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Pigs with a lean genotype were fed diets differing in protein and amino acid contents between 40 and 115 kg live weight. A high protein control regime (C) was compared with one supplying 11% less total protein but the same essential amino acid levels (LP1) and one supplying 16% less protein but lower amino acid levels (LP2). Regime LP2 produced fatter pigs in terms of subcutaneous, intermuscular and intramuscular fat (IMF), the latter measured in longissimus and semimembranosus muscles. The percentage of linoleic acid was lowest and that of oleic acid highest in IMF from LP2 pigs (11.57 and 34.59% respectively in longissimus). Pigs in regime LP1 had more longissimus IMF than C but similar semimembranosus IMF although both muscles had lower percentages of linoleic acid in LP1 than C, suggesting a tendency towards greater fat deposition in LP1. The high IMF content in LP2 produced the most tender, juicy steaks.

All end-of-lay hens must be transported from the production site to the site for slaughter, usually by road. The acts of being crated and transported are likely to be novel and potentially frightening. Frightened birds can be put into tonic immobility (TI), an unlearned, catatonic state, the duration of which is positively related to the fear level of the birds. Ninety ISA Brown free-range birds (in three groups of 30) and 90 caged ISA Brown birds (in similar groups) were transported (one group from cages and free-range per day) on a journey of 68 km (74 min approximately). On their return, each of the birds was subjected to TI. Although no significant differences were recorded between free-range and caged birds after they were transported (P = 0.087), in the comparison between the same birds after 7 wk, without transport, a significant difference in fear levels was observed (P < 0.001). The free-range birds were less frightened than the caged birds. No significant difference was ever found in fear levels for caged birds from different tiers. Handling and transport on this relatively short journey was apparently equally frightening for caged and free-range birds. It cannot be assumed that just because fear levels differ between free-range and caged birds, this difference will be apparent for all novel stimuli. If all birds, at all tiers, receive the same amount of human contact during the production period, there is no reason to expect differences to occur in fear levels of birds from different tiers.

Failure to intubate and cross esophageal tumors by endosonography is reported in as many as 30% of cases and is thought to be associated with an especially poor prognosis. The aim of this study was to audit the above in a large consecutive case series of Endoscopic Ultrasound (EUS) examinations for esophageal cancer performed in a regional specialist cancer network with particular reference to outcome. A consecutive series of 411 patients underwent EUS examination by a specialist radiologist over a period of 9 years. Forty (10%) of patients required dilation, and there was total failure to cross the tumor in 12 patients (2.9%). Failure to traverse the primary tumor was associated with a diagnosis of squamous cell cancer (8 of 12 patients, 66%, rho = -0.182, P = 0.011). Limited staging information was obtained in 7 of these patients, which altered the computed tomography stage in 5 patients (71%, 3 upstaged, 2 downstaged). Six patients received definitive chemoradiotherapy, two patients surgery and four patients palliative chemotherapy. The median and 5-year survival in patients whose tumors were not crossed was 10 months and 28%, respectively, compared with 24 months and 24%, respectively in patients whose tumors were fully assessed. Failure to cross esophageal tumors in practice was far less common than the literature suggests, and esophageal tumor luminal stenosis should no longer be considered a limitation of endosonography.

