Post-operative seizure after first time endoscopic third ventriculostomy in pediatric patients.

PURPOSE: Post-operative seizure rates after endoscopic third ventriculostomy (ETV) are not definitively known. We analyzed our institution's experience for all causes of hydrocephalus in pediatric patients undergoing ETV to determine rates of post-ETV seizure. METHODS: A retrospective review of institutional pediatric patients undergoing ETV from May 2014 to December 2018. Included were < 21 years, with 1-year follow-up. Exclusion criteria included ventriculoperitoneal shunts (VPS) prior to ETV, VPS within 7 days post-ETV, and prior seizure disorder. Data included age, gender, diagnosis, early post-operative seizure (within 7 days post-ETV), late post-operative seizures (after first 7 days and within first year post-ETV), concomitant choroid plexus cauterization (CPC), VPS conversion within 1 year, and administration of prophylactic antiepileptics. RESULTS: Sixty of 81 ETV cases were included; 41% underwent concomitant CPC. Of these, 53% (n = 32) were male, 46% (n = 28) female, averaging 5.8 years, with the most common diagnosis neoplasm-related obstructive hydrocephalus (38.3%, n = 23). Early post-operative seizure occurred in 6.7% (n = 4); late post-operative seizure occurred in 8.3% (n = 5). Late post-operative seizures were higher in patients experiencing early post-operative seizure versus those without (75% vs 3.7%, p = 0.003). Late post-operative seizure occurred in 13.6% (n = 3 patients) requiring VPS versus 5.3% (n = 2 patients) with successful ETV (p = 0.36). Rates did not correlate with pathology. No patients received prophylactic antiepileptics prior to surgery or exhibiting a seizure. CONCLUSIONS: Patients with early post-operative seizures have an increased likelihood of developing late post-operative seizures. Pediatric ETV patients may have a lower rate of both early and late post-operative seizure; underlying pathology may influence these rates.

Demonstration of Single-Barium-Ion Sensitivity for Neutrinoless Double-Beta Decay Using Single-Molecule Fluorescence Imaging.

A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (∼2 nm), and detected with a statistical significance of 12.9σ over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers.

Preliminary safety and biological efficacy studies of ethyl pyruvate in normal mature horses.

REASONS FOR PERFORMING THE STUDY: Endotoxaemia causes substantial morbidity and mortality in horses with colic and sepsis. Ethyl pyruvate is a novel anti-inflammatory medication that improved survival in preclinical models of severe sepsis endotoxaemia and intestinal ischaemia and reperfusion in rodents, swine, sheep and dogs and may be a useful medication in horses. HYPOTHESIS: Ethyl pyruvate has no adverse effects in normal horses and is biologically active based on suppression of proinflammatory gene expression in endotoxin stimulated whole blood, in vitro. METHODS: Physical and neurological examinations, behaviour scores, electrocardiograms and clinicopathological tests were performed on 5 normal healthy horses receiving 4 different doses of ethyl pyruvate. Doses included 0, 50, 100 and 150 mg/kg bwt administered in a randomised crossover design with a 2 week washout period between doses. Biological efficacy was assessed by stimulating whole blood with endotoxin from the horses that received ethyl pyruvate prior to and 1 and 6 h after drug infusion. Gene expression for TNFα, IL-1ß and IL-6 was assessed. RESULTS: There were no effects of drug or dose (0, 50, 100 or 150 mg/kg bwt) on any of the physical or neurological examination, behaviour factors, electrocardiogram or clinical pathological results collected from any of the horses. All parameters measured remained within the normal reference range. There was a significant reduction in TNFα, IL-1ß and IL-6 gene expression in endotoxin stimulated whole blood from horses 6 h after receiving 150 mg/kg bwt ethyl pyruvate. There were no detectable effects on gene expression of any of the other doses of ethyl pyruvate tested. CONCLUSION: We were unable to detect any detrimental effects of ethyl pyruvate administration in normal horses. Ethyl pyruvate significantly decreased proinflammatory gene expression in endotoxin stimulated blood 6 h after drug administration. CLINICAL RELEVANCE: Ethyl pyruvate may be a safe, effective medication in endotoxaemic horses.

Intermittent and continuous enteral nutrition in critically ill dogs: a prospective randomized trial.

