Population PK and PK/PD modelling of microencapsulated octreotide acetate in healthy subjects.
(33/893)
AIMS: To develop a population model that can describe the pharmacokinetic profile of microencapsulated octreotide acetate in healthy cholecystectomized subjects. To investigate the correlation between serum IGF-1 and octreotide concentration. METHODS: A population pharmacokinetic analysis was performed on octreotide data obtained following a single dose of 30 mg microencapsulated octreotide acetate intramuscularly. The relationship between serum IGF-1 concentration and octreotide concentration was effectively described by a population pharmacokinetic/pharmacodynamic model. RESULTS: The pharmacokinetic profile of octreotide was characterized by an initial peak of octreotide followed by a sustained-release of drug. Plateau concentration were sustained up to day 70, and gradually declined to below the detection limit by day 112. A one-compartment linear model was constructed which consisted of two absorption processes, characterized by KIR and KSR, rate constants for immediate-release and sustained-release, respectively, with first-order elimination (Ke; 1.05 h-1). The surface, unencapsulated drug was immediately absorbed into the central compartment with first-order absorption (KIR; 0.0312 h-1), while the microencapsulated drug was first released in a zero-order fashion into a depot before being absorbed into the central compartment with first-order absorption (KSR; 0.00469 h-1) during a period of tau (1680 h). Body weight and gender were important covariates for the apparent volume of distribution. The type of formulation was an important covariate for KIR but had no effect on KSR. An inhibitory Emax population pharmacokinetic/pharmacodynamic model could adequately describe the relationship between IGF-1 (expressed as percent baseline) and octreotide concentration. Baseline IGF-1 concentration was found to be a significant covariate for the baseline effect (E0). A relationship between GH concentration and octreotide concentration was not established. CONCLUSIONS: The pharmacokinetic profile of microencapsulated octreotide acetate was effectively described by the derived population model. The relationship between IGF-1 and drug concentration could be used to guide optimization of therapeutic octreotide dosage regimens. (+info)
Increased sphincter of Oddi basal pressure in patients affected by gall stone disease: a role for biliary stasis and colicky pain?
(34/893)
BACKGROUND AND AIMS: Even if the motor activity of the gall bladder and sphincter of Oddi (SO) are integrated, it is not known if the presence of stones in the gall bladder affects SO function. The aim of the study was to compare SO motor activity in patients with and without gall stones. PATIENTS AND METHODS: In a series of 155 patients consecutively submitted to endoscopic retrograde cholangiopancreatography and SO manometry for suspected biliary or pancreatic disease, 23 gall stone patients had recurrent episodes of biliary or pancreatic pain (colicky group); 52 patients had non-biliary/pancreatic-type abdominal pain/discomfort, and of these, 15 had gall stones (non-colicky group), 25 were free of stones (controls), and 12 had undergone cholecystectomy. RESULTS: SO basal pressure in gall stone patients in the colicky or non-colicky group was significantly higher than in controls (p<0.001). SO basal pressure recorded in postcholecystectomy patients did not differ from controls. SO phasic activity did not differ between the patient groups. SO dysfunction was detected in more than 40% of gall stone patients irrespective of associated biliary/pancreatic pain but in none of the control subjects (p<0.001). CONCLUSIONS: Gall stones are frequently associated with increased SO tone which may obstruct bile flow thus acting to facilitate gall bladder stasis, and may play a role as a cofactor in biliary/pancreatic pain. (+info)
Total parenteral nutrition after surgery rapidly increases serum leptin levels.
