[The role of orlistat in the treatment of obesity]. / Az orlistat szerepe az elhízás kezelésében.

The overweight and obesity represent severe problems for the health management system of developed countries. In the evolution of obesity, beside genetic background, the environmental factors also play important roles. In the daily routine, the majority of obese patients need drug treatment, over the diet and physical activity. Among the available medicines the inhibitors of monoamine re-uptake causes dry mouth, tachycardia, sleeplessness and elevated blood pressure, therefore, due to the frequently associated obesity and hypertension many physicians avoid using these compounds. The orlistat as a selective inhibitor of pancreatic and enteral lipase enzymes impedes the absorption of the highest calorie containing nutrients, the fats exerting beneficial effects in the treatment of obesity. The abdominal bloating and diarrhea as side effects of the drug may act as an advantage in many cases, since these happen especially in those cases when the patient neglects the previously suggested low fat diet and therefore the drug induced diarrhea and bloating may mean a feed-back for the patient in respect of the proper diet. Recent studies show many beneficial biochemical changes in obesity related pathological metabolic processes during the administration of orlistat. The authors, in their present work review in short the role of orlistat in the treatment of slimming cure.

High-performance liquid chromatography/electrospray ionization tandem mass spectrometry for characterization of enzymatic degradation of 2,2'-bis(2-oxazoline)-linked poly-epsilon-caprolactone.

This paper describes a straightforward and rapid on-line characterization using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ESI-MS(n)) of the enzymatic degradation products of 2,2'-bis(2-oxazoline)-linked poly-epsilon-caprolactone (PCL-O). These new PCL-O polymers are expected to be used in a variety of pharmaceutical and biomedical applications since they are degraded enzymatically by surface erosion. PCL-O was polymerized in a three-step reaction and characterized by (1)H-NMR and size-exclusion chromatography (SEC). Solvent cast polymer films were exposed to enzymatic degradation in phosphate buffer (pH 7.5, 1% pancreatin). The enzymatic degradation of the polymer produced a wide variety of water-soluble oligomers which were separated and identified by HPLC/ESI-MS(n). Optimization of the gradient HPLC method resulted in effective separation of the oligomers. Furthermore, specific structures of the oligomers were clearly identified by tandem mass spectrometry. According to these results, ester bonds seem to be most sensitive to enzymatic degradation and, correspondingly, pancreatic lipase seems to be mainly responsible for the enzymatic erosion of the PCL-O films. This novel mass spectrometric method provides important knowledge about the enzymatic degradation process and structure of the polymer which is difficult to ascertain by other conventional methods.

Immobilization of pancreatic lipase on polyvinyl alcohol by cyanuric chloride.

Porcine pancreatic lipase (EC 3.1.1.3) was covalently immobilized onto 2,4,6-trichloro-s-triazine (cyanuric chloride) activated polyvinyl alcohol (PVA). The influence of activating agent and enzyme concentration on the immobilization process were evaluated. Hydrolytic activities of free and immobilized enzyme were determined and the immobilization yield was estimated by measuring the quantity of protein, both in free enzyme solution and in washing solutions after immobilization. After the optimization of immobilization process, the physical and chemical characterization of immobilized enzyme was performed. Additionally, the thermal, pH, storage, and operational stability of the immobilized and free enzymes were tested. Obtained data showed that the immobilized enzyme seemed better and offered some advantages in comparison with free enzyme.

5-Hydroxy-7-(4'-hydroxy-3'-methoxyphenyl)-1-phenyl-3-heptanone: a pancreatic lipase inhibitor isolated from Alpinia officinarum.

