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The in vitro digestion of a self nano-emulsifying drug delivery system (SNEDDS) was visualized by cryogenic transmission electron microscopy (Cryo-TEM). The dynamic lipolysis model, simulating the environment of the gastrointestinal tract in fasted conditions, was used for this purpose. The results revealed that micelles are present during the entire lipolysis process. Oil droplets from the self nano-emulsifying drug delivery system are transformed to spherical or elongated unilamellar vesicles as lipolysis progresses. Low numbers of bilamellar and open vesicles were detected. After 50% hydrolysis a decrease in the number of unilamellar vesicles and oil droplets was observed. Furthermore, the electrical properties of the oil droplets were investigated by measuring their zeta-potential values as a function of time. An increase (in absolute values) to the zeta-potential of the hydrolyzing SNEDDS droplets observed versus time implying (binding or incorporation) of the micelles to the surface. The current data emphasize that Cryo-TEM combined with the in vitro dynamic lipolysis model can offer useful information on the formation of the various colloid phases during in vitro digestion of lipid-based formulations. Furthermore, it can provide a better understanding of the in vivo behavior of these systems, as well the solubilization of lipophilic drug compounds, offering new insights for designing and optimizing oral lipid-based formulations and possibly predicting their in vivo behavior. Such methodology can be a useful tool for the strategic development of lipid-based formulations.

Serum ethanol concentrations may become higher when alcohol is consumed during treatment with histamine receptor antagonists, especially if ethanol is ingested postprandially. Only a few studies have investigated fasting subjects, and women have only been investigated sporadically.The present study compared serum ethanol concentrations after a 4-h fast followed by a low (0.15 g/kg) and a high (0.45 g/kg) dose of ethanol, on two separate occasions in six women and six men. The study was carried out before and after treatment with 400 mg cimetidine twice daily.Cimetidine administration did not change the area under the concentration-time curve or the maximal serum ethanol concentration in either women or men, irrespective of ethanol dose. Ethanol elimination rate was unchanged by cimetidine.Cimetidine does not influence the ethanol concentration-time curve when ethanol is ingested on an empty stomach.

SummaryOBJECTIVE We evaluated the long‐term results in two different groups of patients with primary hyperparathyroidism treated with ultrasonically guided percutaneous ethanol (96%) injection into parathyroid tumours.DESIGN A prospective long‐term follow‐up (more than 6 months). Ethanol (96%) was injected under ultrasonic guidance into biopsy verified solitary parathyroid tumours. Basic treatment included a maximum of three treatments with an interval of about 1 month (group 1) or 1 week (group 2). Dose of ethanol was half the volume of the parathyroid tumour.PATIENTS Two different groups of patients with only one ultrasonically detected and biopsy verified parathyroid tumour were treated. Group 1 (n= 18) were treated regardless of the severity of the hyperparathyroid disease. Group 2 (n= 14) were selected for treatment either due to severe hypercalcaemic symptoms (n= 3), a high surgical risk (n= 5), or refusal of surgery (n= 6).MEASUREMENTS The volume of the parathyroid tumours was measured as half the product of maximum length, width, and depth. Blood tests included measurements of ionized calcium, total calcium and PTH.RESULTS In group 1, 12 of 18 patients (66%) could be followed more than 6 months. Follow‐up ranged from 12 to 58 months (median 45 months). A significant decrease (P < 0 001) in serum concentrations of ionized calcium and total calcium was observed. Eight patients (44%) later underwent surgical parathyroidectomy. Injection therapy was regarded as successful in 10 of 18 patients (56%). In group 2,11 of 14 patients (79%) were followed more than 6 months. Follow‐up ranged from 18 to 50 months (median 39 months). A significant decrease (P <0 001) in serum concentrations of ionized calcium, total calcium and intact PTH (1–84) was observed. Treatment was successful in 11 of 14 patients (79%). Two patients required parathyroid surgery. Re‐examination with ultrasound showed a significant reduction in the volume of the treated parathyroid tumours. Fibrosis surrounding the parathyroid tumours was detected in eight of 10 patients who subsequently had operations. One patient from each group had a complication of a unilateral permanent vocal cord paralysis following injection therapy.CONCLUSION Partial or complete long‐term remission of primary hyperparathyroidism can be achieved using ultrasound‐guided chemical parathyroidectomy. However, the intervals between treatments should be short and the treatment should be reserved only for patients not fit for surgery.