(35/893)
OBJECTIVE: In humans, leptin is regulated by long-term changes in energy intake. However, short-term regulation of serum leptin by nutrients has been difficult to show. The aim of this study was to investigate whether short periods of fasting and stress sensitise the leptin response to nutrients. SUBJECTS AND EXPERIMENTAL PROTOCOL: Fourteen patients of normal weight undergoing elective open cholecystectomy were randomised into two groups. One group received saline infusion during surgery and for 24 h postoperatively. The other group also received saline during the surgical procedure, but total parenteral nutrition (TPN) was started immediately after surgery. Blood samples were drawn before as well as 2, 4, 8, 16, and 24 h after the start of surgery to determine the serum levels of leptin and other hormones. RESULTS: Postoperative TPN induced a significant rise in serum leptin within 6 h, reaching a more than fourfold increase within 14 h (P<0.001). Serum glucose and insulin levels increased within 2 h. Growth hormone and IGF-1 serum levels also increased significantly in the group receiving TPN. Serum cortisol levels increased postoperatively in both groups, which may explain why no significant reduction in serum leptin was observed in the group receiving saline. Free tri-iodothyronine (T3) decreased in both groups, while catecholamines were similar in the groups. CONCLUSION: During fasting and surgical stress, nutrients rapidly increased the serum leptin levels in humans in a manner similar to that previously reported in rodents. This may be mediated by increases in serum glucose, insulin and cortisol. (+info)
Hepaticogastrostomy: ulcerogenic preparation or therapeutic alternative.
(36/893)
Recent laboratory and clinical studies have implicated bile salts in the patogenesis of gastric ulceration. Common hepatic duct to stomach anastomosis results in total diversion of bile to the stomach and has been utilized at the Lahey Clinic occasionally for bypass of the obstructed common bile duct in difficult technical situations where conventional procedures were deemed prohibitively difficult. Of seven patients undergoing hepaticogastrostomy, two had upper gastrointestinal bleeding in followup. One of these patients had documented esophageal varices and stopped bleeding after splenorenal shunt. The other had massive sepsis which predisposed him to gastric ulceration. From this small series it is clear that the entire biliary output of the liver can be shunted into the stomach without greatly increased risk of clinically significant gastric ulceration. Hepaticogastrostomy provided relief from jaundice in all but one of the seven patients in the series and remains an occasionally useful procedure. These data indicate that diversion of the entire flow of bile from the liver into stomach does not cause gastric ulcers. (+info)
Rare side-effects of fenofibrate.
(37/893)
Fibrates are widely prescribed as hypolipidemic drugs and are considered as safe. We report the case of a 69 year-old woman who probably developed a major allergic reaction following a Fenofibrate prescription (generic form) of 300 mg per day. Clinical features included asthenia, hyperthermia (40.5 degrees C) and slight muscular pain. Biological abnormalities were mildly elevated muscular enzymes and pancytopenia rapidly developed. All bacteriologic, virologic, immune and radiologic investigations were normal. Evolution was spontaneously favorable with Fenofibrate withdrawal. This is the first reported case of major fever and pancytopenia following a Fenofibrate prescription. Adverse effects of Fenofibrate are briefly reviewed and their usual favorable outcomes following drug removal are outlined. (+info)
The effect of dextran on the lysability of ex vivo thrombi.
(38/893)
The lysability was determined of thrombi formed in Chandler tubes before and after infusion of 500 ml dextran 70 to patients undergoing cholecystectomy. 125I-labelled fibrinogen was given the day before operation. Following incubation of the thrombi formed in plasmin, radioactivity remaining in the thrombi and released to the supernatant was determined, as well as fibrinolytic degradation products in the supernatant, using an immunoelectrophoretic method. The dextran infusion was found to increase the radioactivity released from the thrombi to the supernatant from 15.5 plus or minus 7.6% to a maximum of 27.3 plus or minus 8.2% four hours after the infusion (P less than 0.001). A corresponding significant rise of the FDP concentration in the supernatant from 16.8 mug/ml to 44.1 mug/ml was found at the same time. After 24 hours the radioactivity had returned to initial values. The results indicate that dextran infused into patients during surgery increases the lysability of thrombi. It is suggested that this finding at least partly explains the antithrombotic effect of dextran. (+info)
The effect of bile acid synthesis on cholesterol secretion into the bile.
(39/893)
Cholesterol secretion into the bile has been shown to be related to the bile acid secretion rate. It has been suggested that the availability of bile acid micelles controls the entry of cholesterol into the bile. However, previous data could have been interpreted to indicate that bile acid synthesis controls cholesterol secretion into the bile. To discover whether bile acid synthesis has a significant influence on cholesterol secretion, Rhesus monkeys were studied during the period of increasing bile acid secretion and bile acid synthesis, which begins 6-10 hours following interruption of the enterohepatic circulation of bile acids. This is the only condition in which bile acid synthesis and bile acid secretion increase simultaneously. The cholesterol secretion rate fell signficantly during this period, and this effect was enhanced by phenobarbital administration. An increasing cholesterol secretion rate would have been expected if micellar attraction controlled cholesterol secretion under these conditions. Bile acid synthesis appears to have an important influence upon cholesterol secretion into the bile. (+info)
Statistical assessment of the learning curves of health technologies.
