Pharmacology in vivo of the phenylindan derivative,lu 19-005, a new potent inhibitor of dopamine,noradrenaline and 5-hydroxytryptamine uptake in rat brain

Summary Behavioural effects on dopaminergic transmission of a phenylindane derivative, Lu 19-005 [(±)-trans-3-(3,4-dichlorophenyl)-N-methyl-l-indanamine, HCl], with potent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake in rats and the effect on DA, NA and 5-HT activity in mice have been studied and compared with those of other known DA, NA and 5-HT uptake inhibitors with different selectivity ratios.Lu 19-005 induced stereotyped behaviour after parenteral and oral administration with a duration of action of more than 24 h. The stereotyped licking and biting induced by Lu 19-005 was antagonized by reserpine and cis(Z)-flupentixol, but not affected by prazosin, p-chlorophenylalanine and -methyl-p-tyrosine pretreatments. Metergoline slightly facilitated the onset of stereotypy. Lower doses of Lu 19-005 induced ipsilateral circling in unilaterally 6-hydroxy-DA-lesioned rats. Finally, Lu 19-005 antagonized the catalepsy induced by perphenazine. In mice, Lu 19-005 potentiated the apomorphine-induced gnawing, reversed tetrabenazine-induced ptosis and potentiated the behavioural effects of 5-HTP within a similar dose range.The effects of Lu 19-005 were compared with those of other reference compounds. Nomifensine had qualitatively similar effects in rats although of much shorter duration. In mice, nomifensine selectively reversed tetrabenazine-induced ptosis. Weaker effects in all test models were found with bupropion, LR 5182 and GBR 13.069, compounds with inhibitory effect on DA and NA uptake. The DA-, NA-and 5-HT-uptake inhibitor diclofensine, however, had no effect in rats except in the 6-hydroxy-DA-circling test and had low potency in mice. The specific 5-HT-and NA-uptake inhibitors citalopram and talsupram, respectively, were ineffective in all rat models. They selectively potentiated 5-HTP or reversed tetrabenazine0induced ptosis in mice, respectively, as expected according to their in vitro profile. These results indicate that effect on DA mechanisms are responsible for the behavioural activity of the test compounds in the rat models and that the circling model is the most sensitive. Since DA may be involved in some depressive states Lu 19-005 could be an attaactive new antidepressant as it combines the pharmacological profile of established antidepressants (effect on NA and/or 5-HT uptake) with equipotent activity on DA uptake.     

Plasma secretin in response to pure bile salts and endogenous bile in man

The effect of exogenous bile salts on plasma concentrations of secretin was studied by infusion of chenodeoxycholate, cholate, glycocholate, and taurocholate into the duodenum of normal subjects. The effect of endogenous bile on plasma secretin was studied by ingestion of a liquid test meal, by reinfusion of postprandial duodenal aspirates with known contents of bile salts, and by stimulation of gallbladder contraction by cholecystokinin. Each experiment was performed in groups of seven subjects. The relative secretin-releasing potencies of glycocholate, cholate, taurocholate and chenodeoxycholate (2.25 mmol) were 1.01.31.93.2. Hydrochloric acid (0.5 mmol) was, on a molar basis, approximately ten times more potent than sodium cholate. The effect of taurocholate was diminished when a liquid meal was used as vehicle instead of saline. Endogenous bile did, in no circumstance, elicit release of secretin. It is concluded that although bile salts have the ability to stimulate secretin release, endogenous secretin release is of minor, if any, importance for secretin release when physiological conditions are approached.This study was supported by grants from the Danish Hospital Foundation for Medical Research, Region of Copenhagen, The Faroe Islands and Greenland (J.nr. 78/45 and 79/48) and Borgen Legatet.     

EEG-Monitored ECT: A Comparison of Seizure Duration under Anesthesia with Etomidate and Thiopentone

Electroencephalogram-monitored electroconvulsive therapy (ECT) was carried out in 20 depressed inpatients. Before treatment, patients were randomly allocated to treatment using etomidate (Hypnomidat) (n = 10) or thiopentone (n = 10) for anesthesia. The groups were matched for sex, age, weight, and type and severity of depression. The seizure duration (seconds) was measured by electroencephalography (EEG), and the electrical energy (Joules, J) was determined for each treatment. A ratio of seizure duration:electrical energy (s/J) was computed. Both seizure duration and seizure duration:electrical energy were greater in the etomidate group than in the thiopentone group, whereas electrical energy did not differ significantly. The number of treatments in the etomidate group did not differ from that in the thiopentone group, as may be expected, perhaps because of the small size.     

“Handedness” of spiral fractures of the tibia

Handedness is a basic property of spirals. In many cases it is possible to determine whether spiral fractures are right or left handed by analysis of radiographs. Spiral fractures of the tibia show striking bilateral symmetry, with right-handed spirals predominating on the left side of the body, and left-handed spirals on the right.     

A Systematic Review of Job Loss Prevention Interventions for Persons with Inflammatory Arthritis

Journal of Occupational Rehabilitation - Purpose To present an overview of the evidence of the effect of job loss prevention interventions, aiming to improve work ability and decrease absenteeism...     

Characterization of Salmonella enterica serovar gallinarum biovars gallinarum and pullorum by plasmid profiling and biochemical analysis

One-hundred-and-five strains of Salmonella enterica serovar gallinarum, biovar pullorum and 43 strains of biovar gallinarum were characterized by biochemical reactions, and 95 strains of biovar pullorum and 32 strains of biovar gallinarum were examined for plasmid content. Twenty-one (66%) of the strains classified as biovar gallinarum contained a 85-kb virulence plasmid. Six of these strains also contained a 2.5-kb plasmid. Ten strains (31%) were without plasmids. Ninety-three strains (98%) belonging to biovar pullorum contained the virulence plasmid and, in addition, these strains contained from one to four small plasmids. Two strains did not contain plasmids. Restriction enzyme digestions of the virulence plasmid showed three different profiles, two of which were common for biovars gallinarum and pullorum. It is suggested that the phenotypic diversity of biovars gallinarum and pullorum, as well as the diversity of plasmid profiles of biovar pullorum, could be used as epidemiological markers. Differences in phenotypic characters were not related to plasmids demonstrated in biovars of S. enterica serovar gallinarum.     

