionally related to RAMPs, a family of coreceptors that physically associate with and modify the activity of G protein–coupled receptors (GPCRs). In membranes from formoside-responsive oocytes, RL-TGR was immunoprecipitated in an apparent complex with β₂AR. In HEK293 cells, coexpression of β₂AR induced the trafficking of RL-TGR from the cytoplasm to the plasma membrane. These results suggest that RL-TGR in the predatory fish physically associates with the β₂AR or another, more physiologically relevant GPCR and modifies its pharmacology to respond to triterpene glycosides found in sponges that serve as a potential food source for the fish. RL-TGR forms a coreceptor that responds to a chemical defense compound in the marine environment, and its discovery might lead the way to the identification of other receptors that mediate chemical defense signaling.     

Fake antimalarials in Southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials

OBJECTIVE: To assess the prevalence of counterfeit antimalarial drugs in Southeast (SE) Asia. DESIGN: Cross-sectional survey. SETTING: Pharmacies and shops selling antimalarial drugs in Myanmar (Burma), Lao PDR, Vietnam, Cambodia and Thailand. MAIN OUTCOME MEASURES: Proportion of artemisinin derivatives or mefloquine containing drugs of substandard quality. RESULTS: Of the 188 tablet packs purchased which were labelled as 'artesunate' 53% did not contain any artesunate. All counterfeit artesunate tablets were labelled as manufactured by 'Guilin Pharma', and refinements of the fake blisterpacks made them often hard to distinguish from their genuine counterparts. No other artemisinin derivatives were found to be counterfeited. Of the 44 mefloquine samples, 9% contained <10% of the expected amount of active ingredient. CONCLUSIONS: An alarmingly high proportion of antimalarial drugs bought in pharmacies and shops in mainland SE Asia are counterfeit, and the problem has increased significantly compared with our previous survey in 1999-2000. This is a serious threat to public health in the region.     

Imipenem: first of a new class of beta-lactam antibiotics

Imipenem, the first of a new class of carbapenem antibiotics, has potent activity against most clinically important species of bacteria, including isolates resistant to other antibiotics. The drug is well distributed to most tissues and fluids after intravenous administration; however, levels in cerebrospinal fluid are modest. Most of the drug is eliminated in the urine, where it is metabolized by an enzyme on the brush border of the renal tubular cells; cilastatin is given simultaneously to inhibit this inactivation. Adverse effects include a syndrome of nausea and hypotension, especially after rapid intravenous infusion, and a predisposition to seizures in certain high-risk patients. Superinfections by resistant bacteria and fungi are infrequent. This new drug may be particularly useful in the treatment of infections caused by mixtures of bacteria for which a combination of antibiotics, often including an aminoglycoside, would otherwise be necessary. Examples include pulmonary, intra-abdominal, and soft-tissue infections.     

疟疾的形势和抗疟药现状

1　疟疾形势疟疾是世界上最严重的虫媒传染病。在所有虫媒传染性疾病中疟疾是发病率和死亡率最高的疾病之一。目前世界仍有90多个国家、24亿人生活在疟疾流行区。每年有5亿人发病,200多万人死亡,平均每15秒钟就有一人因疟疾死亡,死亡主要为儿童[1]。发病和死亡中90%是在非洲和亚洲的贫穷国家。50年代科学家们曾很乐观地认为疟疾能够被消灭。因为那时通过使用DDT和其它蚊虫杀灭剂使疟疾及有关疾病明显下降。但由于蚊子在地球上存在的历史悠久,对环境有很强的适应能力。它很快对所用杀虫剂均产生抗性。随之而来的是恶性疟原虫也对抗疟药产生…     

Dofetilide: a new pure class III antiarrhythmic agent

BACKGROUND: Although there are a variety of antiarrhythmic agents used for the treatment of atrial fibrillation of flutter, each drug has drawbacks, and room exists for new pharmacologic agents. Dofetilide, a pure class III agent, has recently been approved by the Food and Drug Administration for therapy of these arrhythmias and is reviewed. METHODS: Data for dofetilide, published in full or in abstract form, were reviewed, concentrating on the properties related to its efficacy for the therapy of supraventricular arrhythmias. RESULTS: Results from animal and human studies indicate that dofetilide, a renally excreted drug, has pure class III properties related to blockade of the delayed rectifier potassium current. It is effective for the therapy of atrial arrhythmias, particularly atrial fibrillation and flutter, and has no demonstrable negative inotropic effect. Despite an incidence of torsades de pointes of approximately 2% in patients with impaired ventricular function, dofetilide exhibited no association with an increased mortality rate when studied in a large series of patients with a reduced ejection fraction. CONCLUSIONS: Dofetilide's electrophysiologic and clinical profiles suggest that it will be safe and clinically useful for the termination and prevention of atrial fibrillation or flutter, even in patients with impaired ventricular function.     

Identification of a new coeliac disease subgroup: antiendomysial and anti-transglutaminase antibodies of IgG class in the absence of selective IgA deficiency

OBJECTIVE: The aim of the present study was to increase the sensitivity of the antiendomysial antibody (EMA) test by evaluating also EMAs of IgG1 isotype. DESIGN AND SUBJECTS: Over the last 2 years, serum EMAs IgA and IgG1 were determined in 1399 patients, referred to our gastrointestinal unit due to clinical suspicion of malabsorption. Serum anti-tissue transglutaminase (tTG) antibodies IgA and IgG, as well as total IgA levels, were also investigated. Furthermore, EMAs IgA and IgG1 were evaluated in biopsy culture supernatants. Biopsy specimens were also admitted to histological and immunohistochemical evaluation. Twenty-six patients with gastroenterological disease other than coeliac disease (CD) were used as a disease control group. Ninety-nine blood donors were used as a healthy control group. RESULTS: Diagnosis of CD was based on histological findings in the 110/1399 patients showing EMA IgA positivity, and in a further 56/1399 patients presenting both EMA IgA and IgG1 positivity in sera as well as in culture supernatants. Of the remaining 1233 EMA IgA-negative patients, 60 showed only EMA IgG1 positivity both in sera and in culture supernatants. It is noteworthy that anti-tissue transglutaminase antibodies IgG (anti-tTG) were positive in all 60 EMA IgG1-positive patients as well. By contrast, a selective IgA deficiency was found in only 11 out of the 60 EMA IgG1-positive patients. Villous height/crypt depth ratio was < 3:1 in 38 of the 60 EMA IgG1-positive patients (63.3%), whilst overexpression of ICAM-1 and CD25 was observed in all these patients. CONCLUSIONS: In this study, we observed a group of CD patients who were EMA IgG1-positive even in the absence of EMA IgA positivity and IgA deficiency. The diagnosis was based on the finding of the gluten-dependent clinical and histological features typical of CD. Data emerging from the present investigation thus suggest that the prevalence of CD should be reassessed and that the determination of EMA IgG1 could offer a new tool in the diagnostic armamentarium of CD.     

Inositol triphosphate: a new class of intracellular second messenger

Hormones, neurotransmitters and other signaling molecules that mobilize intracellular calcium stimulate the activity of the phospholipase C. This enzyme specifically hydrolyses the phosphoinositides and leads to the generation of two second messengers: the inositol triphosphate which mobilizes calcium from the endoplasmic pools and the diacylglycerol which stimulates the protein kinase C. The integration of these two metabolic pathways lead to the biological effect associated to the hormone or the neurotransmitter considered. In this review we will focussed our attention on the first step of these transducing mechanisms: the receptor-mediated hydrolysis of phosphoinositides.