Intraoperative serum lactate is not a predictor of survival after glioblastoma surgery.

BACKGROUND: Cancer cells can produce lactate in high concentrations. Two previous studies examined the clinical relevance of serum lactate as a biomarker in patients with brain tumors. Patients with high-grade tumors have higher serum concentrations of lactate than those with low-grade tumors. We hypothesized that serum lactic could be used of biomarker to predictor of survival in patients with glioblastoma (GB). METHODS: This was a retrospective study. Demographic, lactate concentrations and imaging data from 275 adult patients with primary GB was included in the analysis. The progression free survival (PFS) and overall survival (OS) rates were compared in patients who had above and below the median concentrations of lactate. We also investigated the correlation between lactate concentrations and tumor volume. Multivariate analyses were conducted to test the association lactate, tumor volume and demographic variables with PFS and OS. RESULTS: The median serum concentration of lactate was 2.3mmol/L. A weak correlation was found between lactate concentrations and tumor volume. Kaplan-Meier curves demonstrated similar survival in patients with higher or lower than 2.3mmol/L of lactate. The multivariate analysis indicated that the intraoperative levels of lactate were not independently associated with changes in survival. On another hand, a preoperative T1 volume was an independent predictor PFS (HR 95%CI: 1.41, 1.02-1.82, p=0.006) and OS (HR 95%CI: 1.47, 1.11-1.96, p=0.006). CONCLUSION: This retrospective study suggests that the serum concentrations of lactate cannot be used as a biomarker to predict survival after GB surgery. To date, there are no clinically available serum biomarkers to determine prognosis in patients with high-grade gliomas. These tumors may produce high levels of lactic acid. We hypothesized that serum lactic could be used of biomarker to predictor of survival in patients with glioblastoma (GB). In this study, we collected perioperative and survival data from 275 adult patients with primary high-grade gliomas to determine whether intraoperative serum acid lactic concentrations can serve as a marker of prognosis. The median serum concentration of lactate was 2.3mmol/L. Our analysis indicated the intraoperative levels of lactate were not independently associated with changes in survival. This retrospective study suggests that the serum concentrations of lactate cannot be used as a biomarker to predict survival after GB surgery.

Congener specific determination of polychlorinated naphthalenes in sediment and biota by gas chromatography high resolution mass spectrometry.

An isotope dilution congener-specific method for the determination of the most abundant and most toxic polychlorinated naphthalenes (PCNs) was developed using gas chromatography with high resolution mass spectrometry (GC-HRMS). The method was used to determine the concentration of 24 target congeners and total PCN concentrations in fish and sediment samples. Tissue samples were extracted using pressurized liquid extraction (PLE) and sediment samples were extracted using Soxhlet extraction. Sample extracts were cleaned up using either a manual two-stage open column procedure or an automated FMS Power Prep System with multi-analyte and multi-sample capability using a three-column cleanup procedure. Sediment extracts were cleaned up with a dual open column cleanup technique involving the use of both a multi-layered silica (silver nitrate/acid/base/neutral silica) column followed by column containing carbon-activated silica. Fish tissue extracts were cleaned up on the automated system involving the use of a high capacity ABN (acid/base/neutral column), carbon celite column, and a basic alumina column. The method is capable of producing instrument detection limits (IDLs) between 0.06 and 0.13pg for each PCN (on column), with method detection limits (MDLs) for the fish extracts ranging from 1.3 to 3.4pg/g (wet weight) and 0.46 to 1.2pg/g (dry weight) for sediments. The average accuracy of 34 spiked fish samples analysed over a period of several months was 100% with a precision (%RSD) of 12%. Similarly, the average accuracy for 28 spiked sediment samples was 104% with a precision (%RSD) of 12%. The application of the method to environmental samples was demonstrated through the analysis of sediment and fish samples obtained from Lake Ontario, Canada. The method is used both for the determination of 24 PCNs and to perform non-targeted screening for the remaining 51 PCN congeners, which are included in the total PCN quantification result. It is currently one of the most comprehensive and accurate congener-specific methods available and was developed from the existing techniques used for the determination of polychlorinated dioxins and furans to produce high quality data with only minor modifications in the clean-up procedure. It can therefore be readily adopted by other laboratories performing dioxin and POP analyses.

The use of isoflurane and desflurane as inhalational agents for glioblastoma surgery. A survival analysis.

