Application of pharmacokinetic-pharmacodynamic modeling to predict the kinetic and dynamic effects of anti-methotrexate antibodies in mice.

We have shown that intravenous (i.v.) administration of anti-methotrexate (MTX) antibodies (AMAb) reduces the systemic exposure of intraperitoneal (i.p.) MTX therapy, and we have proposed that AMAb effects on MTX systemic exposure would allow a reduction in MTX-induced systemic toxicity (i.e., producing a desirable antagonistic effect). However, many literature reports have shown that anti-toxin antibodies occasionally demonstrate unexpected agonist-like activity, increasing the extent of toxicity induced by their ligand. In this report, we have utilized a pharmacokinetic-pharmacodynamic (PKPD) model to predict the potential of AMAb to increase or decrease the magnitude of MTX-induced body weight loss in mice. Simulations predicted that both anti-MTX immunoglobulin G (AMI) and anti-MTX Fab fragments (AMF) would lead to increases or decreases in MTX toxicity, with effects dependent on the dosing protocol used. Based on the computer simulations, two protocols were selected for in vivo evaluation of predicted agonistic or antagonistic effects. Murine monoclonal AMI and AMF were produced, purified, and characterized. Agonistic effects were tested after 24-h infusion of i.p. MTX (10 mg/kg) and i.v. administration of an equimolar dose of AMI. Antagonistic effects were tested after 72-h infusion of i.p. MTX (5 mg/kg) and i.v. infusion of an equimolar dose of AMF. Consistent with model predictions of agonist-like activity, the 24-h AMI protocol led to significantly increased animal mortality (all animals died, p < 0.005) and mean nadir weight loss (p < 0.005). Also consistent with the predictions of the PKPD model, the 72-h AMF protocol significantly decreased animal mortality and mean nadir body weight loss (p < 0.01). Thus, these studies demonstrate that agonistic and antagonistic effects of anti-toxin antibodies may be predicted through the use of an integrated PKPD model. Copyright 2003 Wiley-Liss, Inc.

Weight Loss increases 11beta-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue.

The global epidemic of obesity has heightened the need to understand the mechanisms that underpin its pathogenesis. Clinical observations in patients with Cushing's syndrome have highlighted the link between cortisol and central obesity. However, although circulating cortisol levels are normal or reduced in obesity, local regeneration of cortisol, from inactive cortisone, by 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) has been postulated as a pathogenic mechanism. Although levels of expression of 11betaHSD1 in adipose tissue in human obesity are debated in the literature, global inhibition of 11betaHSD1 improves insulin sensitivity. We have determined the effects of significant weight loss on cortisol metabolism and adipose tissue 11betaHSD1 expression after 10-wk ingestion of a very low calorie diet in 12 obese patients (six men and six women; body mass index, 35.9 +/- 0.9 kg/m2; mean +/- SE). All patients achieved significant weight loss (14.1 +/- 1.3% of initial body weight). Total fat mass fell from 41.8 +/- 1.9 to 32.0 +/- 1.7 kg (P < 0.0001). In addition, fat-free mass decreased (64.4 +/- 3.4 to 58.9 +/- 2.9 kg; P < 0.0001) and systolic blood pressure and total cholesterol also fell [systolic blood pressure, 135 +/- 5 to 121 +/- 5 mm Hg (P < 0.01); total cholesterol, 5.4 +/- 0.2 to 4.8 +/- 0.2 mmol/liter (P < 0.05)]. The serum cortisol/cortisone ratio increased after weight loss (P < 0.01). 11betaHSD1 mRNA expression in isolated adipocytes increased 3.4-fold (P < 0.05). Decreased 11betaHSD1 activity and expression in obesity may act as a compensatory mechanism to enhance insulin sensitivity through a reduction in tissue-specific cortisol concentrations. Inhibition of 11betaHSD1 may therefore be a novel, therapeutic strategy for insulin sensitization.

Calorie intake and meal patterns up to 4 years after Roux-en-Y gastric bypass surgery.

BACKGROUND: Roux-en-Y gastric bypass (RYGBP) is the most popular surgical treatment for morbid obesity in the U.S.A., producing significant and durable weight loss with improvement in co-morbidities. Although a greater number of patients are undergoing surgical treatment for obesity, little data are available regarding their food intake after surgery. This study was undertaken to evaluate the caloric amount, nutrient composition and meal patterns of patients 18 months to 4 years after RYGBP. Ethnic differences in food intake were also investigated. METHODS: Questionnaires were mailed to 360 patients who had undergone RYGBP at least 18 months prior to the onset of the study. RESULTS: Data were available from 69 patients, 52% Caucasian, 25% African-American, 23% Hispanic. 30 months after surgery, the average daily calorie intake was 1733 +/- 630 kcal (n=68, range 624-3486 kcal), with 44% of calories from carbohydrates, 22% from protein and 33% from fat. Sugar-sweetened beverages represented 7% of total caloric intake. Patients consumed 3 meals and 3 snacks per day on average. Food intake from dinner and an evening snack represented 40% of the daily caloric intake. Snacks accounted for 37% of the daily intake. Percent excess weight loss (%EWL) was 58 +/- 17% and was not different among ethnic groups. However, Hispanics reported consuming fewer snacks and fewer calories. %EWL correlated with the total daily caloric intake (r= .446, P <0.001). Follow-up attendance was 54% at 1 year after surgery but fell to 10% at 3 years. Only 77% of patients were taking vitamin supplements. CONCLUSION: RYGBP resulted in significant weight loss. Caloric intake was quite variable. Long-term follow-up remained low, putting patients at risk for metabolic and vitamin deficiencies. The relationship between caloric intake and long-term weight changes remains to be studied.

Nutritional behavior as a predictor of early success after vertical gastroplasty.

BACKGROUND: Patients' nutritional habits are seldom taken in account in planning surgery for clinically severe obesity. Our proposed hypothesis is that the patient's nutritional behavior may influence the outcome of bariatric surgery. METHODS: The impact of nutritional behavior on the postoperative weight-loss was evaluated before and after bariatric surgery. A 6-month prospective consecutive case study was carried out on patients undergoing a Silastic ring vertical gastroplasty (SRVG). Patients were interviewed and examined before and at 1, 3 and 6 months after surgery. Demographic and clinical data were collected from the patients' medical charts. Nutritional data collected from a self-filled questionnaire included information on hunger and satiety perception, nutritional behavior (intake, eating habits and maximum consistency of consumed food) and concomitant symptoms. RESULTS: The sample included 69 patients: 56 were women (81%); average age was 32 years (range 18 50). Average preoperative BMI was 43.4 +/- 5.3 kg/m2 (range 35-58). 6 months after surgery, BMI was 30.3 +/- 3.8 kg/m2 (range 21-42). weight loss forecast models showed a statistically significant role of factors related to: anthropometrical preoperative data, hunger perception, prevalence of oral mucosal sore, and nutritional behavior. CONCLUSION: The short nutrition outcomes after gastric restrictive surgery were looked at, with their impact on weight-loss success. The Eating Status concept should be part of a systematic profiling of morbidly obese patients for preoperative nutritional behavior and postoperative nutritional education, to achieve the best comprehensive treatment in regard to weight loss and quality of life.