The substrate specificity, pH activity curves, inhibition characteristics and in vitro stabilities of the human ADH isozymes characteristic of the structural loci, ADH1, ADH2 and ADH3, have been investigated using crude tissue extracts and partially purified material. Alcohol substrates: Seventeen different alcohols were tested. The products of the three loci showed differences in their relative activities with the different substrates. Thus ADH1 isozymes were most active with ethanol, allyl alcohol, sec propanol and cyclohexanol; the 'usual' ADH2 were most active with ethanol, butanol, octanol and sec butanol; the 'atypical' ADH2 isozymes were most active with ethanol and octanol, but showed relatively low activity with butanol and Ronicol; the ADH3 isozymes were relatively very active with long straight chain primary alcohols. Aldehyde substrates: Six different aldehydes were tested. No significant differences between the isozyme products of the three loci were detected except in the case of chloral hydrate. The ADH1 and 'usual' ADH2 isozymes showed activity with chloral hydrate but this was a very poor substrate for the ADH3 and 'atypical' ADH2 isozymes. pH activity profiles: With ethanol as substrate the pH optimum for the ADH1, 'usual' ADH2 and the ADH3 isozymes was around pH 11.5 and for the 'atypical' ADH2 isozymes was about pH 8.8. With acetaldehyde as substrate the pH optima for the ADH1, 'usual' ADH2, 'atypical' ADH2 and ADH3 isozymes were about pH 8.8, 6.0, 7.0-7.5 and 6.5, resp. Inhibitors: Trichloroethanol was found to be a potent inhibitor of the ADH1 isozymes; isobutyramide an inhibitor of ADH3; and pyrazole and thiourea were shown to be powerful inhibitors of the 'atypical' ADH2 isozymes. In vitro stability: The ADH1 isozymes appeared to be relatively less stable than the 'usual' ADH2 and ADH3 isozymes. The 'atypical' ADH2 isozymes were found to be relatively very labile and particularly susceptible to freezing and thawing or storage at 10° C. The ADH 1;3 and ADH 2;3 isozymes were not demonstrably different in the properties tested.

Preclinical studies in rodents have demonstrated inhibitory effects of glucagon-like peptide-1 (GLP-1) receptor stimulation on alcohol consumption. The effects of GLP-1 receptor stimulation on alcohol intake in primates have not been investigated.We performed placebo-controlled studies on the effects of the GLP-1 receptor agonists exenatide and liraglutide on alcohol consumption in alcohol-preferring male African vervet monkeys. Monkeys selected for voluntary alcohol drinking were observed for at least 10 days of baseline drinking and allocated to drug or vehicle (n = 11-12 per group) balanced with respect to alcohol intake. Monkeys had access to alcohol 4 h/day. In a first study, monkeys were treated with exenatide 0.04 mg/kg or vehicle once weekly for 5 weeks to obtain steady-state plasma levels. In a second study, monkeys were treated daily with liraglutide (increasing dosing, 10 to 50 μg/kg/day) or vehicle over 2 weeks. In both studies, access to alcohol was suspended during drug up-titration. Then, alcohol was again made available 4 h/day and treatment was continued for 2 weeks, during which alcohol intake was recorded. Observation of alcohol intake was continued for a week of drug washout.Liraglutide and to a lesser extent exenatide significantly reduced alcohol consumption without causing any signs of emesis and with no effect on water intake as compared to vehicle.The present study demonstrates for the first time that GLP-1 receptor agonists can reduce voluntary alcohol drinking in non-human primates. The data substantiate the potential usefulness of GLP-1 receptor agonists in the treatment of alcohol use disorder.