Falipamil (2-[3-[3-(3,4-dimethoxyphenetylmethylamino]propyl]-5,6- dimethoxyphthalamidine; 1) is a new specific bradycardic agent for the treatment of sinus tachycardia. Pharmacokinetics of falipamil in humans (n = 6) was determined in plasma and urine after iv administration of 100 mg (1.85 MBq) per person of 14C-labeled drug by liquid scintillation counting and by a specific, sensitive reversed-phase totally automated HPLC system with fluorimetric detection. Recovery of total radioactivity was 91.8 +/- 3.7%, with 68.2 +/- 4.3% in urine and 23.6 +/- 2.5% in the feces. The majority of radioactivity was excreted within 24 to 48 h. The parent drug, falipamil (1), and its N-desmethyl-metabolite (2), which is approximately 100 times less active than 1, contributed 14.1 +/- 1.6 and 4.5 +/- 0.7%, respectively, of the dose to urinary excretion. Plasma protein binding of 1 and 2 was 87.9 +/- 1.2 (concentration range: 2000-8000 ng/mL) and 89.7 +/- 0.5% (concentration range: 62.5-1000 ng/mL), respectively. Plasma concentrations of 1 peaked at 2 min at 724 +/- 173 ng/mL, declined biphasically, and were fitted to a two-compartment open model. Plasma concentrations of 2 were very low, in all cases ranging from 0 to 35 ng/mL. The dominant terminal half-life (beta-phase) of 1 from plasma was 1.8 +/- 0.6 h (range 1.4-2.9 h), mean residence time was 2.4 +/- 0.4 h, total body clearance was 1108.5 +/- 119 mL/min, and renal clearance was 117 +/- 20 mL/min. All parameters demonstrated very low intersubject variability.

An open study to investigate the PAF-acether antagonist activity of Tanakan in healthy male volunteers examined the effect of a single 15-ml oral dose on ex vivo platelet aggregation induced by adrenaline, adenosine diphosphate (ADP), collagen or PAF-acether. Aggregometry was performed on platelet-rich plasma samples from blood taken 1 h before dosing with Tanakan and 2, 4 and 8 h after intake of Tanakan. Following dosing with Tanakan there was a reduction in platelet aggregation at all doses of PAF, with 1 μM ADP and adrenaline, the most significant decreases occurred with 75 nM PAF-acether 4 h after intake (p < 0.05) and 300 nM PAF-acether 4 h (p < 0.01) and 8 after intake (p < 0.05). There were no concomitant changes in coagulation, skin bleeding time, haematological and biochemical laboratory tests, blood pressure or pulse. The results provide a possible explanation for the clinical efficacy of Tanakan in the treatment of peripheral vascular disease; they also confirm that a single oral dose of 15 ml Tanakan is well tolerated.

The liniment used is a topical analgesic and anti-inflammatory preparation containing two active constituents, 3-phenylpropylsalicylate and ethyl-5-methoxysalicylate, in solution in isobutyl decanoate. It is known that 3-phenylpropylsalicylate is metabolised to salicylic acid and salicyluric acid and ethyl-5-methoxysalicylate is metabolised to 5-methoxysalicylic acid and gentisic acid. In the present study the separation of the salicylates and their metabolites was carried out on a Waters mu Bondapak C18 column using two different mobile phases, methanol-water (80:20) for the parent drugs and methanol-5% aqueous acetic acid (27:73) for their metabolites. The salicylates and their metabolites were detected by absorption at 310 nm. The limits of detection for parent drugs and metabolites were respectively 0.2 and 0.1 microgram/ml in plasma, using a 1-ml plasma sample and a 20-microliter injection from a reconstituted volume of 250 microliter. Mean percentage coefficients of variation for intra-assay and inter-assay precision were between 3.3 +/- 1.9% to 9.1 +/- 3.7% and 6.8 +/- 2.2% to 15.7 +/- 10.1%, respectively. Linearity, as measured by the correlation coefficient of intra-assay linear regression curves, was better than 0.998 in all cases.

The uptake of sulphamethoxazole, sulphadiazine, sulphamerazine, sulphanilamide, trimethoprim and brodimoprim by human peripheral blood leucocytes, has been investigated. High performance liquid chromatography (HPLC) was used to assay drug concentrations before and after incubation with leucocyte suspensions. Using radiolabelled material the intracellular localization of two of these compounds was also determined. The results indicated that all the investigated drugs were taken up by leucocytes. Differential studies demonstrated that mononuclear cells accumulated higher drug concentrations (0.13-0.55 microgram/10(7) cells), than resting neutrophils (0.02-0.26 microgram/10(7) cells) with the exception of sulphanilamide, which was taken up to a greater extent by neutrophils (0.75 microgram/10(7) cells). During neutrophil phagocytosis intracellular levels of all the drugs except brodimoprim increased from 3 to 130-fold as compared to resting neutrophils. The uptake of 14C-sulphanilamide and 14C-trimethoprim, in neutrophils and mononuclear blood cells, as assessed by measurement of the cell-associated radioactivity, correlated well with that determined by the HPLC procedure. In the intracellular localization studies 14C-sulphanilamide and 14C-trimethoprim exhibited similar distribution profiles. In neutrophils, 35-40% of radiolabelled drug was located in both the microsome and cytosol fractions whereas in peripheral blood mononuclear cells 40-60% was found in the cytosol and 10-20% in the microsome fraction. The results of this study suggest that, following activation, leucocytes may actively transport these drugs and release them locally at sites of infection. The ability of neutrophils to further concentrate the drugs during phagocytosis may result in reduced survival time of some ingested bacteria. These concepts may be important in designing treatment stratagems for intracellular pathogens.

