Prucalopride, a systemic enterokinetic, for the treatment of constipation.

BACKGROUND: Laxatives are frequently ineffective in treating constipation. An alternative therapeutic approach is to target serotonin-4 receptors, which are involved in initiating peristalsis. AIM: In a double-blind, placebo-controlled trial, to assess the efficacy and safety of a systemically active serotonin-4 agonist, prucalopride. METHODS: Seventy-four women with constipation were stratified into slow or normal transit groups, and each group was randomized to receive either placebo or 1 mg prucalopride daily for 4 weeks. A bowel function diary was maintained. Whole-gut and orocaecal transit, visceral sensitivity, quality of life and psychological state were assessed before and after treatment. RESULTS: Prucalopride, not placebo, increased spontaneous stool frequency (P=0.008) and reduced time to first stool (P < 0.001). Prucalopride reduced the number of retained markers in all patients compared to placebo (P=0.004). Prucalopride reduced the mean number of retained markers in slow transit (P=0.069), but did not alter the marker count in normal transit (P=0.86). Orocaecal transit was accelerated by prucalopride, not placebo (P=0.004). Prucalopride, notplacebo, increased rectal sensitivity to distension (urge volume, P=0.01) and electrical stimulation (P=0.001). Prucalopride significantly improved several domains of the Short Form Health Status Survey and the disease-specific quality of life. Adverse effects were similar for prucalopride and placebo. CONCLUSIONS: Prucalopride improves symptoms, upper gut transit and gut sensitivity in constipated patients with both slow and normal transit. It improves transit in patients with slow transit. These changes are associated with improved well-being.

Lectins in drug delivery: a study of the acute local irritancy of the lectins from Solanum tuberosum and Helix pomatia.

Lectins are proteins or glycoproteins of non-immune origin capable of binding to one or more specific sugar residues. The potential for using lectins as a means of 'anchoring' a drug delivery system to the mucosal surfaces of the eye has been investigated in previous work, with the lectins from Solanum tuberosum and Helix pomatia showing particular promise. In this study the acute local dermal irritancy of these lectins, in terms of their potential to cause inflammation and tissue necrosis, was investigated. After an initial study in terminally anaesthetised animals (to ensure no gross toxicity was evident), five male New Zealand white rabbits from the same litter were briefly anaesthetised and Evans blue injected intravenously as a marker of inflammation. Sterile lectin solutions in normal saline at a range of concentrations from 50 to 500 microg ml(-1) were prepared and 50-microl volumes injected intradermally at 18 sites across a shaved area of each rabbit's back. The rabbits were then allowed to regain consciousness. There was no evidence of tissue necrosis, oedema or Evans blue infiltration with any of the lectin solutions administered. The rabbits did not display any signs of discomfort such as scratching or continued grooming throughout the experiment. Histological examination of the injection sites revealed little sign of any inflammation, such as heterophil migration, oedema or tissue damage. It was concluded that these lectins demonstrate minimal acute irritancy, and will, therefore, be taken forward for formulation and in vivo studies.

Public health hazards of meat from small ruminants: the perspective of Australia.

The production of meat from sheep and goats in Australia occurs almost entirely at pasture in zones known as the semi-arid pastoral zone, the wheat-sheep zone (where sheep and crops form an agricultural rotation system) and the high rainfall zone. Each zone has particular factors which affect the human health hazards associated with sheep and goat meat and the opportunities for prevention. The authors provide an overview of small ruminant production in Australia and a synopsis of the diseases encountered, including the factors which influence epidemiology. Animal health arrangements for underwriting food safety at the pre-harvest and post-harvest stages of production in Australia are also outlined. Specific public health hazards related to sheep and goat meat, together with measures for prevention, are considered under the headings of zoonoses, enteropathogens and chemical residues.

Residues from long-acting antimicrobial preparations in injection sites in cattle.

OBJECTIVE: To investigate tissue residues of two long-acting oxytetracycline (OTC) preparations in cattle. DESIGN: A randomised drug residue trial. ANIMALS: Two hundred and forty beef cattle in 24 groups of ten. PROCEDURE: Two blind-coded 200 mg/mL OTC preparations were used in five treatment regimens of various combinations of injection sites (from one to five) and administrations (one or two). Five cattle from each group were slaughtered at 21, 30 and 60 days after injection and the injection site, urine, kidney and diaphragm muscle analysed for residues. RESULTS: The OTC concentration exceeded the maximum residue limit in kidney in animals slaughtered 21 days after treatment, which is the prescribed withholding period. Concentration at the injection site was much greater than the maximum residue limit 30 days post-treatment, but not 45 days post-treatment. The residue was smaller when OTC had been injected in multiple sites. There was no difference between the two OTC preparations. CONCLUSION: A review of the maximum injection volume, site of injection and the withholding period is needed for long-acting OTC formulations.

Food safety and residues in Australian agricultural produce.

