Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes.

Pancreatic islet autoimmunity leading to type 1 diabetes could be triggered by viruses in genetically susceptible individuals. Rotavirus (RV), the most common cause of childhood gastroenteritis, contains peptide sequences highly similar to T-cell epitopes in the islet autoantigens GAD and tyrosine phosphatase IA-2 (IA-2), suggesting T-cells to RV could trigger islet autoimmunity by molecular mimicry. We therefore sought an association between RV infection and islet autoantibody markers in children at risk for diabetes who were followed from birth. There was a specific and highly significant association between RV seroconversion and increases in any of these antibodies: 86% of antibodies to IA-2, 62% to insulin, and 50% to GAD first appeared or increased with increases in RV IgG or IgA. RV infection may therefore trigger or exacerbate islet autoimmunity in genetically susceptible children.

A multi-centre study of zomepirac in painful conditions: an analysis of clinical data for 15,484 patients.

An open, multi-centre study was carried out in patients with various moderate to severe painful conditions to assess the effectiveness of zomepirac in relieving pain. Patients were treated with 300 mg to 600 mg zomepirac daily for 7 days. Data from 15,484 patients have been analyzed. Most of the patients (75%) were already being treated with an analgesic on entry and more than half of them had been prescribed this by their doctor. Almost half, however, had still been in pain for more than 4 weeks before receiving zomepirac. An analysis of pain severity assessments showed a reduction from an initial score of 2.4 to 1.3 (on a 4-point rating scale). Global responses were recorded and 71.7% of the patients were considered to have improved according to the opinion of both doctors and patients, with the best response (84.1%) being observed in those with acute painful states such as sprains, strains and fractures and with pain of short duration. Pain frequently disrupts sleep, and 46.2% of patients reported their sleep as 'bad' or 'very bad' on entry to the study. After treatment, this figure was reduced to 15.1%. The side-effects reported, which were mainly gastro-intestinal, were mild in general and led to withdrawal of only 7.2% of the patients before completion of treatment.

A double-blind crossover comparison of tolmetin sodium and phenylbutazone in the treatment of rheumatoid arthritis.

A double-blind crossover study was carried out in 24 patients with rheumatoid arthritis to investigate the relative efficacy of tolmetin (1600 mg/day) and phenylbutazone (400 mg/day). Each drug was given for 4 weeks, preceded by a 2-week wash-out period during which patients received paracetamol alone for pain relief. Assessments were made of duration of morning stiffiness, grip strength, articular index, joint size, and degree of pain. Both drugs produced significant improvements compared to paracetamol, particularly in pain relief and, apart from morning stiffness, tolmetin proved equally effective as phenylbutazone. Three patients (2 on tolmetin and 1 on phenylbutazone) were withdrawn because of side-effects. In general, however, both drugs gave rise to only minor side-effects.

Tolmetin in osteoarthrosis of the hip and knee: double-blind crossover trials.

A double-blind crossover study was carried out in 24 patients with osteoarthrosis of the hip or knee to compare the efficacy of a 1200 mg tolmetin daily dose with a 600 mg daily dose, each given for 2 weeks. Both regimens were well tolerated and appeared to give satisfactory relief of pain, but no differences in response between the two dosages were noted either because the number of patients involved were small or because the methods of monitoring clinical improvement were not sufficiently sensitive. A further double-blind crossover study was carried out in 40 patients to compare the efficacy of 1200 mg tolmetin daily with 150 mg ketoprofen daily, each drug being given for 2 weeks after an initial 1-week period on placebo. Pain was monitored using a visual analogue line technique and significant differences were found between both active and placebo periods. Analysis of the biochemical monitoring of both trials showed statistically significant rises in blood urea for all active treatment periods. There were no concomitant changes in serum creatinine, suggesting this effect to be extra-renal in origin. In general, side-effect incidence was low; 1 patient withdrew from ketoprofen treatment because of weight increase and urine retention.

Tolmetin sodium and indomethacin in the treatment of osteoarthrosis of the hip: a double-blind crossover study.

