Potency mismatch for behavioral and biochemical effects by dopamine receptor antagonists: implications for the mechanism of action of clozapine

Clozapine (3.8–60.0 µmol kg^?1) did not produce any alterations in DOPA accumulation (following inhibition of cerebral aromaticl-amino acid decarboxylase) in the prefrontal cortex or in three regions of the neostriatum, i.e. the ventral, the dorso-lateral and the posterior regions, in the rat. In contrast, clozapine produced a reduction in the 5-HTP accumulation in all these brain areas, except for the prefrontal cortex. Raclopride (0.08–20.0 µmol kg^?1) produced a marked increase in DOPA accumulation in all four brain regions and an increase in 5-HTP accumulation in the dorso-lateral neostriatum (2.5–20.0 µmol kg^?1), but not in the other forebrain regions. Treatment with SCH-23390 (0.4–1.6 µmol kg^?1) resulted in increased DOPA accumulation in the ventral and posterior parts of the neostriatum. No other changes in the DOPA or 5-HTP accumulation were seen with SCH-23390. Considering the doses of these three compounds needed for suppression of conditioned avoidance behavior and for the induction of cataleptic rigidity, it is concluded that raclopride produces an increased DA synthesis at much lower doses than those needed for behavioral effects. In contrast, the behavioral effects of SCH-23390 or clozapine precedes effects on brain DA synthesis on the dose-effect curve. In fact, the only biochemical effect of clozapine, which was observed in low, yet behaviorally active doses, was a decrease in forebrain 5-HTP accumulation. In conclusion, the present results demonstrate a mismatch, in different directions for raclopride and SCH-23390, as regards the doses needed to produce effects on brain dopamine synthesis and on behavior. Thus, the biochemical effects are seen with lower doses than the behavioral effects for the DA D₂ receptor blocking agent, whereas the opposite relationship is the case for the DA D₁ receptor antagonist. Taking these two DA receptor subtypes into consideration, the possibility should be considered that clozapine produces its antipsychotic-like behavioral effects on animal behavior primarily by a blockade of brain DA D₁, rather than D₂, receptors.     

High exposures to organic solvents among graffiti removers

Summary The exposure to organic solvents among 12 graffiti removers was studied. Health effects were also assessed by structured interview and a symptom questionnaire. Blood and urine samples were collected at the end of the day of air sampling. The concentrations of dichloromethane, glycol ethers, trimethylbenzenes and N-methyl-2-pyrrolidinone in the breathing zone of each worker were measured during one working day. The 8-h time-weighted average exposure to dichloromethane ranged from 18 to 1200 mg/m³. The Swedish Permissible Exposure Limit value for dichloromethane is 120 mg/m3. The air concentrations of glycol ethers, trimethylbenzens and N-methyl-2-pyrrolidinone were low or not detectable. No exposure-related deviations in the serum concentrations of creatinine, aspartate transaminase, alanine transaminase, -glutamyl transpeptidase or hyaluronan or the urine concentrations of ₁-microglobulin, R2-microglobulin or N-acetyl--glucos-aminidase were found. Irritative symptoms of the eyes and upper respiratory tract were more prevalent than in the general population. This study demonstrates that old knowledge about work harzards is not automatically transferred to new professions. Another aspect is that the public is also exposed as the job is performed during daytime in underground stations. At least for short periods, bystanders may be exposed to high concentrations of organic solvent vapours. People with predisposing conditions, e.g. asthmatics, may risk adverse reactions.     

A cyclic adenosine monophosphate agonist elevates the b- and c-waves of the rabbit direct-current electroretinogram

The effects of the stable cyclic adenosine monophosphate analogue adenosine 3, 5-cyclic monophosphorothioate Sp-isomer (Sp-cAMPS) on the direct-current electroretinogram and the standing potential of the eye were studied. Corneal recordings were obtained from unilaterally vitrectomized albino rabbit eyes during alternating intravitreal perfusions with Sp-cAMPS and a control solution (Pharmacia eye irrigating solution). The contralateral eye was used as a control. To evaluate further the effects on the c-wave,in vivo intraretinal microelectrode measurements were made during simultaneous intravitreal perfusion of Sp-cAMPS and irrigating solution, respectively. Sp-cAMPS in concentrations of 1, 10 and 100µM was tested by corneal direct-current electroretinography. There was no significant effect on the a-wave amplitude. The b-wave amplitude was reversibly elevated at an Sp-cAMPS concentration of 100µM (p<0.01, n=7). The c-wave amplitude was reversibly elevated at a concentration of 10µM (p<0.001, n=8), and this effect was more pronounced at 100µM (p<0.001, n=7). The SP increased reversibly at a concentration of 100µM (p<0.001, n=7). Microelectrode recordings were performed with Sp-cAMPS at a concentration of 100µM. The recordings showed significant increases in both the transepithelial potential (p<0.01, n=3) and the slow PIII (p<0.01, n=3). The effects of Sp-cAMPS on the b-wave as well as on the two components of the c-wave suggest influences on both the inner retina and the retinal pigment epithelium of the rabbit eye.Abbreviations PHS Pharmacia eye irrigating solution - AMP adenosine monophosphate - Sp-cAMPS adenosine 3, 5 - cyclic monophosphorothioate Sp-isomer     