The relative biological effectiveness (RBE) varies along the treatment field. However, in clinical practice, a constant RBE of 1.1 is assumed, which can result in undesirable side effects. This study provides an accurate overview of current clinical practice for considering proton RBE in Europe.A survey was devised and sent to all proton therapy centres in Europe that treat patients. The online questionnaire consisted of 39 questions addressing various aspects of RBE consideration in clinical practice, including treatment planning, patient follow-up and future demands.All 25 proton therapy centres responded. All centres prescribed a constant RBE of 1.1, but also applied measures (except for one eye treatment centre) to counteract variable RBE effects such as avoiding beams stopping inside or in front of an organ at risk and putting restrictions on the minimum number and opening angle of incident beams for certain treatment sites. For the future, most centres (16) asked for more retrospective or prospective outcome studies investigating the potential effect of the effect of a variable RBE. To perform such studies, 18 centres asked for LET and RBE calculation and visualisation tools developed by treatment planning system vendors.All European proton centres are aware of RBE variability but comply with current guidelines of prescribing a constant RBE. However, they actively mitigate uncertainty and risk of side effects resulting from increased RBE by applying measures and restrictions during treatment planning. To change RBE-related clinical guidelines in the future more clinical data on RBE are explicitly demanded.

Freshwater snails are intermediate hosts for a number of trematodes of which some are of medical and veterinary importance. The trematodes rely on specific species of snails to complete their life cycle; hence the ecology of the snails is a key element in transmission of the parasites. More than 200 million people are infected with schistosomes of which 95% live in sub-Saharan Africa and many more are living in areas where transmission is on-going. Human infection with the Fasciola parasite, usually considered more of veterinary concern, has recently been recognised as a human health problem. Many countries have implemented health programmes to reduce morbidity and prevalence of schistosomiasis, and control programmes to mitigate food-borne fascioliasis. As these programmes are resource demanding, baseline information on disease prevalence and distribution becomes of great importance. Such information can be made available and put into practice through maps depicting spatial distribution of the intermediate snail hosts.A biology driven model for the freshwater snails Bulinus globosus, Biomphalaria pfeifferi and Lymnaea natalensis was used to make predictions of snail habitat suitability by including potential underlying environmental and climatic drivers. The snail observation data originated from a nationwide survey in Zimbabwe and the prediction model was parameterised with a high resolution Regional Climate Model. Georeferenced prevalence data on urinary and intestinal schistosomiasis and fascioliasis was used to calibrate the snail habitat suitability predictions to produce binary maps of snail presence and absence.Predicted snail habitat suitability across Zimbabwe, as well as the spatial distribution of snails, is reported for three time slices representative for present (1980-1999) and future climate (2046-2065 and 2080-2099).It is shown from the current study that snail habitat suitability is highly variable in Zimbabwe, with distinct high- and low- suitability areas and that temperature may be the main driving factor. It is concluded that future climate change in Zimbabwe may cause a reduced spatial distribution of suitable habitat of host snails with a probable exception of Bi. pfeifferi, the intermediate host for intestinal schistosomiasis that may increase around 2055 before declining towards 2100.

To investigate the influence of alcohol on glucose counterregulation and recovery during acute insulin-induced hypoglycemia in type 2 diabetic subjects, 8 diet-treated type 2 diabetic subjects were examined twice after an overnight fast. A graded hyperinsulinemic (1 mU/kg/min, 60 to 195 minutes) euglycemic/hypoglycemic clamp was performed with concomitant infusion of 3-(3)H-glucose to assess glucose turnover. After a euglycemic baseline period (150 to 180 minutes), 200 mL of water was taken either alone or with alcohol (0.4 g/kg body weight). Hypoglycemia (plasma glucose nadir, 2.8 mmol/L) was subsequently induced, and the recovery period followed after discontinuation of insulin and the variable glucose infusion. On both study days, circulating concentrations of insulin and glucose were comparable. Alcohol intake markedly increased plasma lactate (area under the curve [AUC], recovery period) (244 +/- 30 v 12 +/- 4 mmol/L x 240 minutes; P = .00009) and suppressed plasma nonesterified fatty acids (NEFA) (AUC, recovery period) (95 +/- 13 v 161 +/- 18 mmol/L x 240 minutes; P = .0008). No differences were found in the counterregulatory response of catecholamines, cortisol, and growth hormone (GH). However, alcohol intake decreased peak glucagon significantly (155 +/- 12 v 200 +/- 17 pg/mL; P = .038). In diet-treated, mild type 2 diabetic subjects, alcohol does not modify recovery from insulin-induced hypoglycemia.