BACKGROUND: Several studies have examined the impact of anesthetics on cancer recurrence. Isoflurane but not desflurane has protumoral effects. We hypothesize the use of isoflurane but not desflurane during surgery for primary GBM is an independent predictor of disease progression and mortality. METHODS: 378 adult patients were included in the study. The progression free survival (PFS) and overall survival (OS) rates at 1 and 5years were compared in patients who had either desflurane or isoflurane alone or in combination with propofol infusion. Multivariate analyses were conducted to test the association between preoperative, intraoperative and postoperative hyperglycemia with PFS and OS. RESULTS: Kaplan-Meier curves demonstrated similar survival in patients who had either desflurane or isoflurane. The use of a propofol infusion during surgery did not affect survival. Univariate analysis demonstrated that age, body mass index and the adjusted Charlson comorbidity score were associated with reduced survival. The multivariate analysis confirmed that age and BMI but not the type volatile anesthetic use were independent prognostic factors for PFS (HR, 95%CI: 1.07, 0.85-1.37, 9=0.531) and OS (HR, 95%CI: 1.13, 0.86-1.48, p=0.531). CONCLUSION: The use of isoflurane or desflurane during GBM surgery is not associated with reduced PFS or OS.

Preoperative statin use is not associated with improvement in survival after glioblastoma surgery.

Cohort studies have suggested that the use of statins is associated with decreased risk of glioma formation and mortality. Here, a cohort of patients with glioblastoma multiforme (GBM) was analyzed to further investigate associations between preoperative use of statins and recurrence, and progression free and overall survival. Patients who had surgery for GBM (N=284) were followed up for a median of 18.1months. Seventy-eight patients were taking statins preoperatively while the rest were not. Cox proportional hazards models adjusted for several covariates of interest were applied before and after propensity score matching. Compared with statin users, those not taking the lipid-lowering drugs had similar progression free survival before (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.70-1.26; p=0.68) and after propensity score matching (HR 0.95, 95% CI 0.67-1.35; p=0.68). Mortality was similar between both groups of patients before (HR 0.94, 95% CI 0.70-1.22; p= 0.73) and after propensity score matching (HR 1.13, 95% CI 0.78-1.64; p=0.49). Age and dexamethasone use were independent prognostic factors of survival. Contrary to previously published evidence, this study could not find an association between preoperative statin use and longer survival in GBM patients. Due to the small number of patients and retrospective nature of the study, further work is needed to understand the role of perioperative statins in GBM patients.

Hematological and Immunological Changes Due to Short-term Oral Administration of Acephate.

To evaluate immunotoxicological effects of environmental chemical, subacute toxicity of repeated (28 day) oral administration of acephate (Ace) in BALB/c mice was assessed. Thirty two (sixteen male and sixteen female) mice were divided into four different groups with each group containing eight (four male and four female) mice. Mice of Group C1 were administered normal saline only and served as control. Group T1 was given 1/40(th) of apparent LD(50) (ALD(50)) (8.78 mg/kg), and group T2 was put on 1/30(th) of ALD(50) [11.7 mg/kg], while group T3 received 1/20(th) of ALD(50) [17.55 mg/kg] of Ace suspended in normal saline. The blood samples were collected from mice after 28 days of oral administration and analyzed for hematological, biochemical, and immunological parameters. The study showed that hematological parameters (monocytes and granulocytes) remained unaffected except total leukocyte count and lymphocyte which were decreased highly significantly [P≤0.01] in mice of group T3 on the 28(th) day of experiment. Serum total protein (TP) and serum globulin decreased significantly in mice of treatment groups dose dependently; however, no significant change was seen in serum albumin. Progressive increase in live body weight of mice decreased significantly in extremely toxic group only while spleen:body weight ratio decreased significantly in dose-dependent manner. Furthermore, Ace produced suppressed humoral immune response and the delayed-type hypersensitivity response to Sheep red blood cells (SRBCs) was altered nonsignificantly. The results of this study describe the suppression of immune responses following exposure to Ace at low concentrations in experimental mice.

Pharmacokinetics of gatifloxacin in broiler chickens following intravenous and oral administration.

1. The pharmacokinetics of gatifloxacin were investigated following intravenous and oral administration of a single dose at a rate of 10 mg/kg body weight in broiler chicks. 2. Drug concentration in plasma was determined using High Performance Liquid Chromatography with ultraviolet detection on samples collected at frequent intervals after drug administration. 3. Following intravenous administration, the drug was rapidly distributed (t(1/2α): 0·33 ± 0·008 h) and eliminated (t(1/2ß): 3·62 ± 0·03 h; Cl(B): 0·48 ± 0·002 l/h/kg) from the body. 4. After oral administration, the drug was rapidly absorbed (C (max): 1·74 ± 0·024 µg/mL; T (max): 2 h) and slowly eliminated (t(1/2ß): 3·81 ± 0·07 h) from the body. The apparent volume of distribution (V(d(area))), total body clearance (Cl(B)) and mean residence time (MRT) were 3·61 ± 0·04 l/kg, 0·66 ± 0·01 l/h/kg and 7·16 ± 0·08 h, respectively. The oral bioavailability of gatifloxacin was 72·96 ± 1·10 %. 5. Oral administration of gatifloxacin at 10 mg/kg is likely to be highly efficacious against susceptible bacteria in broiler chickens.

