Caspofungin as second-line therapy for fever of unknown origin or invasive fungal infection following allogeneic stem cell transplantation.

Caspofungin (CAS) is the first of a new class of antifungal agents, the echinocandins, that interfere with fungal cell wall synthesis by inhibition of glucan synthesis. Here, we report the results of 31 patients treated with CAS following allogeneic SCT. CAS was administered as a second-line agent to patients with invasive fungal infection (IFI) (n=15) or fever of unknown origin (n=16) who were recalcitrant to or intolerant of prior antifungal therapy. Unsuccessful first-line regimes included amphotericin B (n=17), liposomal amphotericin B (n=5), fluconazole (n=3), itraconazole (n=1), and voriconazole (n=2). All patients received concomitant immunosuppressive therapy for graft-versus-host disease. In 23 patients, cyclosporin A (CSA) and CAS were administered concurrently without any major side effects detected. Observed increases in GPT were not clinically significant. Normalization of serum creatinine and significant reductions in C-reactive protein were observed in response to CAS. Favorable outcome to CAS were documented in eight of 15 patients with IFI and in 15 of 16 patients with fever of unknown origin. CAS is a promising alternative in patients with IFI and fever of unknown origin in the setting of allogeneic SCT.

Successful treatment of patients with respiratory failure due to fungal infection after allogeneic hematopoietic stem cell transplantation.

The mortality rate associated with respiratory failure due to invasive fungal infections after allogeneic hematopoietic stem cell transplantation (HSCT) is exceedingly high. We present a retrospective analysis of 4 HSCT recipients who survived long-term artificial respiration subsequent to pulmonary mycosis, and compare our current findings with historic data. Several clinical parameters indicate a remarkable improvement in the clinical courses of those patients in recent years: weaning time, extubation rate, and improvement of additional organ failures were all significantly better in patients treated after the emergence of new antimycotic agents, resulting in prolonged overall survival. We propose that our observations reflect an improved management of these patients, mainly because of the use of new antimycotics with alternative mechanisms of action and decreased toxicity, allowing for earlier, more aggressive, and more effective antifungal treatment approaches. In addition, the optimized use of new technologies designed to augment spontaneous breathing efforts by patients, mechanical ventilation, as well as the advantages of early tracheotomy will contribute to better outcomes in the treatment of respiratory failure due to pulmonary mycoses following allogeneic HSCT.

Chemical specificities and intestinal distributions of nutrient-driven satiety.

We measured intakes of sham- and naturally feeding rats during gut perfusions of nutrients. Our objectives were to determine 1) which nutrient products in gut lumen suppressed intakes; 2) how suppression by various nutrients is distributed along gut; and 3) whether time courses of suppression were similar among different nutrients. We found that satiating nutrients consisted of fatty acids only longer than 10 carbons, of monomeric carbohydrates only with affinity for the glucose transporter, and, among several amino acids, of only phenylalanine and tryptophan. Dimeric maltose had about the same potency as an isocaloric mixture of longer glucose polymers; since responses to either were blocked by a glucosidase inhibitor, each probably acted after hydrolysis to free glucose. Effective nutrients suppressed intakes about equally on infusion into duodenum vs. midgut, and the same nutrients also suppressed intakes when infused into colon. Food intakes were suppressed only while maltose was infused, not after it was stopped, but suppression persisted for 2 h after stopping perfusions with fatty or amino acids.

Role of small intestine in caloric compensations to oil premeals in rats.

We postulated that dose-responsive satiety after oil premeals varies with the number of gut sensors stimulated by lipolytic products along intestine. These experiments in fasted rats on satiety after oil premeals were performed to 1) determine whether satiety was induced by lipolytic products but not triglycerides; 2) confirm that oil empties from the stomach at rates that vary with oil loads; 3) ascertain that increasing rates of oil entry into duodenum extend the length of gut contacted by lipolytic products; and 4) judge whether length of gut contacted correlated with dose-responsive satieties to dietary oils. 5) Using specific antagonists, we attempted to define how satiety was signalled by gut sensors. Timing and degrees of satiety did not correlate with timing and extent of gastric distensions but, rather, with the timing and extent of spread of lipolytic products along small bowel. Satiety after the highest premeal load of oil was blocked by Pluronic L-81, an inhibitor of intestinal secretion of apolipoprotein A-IV, but was unaffected by MK-329 (a specific antagonist of cholecystokinin) or by capsaicin blockade of chemosensory nerves.

Length of intestinal contact on nutrient-driven satiety.

