Optimal dose finding for novel antimalarial combination therapy.

A recent discussion meeting convened by the Medicines for Malaria Venture examined how best to manage the discovery and preclinical pipeline to achieve novel combination therapies which would address the key clinical needs in malaria. It became clear that dose optimisation of components within combination therapy was a key issue in achieving antimalarial efficacy and for preserving that efficacy against parasite resistance emergence. This paper outlines some of the specific issues in malaria that cause dose-ranging and dose-optimisation studies to be particularly challenging and discusses the potential of factorial study design to address such challenges.

Gastric impaction and obstruction of the small intestine associated with persimmon phytobezoar in a horse.

Signs of mild colic, intermittent lethargy, and weight loss of 6 weeks' duration in a 2-year-old Quarter Horse gelding were attributed to persimmon (Diospyros virginiana) phytobezoar formation. Diagnosis of the phytobezoar was facilitated by gastric endoscopy. Signs of gastrointestinal tract obstruction were associated with a large phytobezoar in the lumen of the stomach, gastric ulceration, and obstruction of the small intestine (as a consequence of fragmentation of the primary bezoar). Conservative treatment, using mineral oil and dioctyl sodium sulfosuccinate, was unsuccessful. A celiotomy was performed, and gastric impaction and partial obstruction of the small intestine associated with phytobezoar formation and fragmentation were identified. The horse made a complete recovery following removal of all phytobezoars. Persimmon phytobezoar should be considered in the fall and winter as a possible cause of lethargy, colic, and weight loss in horses allowed access to persimmon fruit.

Presumed moxidectin toxicosis in three foals.

Outcome and complications associated with administration of moxidectin gel to 3 foals < 4 months old are described. Two foals became comatose but survived following supportive treatment. One foal died following loss of consciousness associated with moxidectin administration. Risk of moxidectin overdose exists, because horse owners often fail to read or comprehend the package insert instructions pertaining to use of the syringe-locking mechanism. In addition, moxidectin should not be administered to foals < 4 months old, because it is likely that treated foals will become comatose.

Accessory bile duct and laparoscopic cholangiography: report of three cases.

Laparoscopic cholangiography can be useful in identifying an accessory bile duct. Failure to identify an accessory bile duct during laparoscopic cholangiography may lead to complications and prolonged hospitalizations. At times, the accessory duct can be clearly seen filling with contrast; at other times, the only clue to the possible presence of an accessory duct is opacification of the gallbladder. If the cystic duct has been clipped on the gallbladder side of the cholangiocatheter, the only way for the gallbladder to fill is through an accessory duct. If the actual accessory duct cannot be demonstrated and ligated, then drains should be placed in the gallbladder bed. The three cases presented here illustrate these points.

Diastolic mitral regurgitation in acute but not chronic aortic regurgitation: implications regarding the mechanism of mitral closure.

In acute aortic regurgitation, left ventricular pressure rises rapidly during diastole, which produces presystolic mitral valve closure. This does not occur in chronic aortic regurgitation. Since normal, nonregurgitant mitral valve closure may depend on properly coordinated atrial and ventricular contractions, we hypothesized that abnormal mitral valve closure occurring before systole in acute aortic regurgitation may produce diastolic mitral regurgitation detectable by Doppler echocardiography. Accordingly, we performed ultrasonic Doppler examination of seven patients with acute aortic regurgitation and 12 patients with chronic aortic regurgitation. Regurgitant aortic flow was severe in all cases. Doppler sampling within the left atrium demonstrated regurgitant mitral flow in late diastole in all patients with acute aortic regurgitation. The onset of diastolic mitral regurgitation coincided with mitral valve preclosure in patients with acute aortic regurgitation and occurred regardless of the position of the mitral leaflets at the initiation of closure. In contrast, none of the 12 patients with chronic aortic regurgitation had mitral valve preclosure or diastolic mitral regurgitation (p less than 0.05 versus acute aortic regurgitation). We conclude that diastolic mitral regurgitation accompanies mitral valve preclosure, which occurs in acute but not chronic aortic regurgitation. Thus diastolic mitral regurgitation may be a Doppler sign of acute aortic regurgitation, in the absence of a markedly prolonged PR interval. Furthermore, this observation suggests that normal, nonregurgitant mitral closure requires more than an increase in left ventricular pressure above left atrial pressure, regardless of the position of the mitral leaflets before closure.