OBJECTIVE: Assessment of the effects of orlistat 120 mg three times daily vs placebo on weight loss and serum lipids in obese hypercholesterolemic patients. DESIGN: A 24 week multicentre, double-blind, randomized, placebo-controlled trial. After a 2-week single-blind run-in period (placebo þ diet (7600 kcal=day; 30% of calories as fat)), 294 patients were submitted to the hypocaloric diet and randomly assigned to either orlistat 120 mg or placebo three times daily. Patients who completed the double-blind study (n ¼ 255) were eligible for participation in a subsequent 24 week open-label orlistat extension phase. SUBJECTS: Patients with body mass index (BMI) 27 -40 kg=m 2 and hypercholesterolemia (low-density-lipoprotein cholesterol, LDL-C, 4.1 -6.7 mmol=l). MEASUREMENTS: Efficacy assessments included weight loss, lipid levels, other cardiovascular risk factors and anthropometric parameters. Safety assessments. RESULTS: Weight loss during run-in was similar in both groups. After randomization, orlistat-treated patients lost significantly more weight than placebo recipients: mean percentage weight loss from start of run-in to week 24 was76.8% in the orlistat group and 73.8% in the placebo group (P<0.001). Moreover, more patients in the orlistat group than in the placebo group achieved clinically meaningful weight loss of ! 5% (64 vs 39%) or ! 10% (23 vs 13%) at week 24. Treatment with orlistat was associated with significantly greater changes in total cholesterol (711.9% vs 74.0%; P<0.001) and LDL-C (717.6 vs 77.6%; P<0.001). For any category of weight loss during the double-blind treatment period, change in LDL-C was more pronounced in orlistat-treated patients than in placebo recipients, indicating that orlistat had a direct cholesterol-lowering effect that was independent of weight reduction (P<0.001). Adjunction of orlistat during the extension phase in patients who initially received placebo induced a further decrease in weight, total cholesterol and LDL-C. Orlistat was generally well tolerated with a safety profile comparable to placebo, with the exception of a higher incidence of gastrointestinal events ( ! 1 event in 64 vs 38% of patients). CONCLUSION: Orlistat as an adjunct to dietary intervention promotes weight loss and reduces LDL-C beyond the effect of weight loss in overweight or obese patients with concomitant hypercholesterolemia.

To evaluate the role of dietary polyamines in maturation of the rat small intestine, spermine was given orally twice daily to suckling pups from day 10 to day 14 postpartum at different doses: 0, 0.2, 0.5, 1, 2.5, and 5 mumol/dose. Compared to saline treated controls, spermine (5 mumol) produced significant increases in mucosal mass parameters (+12 to +57%, P < 0.05), induced prematurely an adult pattern of microvillous enzymes, and enhanced, respectively, by 19- and 3.5-fold (P < 0.01 vs controls) the concentration of the secretory component of p-immunoglobulins in villous and crypt cells. The response of microvillous enzymes (lactase, sucrase, maltase, and aminopeptidase) to spermine was dose-dependent and -specific since oral administration of arginine (5 mumol) or ornithine (5 mumol) was without effect. Intestinal changes were found to be significant (P < 0.05) for doses of spermine exceeding 1 mumol/day, which is in the range of the amount of polyamines provided by solid pellets at weaning (0.4 mumol/g). However, intestinal changes were undetectable at the physiological amounts of polyamines consumed by pups from rat milk during the suckling period (less than 0.3 mumol/day). Consistent with a direct effect of spermine on the intestinal cell, the cytosolic activity of ornithine decarboxylase was depressed by 27-fold (P < 0.005 vs controls) in the jejunum, while inhibition of ornithine decarboxylase by alpha-difluoromethylornithine did markedly decrease but did not suppress the cell response to spermine. Alternately, plasma corticosteronemia, which was virtually absent by day 14 in controls, ranged between 1.4 and 4.6 micrograms/dl in 60% (N = 9) of the spermine-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