Outpatient Induction of Labor – Are Balloon Catheters an Appropriate Method?

As the number of labor inductions in high-income countries has steadily risen, hospital costs and the additional burden on obstetric staff have also increased. Outpatient induction of labor is therefore becoming increasingly important. It has been estimated that 20 – 50% of all pregnant women requiring induction would be eligible for outpatient induction. The use of balloon catheters in patients with an unripe cervix has been shown to be an effective and safe method of cervical priming. Balloon catheters are as effective as the vaginal administration of prostaglandin E ₂ or oral misoprostol. The advantage of using a balloon catheter is that it avoids uterine hyperstimulation and monitoring is less expensive. This makes balloon catheters a suitable option for outpatient cervical ripening. Admittedly, intravenous administration of oxytocin to induce or augment labor is required in approximately 75% of cases. Balloon catheters are not associated with a higher risk of maternal and neonatal infection compared to vaginal PGE ₂ . Low-risk pregnancies (e.g., post-term pregnancies, gestational diabetes) are suitable for outpatient cervical ripening with a balloon catheter. The data for high-risk pregnancies are still insufficient. The following conditions are recommended when considering an outpatient approach: strict selection of appropriate patients (singleton pregnancy, cephalic presentation, intact membranes), CTG monitoring for 20 – 40 minutes after balloon placement, the patient must be given detailed instructions about the indications for immediate readmission to hospital, and 24-hour phone access to the hospital must be ensured. According to reviewed studies, the balloon catheter remained in place between 12 hours (“overnight”) and 24 hours. The most common reason for readmission to hospital was expulsion of the balloon catheter. The advantages of outpatient versus inpatient induction of cervical ripening with a balloon catheter were the significantly shorter hospital stay, the lower costs, and higher patient satisfaction, with both procedures having been shown to be equally effective. Complication rates (e.g., vaginal bleeding, severe pain, uterine hyperstimulation syndrome) during the cervical ripening phase are low (0.3 – 1.5%); severe adverse outcomes (e.g., placental abruption) have not been reported. Compared to inpatient induction of labor using vaginal PGE ₂ , outpatient cervical ripening using a balloon catheter had a lower rate of deliveries/24 hours and a significantly higher need for oxytocin; however, hospital stay was significantly shorter, frequency of pain during the cervical ripening phase was significantly lower, and patientsʼ duration of sleep was longer. A randomized controlled study comparing outpatient cervical priming with a balloon catheter with outpatient or inpatient induction of labor with oral misoprostol would be of clinical interest. Key words: outpatient/inpatient induction of labor/cervical priming, balloon catheter, prostaglandins, efficacy, safety     

The effect of lithium on amphetamine-induced locomotor stimulation

Rats were treated chronically with -methyl-p-tyrosine methyl-ester HCl (-MT) twice daily for 0–14 days. At 1 h after the (last) -MT injection, d-amphetamine sulphate was given and motor activity was measured in an ANIMEX activity meter for 4 h. Amphetamine-induced excitatory and stereotyped behaviour was scored according to a rating scale in a separate experiment. A single dose of -MT markedly reduced the activity response after amphetamine. After 1–3 days of -MT treatment, tolerance to its amphetamine-antagonistic affect started to develop, reaching a maximal degree after 7–14 days. The pattern of the amphetamine response, monophasic in control rats, became biphasic in the -MT tolerant rats with an early (at 0–1 h) and a late (2–4 h) peak of motor activity. The late peak appeared within 3 days, while the early peak appeared after 7 days of -MT treatment. The results on amphetamine-induced excitatory and stereotyped behaviour in essence agreed with the motor-activity data. It is concluded that tolerance to the amphetamine-antagonistic action of -MT is not complete. Its rate of development varies in a complex pattern, indicating the presence of more than one mechanism of tolerance.     