(40/893)
OBJECTIVES: (1) To describe systematically studies that directly assessed the learning curve effect of health technologies. (2) Systematically to identify 'novel' statistical techniques applied to learning curve data in other fields, such as psychology and manufacturing. (3) To test these statistical techniques in data sets from studies of varying designs to assess health technologies in which learning curve effects are known to exist. METHODS - STUDY SELECTION (HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW): For a study to be included, it had to include a formal analysis of the learning curve of a health technology using a graphical, tabular or statistical technique. METHODS - STUDY SELECTION (NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH): For a study to be included, it had to include a formal assessment of a learning curve using a statistical technique that had not been identified in the previous search. METHODS - DATA SOURCES: Six clinical and 16 non-clinical biomedical databases were searched. A limited amount of handsearching and scanning of reference lists was also undertaken. METHODS - DATA EXTRACTION (HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW): A number of study characteristics were abstracted from the papers such as study design, study size, number of operators and the statistical method used. METHODS - DATA EXTRACTION (NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH): The new statistical techniques identified were categorised into four subgroups of increasing complexity: exploratory data analysis; simple series data analysis; complex data structure analysis, generic techniques. METHODS - TESTING OF STATISTICAL METHODS: Some of the statistical methods identified in the systematic searches for single (simple) operator series data and for multiple (complex) operator series data were illustrated and explored using three data sets. The first was a case series of 190 consecutive laparoscopic fundoplication procedures performed by a single surgeon; the second was a case series of consecutive laparoscopic cholecystectomy procedures performed by ten surgeons; the third was randomised trial data derived from the laparoscopic procedure arm of a multicentre trial of groin hernia repair, supplemented by data from non-randomised operations performed during the trial. RESULTS - HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW: Of 4571 abstracts identified, 272 (6%) were later included in the study after review of the full paper. Some 51% of studies assessed a surgical minimal access technique and 95% were case series. The statistical method used most often (60%) was splitting the data into consecutive parts (such as halves or thirds), with only 14% attempting a more formal statistical analysis. The reporting of the studies was poor, with 31% giving no details of data collection methods. RESULTS - NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH: Of 9431 abstracts assessed, 115 (1%) were deemed appropriate for further investigation and, of these, 18 were included in the study. All of the methods for complex data sets were identified in the non-clinical literature. These were discriminant analysis, two-stage estimation of learning rates, generalised estimating equations, multilevel models, latent curve models, time series models and stochastic parameter models. In addition, eight new shapes of learning curves were identified. RESULTS - TESTING OF STATISTICAL METHODS: No one particular shape of learning curve performed significantly better than another. The performance of 'operation time' as a proxy for learning differed between the three procedures. Multilevel modelling using the laparoscopic cholecystectomy data demonstrated and measured surgeon-specific and confounding effects. The inclusion of non-randomised cases, despite the possible limitations of the method, enhanced the interpretation of learning effects. CONCLUSIONS - HEALTH TECHNOLOGY ASSESSMENT LITERATURE REVIEW: The statistical methods used for assessing learning effects in health technology assessment have been crude and the reporting of studies poor. CONCLUSIONS - NON-HEALTH TECHNOLOGY ASSESSMENT LITERATURE SEARCH: A number of statistical methods for assessing learning effects were identified that had not hitherto been used in health technology assessment. There was a hierarchy of methods for the identification and measurement of learning, and the more sophisticated methods for both have had little if any use in health technology assessment. This demonstrated the value of considering fields outside clinical research when addressing methodological issues in health technology assessment. CONCLUSIONS - TESTING OF STATISTICAL METHODS: It has been demonstrated that the portfolio of techniques identified can enhance investigations of learning curve effects. (ABSTRACT TRUNCATED) (+info)