A brief history of food safety in Australia in the context of the development of scientific knowledge is presented. Australia's food and food commodity residue and contamination surveillance and monitoring programs are outlined. Although chemical residues are perceived as a major health risk by the general community, the risk of food causing illness or death because of chemical residues is low. The major threat to human health from food is microbiological contamination, in terms of deaths, sickness and economic loss. The emerging influences in food safety are scientific and technical developments, deregulation, social and demographic factors, and the media. The risk of disruption of domestic and export markets by food safety issues is considerable. The emergence of international standards for food production and processing will enable commercial contractual arrangements to minimise the frequency of disruptive food safety incidents.

Programs for surveillance and monitoring of antibacterial residues in Australia, 1989 to 1993.

The development of a State-based confirmatory testing capability for antibiotic residues in meat in Australia has allowed the rapid feedback to producers failing to comply with antibiotic maximum residue limits. The identification of problem areas in various categories of livestock, and subsequent focused surveillance programs, has reduced the prevalence of antibacterial residues in both domestic and export meat products. Failure to observe withholding periods of antibacterial drugs after treatment is the most significant cause of non-compliance. In the period July 1991 to June 1993 the compliance rate for antibacterial residues for all species was 99.9%.

Monitoring and surveillance in abattoirs of residues of antibacterial substances--a description of programs in Australia and the USA.

Australia and the USA are major international meat exporting countries. Both countries conduct programs to monitor and survey for antibacterial residues. Australian programs use a urine screening test, whereas the US programs use tissue fluids as the test medium. The development of surveillance programs to provide rapid feedback to producers is a feature of the Australian programs. The programs in each country compare favourably with regard to numbers of animals tested, results and action taken to prevent residues. The results of the Australian programs justify the promotion of a 'clean food' image for Australian meat products with respect to antibacterial drugs.

Strategies for mastitis control: dry cow therapy and culling.

The effects of three selection strategies for dry cow therapy on prevention of new infections and rate of antibiotic usage were compared. Quarter infection status of 1044 cows in 12 herds was determined by bacteriological methods at drying off, calving and three to five months into the following lactation. Cows that were uninfected at drying off were randomly allocated to treatment (whole udder, dry cow therapy) and non-treatment groups. Infected cows were randomly allocated to whole udder or infected quarter only treatments. The strategies compared were blanket treatment (treat all quarters of all cows), selective cow treatment (treat all quarters of any cow infected in one or more quarters) and selective quarter treatment (treat infected quarters only). Selective cow treatment was identified as the preferred strategy. Blanket treatment resulted in increased antibiotic usage (15.5 vs 6.4 tubes per infection eliminated) with no additional benefit, and selective quarter treatment resulted in a higher new infection rate (6.4% vs 3.9% quarters) in the dry period. The prevalence of infection within a herd at drying off had no influence on new infection rates in the dry period or early lactation. The cure rate after dry cow treatment (mean of 66%) decreased significantly with increasing age (P < 0.001). Cows infected in the previous lactation contributed over 76% of infections at calving and nearly 70% at mid-lactation. To lower the incidence of mastitis in a herd, a greater emphasis on culling of older infected cows and prevention of new infections during lactation is needed.

Effects of antibiotic therapy at drying off on mastitis in the dry period and early lactation.

Four strategies for selecting cows for intramammary therapy with benzathine cloxacillin at drying off were compared in 12 Victorian dairy herds. The bacteriological status of all quarters of all (1044) cows was determined just before drying off, within 2 d of calving, and again 3 to 5 months after calving. All cases of clinical mastitis (from calving to mid-lactation) were recorded. Cows not infected at drying off were allocated randomly to 2 subgroups of approximately 350 cows each: not infected, not treated (NI-NT), or not infected, all quarters treated (NI-AT). New infection rates in the dry period (3.8% for NI-NT vs 2.1% for NI-AT) and in early lactation (4.1% for NI-NT vs 3.9% for NI-AT) were low and these differences were not significant. Incidence of clinical mastitis in early lactation was almost 50% higher for the treated group of uninfected cows compared with the untreated group (0.05 less than p less than 0.1). Cows infected in one or more quarters at drying off were split randomly into 2 subgroups of approximately 170 cows each: infected, all quarters treated (I-AT), or infected quarters treated only (I-QT). The new infection rate during the dry period was nearly 4 times higher for I-QT (15.3%) due to significantly more new infections by Staphylococcus aureus and Streptococcus uberis.(ABSTRACT TRUNCATED AT 250 WORDS)

Photoperiodic control of the development of the LHRH neurosecretory system of European starlings (Sturnus vulgaris) during puberty and the onset of photorefractoriness.