A pancreatic lipase inhibitor, 5-hydroxy-7-(4'-hydroxy-3'-methoxyphenyl)-1-phenyl-3-heptanone (HPH), from the rhizome of Alpinia officinarum (AO) was isolated and its antihyperlipidemic activity was measured. HPH inhibited a pancreatic lipase with an IC(50) value of 1.5 mg/ml (triolein as a substrate). HPH significantly lowered the serum TG level in corn oil feeding-induced triglyceridemic mice, and reduced serum triglyceride (TG) and cholesterol in Triton WR-1339-induced hyperlipidemic mice. However, HPH did not show hypolipidemic activity in high cholesterol diet-induced hyperlipidemic mice. Based on these findings, we propose that PL inhibitors may be effective as hypolipidemic agents.

Pancreatic toxicity after liposomal amphotericin B.

Though liposomal amphotericin B has been available in Germany since 1992, efficacy and safety of this formulation of amphotericin B are still not well-documented in children. As far as gastrointestinal side-effects are concerned, an elevated alkaline phosphatase and elevated transaminases have been reported. In our department, liposomal amphotericin B had been used since 1994 to treat patients with proven or suspected fungal infections in a daily dose of 1-3 mg kg-1. Additionally, patients with high-dose chemotherapy and autologous stem cell support received liposomal amphotericin B prophylactically in a dose of 1 mg kg(-1) three times per week. We performed a retrospective analysis of all 31 patients who had received liposomal amphotericin B by 1999. In five patients, an isolated transient elevation of the serum lipase level during, or shortly after, the therapy with liposomal amphotericin B was detected. Three of these patients showed clinical signs of pancreatitis, with one patient displaying slightly elevated transaminases. So far, elevated levels of serum lipase have not been described as a possible side-effect of a liposomal amphotericin B therapy. The pathogenesis of this elevation is unclear. As possible reasons, an enzyme induction due to fat overload or a toxic damage of the pancreatic tissue by the liposomes or amphotericin B itself are discussed.

Pancreatic enzyme replacement therapy in post-pancreatectomy patients.

The occurrence of malnutrition and maldigestion was studied in nine patients who underwent pancreatoduodenectomy and sclerosis of the residual pancreatic stump with neoprene. The operation causes a complete loss of exocrine pancreatic function, but spares islet cell function. Upon discharge from the hospital, patients received pancreatin powder as a dietary enzyme supplement (18,000 lipase U/meal). Patients were again hospitalized 2 y after surgery for evaluation of nutritional status and digestive function (hospital checkup). Nutritional status was evaluated by measuring serum albumin, total iron binding capacity, and total lymphocytes. Digestive function was assessed by the D-xylose tolerance test and determination of fecal fat excretion. Patients were then discharged with pancrelipase enteric-coated microspheres (ECM) as a dietary enzyme supplement (16,050 lipase U/meal). Malnutrition, defined as the occurrence of at least two abnormal nutritional parameters, was observed in three patients at the time of the hospital checkup. Upon reevaluation of nutritional status after 6 mo on pancrelipase ECM, all patients were well nourished. The mean body weight, which had been 52.8 Kg immediately after surgery, increased to 54.9 Kg at the time of the hospital checkup (p less than 0.01) and to 58.0 Kg after six months of pancrelipase ECM therapy (p less than 0.05). At the hospital checkup, the D-xylose test was normal in all patients and steatorrhea had decreased from a mean of 32.8 g/d without enzyme supplementation to 16.7 g/d with pancrelipase therapy (16,050 lipase U/meal). The complete loss of exocrine pancreatic function following surgery was well tolerated. In fact, when patients were on pancrelipase therapy, much of the original body weight was recovered and the biochemical indices of malnutrition were normalized.

Use of pancreatic Schilling test to determine efficiency of pancreatic enzyme delivery in pancreatic insufficiency.