Prophylactic use of anti-emetic medications reduced nausea and vomiting associated with exenatide treatment: a retrospective analysis of an open-label, parallel-group, single-dose study in healthy subjects.

AIMS: Transient nausea and, to a lesser extent, vomiting are common adverse effects of exenatide that can be mitigated by dose titration and usually do not result in treatment discontinuation. This retrospective analysis of data from a phase 1, open-label, parallel-group, single-dose study in healthy subjects evaluated the effect of oral anti-emetics on exenatide-associated nausea and vomiting and on the pharmacokinetics of exenatide. METHODS: A single subcutaneous dose (10 µg) of exenatide was administered to 120 healthy subjects (19-65 years, BMI 23-35 kg/m(2) ). Incidences of nausea and vomiting were compared between 60 subjects premedicated with two oral anti-emetics 30 min before the exenatide dose and 60 non-premedicated subjects. Similarly, the area under the concentration-time curve (AUC) and the maximum observed concentration (C(max) ) of plasma exenatide concentrations over 8 h post-dose were compared. RESULTS: Among all subjects [61% male, 32 ± 12 years, body mass index (BMI) 29.1 ± 3.4 kg/m(2) (mean ± sd)], mild to moderate nausea was the most frequent adverse event after exenatide dosing. Vomiting was also observed. Subjects premedicated with anti-emetics experienced significantly less nausea and vomiting (16.7 and 6.7%, respectively) vs. non-premedicated subjects (61.7 and 38.3%, respectively; P-value <0.0001 for both nausea and vomiting). The mean area under the concentration-time curve and the maximum observed concentration AUC and C(max) of plasma exenatide concentrations during 8 h post-dose were not significantly different between groups. CONCLUSION: Administration of oral anti-emetics before a single 10-µg exenatide dose was associated with significant reductions in treatment-emergent nausea and vomiting, with no discernible effect on the pharmacokinetics of exenatide. Use of anti-emetic therapy may provide a short-term strategy to minimize the nausea and vomiting associated with exenatide treatment.

HPLC Method for Determination of Enantiomeric Purity of a Novel Respiratory Fluoroquinolone: WCK 1152.

A sensitive, simple, specific, precise, accurate and rugged method for determination of enantiomeric purity of S-(-)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-{4-amino-3,3-dimethylpiperidin-1-yl}-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate, WCK 1152, a new drug substance has been developed. The method is based on prederivatization of analyte to diastereomer followed by RP-HPLC using endcapped C-18 stationary phase. Column was maintained at 30 degrees C. The UV/Vis detector was operated at 290 nm. Flow rate of the mobile phase was 1.25 ml/min. The method offers excellent separation of two enantiomers with resolution more than 4 and tailing factor less than 1.5. The method was validated for the quantification of R-(+)-enantiomer impurity, WCK 1153 in the bulk drug. Calibration curves showed excellent linearity over the concentration range of 0.1 to 1.5 mg/ml for WCK 1152 and 0.01 to 0.15 mg/ml for WCK 1153. Precision of the method was 1.13%. Limit of detection and limit of quantitation of the method for WCK 1152 were 0.0006 mg/ml and 0.0018 mg/ml and for WCK 1153 were 0.0007 mg/ml and 0.0021 mg/ml, respectively. Average recovery of the WCK 1153 in WCK 1152 was 94.4%. This method was employed in determining enantiomeric purity of clinical trial batches of WCK 1152.

Effect of temperature on growth and chemotactic behaviour of Campylobacter jejuni.