Indications for thyroxine therapy after surgery for nontoxic benign goitre

Of 287 consecutive patients, surgically treated at our department for benign, nontoxic goitre during a six-year period, 261 could be followed up, on average, 8.0 years postoperatively. Unilateral surgical procedures had been used in 199 patients, subtotal thyroidectomy in 62. 29 patients were treated with thyroxine (T4) immediately postoperatively ("recurrence prophylaxis"); in the other patients thyroxine was only given in cases of hypothyroidism (significant increase of s-TSH). 26 patients had a goitre recurrence 0.5-10 years after surgery; of these 3 had got T4 as "recurrence prophylaxis" and 23 had not. There was no significant difference between patients with and without T4 postoperatively regarding the rate of recurrence. Of 55 patients treated with subtotal thyroidectomy, 33 had postoperative latent (n = 26) or manifest (n = 7) hypothyroidism. Only 13 of 177 patients operated on unilaterally developed hypothyroidism; two of these had Hashimoto's thyroiditis. All cases of hypothyreosis except 4 were detected within the first 12 months of follow-up. This study indicates that routine use of thyroxine as prophylaxis against recurrence after surgery for benign nontoxic goitre can be strongly questioned and that the risk of hypothyroidism is high after subtotal thyroidectomy.     

Continuous blockade of the lumbar plexus after knee surgery: a comparison of the plasma concentrations and analgesic effect of bupivacaine 0.250% and 0.125%

In 20 patients a continuous block of the lumbar plexus was administered after knee-joint surgery, and the analgesic effect of two different concentrations of bupivacaine was compared. The same volume of bupivacaine was given to both groups of patients: a bolus dose of 0.4 ml/kg, 0.5% or 0.25%, followed by infusion of 0.14 ml/kg/h, 0.25% or 0.125%, respectively, via a catheter placed in the neurovascular fascial sheath of the femoral nerve according to the "3-in-1 block" technique. The median morphine consumption during the first 16 h postoperatively was 6.0 mg when bupivacaine 0.5/0.25% was used and 9.5 mg when 0.25/0.125% was used. This difference is not significant. The visual analogue pain scores were also similar in the two groups (P greater than 0.05). All plasma concentrations were below 4 micrograms/ml, the highest concentration measured being 3.6 micrograms/ml. It is concluded that when used for a continuous block of the lumbar plexus after knee-joint surgery, bupivacaine in a concentration of 0.125% offers the same pain relief as a concentration of 0.25%, and the risk of toxic reactions is reduced.     

Screening methods for thyroid hormone disruptors

The U.S. Congress has passed legislation requiring the EPA to implement screening tests for identifying endocrine-disrupting chemicals. A series of workshops was sponsored by the EPA, the Chemical Manufacturers Association, and the World Wildlife Fund; one workshop focused on screens for chemicals that alter thyroid hormone function and homeostasis. Participants at this meeting identified and examined methods to detect alterations in thyroid hormone synthesis, transport, and catabolism. In addition, some methods to detect chemicals that bind to the thyroid hormone receptors acting as either agonists or antagonists were also identified. Screening methods used in mammals as well as other vertebrate classes were examined. There was a general consensus that all known chemicals which interfere with thyroid hormone function and homeostasis act by either inhibiting synthesis, altering serum transport proteins, or by increasing catabolism of thyroid hormones. There are no direct data to support the assertion that certain environmental chemicals bind and activate the thyroid hormone receptors; further research is indicated. In light of this, screening methods should reflect known mechanisms of action. Most methods examined, albeit useful for mechanistic studies, were thought to be too specific and therefore would not be applicable for broad-based screening. Determination of serum thyroid hormone concentrations following chemical exposure in rodents was thought to be a reasonable initial screen. Concurrent histologic evaluation of the thyroid would strengthen this screen. Similar methods in teleosts may be useful as screens, but would require indicators of tissue production of thyroid hormones. The use of tadpole metamorphosis as a screen may also be useful; however, this method requires validation and standardization prior to use as a broad-based screen.     

Health education pamphlets about smoking—their benefit to smokers and non-smokers

The aim of this present study was to compare the use by smokers and non-smokers of pamphlets about smoking as delivered from different settings. The study was a nation-wide cross-sectional survey of 1924 randomly selected, Danish men and women, aged 14–77 y, who had answered a mailed questionnaire in 1994. Of these 71% also participated in a telephone interview enquiring about the use of health education material, smoking status and socio-demographic variables, 39% of readers of household-delivered anti-smoking pamphlets reported having gained information from them and 22% reported having made changes in their own smoking behaviour such as avoiding smoking in the presence of non-smokers. In general practice settings, these percentages were higher among smokers. Smokers who were thinking of stopping smoking in the near future were in addition more likely to take and to read smoking related health education materials from other places. Non-smokers received (3–49%) and read pamphlets about smoking as frequently as did smokers who did not intend to quit. In conclusion, written health education material was well received by readers, but, when distributed in a more open setting it needs to be targeted towards smokers who are considering stopping smoking. In general practice, smokers not thinking of stopping were open to health education, and pamphlets used in this setting should also target this group. Non-smokers contribute indirectly to smokers quitting by providing support to smokers and pamphlets for non-smokers need to be more targeted towards this social role.