BACKGROUND: Malnutrition is a common problem in critically ill dogs and is associated with increased morbidity and mortality in human medicine. Enteral nutrition (EN) delivery methods have been evaluated in humans to determine which is most effective in achieving caloric goals. OBJECTIVES: To compare continuous infusion and intermittent bolus feeding of EN in dogs admitted to a critical care unit. ANIMALS: Fifty-four dogs admitted to the critical care unit and requiring nutritional support with a nasoenteric feeding tube. METHODS: Prospective randomized clinical trial. Dogs were randomized to receive either continuous infusion (Group C) or intermittent bolus feeding (Group I) of liquid EN. The percentage of prescribed nutrition delivered (PPND) was calculated every 24 hours. Frequencies of gastrointestinal (GI), mechanical, and technical complications were recorded and gastric residual volumes (GRVs) were measured. RESULTS: PPND was significantly lower in Group C (98.4%) than Group I (100%). There was no significant difference in GI or mechanical complications, although Group C had a significantly higher rate of technical complications. GRVs did not differ significantly between Group C (3.1 mL/kg) and Group I (6.3 mL/kg) and were not correlated with the incidence of vomiting or regurgitation. CONCLUSIONS AND CLINICAL IMPORTANCE: There was a statistically significant difference in the PPND between continuously and intermittently fed dogs, but this difference is unlikely to be clinically relevant. Critically ill dogs can be successfully supported with either continuous infusion or intermittent bolus feeding of EN with few complications. Increased GRVs may not warrant termination of enteral feeding.

Orlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight loss.

BACKGROUND: Both obesity and type 2 diabetes are associated with increased morbidity and mortality. Published data suggest that orlistat 120 mg, a lipase inhibitor used to treat obesity, may improve glycaemic parameters through weight loss-independent effects. AIM: To investigate the effect of orlistat 120 mg on weight loss, and assess whether changes in glycaemic parameters [fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c)] are independent of weight loss. METHODS: This retrospective analysis of pooled data from seven multicentre, double-blind, placebo-controlled studies involved overweight or obese patients with type 2 diabetes (aged 18-70 years). Patients were required to have a body mass index of 27-43 kg/m2, HbA1c of 6.5 to <13%, and stable weight for > or =3 months. Subjects received orlistat 120 mg tid or placebo for 6 or 12 months. RESULTS: A total of 2550 overweight or obese patients with type 2 diabetes were enrolled and randomized to treatment with orlistat 120 mg tid (n = 1279) or placebo (n = 1271). For the whole population, patients treated with orlistat 120 mg had significantly greater mean decreases in FPG compared with placebo-treated patients (-1.39 mmol/l vs. -0.47 mmol/l; p < 0.0001). In addition, orlistat 120 mg provided significantly larger mean decreases in HbA1c compared with placebo (-0.74% vs. -0.31%; p < 0.0001). For patients with minimal weight loss (< or =1% of baseline body weight), orlistat 120 mg still provided a significantly greater decrease in the least squares mean value for both FPG (-0.83 mmol/l vs. +/-0.02 mmol/l; p = 0.0052) and HbA1c -0.29% vs. +/-0.14%; p = 0.0008). This suggested that the improvement of glycaemic control with orlistat 120 mg was independent of weight loss. Using linear regression analysis, improvement in glycaemic control (FPG and HbA1c) with orlistat 120 mg was less strongly correlated with weight loss than for placebo. CONCLUSION: Orlistat 120 mg appears to improve glycaemic control more than would be predicted by weight loss alone in overweight or obese patients with type 2 diabetes. Postulated mechanisms underlying this effect include an improvement of insulin sensitivity, a slower and incomplete digestion of dietary fat, reduction of postprandial plasma non-esterified fatty acids, decreased visceral adipose tissue, and stimulation of glucagon-like peptide-1 secretion in the lower small intestine.

Effect of magnitude and direction of force on laryngeal abduction: implications for the nerve-muscle pedicle graft technique.