The development of the reproductive system was studied in juvenile starlings during the acquisition of photosensitivity, the attainment of sexual maturation after photostimulation and the subsequent onset of photorefractoriness, using immunohistochemistry for LHRH and radioimmunoassay measurements of hypothalamic, pituitary and plasma hormone concentrations. The first stage of sexual development induced by exposure of photorefractory immature starlings to short days (8 h light:16 h darkness; 8L:16D) was characterized by a decrease in pituitary prolactin content within 1 week and an increase in hypothalamic LHRH content, in the size of the LHRH perikarya and in the intensity of immunostaining in the median eminence in 4-6 weeks. Sexual maturation occurring after exposure to long days (18L:6D) was associated with further increases in LHRH content and cell size, and increases in LH and prolactin concentrations. During testicular regression, LHRH perikarya were reduced in size and staining intensity but LHRH immunostaining in the median eminence and content in the hypothalamus remained high until gonadal regression was almost complete. Prolactin levels were maximal during testicular regression. These results suggest that gonadal regression is initiated by a reduction in LHRH synthesis and possibly, in addition, an external inhibitory influence on LHRH release. Hypothalamic LHRH content eventually declined and LHRH immunostaining in the median eminence was much reduced in fully photorefractory starlings maintained under long days.

Reproductive refractoriness in the Welsh Mountain ewe induced by a short photoperiod can be overridden by exposure to a shorter photoperiod.

The objectives were to determine if relative lengths of photoperiods that induce reproductive cycles in ewes affect the length of the subsequent breeding season, if duration of the refractoriness that terminates breeding is affected by photoperiod length, and if the resulting refractoriness to an inductive photoperiod is absolute. Groups of Welsh Mountain ewes were exposed to either 12L:12D (n = 12) or 8L:16D (n = 6) photoperiods beginning at the summer solstice when daylengths reach a maximum of 17.5 h at Bristol, England. A control group (n = 10) was exposed to natural daylengths. Ovarian cycles in the controls, as judged by monitored plasma progesterone levels, commenced in early October, about 1 mo later (p less than 0.001 in both cases) than in sheep exposed to 12L:12D or 8L:16D. The advancement in cycle onset was similar under 12L:12D and 8L:16D (69 +/- 2 and 77 +/- 4 days after the summer solstice compared with 102 +/- 2 days in the controls). Duration of the breeding season (100 +/- 4 days) in ewes exposed to 12L:12D was significantly shorter (p less than 0.001 in both cases) than in ewes exposed to natural daylengths or 8L:16D (153 +/- 3 and 133 +/- 5 days, respectively). Approximately 70 days after the ending of ovulatory cycles in the 12L:12D group, half of the animals (n = 6) were transferred to 8L:16D. This treatment greatly (p less than 0.001) reduced the duration of anestrus and cycles began again 62 +/- 4 days after transfer to 8L:16D, or about 90 days earlier than in ewes (n = 6) remaining in 12L:12D.(ABSTRACT TRUNCATED AT 250 WORDS)

Possible homologies between photorefractoriness in sheep and birds: the effect of thyroidectomy on the length of the ewe's breeding season.

Comparisons are drawn between the photoperiodically driven breeding cycles in "long-day" birds and "short-day" mammals, emphasizing the importance of photorefractoriness as a key regulator in the timing processes. It is argued that the two types of breeding cycle may not be so radically different as previously thought and, indeed the cycles may be strictly homologous. Evidence in support of this comes from the role of the thyroid glands in seasonality. In starlings and quail, thyroidectomy prevents refractoriness developing and the birds remain in breeding indefinitely under long days. If the processes underlying refractoriness are similar across species then thyroidectomy should greatly alter the ewe's breeding cycle. In two experiments, Welsh Mountain ewes were thyroidectomized in the summer during anoestrus and their subsequent periods of oestrus monitored under various daylengths. There was no effect of thyroidectomy on the time when oestrous cyclicity began in the Autumn but the onset of anoestrus was profoundly disrupted. All the ewes continued to cycle well beyond the end of the normal breeding season and a number have continued throughout the entire period of anoestrus.

Detection of antibodies to Eperythrozoon ovis by the use of an enzyme-linked immunosorbent assay.

Specific antibody to Eperythrozoon ovis was detected by an enzyme-linked immunosorbent assay (ELISA) in the sera of infected sheep. In the presence of parasite antigen, positive control serum showed a reaction approximately eight times that of negative serum. When compared to an immunofluorescent antibody test (IFAT), the ELISA was eight times more sensitive. Positive control sera gave a titre of 1:3200 by IFAT and 1:25,600 by ELISA. Through the use of a reference titration curve ELISA could be used as a semi-quantitative system to determine antibody levels in test sera.

Short days induce premature reproductive maturation in juvenile starlings, Sturnus vulgaris.

Castration of juvenile and photorefractory adult starlings caused no immediate increase in circulating concentrations of LH. In castrated juveniles and adults exposed to natural changes in daylength, plasma LH increased between mid-October and mid-November, although the increase was more rapid in adults. In castrated photorefractory adults, plasma LH increased 3-5 weeks after transfer to artificial short days (8L:16D). In castrated juvenile starlings plasma LH increased 4-6 weeks after transfer to 8L:16D, irrespective of the age of the birds. Birds as young as 17 weeks had high LH concentrations. These results suggest that the reproductive system of juvenile starlings is in the same state as that of photorefractory adults, and therefore the activation of the hypothalamo-pituitary axis for the first time in juveniles is analagous to the termination of photorefractoriness in adults.