In a double-blind, placebo-controlled three-way cross over study, the efficacy of Ro 15-1788 200 mg, a new benzodiazepine antagonist, in blocking the amnesic, cognitive, psychomotor and subjective effects of diazepam 20 mg, was investigated in a group of six healthy male volunteers. The amnesic effects of diazepam were markedly attenuated by the combined administration of Ro 15-1788. The psychomotor and subjective effects of diazepam by mouth were most pronounced 2.5 h after administration. Concurrent oral administration of Ro 15-1788 completely prevented these effects at 2.5 h. Plasma diazepam concentrations observed after administration of the combination of diazepam and the antagonist did not differ from those observed following diazepam alone.

1 In a double-blind, placebo controlled study, the efficacy of Ro 15-1788, a new benzodiazepine antagonist, in blocking the cognitive, psychomotor and subjective effects of diazepam, was investigated in a group of six healthy male volunteers. 2 The central effects of orally administered diazepam (40 mg) were most pronounced 1 h after dosing and persisted for 9 h with decreasing severity. 3 Concurrent oral administration of Ro 15-1788 (200 mg) completely prevented the impairment in cognitive and psychomotor function observed after diazepam alone. 4 The duration of action of Ro 15-1788 was shorter than that of diazepam. 5 Plasma diazepam levels after administration of the diazepam/antagonist combination were very similar to those observed following diazepam alone.

The tolerance and diuretic properties of torasemide after oral or intravenous administration to healthy volunteers were studied. Six groups, each of 6 subjects, were given single rising oral doses ranging from 10 to 100 mg; 8 subjects received ascending i.v. doses on alternate days, ranging from 2.5 to 80 mg. At the highest oral doses investigated (80 mg and 100 mg) a number of volunteers complained of cramps in the knees, calves and feet. These symptoms were generally of short duration. Similar effects were not encountered during the intravenous study. There were no significant changes in ECG. Some significant drug-related changes were encountered in the within-study biochemistry and haematology assessments. Torasemide proved to be a potent diuretic following oral administration at all the doses investigated and following intravenous administration at all doses except 2.5 mg. A linear relationship existed between the urine output and the logarithm of the dose, and both sodium and chloride excretion were linearly correlated with urine volume. The rate of potassium excretion was markedly lower than that of sodium and chloride and was linearly correlated with the logarithm of the urine volume. Torasemide was well tolerated from all perspectives studied. It showed a potent diuretic property, and was equally effective by the oral and intravenous routes.

50 patients with actinic keratosis were studied over four months of treatment with either etretinate ('Tigason') or placebo. Each treatment was given for two months and the order of administration was randomised. The clinical response to treatment was assessed by direct measurement and photographs of the lesions at monthly intervals. Of the 44 patients who completed treatment with etretinate 37 had a complete or partial response. Of the 42 patients who completed treatment on placebo only 2 showed a complete or partial response. The response to treatment occurred within the first month of therapy and was maintained even when the dose was reduced because of toxicity.

A randomized controlled study in a family practice setting was conducted on the use of hypnosis in helping people quit smoking. In the hypnosis group 21 percent of patients quit smoking by the three month follow-up compared with 6 percent in the control group. By six months there were no significant differences between the two groups, and at one year 22 percent in the hypnosis group and 20 percent in the control group had quit. The only significant predictor of success with quitting was having a college education.