REASONS FOR PERFORMING STUDY: The nerve-muscle pedicle graft technique is a treatment for recurrent laryngeal neuropathy (RLN), but the optimal placement of the pedicles within the cricoarytenoideus dorsalis (CAD) muscle is unknown. HYPOTHESIS: The magnitude and direction of force placed on the muscular process of the left arytenoid cartilage affects the magnitude of laryngeal abduction. METHODS: Five larynges were harvested from cadavers. Using increments of 0.98 N, a dead-weight force generator applied a force of 0-14.7 N for 1 min each to the left muscular process at 0, 10, 20, 30, 40, 50, 60 and 70 degrees angles. The rima glottis was photographed digitally 1 min after each force had been applied. Distances between biomarkers (Lines 1-4) and right to left angle quotient (RLQ) were used to assess the degree of left arytenoid abduction. RESULTS: Increasing force from 0-14.7 N progressively and significantly increased the length of all lines and RLQ, indicating abduction. Furthermore, there was a significant interaction between force and angles. Applying forces of 7.84 N or greater (Lines 2-4 and RLQ) or 11.76 N or greater (Line 1) at angles 0, 10, 20 and 30 degrees resulted in significantly greater abduction than applying the same forces at 40, 50, 60 and 70 degrees. Angles of 0-30 degrees correspond with the direction of pull exerted by the lateral compartment of the CAD muscle. CONCLUSION: In RLN, nerve-muscle pedicle grafts should be placed preferentially in the lateral rather than in the medial compartment of the CAD muscle. POTENTIAL RELEVANCE: The information presented can be used to assist surgeons in the planning and application of the nerve-muscle pedicle graft procedure.

Incidence of transfusion reactions and retention of procoagulant and anticoagulant factor activities in equine plasma.

BACKGROUND: The extent of preservation of clotting factors and incidence of transfusion reactions to noncommercial equine plasma is not documented. HYPOTHESIS: Equine frozen plasma would retain its coagulation factor activity within the reference range and the incidence of transfusion reactions would be low. ANIMALS: Ten plasma donor horses. Fifty clinically ill hospitalized horses receiving plasma were reviewed to determine the incidence of reactions. METHODS: In vitro study and retrospective case review. Plasma was prepared by gravity sedimentation from whole blood refrigerated for 48 hours. The activities of factors VII through XII, antithrombin (AT), and Protein C were measured. Factor activities were compared for plasma samples obtained before blood collection (S0), after 48 hours of gravity sedimentation at 5 degrees C and after plasma separation (S1), and after 90 days of storage at -20 degrees C (S90). The medical records of 50 consecutive clinically ill horses receiving frozen plasma were reviewed to determine the incidence of transfusion reactions. RESULTS: The combined effect of plasma harvest, gravity sedimentation, decantation, and freezing caused significant reductions in factors IX, (43%P= .0013), X, (33%P= .0001), XI, (48%P= .0008), AT, (10%P= .02), and Protein C (26%P= .0001). Activities for all factors analyzed, except factor X, remained within the reference ranges. Transfusion reactions were recorded for 5/50 horses. CONCLUSIONS AND CLINICAL RELEVANCE: Clotting factors, AT, and Protein C were well preserved. The incidence of reactions to frozen plasma was 10%.

Effect of Prophylactic Calcitriol Administration on Serum Ionized Calcium Concentrations after Parathyroidectomy: 78 Cases (2005-2015).

BACKGROUND: Prophylactic administration of calcitriol has been suggested to mitigate the risk of hypocalcemia after parathyroidectomy. The effect of calcitriol on postoperative serum ionized calcium concentrations has not been evaluated in dogs after parathyroidectomy. HYPOTHESIS/OBJECTIVES: To determine the effect of prophylactic calcitriol administration on postoperative serum ionized calcium (iCa) concentrations in dogs with primary hyperthyroidism (PHPTH) treated by parathyroidectomy. ANIMALS: Seventy-eight dogs with primary hyperparathyroidism treated surgically. METHODS: Multi-institutional retrospective case study. Medical records from 2005 to 2015 were evaluated. Dogs were included if they had a diagnosis of PHPTH and had surgery to remove parathyroid tissue. Serum iCa concentrations were monitored for a minimum of 2 days postoperatively. Two study groups were evaluated: calcitriol administration and no calcitriol administration. RESULTS: Serial postoperative iCa concentrations measured at 12-hour time intervals for 2 days postoperatively were positively associated with preoperative iCa concentrations. This association was evident at each time interval, and the effect of preoperative iCa concentrations on postoperative iCa concentrations decreased as time elapsed (12 hours, P < 0.0001; 24 hours, P < 0.0001; 36 hours, P < 0.04; and 48 hours, P = 0.01). Prophylactic calcitriol administration was not found to be significantly associated with postoperative iCa concentrations or its rate of decrease after parathyroidectomy. CONCLUSION AND CLINICAL IMPORTANCE: We found no protective value in administering calcitriol prophylactically to prevent hypocalcemia in the immediate postoperative period (48 hours) after parathyroidectomy. Preoperative iCa concentrations had a significant positive association with postoperative iCa concentrations throughout the monitoring period.