A double-blind crossover study was carried out in 21 patients with osteoarthrosis of the hip to compare the effectiveness and tolerance of 1200 mg tolmetin sodium daily with 75 mg indomethacin daily. Each drug was given in 3 equally divided doses daily for a period of 2 weeks, both active treatment periods being preceded by 1 week on placebo. Active treatment sequence was at random. Patients were seen again after 1, 3, 4 and 6 weeks and assessments made of pain at rest, on standing, on walking, degree of sleep disturbance, and degree of limitation of everyday activity. Intermalleolar distance was also measured. A record was kept of the clinician's opinion of change with treatment, any side-effects and the patient's preference. The results from 19 patients completing the study showed that both drugs produced a good analgesic response, particularly in night pain, and most patients found their incapacitation decreased with active treatment as compared to placebo. The few side-effects reported were mild and transient, except in 1 patient who withdrew from tolmetin sodium treatment because of limiting gastrointestinal symptoms.

Post-implantation whole embryo culture and the study of teratogenesis.

The two major applications of whole post-implantation rat embryo culture (WEC) are as a test for teratogenicity in safety evaluation studies and as a tool in the investigation of mechanisms of teratogenesis. As a test system, WEC possesses many of the characteristics necessary for an in vitro screen. However, its use on a large scale is disqualified for reasons of cost and the demand for technical expertise to perform cultures and interpret findings, compared with other in vitro teratogenicity screens, although its use might be preferred when only a few compounds require testing. The major value of WEC lies in its use for studying mechanisms of teratogenesis. The opportunity to study the embryo in isolation and the versatility afforded by the technique offer considerable advantages in this context.

Effect of Spirulina maxima consumption on reproduction and peri- and postnatal development in rats.

Spirulina maxima, an edible micro-organism useful in human nutrition, was examined for its effect on general reproductive performance and for peri- and postnatal toxicity in rats at levels of 0, 10, 20 and 30% (w/w) incorporated into the diet. There was no reduction in body weight gain in males or females and no deaths or clinical signs of toxicity. Treatment was not associated with any adverse effect on any measure of reproductive performance, including male and female fertility and duration of gestation. There was no increase in the number of abnormal pups at caesarean section or at birth. S. maxima consumption did not result in adverse effects on developmental markers of the pups.

Whole embryo culture and teratogenesis.

Whole embryo culture (WEC) is under evaluation in numerous laboratories to determine the role it should play in teratogen testing. There is general agreement that its role is to complement the Segment II Teratology studies required by regulatory authorities. Currently it is used as a 'screen' in order to minimize the number of compounds used in animal tests and also to determine the mechanism(s) of teratogenesis. This brief review focuses on the study of retinoid teratogenicity in WEC in order to illustrate these points.

Human serum as a culture medium for rat embryos.

A comparison was made between the development of post-implantation rat embryos in human serum and rat serum. Protein synthesis (growth) and somite number (differentiation) were retarded in human serum and there was an increased frequency of neural tube defects. Male and female human sera supported development equally well.

Treatment of vaginal candidosis with econazole nitrate and nystatin. A comparative study.

A study carried out to compare the efficacy of econazole nitrate and nystatin in the treatment of vaginal candidosis showed that a three-day course of econazole nitrate pessaries was as effective as a 14-day course of nystatin pessaries and is more acceptable to patients.

Comparison of the effects of retinol and retinoic acid on postimplantation rat embryos in vitro.

Rat embryos were explanted on day 8 or 9 of pregnancy and cultured for up to 48 hours in serum containing added retinol (vitamin A), retinoic acid (vitamin A acid), or absolute ethanol. They were examined morphologically and their protein content determined. Retinoic acid was more teratogenic and growth-retarding than retinol. Electron microscopy of embryos cultured for 30 minutes or one hour revealed that both forms of vitamin A brought about similar ultrastructural effects on the embryonic cells; however, the abnormally large intracellular lipid droplets observed in a previous study following exposure to retinol in vitro and retinyl palmitate in vivo were not observed in embryos exposed to retinoic acid. It is possible that the differential teratogenicity may be due to the inability of the embryonic cells to convert and store retinoic acid in a less teratogenic form.

An in vivo/in vitro evaluation of the teratogenic action of excess vitamin A.