The novel benzodiazepine derivative, meclonazepam (3-methylclonazepam) has been found to be orally effective at high doses against all stages of schistosomiasis. Animals studies have shown it to have a high therapeutic index and a profile of behavioural activity typical of the benzodiazepines. The effects of single oral doses of meclonazepam, 1, 2 and 4 mg on central arousal, psychomotor performance and subjective mood were studied in two double-blind placebo controlled studies in healthy volunteers. In doses exceeding 1 mg, meclonazepam caused marked dose-related impairment in cognitive and psychomotor functions as well as shifts in mood reflecting sedation and ataxia. These effects were most prominent in the first 3 h after administration, with moderate sedation still present 6 h after the 4 mg dose. The implications of these findings for the use of benzodiazepine agents in the treatment of schistosomiasis are discussed.

In women with preexisting virilization, it is advisable to prescribe contraceptive agents that do not provoke a further increase in free circulating androgens. This study evaluated the influence of 3 gestagens without androgenic effects on the endogenous sex hormone equilibrium and sex hormone-binding globulin (SHBG) concentrations. 122 women were administered 4 different combined contraceptives for up to 6 cycles. The estrogen component of each of the 4 preparations was estradiol estrogen (EE), while the gestagens were desogestrel (in 2 formulations in 2 different dosages), cyproterone acetate, and chlormadinone acetate. Most subjects had irregular cycles before treatment, and exhibited seborrhea, acne, and hirsutism. Luteinizing hormone, follicle-stimulating hormone, estrone, estradiol, progesterone, free testosterone, and dehydropeiandrosterone-sulfate levels were significantly reduced in all 4 treatment groups during tablet intake. However, SHBG concentrations increased in a highly significant manner during treatment. The elevation of SHBG is an expression of increased hepatic synthesis induced by EE. Concentrations of circulating SHBG determine the balance between estrogens and androgens. Since SHBG binds androgens better than estrogens, it effectively monitors androgenic activity. Because of their role in significantly lowering the active fraction of androgens, the preparations studied are considered appropriate contraceptives for androgenized women.

A sensitive and selective gas—liquid chromatographic method for the determination of plasma levels of mefloquine in human and dog plasma is described. The drug and internal standard were extracted from plasma at pH 9.0 into isopropyl acetate. After evaporation of the solvent, the residue was taken up in toluene and derivatised with heptafluorobutyrylimidazole. The derivative was quantified by gas—liquid chromatography on a 3% GC GE-SE30 column with electron-capture detection. The limit of detection for mefloquine in plasma was 10 ng/ml. The mean overall recovery from plasma was 102.7 ± 3.3%. The method was shown to be specific for mefloquine without any interference from endogenous compounds in plasma or from the drugs pyrimethamine and sulfadoxine (compounds often administered in combination with mefloquine). The assay described was successfully applied to the determination of plasma levels of mefloquine in man and dog following oral and intravenous administration, respectively.

Varicose veins in pregnant women often appear early in the first trimester of pregnancy. Blood progesterone levels in pregnant women were measured to ascertain if these differ significantly in women with and without varicose veins. A significant difference was not found. Taken in conjunction with previous results (Fegan,et al., 1967) it would appear that symptoms associated with varicose veins in pregnancy may be due to sub-normal oestrogen levels in these patients rather than excessively high levels of circulating progesterone.

A volunteer participating in a study of eproxindine, a new antiarrhythmic agent, had a sudden cardiorespiratory arrest and died. Subsequently it became known that he had received a depot injection of flupenthixol on the day before his death; an interaction between these two drugs seems likely. This incident illustrates that it is impossible to guarantee absolute safety in volunteer studies if details of medical history are witheld.

The possibility that painful symptoms in varicose veins may be associated with abnormal circulating levels of œstrogens and/or pro- gesterone is being investigated. In this preliminary study the urinary excretion of some œstrogen and progesterone metabolites has been examined in selected groups of women. Urinary excretion of œstriol and pregnanediol in women with painful varices in pregnancy was lower than that in a control group.