The effect of uterine torsion on mare and foal survival: a retrospective study, 1985--2005.

REASONS FOR PERFORMING STUDY: Anecdotal speculation suggests that prognosis for survival of mares and foals following correction of uterine torsion has improved over the past 30 years. OBJECTIVES: To determine statistically the outcome of uterine torsion according to duration of clinical signs, stage of gestation, parity, physical examination findings, method of correction, prognosis for survival and reproductive health of the mare, and prospects for the foal within the neonatal period. METHODS: This retrospective study combined cases from 4 equine referral hospitals. RESULTS: The stage of gestation at which uterine torsion occurred was a risk factor for survival of mare and foal. Overall mare survival was 53/63 (84%); when uterine torsion occurred at < 320 days gestation, 36/37 (97%) of mares survived compared to 17/26 (65%) survival rate when uterine torsion occurred at > or = 320 days gestation. Overall foal survival was 54% (29/54). When uterine torsion occurred at < 320 days gestation, 21/29 (72%) foals survived compared to 8/25 (32%) when uterine torsion occurred at > or = 320 days gestation. Thirty mares were discharged from the hospital carrying a viable fetus following uterine torsion correction and 25/30 (83%) of these mares delivered live foals that survived beyond the neonatal period. CONCLUSIONS: Prognosis for survival for mares and foals following uterine torsion is good and improves if torsion occurs < 320 days compared to > or = 320 days gestation. CLINICAL RELEVANCE: Gestational timing of uterine torsion should be considered when advising clients about the prognosis for survival of the mare and foal. The prognosis for a mare delivering a live foal is good if the mare is discharged from the hospital following uterine torsion correction with a viable fetus.

Quantification of Urine Elimination Behaviors in Cats with a Video Recording System.

BACKGROUND: Urinary disorders in cats often require subjective caregiver quantification of clinical signs to establish a diagnosis and monitor therapeutic outcomes. OBJECTIVE: To investigate use of a video recording system (VRS) to better assess and quantify urination behaviors in cats. ANIMALS: Eleven healthy cats and 8 cats with disorders potentially associated with abnormal urination patterns. METHODS: Prospective study design. Litter box urination behaviors were quantified with a VRS for 14 days and compared to daily caregiver observations. Video recordings were analyzed by a behavior analysis software program. RESULTS: The mean number of urinations per day detected by VRS (2.5 ± 0.7) was significantly higher compared with caregiver observations (0.6 ± 0.6; P < .0001). Five cats were never observed in the litter box by their caregivers. The mean number of urinations per day detected by VRS was significantly higher for abnormal cats (2.9 ± 0.7) compared with healthy cats (2.1 ± 0.7; P = .02); there were no apparent differences in frequency between these groups reported by caregivers (0.7 ± 1.0 and 0.5 ± 1.0, respectively). There were no differences in mean urination time between healthy and abnormal cats as determined by VRS or caregivers. Mean cover-up time determined by VRS was significantly longer in healthy cats (22.7 ± 12.9 seconds/urination) compared with abnormal cats (8.7 ± 12.9 seconds/urination; P = .03); differences in cover-up time were not detected by caregivers. CONCLUSIONS AND CLINICAL IMPORTANCE: Caregivers commonly underestimate urination frequency in cats when compared to video-based observations. Video recording appears to facilitate objective assessment of urination behaviors and could be of value in future clinical studies of urinary disorders in cats.

Thermographic study of in vivo modulation of vascular responses to phenylephrine and endothelin-1 by dexamethasone in the horse.