The pancreatic Schilling test (PST), a noninvasive, sensitive pancreatic function test, was studied to determine its ability to detect pancreatic proteolytic enzyme replacement in patients with pancreatic insufficiency. Seven subjects with well-documented pancreatic insufficiency and an abnormal PST consistent with pancreatic insufficiency were studied with three enzyme regimens: (1) Viokase (four tablets), (2) Pancrease (three capsules), and (3) Pancrease (10 capsules). The effect of cimetidine on the results of the PST with high-dose Pancrease was also determined in two subjects with pancreatic insufficiency and in two normal volunteers. The results of the investigation demonstrate that the PST is a sensitive noninvasive test for the presence of orally administered proteolytic enzymes in subjects with pancreatic insufficiency and in normals. Furthermore, the studies illustrate that the administration of enzymes in a form of enteric-coated microspheres does not enhance the delivery of proteolytic enzymes to the small intestine when compared to conventional high-dose enzyme replacement. Cimetidine appears to decrease the inactivation of the proteolytic enzymes in enteric-coated microspheres, suggesting that a low pH in the small intestine and stomach are responsible for the poor delivery of the enzymes into the small intestine.

Correction of malnutrition and maldigestion with enzyme supplementation in patients with surgical suppression of exocrine pancreatic function.

We studied the occurrence and extent of malnutrition and maldigestion in 13 patients who underwent pancreatoduodenectomy (PD) and injection of Neoprene (polychloroprene) (NI) into the duct of Wirsung, which results in sclerosis of hte acinar pancreatic tissue, but spares the endocrine function. At discharge, patients under took an enzyme supplementation regimen with pancreatin (18, 00 United States Pharmacopoeia units of lipase per meal). Patients were rehospitalized 24.9 months after PD plus NI to undergo nutritional and metabolic evaluation (hospital control). Nutritional status was evaluated by measuring the serum albumin level, total iron binding capacity and total lymphocyte count. Digestive function was assessed by the D-xylose tolerance test and determination of fecal fat excretion. Patients were then discharged with pancrelipase, enteric-coated microspheres (ECM) supplementation (16,050 United States Pharmacopoeia units of lipase per meal). Malnutrition, defined as the occurrence of at least two abnormal nutritional parameters, was observed in six patients at hospital control. After six months on pancrelipase ECM, the nutritional status was re-evaluated in nine patients (three previously malnourished) who were all well nourished. The mean body weight was 84.7 per cent of usual body weight at discharge after PD plus NI and raised to 88.0 per cent at the hospital control (p less than 0.01) and to 93.7 per cent )p less than 0.05) after six months on pancrelipase ECM. At hospital control, results from the D-xylose test were normal in all patients, and steatorrhea dropped from 33.6 grams per day without enzyme supplementation to 15.3 grams per day with pancrelipase ECM (16,050 United States Pharmacopoeia units of lipase per meal). Steatorrhea was incompletely but satisfactorily corrected by pancrelipase ECM. On supplementation therapy with pancrelipase ECM, patients recover a good deal of the body weight and normalize the biochemical indices of malnutrition.

Malabsorption in cystic fibrosis: mechanisms and treatment.

Malabsorption of nutrients in cystic fibrosis (CF) has a multifactorial origin. The factors involved in malabsorption include malfunction of the exocrine pancreas and liver, bile acid metabolism, and disordered intestinal resorptive processes. Therapeutic measures presently employed are only partially effective. Improvement of fat malabsorption is attained by using a pancreatic enzyme supplement consisting of pH-sensitive, enteric-coated microspheres (microsphere preparations) that prevent enzyme degradation in the stomach and travel with the chyme to the small intestine. Microsphere preparations, however, do not improve bile salt deficiency. The detergent Tween-80, given orally to simulate bile salt activity, does not improve fat absorption. The mucus viscosity is probably enhanced in the intestinal epithelium of CF patients and can be decreased by N-acetylcysteine, which breaks down sulfide bonds. However, the addition of a high oral dose of this mucus solvent to pancreatin preparations does not improve fat absorption. Further studies on the disturbed intestinal resorptive mechanism seem warranted since recent investigations point to an abnormal chloride secretion as the primary defect in the intestinal epithelia of CF patients.