Modulation of dopaminergic neurotransmission by morphine in the rat

The pleasant effects of opium were already known 6000 years ago and opium has been used for medical purposes for at least 3500 years. Opium, and its r.1ain constituent morphine, evoke a feeling of well-being and always relieve pain of any origin, in other words, a perfect analgesic and euphoric drug. However, there are unpleasant repercussions. Thus, the pleasant effects are followed by a period of dysphoria. With the first, moderate dose of opiate this rebound is not important. But euphoric and analgesic effects disappear with repeated administration unless the dose is steadily increased. When the opiate is withcirawn after repeated administration of high doses, the dysphoric rebound wi 11 gain dangerous proportions and this is one of the reasons for continued (addicted) use of the opiate. Thus, the perfect analgesic and euphoric drug produces a perfect dependence. One of the most important stimuli to the promotion of research into the mechanism of action of opiates is the desire to control opiate-dependence. Such control would help two groups of users: those who need a strong analgesic would not necessarily become dependent and those who become dependent would not necessarily always need opiates. The acute effects of morphine are highly interrelated phenomena such as analgesia and euphoria, while dependence is ascribed to an adaptation of the cells of the body. In order to relate or dissociate these effects of opiates it is necessary to analyse the eel lular and molecular events related to the acute effects of the opiate. If these cellular and molecular events are the same as those underlying opiate-dependence, it will not be possible to dissociate the analgesic and euphoric effects of opiates from their ability to produce dependence. However, if it appears that differences do exist between the mechanism of these two opiateinduced phenomena then control of opiate-dependence may be possible. In the experiments described here, the effects of acute morphine administration on dopaminergic neurons in the rat were investigated. Dopamine is an important neurotransmitter in 1 imbic and extrapyramidal brain areas and plays an important role in the integration of emotional responses. