Inhibitors of the Plasmodium falciparum parasite aspartic protease plasmepsin II as potential antimalarial agents.

Malaria is a very serious infectious disease against which the currently available drugs are loosing effectiveness. The main problem is the emergence and the spreading of resistant parasite strains. New treatments are needed in order to regain control over the disease. Drug discovery efforts towards this goal are likely to be more successful, if they focus towards novel mechanisms of action. Such efforts will result in drugs that are functionally and structurally different from the existing drugs and therefore will overcome existing resistances. Here we focus on the aspartic protease plasmepsin II, which is a promising new drug target. We review the drug discovery efforts that were published in the literature on this enzyme, and we present the compounds synthesized at Actelion Pharmaceuticals Ltd.

Endothelin receptor antagonists: structures, synthesis, selectivity and therapeutic applications.

Endothelin (ET) was discovered in 1988 and is the most potent vasoconstrictive peptide known to date. It exists in three isoforms (ET-1 to ET-3) and acts on two endothelin receptor subtypes, the endothelin-A (ET(A))-receptor and the endothelin-B (ET(B))-receptor. Endothelin receptor antagonists are novel therapeutics in clinical development for different cardiovascular, cerebrovascular, and renal diseases. Several different structural classes of endothelin receptor antagonists have been discovered within the last decade, starting from peptidic- and peptidomimetic structures to small organic molecules suitable as therapeutics for oral administration. Focussing on the small organic molecules, the different structural classes of ET-receptor antagonists are described with respect to synthesis, structure-activity-relationships, receptor-subtype-selectivity profile, and where possible, intended therapeutic indications.

Concurrent paclitaxel and radiation in the treatment of locally advanced head and neck cancer.

PURPOSE: To determine the feasibility of an organ preservation regimen consisting of infusional paclitaxel administered concurrently with radiotherapy to patients with locally advanced head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Thirty-three previously untreated patients with stage III or IV tumors were enrolled onto the study. Paclitaxel was administered as a 120-hour continuous infusion every 3 weeks during the course of radiation therapy. Sixteen patients received a paclitaxel dose of 105 mg/m(2), and 17 patients received 120 mg/m(2). Radiation was delivered in a standard format at 1.8 Gy/d to a total dose of 70.2 to 72 Gy. RESULTS: Three months after therapy, a 76% complete response (CR) at the primary site and a 70% overall CR was achieved. At 36 months, locoregional control was 55.7%, overall survival was 57.8%, and disease-free survival was 51.1%. The median survival duration for all 33 patients was greater than 50 months at the time of this report. Local toxicities including mucositis, dysphagia, and skin reactions were severe but tolerable. All patients retained functional speech, and all but four patients were swallowing food 3 months after treatment. Steady-state plasma concentrations for paclitaxel were not achieved during a 120-hour infusion, suggesting a nonlinear process. Tumor volume quantified by pretreatment computerized tomography imaging was associated with likelihood of response and survival. CONCLUSION: Paclitaxel administered as a 120-hour continuous infusion in combination with radiotherapy is a feasible and promising treatment for patients with advanced HNSCC.

The effect of the nonselective opioid antagonist diprenorphine on vasopressin secretion in the rat.

Although endogenous opioids are thought to be involved in the regulation of vasopressin secretion, their precise role is unclear. We studied the effect of the potent nonselective opioid antagonist diprenorphine on the vasopressin response to osmotic (hypertonic saline, ip), hypovolemic (polyethylene glycol, ip), and hypotensive (sodium nitroprusside, sc) stimuli in male rats. We found that diprenorphine sc produced a time- and dose-dependent inhibition of the plasma vasopressin response to the hypovolemic stimulus. This inhibition was greatest 30 min after injection of the drug, but lasted for at least 4 h, was evident at doses as low as 0.0022 mumol/kg, and reached a maximum of about 85% of the stimulated control at a dose of 2.2 mumol/kg. Diprenorphine also inhibited the vasopressin response to an osmotic or a hypotensive stimulus, but the effect was less complete (approximately 50%), required 100-fold higher doses of the drug, and appeared to be bimodal. The potent kappa 1-selective opioid agonist U-50,488H also suppressed the vasopressin response to these stimuli, but the effect was not selective for hypovolemia, and the doses required (0.135-13.5 mumol/kg) were about 10- to 100-fold higher than those of diprenorphine. We postulate, therefore, that diprenorphine potently and preferentially inhibits the vasopressin response to an acute hypovolemic stimulus by antagonizing the effect of some endogenous opioidergic system critical in the volume control system.

Influence of graphite furnace tube design on vapour temperatures and chemical interferences in ETA-AAS.

A two-line atomic absorption method for determination of lead was used for calculation of the temperatures experienced by analyte atoms in the gas phase after wall atomization with modified Philips SP-9 graphite tubes. For each tube, the influence of the temperature gradient on the vapour phase temperature and chemical interferences experienced by Cd, Mn and Pb in ETA-AAS was investigated. A higher vapour temperature and lower chemical interference by chlorides were observed when the tube temperature gradient was reversed through a reduction in the wall thickness towards the ends of the tube.

Cutaneous spider nevi in liver cirrhosis: capillary microscopical and hormonal investigations.

Nailfold capillary microscopical and hormonal investigations were carried out in 25 patients with cirrhosis of the liver and in 20 age- and sex-matched controls. Several structural and functional capillary microscopical parameters were significantly different between the group of cirrhotics as a whole and the controls; no capillaroscopic feature helped to distinguish cirrhotics with spiders from those without. Serum estradiol and total testosterone were comparable in cirrhotics and controls; free serum testosterone was reduced in male cirrhotics, particularly in cirrhotics with spider nevi. The estradiol/free testosterone ratio was highest in male cirrhotics with spiders. Cirrhosis, thus, leads to both structural and functional effects on the cutaneous capillary system whether or not spider nevi are present. The presence of spider nevi is accompanied by an increased serum estradiol/free testosterone ratio in male cirrhotics. It remains to be determined whether the hormonal alterations described do indeed play a role in spider nevi formation.

Evaluation and clinical application of the flying spot method in clinical nailfold capillary TV-microscopy.

A video flying spot device was developed for the measurement of red blood cell velocity for clinical skin capillarscopy. The method relies on the advancing of a light spot on the TV-screen utilizing horizontal and vertical synchronized video pulses. Practical evaluation showed satisfactory accuracy in comparison to the frame-to-frame technique as well as reproducibility in the velocity range from 0 to 1.1 mm/s (correlation coefficients = 0.94). The advantage of this device lies in its simplicity and low cost. The suitability for application in the clinical laboratory is demonstrated in normal subjects and patients with Raynaud's phenomenon during a local cooling test using both the flying spot and the frame-to-frame technique.