REASONS FOR PERFORMING STUDY: In vitro, glucocorticoids potentiate vasoconstriction of equine digital vessels to catecholamines and this has been implicated as a mechanism of glucocorticoid-induced laminitis. This observation has never been confirmed in vivo. OBJECTIVES: To study the effects of glucocorticoid therapy on vasoconstrictor responsiveness in the horse in vivo. METHODS: In a blinded, randomised cross-over experiment, 9 horses were treated with either dexamethasone (0.1 mg/kg bwt i.v. q. 24 h) or saline i.v. for 6 days. The changes in local average skin temperature before (baseline) and after intradermal injections of the alpha1-adrenoceptor agonist phenylephrine (PHE; 10(-4), 10(-5), 10(-6), 10(-7) and 10(-8) mol/l), endothelin-1 (ET-1; 10(-5), 10(-6), 10(-7), 10(-8) and 10(-9) mol/l) or ET-1 plus a blocker (BQ-123 10(-6) mol/l; RES-701 10(-6) mol/l; and L-NAME 10(-4) mol/l) were investigated with a thermograph. RESULTS: Dexamethasone (DEX) decreased baseline skin temperatures, suggesting reduced blood flow as a consequence of an increase in vasomotor tone. This was accompanied by potentiation of the response to PHE as demonstrated by a left shift in the dose-response curve and a decrease in the EC50. Dexamethasone did not potentiate ET-1, but the interplay with the lower baseline temperature resulted in a significantly lower skin temperature for this vasoconstrictor after DEX. The different ET-1 blockers had no effect on ET-1 modulated skin temperatures. CONCLUSIONS: Dexamethasone decreases skin perfusion. This is accompanied by a potentiated alpha1-adrenoceptor agonist response and a greater response to ET-1. POTENTIAL RELEVANCE: Glucocorticoid therapy probably decreases perfusion of the equine hoof. During disease states that already are characterised by hypoperfusion and/or increased levels of circulating catecholamines, glucocorticoid therapy could, according to the vascular model of laminitis, tilt the balance in favour of laminitis.

Laryngeal advancement surgery improves swallowing function in a reversible equine dysphagia model.

REASONS FOR PERFORMING STUDY: Pharyngeal dysphagia is a debilitating, sometimes fatal condition in horses, with multiple aetiologies. The pathophysiology is complex and not fully understood. Treatment is largely supportive. Laryngeal advancement surgery may diminish symptoms of dysphagia and improve swallowing in affected horses. OBJECTIVES: 1) to induce reversible moderate and marked pharyngeal dysphagia by regional anaesthesia of branches of the glossopharyngeal (IX), vagus (X) and hypoglossal (XII) nerves; 2) to characterise the dysphagia produced by each model; and 3) to determine whether laryngeal advancement surgery improves swallowing in these models. STUDY DESIGN: Experimental design using 6 adult horses. METHODS: Two dysphagia models were produced by blocking IX, the pharyngeal branch of X and XII unilaterally (moderate model) and only the pharyngeal branch of X bilaterally (marked model) within the guttural pouches. Both models were performed on each horse before and after surgery in order to assess the effectiveness of the surgical procedure as a potential treatment for pharyngeal dysphagia. Dysphagia was scored by partly blinded observers on a scale of 0-12 based on observations of eating (nonblinded), endoscopic examinations and fluoroscopic swallowing (blinded), where 0 = normal swallow and 12 = severe dysphagia with tracheal aspiration. Data were analysed by 3-factor ANOVA, with significance taken as P<0.05. RESULTS: Dysphagia models were reversible, and horses swallowed normally within 3 h of model induction. The marked dysphagia model impaired movement of feed from the base of the tongue to the oesophagus and caused severe airway contamination. The average dysphagia score (mean ± s.d.) for the marked dysphagia model was 10.6 ± 1.1 before surgery and 6.1 ± 4.3 after surgery (P = 0.007). Laryngeal advancement surgery did not significantly improve the dysphagia scores in the moderate model (P = 0.5). CONCLUSIONS: Laryngeal advancement surgery may improve swallowing and reduce aspiration in horses affected with diseases that cause pharyngeal dysphagia.

Pheochromocytoma resistant to alpha-adrenergic blockade.

In a 54-year-old man with a norepinephrine-secreting pheochromocytoma, resistance developed to the alpha-adrenergic blocking agent, phenoxybenzamine hydrochloride. Dosages of 240 mg/day were ineffective. Intravenous phentolamine mesylate reduced his BP at first, but resistance developed to this also. Therapy with alpha-methylparatyrosine, an inhibitor of catecholamine biosynthesis, finally controlled his BP, and the tumor was removed.

Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults.

BACKGROUND: Orlistat is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, promotes weight loss, and may reduce the risk of developing impaired glucose tolerance and type 2 diabetes in obese subjects. OBJECTIVE: To test the hypothesis that orlistat combined with dietary intervention improves glucose tolerance status and prevents worsening of diabetes status more effectively than placebo. METHODS: We pooled data from 675 obese (body mass index, 30-43 kg/m2) adults at 39 US and European research centers in 3 randomized, double-blind, placebo-controlled multicenter clinical trials. Subjects received placebo plus a low-energy diet during a 4-week lead-in period. On study day 1, the diet was continued, and subjects were randomized to receive placebo 3 times a day (n=316) or treatment with orlistat, 120 mg 3 times a day (n=359), for 104 weeks. A standard 3-hour oral glucose tolerance test was performed on day 1 and at the end of treatment. MAIN OUTCOME MEASURES: The categorical assessment of glucose tolerance status (normal, impaired, diabetic) and changes in status from randomization to end of treatment were the primary efficacy measures. The secondary measures were fasting and postchallenge glucose and insulin levels. RESULTS: The mean length of follow-up was 582 days. Subjects who were treated with orlistat lost more weight (mean +/- SEM, 6.72 +/- 0.41 kg from initial weight) than subjects who received placebo (3.79+/-0.38 kg; P<.001). A smaller percentage of subjects with impaired glucose tolerance at baseline progressed to diabetic status in the orlistat (3.0%) vs placebo (7.6%) group. Conversely, among subjects with impaired glucose tolerance at baseline, glucose levels normalized in more subjects after orlistat treatment (71.6%) vs placebo (49.1%; P=.04). CONCLUSIONS: The addition of orlistat to a conventional weight loss regimen significantly improved oral glucose tolerance and diminished the rate of progression to the development of impaired glucose tolerance and type 2 diabetes.

Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study.

OBJECTIVE: Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS: In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS: After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS: Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.

Retrospective population-based analysis of the dose-response (fecal fat excretion) relationship of orlistat in normal and obese volunteers.

Orlistat, an inhibitor of gastrointestinal lipases, limits the absorption of ingested fat and could become a potential treatment for obesity. This analysis was performed to elucidate the relationship between orlistat dose and intensity of inhibition of dietary fat absorption (assessed by measuring fecal fat excretion). In 11 phase I double-blind, placebo-controlled, parallel-group randomized studies, a total of 171 subjects received oral daily doses that ranged from 30 to 1200 mg orlistat or matching placebo three times a day for 9 to 10 days. The results of the daily mean fecal fat excretion percentage (relative to ingested fat) were correlated to the orlistat daily dose. A simple maximum-effect model that included a basal value was used to fit the dose-response relationship for all evaluable subjects. The mean maximum percentage of ingested fat excreted in the feces was approximately 32% during orlistat administration compared with 5% during placebo administration. The orlistat daily dose that produced 50% of the maximum effect was 98 mg/day. The model-fitting suggests the existence of a steep portion of the dose-response curve up to approximately 400 mg/day, with a subsequent tendency to plateau at higher doses. Such an analysis was instrumental in identifying appropriate doses to be used in therapeutic trials for weight loss in obese patients.

Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18-0647 (tetrahydrolipstatin).

Excessive intake of dietary fat contributes to the development and maintenance of both obesity and hyperlipidemia. Inhibition of gastrointestinal lipases could decrease the amount of ingested fat that is absorbed systemically by preventing the hydrolysis of triglycerides. Ro 18-0647, a chemically synthesized derivative of the natural product lipstatin, inhibits the action of gastrointestinal lipases. Initial studies in humans have shown that Ro 18-0647 can reliably increase fecal fat excretion. Ro 18-0647 has also been shown to be well tolerated in the majority of normal volunteers and obese patients studied. Further research must be conducted to determine whether clinical endpoints of weight loss or cholesterol lowering can be produced by using this new pharmacologic principle.

Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study.