While the prevalence of hypertension is clearly increased among the overweight persons, the pathophysiological mechanisms underlying this frequent association of obesity and hypertension are still poorly understood. The expansion of extracellular volume, inducing hypervolaemia and increased cardiac output, represents the characteristic haemodynamic feature of the obesity-related hypertension. The maintenance of hypervolemia in the face of elevated blood pressure, indicates a resetting of pressor natriuresis toward higher blood pressure. The development of hypertension also indicates an increase in peripheral vascular resistance, thus the lack of physiological adaptation of peripheral resistance to increased cardiac output. The mechanisms underlying these changes in renal function and vascular reactivity can no longer be attributed to hyperinsulinaemia as such, but might be related to insulin resistance responsible for the enhancement in pressor activity of noradrenaline and angiotensin II. This increased reactivity to pressor factors may be due to an inadequate nitric oxide generation by vascular endothelium and to increased sodium and calcium concentration in vascular smooth muscle cells. The role of increased neuropeptide Y (NPY) activity, may also be involved. As to enhancement of tubular sodium reabsorption, it could be related to histological changes within the renal medulla, leading to compression of tubules and vasa recta, hence a more ef®cient sodium reabsorption. As to the therapeutic approach, the low-energy sodium-restricted diet associated with increased physical activity, represents the cornerstones of treatment for the obesity-related hypertension. If this approach fails, the pharmacological treatment becomes necessary, and the use of the converting enzyme inhibitors seems to be the most appropriate choice of drug therapy for hypertensive obese patients.

Weight reduction is essential in the management of most noninsulin‐dependent diabetics, but this therapeutical goal is difficult to obtain. In this double‐blind parallel study, 82 noninsulin‐dependent diabetics, moderately obese (BMI = 30–39 kg/nr2), were given for an 8‐week period either placebo (P) or fluoxetine (F), a specific serotonin reuptake inhibitor, in addition to their usual antidiabetic treatment. Thirty‐nine of them received 60 mg fluoxetine a day and 43 were given the placebo. At admission, both groups had similar weight excess, metabolic control and serum lipid values. In comparison with the P‐treated subjects, those treated with fluoxetine (F) lost more weight after 3 weeks (‐1.9 vs. −0.7 kg, p<0.0009) and after 8 weeks (‐3.1 vs. −0.9 kg, p<0.0007). Fasting blood glucose decreased in group F after 3 weeks (‐ 1.5 vs. −0.4 mmol/L, p<0.003) and after 8 weeks (‐1.7 vs. −0.02 mmol/L, p<0.0004). HbAlc decreased from 8.5% to 7.7% in group F and from 8.6% to 8.3% in group P (p=0.057). Mean triglyceride level was also reduced in group F after 8 weeks (p=0.042). Fasting C‐pep‐tide did not change in either group, but fasting insulin values decreased in group F after 3 weeks (p<0.02) and after 8 weeks (p<0.05). The insulin/C‐peptide molar ratio decreased significantly in group F after 3 weeks (p<0.04) and after 8 weeks (p<0.05) in comparison with group P. The drug was generally well tolerated and no major side effects were reported. In conclusion, the addition of fluoxetine to the usual oral hypoglycemic agent therapy might be beneficial in obese non‐insulin‐dependent diabetics, at least on a short‐term basis.

This study indicates that prevalence of obesity is particularly high in Belgium. Low level of education and reduced physical activity, increased fat intake and especially elevated fat to sugar ratio appear to be powerful determinants of obesity in this Belgian population.