AIM: To determine the effect of two physiologically important temperatures on growth and chemotaxis in Campylobacter jejuni. METHODS AND RESULTS: Growth curves of Camp. jejuni were compared at 37 degrees C and 42 degrees C. Chemotaxis was compared at 37 degrees C and 42 degrees C by the disc and capillary assays. Student's t-test was applied to the results of the capillary assay to assess the significance in the difference between chemotaxis at the two temperatures. Both, the growth rate and chemotactic ability of the isolate, were found to be greater at 37 degrees C. CONCLUSIONS: Quorum sensing (related to population density), a regulation mechanism of virulence in micro-organisms, has been reported in Campylobacter. Chemotaxis is also a known virulence factor of Campylobacter. Both, growth (in terms of population density) and chemotaxis, being greater at 37 degrees C than at 42 degrees C, suggests that the physiological temperature of humans (37 degrees C) might be more favourable for the expression of virulence in Campylobacter than that of birds (42 degrees C). SIGNIFICANCE AND IMPACT OF THE STUDY: It is as yet not known why Campylobacter causes disease in humans but is avirulent in birds. This study suggests that the human body temperature is optimum for growth and chemotaxis in Campylobacter. There is scope for the study of temperature regulation of other virulence determinants of Campylobacter.

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures.

BACKGROUND: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. OBJECTIVE: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. METHODS AND RESULTS: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 microg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 microg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 microg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 microg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. CONCLUSION: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

A non-polyene antifungal antibiotic from Streptomyces albidoflavus PU 23.

In all 312 actinomycete strains were isolated from water and soil samples from different regions. All these isolates were purified and screened for their antifungal activity against pathogenic fungi. Out of these, 22% of the isolates exhibited activity against fungi. One promising strain, Streptomyces albidoflavus PU 23 with strong antifungal activity against pathogenic fungi was selected for further studies. Antibiotic was extracted and purified from the isolate. Aspergillus spp. was most sensitive to the antibiotic followed by other molds and yeasts. The antibiotic was stable at different temperatures and pH tested and there was no significant loss of the antifungal activity after treatment with various detergents and enzymes. Synergistic effect was observed when the antibiotic was used in combination with hamycin. The antibiotic was fairly stable for a period of 12 months at 4 degree C. The mode of action of the antibiotic seems to be by binding to the ergosterol present in the fungal cell membrane resulting in the leakage of intracellular material and eventually death of the cell. The structure of the antibiotic was determined by elemental analysis and by ultraviolet (UV), Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR) and liquid chromatography mass spectra (LCMS). The antibiotic was found to be a straight chain polyhydroxy, polyether, non-proteinic compound with a single double bond, indicating a nonpolyene antifungal antibiotic.

Production of a growth dependent metabolite active against dermatophytes by Streptomyces rochei AK 39.

BACKGROUND & OBJECTIVE: Dermatophytes responsible for causing dermatophytoses in humans have acquired resistance to certain antimycotic drugs. We isolated naturally occurring actinomycetes with an ability to produce metabolites having antimycotic property. The timecourse of antifungal metabolite production in terms of arbitrary units (AU) under optimum conditions was studied. METHODS: Water and soil samples were collected from various locations. The actinomycetes were isolated on starch casein medium and screened for their antifungal activity against yeasts and molds including dermatophytes. One promising isolate which showed a unique, stable and interesting property of inhibiting only dermatophytes was selected and characterized. Optimization of antifungal metabolite production in terms of AU using Trichphyton rubrum as target was done. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values of the culture supernatant from the isolate and that of griseofulvin were determined for all dermatophytes. RESULTS: Of the 218 actinomycete isolates, 14 per cent produced the metabolites having antifungal activity. The selected actinomycete, identified as Streptomyces rochei AK 39 produced metabolite, which was active against only dermatophytes whereas yeasts and other molds were resistant to it. Starch casein medium was found to be good for inducing antifungal activity in the isolate. The maximum antifungal metabolite production (400 AU/ml) was achieved in the late log phase, which remained constant during the stationery phase, and it was extracellular in nature. The MIC and MFC values of the culture supernatant from the isolate against the dermatophytes were within the range 1.25 to 5 and 1.25 to 10 AU/ml respectively. INTERPRETATION & CONCLUSION: The metabolite from Streptomyces rochei AK 39 was produced during late log phase and was active against only dermatophytes with a greater potency than griseofulvin. However, this needs further investigation using purified powdered form of the active component.

Isolation, characterization and optimization of antifungal activity of an actinomycete of soil origin.

About 312 actinomycetes were isolated from soil samples on chitin agar. All these isolates were purified and screened for their antifungal activity against pathogenic fungi. Out of these, 22% of the isolates exhibited activity against fungi. One promising isolate with strong antifungal activity against pathogenic fungi was selected for further studies. This isolate was from Pune, and was active against both yeasts and molds. Various fermentation parameters were optimized. Based on morphological and biochemical parameters, the isolate was identified as Streptomyces. The correlation of antifungal activity with growth indicated growth dependent production of antimetabolite. Maximum antifungal metabolite production (600 units/ml) was achieved in the late log phase, which remained constant during stationery phase, and it was extracellular in nature.