Chemosensors throughout small bowel and colon inhibit food intakes when contacted by monomeric nutrients. We postulated that calorie-dependent inhibition of food intakes depended on additions of feedbacks from sensors in proximal and distal bowel contacted after high intakes of nutrients. Therefore, we determined how feedback from sensors in proximal gut interacted with feedback from simultaneously contacted sensors in distal bowel and whether suppression of nutrient intakes by intestinally perfused nutrients depended on length of gut contacted. Suppression of food intakes by maltose simply added to that from dodecanoate when both were present together either in proximal or distal small bowel. When dodecanoate was infused into proximal gut while maltose was infused distally, suppression of intake was threefold higher and was thus potentiated. Limiting contact of slowly absorbed lactose or oleate to 35 cm of jejunum nearly abolished the satiating potencies each exhibited during access to whole gut. The observations were consistent with our hypothesis.

Gastric emptying of oil from solid and liquid meals. Effect of human pancreatic insufficiency.

Digestion of fat in pancreatic insufficiency (PI) is strongly affected by how rapidly fat enters the duodenum. We postulated that: (1) oil empties faster in PI than in normals and (2) in both, it empties in a load-dependent fashion. We used a gamma camera to test these ideas by comparing gastric emptying of iodine-123 iodinated oil in normal and pancreatic-insufficient subjects after 15 g of free oil were ingested in a small spaghetti meal and 60 g of oil were ingested in a large spaghetti meal and in a milk emulsion. Indium-113m marked gastric emptying of water in the milk. In both groups after all meals, oil emptied fastest initially, slowing later; and oil emptied three to four times faster when 60 g vs 15 g were ingested. There were no significant differences between the groups of subjects with respect to gastric emptying of the spaghetti meals, but the pancreatic-insufficient subjects emptied both oil and water faster from the milk emulsion than did the normal subjects. The slower emptying of oil in the normal subjects was associated with significantly more layering of oil to the top of the intragastric milk emulsion.

Preduodenal mechanisms compensate completely for absent pancreatic enzymes to stimulate gallbladder after meals.

We studied gallbladder emptying with gamma scintigraphy in nine dogs prepared with chronic pancreatic fistulas, so that pancreatic enzymes could be either completely excluded from the duodenum or supplied in normal amounts. During duodenal perfusion of the fasted dogs with fat emulsions, gallbladder emptying was significantly less rapid when the emulsion contained inactive vs active enzymes, confirming the potency of lipolytic products in the intestine as stimuli of gallbladder emptying. However, after feeding either a 115-g or a 460-g meal, each 18% fat, the gallbladders emptied identically whether or not pancreatic enzymes were excluded from the duodenum. We concluded that while products of pancreatic lipolysis in the small intestine are potent stimuli of gallbladder contraction, preduodenal mechanisms can compensate completely for the absence of pancreatic hydrolysis in stimulating gallbladder emptying after a meal.

Control of canine gastric emptying of fat by lipolytic products.

Dietary fat is ingested in three forms: 1) in solid food, 2) as aqueous emulsions, and 3) as unemulsified, liquid oil. On the basis of a scant previous literature, we postulated that liquid fat (emulsions or oils) would empty from the stomach at speeds that varied with the amounts ingested but that this dynamic would be modulated by feedback inhibition from lipolytic products. To test these ideas, we used a gamma camera to track gastric emptying of 123I-labeled fat in dogs with chronic pancreatic fistulas by which lipase was excluded from or replenished in the duodenum in varied amounts after dogs were fed 15-, 30-, and 60-g loads of liquid fat given with solid foods or as emulsions. We also tracked concurrent gastric emptying of 113mIn, which marked the solid food phase or the water phase of emulsions. In some studies, we used a potent and specific inhibitor (orlistat) of pancreatic and gastric lipases to assess how lipolytic products modulated emptying of liquid fat. In the absence of pancreatic enzymes, both oils and emulsions emptied initially at high speeds that varied with fat loads, but emptying slowed 20 min after ingestion of emulsions and 60 min after ingestion of unemulsified oil. Studies with orlistat indicated that these changes in rates resulted from liberation of gastric lipolytic products. Emptying of oil emulsions was not altered by duodenal replenishment with pancreatic enzymes, but emptying of unemulsified oil was inhibited in a dose-related fashion, such that maximal inhibition was achieved when pancreatic enzymes were replenished at > or = 40% of normal amounts. Studies with orlistat confirmed that this dose-dependent slowing was due specifically to lipase. Emptying of solid food was much more sensitive to replenishment with enzymes, so that a 10% replenishment maximally inhibited solid emptying.