Possibilities of controlling blood less in liver resection]

The methods are described by which blood loss can be reduced during hepatic surgery. This requires the proper surgical techniques (control method of hepatic lobectomy and occasionally the atypical resection with the use of a clamp- "crush" method). In additions clamping of the liver hilus and resection under hypothermia, the resection of the isolated bloodless organ under hypothermia, the application of an internal caval shunt, intraoperative autotransfusion, and acute preoperative hemodilution should be performed. The internal caval shunt can be successfully used in the case of emergency as well as during excision of large tumors which have involved the liver tissue adjacent to the vena cava. In these cases the method of complete vascular isolation and hypothermic perfusion should be performed additionally. Acute preoperative hemodilution should be widely applied with hepatic surgery; blood clotting is not impaired by this method.     

Interphase cell death as related to the cell cycle of melphalan-treated human myeloma cells

The effect of melphalan on cell loss, cell growth and cell-cycle traverse was studied on the human myeloma cell line RPMI 8226. Melphalan treatment resulted in arrest of cells in late S- and G₂-phases in a population of unsynchronized cells. At high concentrations of melphalan (e.g. 40 μm), cell loss was noticed duringthe first cell cycle after melphalan treatment in addition to the aforementioned arrest of cells in late S and G₂. The cell loss after melphalan treatment was further analysed in cells enriched for G₁-phase. Cell death in this population of cells occurred between 24 and 48 hr after treatment as the cells were in S and moving over to G₂.     

Prolongation of the ejaculation latency in the male rat by thioridazine and chlorimipramine

Thioridazine (3 mg/kg) and chlorimipramine (1.5–6.0 mg/kg) prolonged the ejaculation latency and increased the number of mounts but did not change the number of intromissions preceding ejaculation. Blockade of peripheral and central noradrenaline receptors by phentolamine and phenoxybenzamine respectively resulted in a suppression of all aspects of the sexual behavior with increasing doses. dl-5-HTP (25–100 mg/kg) in combination with an inhibitor of peripheral 5-HTP decarboxylase (benserazide, 25 mg/kg) produced, like chlorimipramine and thioridazine, a prolongation of ejaculation latency and an increase in the number of mounts preceding ejaculation. Selective inhibition of 5-HT reuptake however, by zimelidine (0–20 mg/kg) or alaproclate (0–20 mg/kg) did not affect the mating behavior. At higher doses of these drugs some animals failed to initiate sexual activities. There was an increase in the postejaculatory interval but no change in the ejaculatory latency.It is concluded that the prolonged ejaculation latencies observed following treatment with thioridazine or chlorimipramine is not due to a blockade of central or peripheral adrenergic -receptors.     

Steady-state kinetics of imipramine in patients

Steady-state plasma level kinetics were studied in 76 patients given imipramine (IP) 150 to 225 mg/day for 2–5 weeks. IP was given in three divided doses at 8.00 a.m., 1.00 p.m. and 5.00 p.m. Plasma concentrations of IP and its active metabolite desipramine (DMI) were determined by quantitative in situ thin-layer chromatography. The plasma levels of IP and DMI showed pronounced flucutations throughout the day with a ratio of about 2 between highest and lowest level. Patients with steady-state levels of IP and/or DMI below 50 g/l reached this within 1 week of treatment. Patients with higher steady-state levels reached steady-state concentrations within 2–3 weeks. There were some intraindividual fluctuations in plasma levels from week to week after steady state had been reached (coefficient of variation: 10–20%). Interindividually, the steady-state levels corrected to a dose of 3.5 mg/kg per day varied considerably: IP: 6–356 g/l, DMI: 24–659 g/l and IP+DMI: 58–809 g/l. The steady-state plasma levels showed a skew distribution that became normal by logarithmic transformation. The IP/DMI ratio ranged from 0.07 to 5.5 with a median value of 0.47. Compared to data from amitriptyline treated patients the IP/DMI ratios had significantly lower median value and larger variation than the corresponding plasma level ratios of amitriptyline/nortriptyline. Several statistically significant differences in steady-state levels between age groups were found. For IP: Women aged 30–39 had lower levels than women aged 20–29, 40–49, and 50–59, and men aged 50–59 and 60–65; men aged 30–39 had lower levels than men aged 60–65. For DMI: Women aged 30–39 had lower levels than women aged 50–59.