Effects of PYY[3-36] in rodent models of diabetes and obesity.

BACKGROUND: Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L cells following meals. The cleaved subpeptide PYY[3-36] is biologically active and may constitute the majority of circulating PYY-like immunoreactivity. The peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted for its orexigenic effect following intracerebroventricular administration. OBJECTIVE: To investigate the effects of peripheral (intraperitoneal and chronic subcutaneous) infusions of PYY[3-36] on food intake, body weight and glycemic indices. DESIGN/RESULTS: Food intake was measured in normal mice and in several rodent models of obesity and type II diabetes. In marked contrast to the reported central orexigenic effects, in the present study, PYY[3-36] acutely inhibited food intake by up to 45%, with an ED(50) of 12.5 microg/kg in fasted female NIH/Swiss mice. A 4-week infusion reduced weight gain in female ob/ob mice, without affecting the cumulative food intake. In diet-induced obese male mice, PYY[3-36] infusion reduced cumulative food intake, weight gain and epididymal fat weight (as a fraction of carcass) with similar ED(50)'s (466, 297 and 201 microg/kg/day, respectively) and prevented a diet-induced increase in HbA1c. Infusion at 100 microg/kg/day for 8 weeks in male fa/fa rats reduced the weight gain (288+/-11 vs 326+/-12 g in saline-infused controls; P<0.05), similar to effects in a pair-fed group. In female ob/ob and db/db mice, there was no acute effect of PYY[3-36] on plasma glucose concentrations. In male diabetic fatty Zucker rats, PYY[3-36] infused for 4 weeks reduced HbA1c and fructosamine (ED(50)'s 30 and 44 microg/kg/day). CONCLUSION: Peripheral PYY[3-36] administration reduced the food intake, body weight gain and glycemic indices in diverse rodent models of metabolic disease of both sexes. These findings justify further exploration of the potential physiologic and therapeutic roles of PYY[3-36].

Effect of gamma radiation on survival of Campylobacters in various food samples.

PURPOSE: Campylobacter spp. is a major food borne pathogen and shows resistance towards gamma radiation. In the present study, effect of gamma radiation was assessed on the indigenous strains of Campylobacter spp. inoculated in food and water samples. METHODS: Campylobacter spp. were isolated from river water and faeces of various birds and animals. The growth rate was studied for these isolates by propagating them in Kapadnis-Baseri medium. The survival of Campylobacter spp. inoculated in food and water samples was tested after exposing them to gamma radiation. RESULTS: The isolates survived well in meat and milk samples and were sensitive to 1.8 KGy dose of gamma radiation, which lies with in the FDA limit. The effect of radiation on Campylobacter spp. varied with the species and the type of food. CONCLUSIONS: The results obtained suggest that the dose of gamma radiation should be standardized depending on the Campylobacter spp. and the type of food that is being processed.

Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).

Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.

Synergy between amylin and cholecystokinin for inhibition of food intake in mice.

Several gastrointestinal peptides which are secreted in response to nutrients have been reported to suppress food intake. Amylin is a peptide hormone co-secreted with insulin from pancreatic beta-cells in response to nutrient stimuli. Cholesystokinin (CCK) is secreted from duodenal and jejunal mucosal cells in response to fat and protein. Amylin and CCK-8 have been reported to reduce food intake in rodents when given centrally as well as peripherally. Amylin injected intraperitoneally (i.p.) reduced food intake over the subsequent 30 min in overnight fasted mice by a maximum of 57 +/- 6% with an ED50 of 0.93 nmol/kg (3.63 microg/kg) +/- 0.34 log units. On a molar basis, this potency was similar to that of CCK-8 (ED50 0.85 nmol/kg (0.97 microg/kg) +/- 0.28 log units; p = 0.93) which inhibited food intake by a maximum of 71 +/- 7%. When amylin and CCK-8 were injected i.p. as an amylin:CCK-8 mixture, immediately before presentation of food in overnight fasted mice, food intake in the subsequent 30 min was reduced by a maximum of 91%, an amount that was greater than that producable by i.p. injection of amylin or CCK-8 alone. Isobolar analysis revealed a marked synergy between amylin and CCK-8 in reducing food intake, such that statistically ineffective doses of amylin and CCK, when combined, evoked near-maximal inhibition of food intake. Because the typical physiological event is for amylin and CCK both to be secreted in response to mixed meals, the synergy between them could indicate a shared role in physiological appetite control.