ABSTRACT. To further document the effect of insulin on intestinal maturation, suckling rats were treated either with exogenous insulin (12.5 mU.g body wt, intraperitoneally, twice daily) or with saline from d 8 to 12 postpartum. Sucrase activity in brush border membrane extracts was precociously induced by insulin, whereas the activities of other brush border membrane enzymes (maltase, aminopeptidase, and neutral lactase) were enhanced (+30 to +131%, p < 0.01 versus controls). The lysosomal enzyme, N-acetyl-8-glucosaminidase, which normally declines at weaning was significantly ( p < 0.025) decreased in both villus (-51%) and crypt cells (-57%) isolated from the jejunum of insulin-treated rats. The microsomal enzyme, sulfatase C, and the cytosolic enzyme, lactate dehydrogenase, were also sensitive to insulin with decreases in activity ranging from -37 to -63% ( p < 0.05) compared to salinetreated control rats. Insulin at doses of 0.5 or 12.5 m u did not influence plasma total corticosterone levels, which were about 9-fold lower in suckling than in 25-d-old weaned rats. In weaned rats (from d 25 to 32) insulin treatment (12.5 mu) failed to influence the activity of brush border membrane hydrolases or of lysosomal, microsomal, and cytosolic enzymes. The synthesis rate of mature sucraseisomaltase, measured in weaned rats (32 d) by the incorporation of I4C-leucine into the enzyme precursor protein, was equivalent in both groups. These data demonstrate that the immature enterocyte of the suckling rat is responsive to insulin, whereas the mature enterocyte of the weaned rat is unresponsive. The effect of insulin on the intestinal cell appears not to be mediated via an endogenous stimulation of corticosterone release. (Pediatr Res 27:161-164,1990) Abbreviations BBM, brush border membrane S-I, sucrase-isomaltase ip, intraperitoneal During the weaning period (d 14 to 21) the rat small intestine undergoes rapid changes in its pattern of enzyme expression.

This review evaluates the benefits and potential health risks of the currently used drugs that are approved for the pharmacological treatment of obesity. Analysis of several long term clinical trials indicates that all of these drugs are efficient in reducing excess bodyweight, and that the majority of them allow the maintenance of the reduced bodyweight for at least 1 year. However, the loss of bodyweight attributable to these drugs is in general rather modest, approaching only 0.2 kg per week during the first 6 months of treatment, and at least a partial regain of bodyweight occurs when these drugs are used for periods longer than 1 year. All of these drugs induce several adverse effects. Although most of these adverse effects are mild and transient, the prolonged use of adrenergic or serotonergic anorectic drugs, or their use as combination treatment, may induce serious and potentially life-threatening complications, such as primary pulmonary hypertension or valvular heart disease. The adrenergic appetite-suppressing drugs are not recommended for the treatment of obesity, since their safety has never been evaluated in long term clinical trials, and because of their stimulatory effects on the cardiovascular and nervous systems. The serotonergic drugs, such as fenfluramine and dexfenfluramine, have been the most widely used during the past decade; however, both these compounds have recently been withdrawn from the market, since their use was associated with serious cardiovascular complications. The safety of the prolonged therapeutic use of newer compounds such as sibutramine and orlistat has not yet been demonstrated. Therefore, none of the currently available anti-obesity medications meets the criteria of an 'ideal anti-obesity drug' and, if prescribed, these medications should be used with caution and only under careful medical supervision. Since obesity is recognised as a chronic health-threatening condition, and since classical behavioural therapeutic approaches lack long term efficacy, there is clearly a need for an efficient pharmacological treatment offering an acceptable safety profile. Such a treatment is not available at present. Development of new agents and a more careful assessment of the safety of currently available drugs are needed.

This study was undertaken to determine whether the rat colon exhibits ontogenic changes in epithelial cell proliferation and DNA synthesis during growth. DNA synthesis was measured at intervals after birth in four colonic segments by the incorporation rates of [3H]thymidine. The labeled crypt cell index was determined by radioautography. New findings from our study are that 1) in each colonic segment of suckling rats, [3H]thymidine incorporation rate overshot the adult levels (49-119%) with a peak occurring at day 14 postpartum, 2) between days 14 and 20, the incorporation rates declined sharply to adult values and remained thereafter unchanged until adulthood; during the same period, the labeled and mitotic index decreased, respectively, from 52 to 19% and from 3.58 to 1.43%, 3) the decrease in DNA synthesis and in cell proliferation rates was concomitant with an upsurge in plasma total corticosterone initiated on day 14, and 4) treatment of 10-day-old sucklings with physiological doses of hydrocortisone for 4 consecutive days significantly depressed (P less than 0.01) colonic DNA content and DNA synthesis rates to levels about 45-67% of the control values. These data indicate that growth of the colon may be under the control of glucocorticoid secretion at the weaning period.