Pregnant rats of CFHB strain were injected 81/2 days postcoitum with a 1% suspension of retinoic acid (RA) in arachis oil to give 20 mg RA per kg body weight. Control rats were injected with arachis oil only. After 26 hours, one uterine horn was removed from each rat and the embryos cultured in serum from untreated rats. The embryos in the other horn were allowed to continue development in vivo. After a further 48 hours the cultures were terminated and the second uterine horn removed from each rat. This provided four groups of embryos for comparison: (1) embryos from RA-treated rats, (2) cultured embryos from RA-treated rats, (3) embryos from control rats, and (4) cultured embryos from control rats. The results showed that the effects of the teratogen on the cultured embryos were similar to those on the embryos allowed to continue development for the same period in the mother. In both groups RA reduced protein synthesis, inhibited somite and limb bud formation, and caused various neural tube defects, particularly microcephaly and abnormalities in the closure of the anterior and posterior neuropores.

In-vitro teratogenicity of retinoids.

Mid-gestation rat conceptuses were cultured for 48 h in serum containing the retinoids all-trans-retinoic acid (TRA), 13-cis-retinoic acid (13-CRA), etretinate (ETR), etretin or one of six retinamides at concentrations ranging from 0.5 to 400 micrograms/ml. TRA was toxic at a concentration of 0.5 microgram/ml. 13-CRA and etretin caused abnormal development at 1.0 microgram/ml. However, the six retinamides were less toxic and adverse developmental effects were only evident at concentrations of 50 or 100 micrograms/ml. ETR was without effect at 100 micrograms/ml, the highest dose level of this compound tested. In vivo, TRA, 13-CRA and ETR are highly teratogenic. In this culture system, TRA and 13-CRA caused abnormal development at very low concentrations but in contrast, ETR was non-toxic at 100 micrograms/ml. Therefore these findings indicate that in vivo, maternal pharmacokinetics, and bioactivation in particular, play a major role in inducing abnormal development. Cis/trans isomerization was not a major determinant of toxicity. However, there appeared to be a relationship between abnormal development and the actual or estimated pKa values of the 10 retinoids tested.

Teratogenic action of hypolipidemic agents: an in vitro study with postimplantation rat embryos.

Two hypolipidemic agents known to be embryotoxic and teratogenic in vivo were found also to cause developmental abnormalities when added to the culture serum of rat embryos growing in vitro. However, development was normal when the embryos were grown in hypolipidemic serum (low in cholesterol and triglycerides) prepared from rats dosed with the hypolipidemic agents. The results indicated that it is a direct action of the agents on the embryos, and not the hypolipidemia, which is harmful to embryonic development.

Comparative teratogenicity of nine retinoids in the rat.

he comparative teratogenicity of nine retinoids in Wistar rats was investigated. The compounds studied and dose levels tested (mg/kg) were: all-trans-retinoic acid (TRA), 6.25, 12.5, 25, 50, 100; etretinate (ETR), 25, 50; acitretin (ACIT), 25, 50; 13-cis-retinoic acid (13CRA), 100, 200; and five retinamides, each at 300 and 600 mg/kg, N-(4-hydroxyphenyl)-retinamide (4HPR); N-tetrazol-5-ylretinamide (TZR); N-butylretinamide (NBR); N-ethylretinamide (NER); 13-cis-N-ethylretinamide (13CNER). Retinoids were administered by oral intubation on days 10 and 11 post coitum (p.c.). Dams were killed on day 22 p.c. and examinations carried out to assess teratogenic potential. TRA, ETR, ACIT, 13CRA and 4HPR increased the incidence of resorptions. The incidence of abnormal fetuses, irrespective of the specific abnormalities induced, was markedly increased (50-100%) by TRA, ETR, ACIT, 13CRA and 4HPR, whereas TZR and NBR caused moderate increases (20-50%), and NER and 13CNER induced mild increases (10-20%). The incidences of CNS, craniofacial and urinogenital defects were generally high with TRA, ETR, ACIT and 13CRA. Cardiac vessel defects were markedly increased by 4HPR. Using a number of criteria, a generalized ranking order of the toxicity of the compounds was drawn up: TRA > ETR > ACIT > 13CRA > 4HPR > TZR identical to NBR > NER identical to 13CNER. The ranked order of relative in-vivo teratogenicity for the nine retinoids is compared with a previously reported in-vitro assessment of the compounds using a rat whole embryo culture technique.