BACKGROUND: Long-term maintenance of weight loss remains a therapeutic challenge in obesity treatment. OBJECTIVE: This multicenter, double-blind, placebo-controlled study was designed to test the hypothesis that orlistat, a gastrointestinal lipase inhibitor, is significantly more effective than a placebo in preventing weight regain. DESIGN: Obese subjects who lost > or = 8% of their initial body weight during a 6-mo lead-in of a prescribed hypoenergetic diet (4180-kJ/d deficit) with no adjunctive pharmacotherapy were randomly assigned to receive placebo, 30 mg orlistat, 60 mg orlistat, or 120 mg orlistat 3 times daily for 1 y in combination with a maintenance diet to help prevent weight regain. Of 1313 recruited subjects [body mass index (in kg/m2): 28-43], 729 subjects lost > or =8% of their initial body weight during the 6-mo weight-loss lead-in period and were enrolled in the double-blind phase. RESULTS: After 1 y, subjects treated with 120 mg orlistat 3 times daily regained less weight than did placebo-treated subjects (32.8 +/- 4.5% compared with 58.7 +/- 5.8% regain of lost weight; P < 0.001). Moreover, more subjects in the 120-mg orlistat group than in the placebo group regained < or = 25% of lost weight (47.5% of subjects compared with 29.9%). In addition, orlistat treatment (120 mg 3 times daily) was associated with significantly greater reductions in total and LDL-cholesterol concentrations than was placebo (P < 0.001). CONCLUSION: The use of orlistat during periods of attempted weight maintenance minimizes weight readjustment and facilitates long-term improvement in obesity-related disease risk factors.

Effect of orlistat-assisted weight loss in decreasing coronary heart disease risk in patients with syndrome X.

This study describes the changes in risk factors for coronary heart disease in obese persons with syndrome X after orlistat-assisted weight loss. Data were available for 1,700 patients who completed 52 weeks of weight loss; 128 were defined as having syndrome X by being in the quintile with the highest plasma triglyceride levels (>2.2 mM/L) and the lowest high-density lipoprotein cholesterol (HDL, <1.0 mM/L) concentrations. Initial characteristics of those with syndrome X were similar to the 119 subjects (non-syndrome X) in the lowest quintile of plasma triglyceride (<0.975 mM/L) and highest quintile of HDL cholesterol (>1.5 mM/L). Subjects were placed on a calorie-restricted diet, and randomized to receive orlistat or placebo. Initial values were higher in those with syndrome X for diastolic blood pressure (p = 0.03), plasma insulin (p = 0.0001), triglyceride (p = 0.0001) concentrations, and ratio of low-density lipoprotein cholesterol to HDL cholesterol (p = 0.0001), and were lower for HDL cholesterol (p = 0.001) concentrations. Weight loss was greater in both groups of orlistat-treated patients (p = 0.026); in those with syndrome X, it was associated with a significant reduction in plasma insulin (p = 0.019) and triglyceride (p = 0.0001) concentrations, an increase in HDL cholesterol concentration, and a decrease in low-density lipoprotein/HDL cholesterol ratio (p = 0.0001). There were no significant changes in plasma insulin, triglycerides, or HDL cholesterol concentration in the non-syndrome X group. In conclusion, weight loss attenuates coronary heart disease risk factors in obese persons with syndrome X, and the risk factor reduction is enhanced with administration of orlistat.

The efficacy of heparin and antithrombin III in fluid-resuscitated cecal ligation and puncture.

Sepsis/septic shock and multiple organ failure are important causes of morbidity and mortality. Our objective was to study sepsis and organ failure in a fluid-resuscitated septic model. Males S-D rats were anesthetized with halothane, the jugular vein catheterized, and CLP performed. Each rat was maintained in a metabolism cage on continuous intravenous fluid (3 mL/rat). Urine rate and [creatinine]urine were measured daily. At day 5, serum creatinine with chemistry profile, complete blood count, clotting times, and wet lung/body weight ratios were also measured. Glomerular filtration rate (GFR) was measured according to the principle of endogenous creatinine clearance. GFR was correlated with the product of urine rate x [creatinine]urine (R = .79), so that product was used as a daily indicator of GFR. Urine output remained > or = normal during sepsis. Heparin and antithrombin III were tested in this model. The model was associated with 40% mortality, a 60% reduction in platelet count, liver damage, a 75% reduction in renal function, muscle damage, and a normal wet lung/body weight ratio. Treatment with heparin/antithrombin III ameliorated the decrease in GFR (p < .05) observed in the nontreated animals, prevented the septic-induced thrombocytopenia (p < .05), and improved survival (p = .05).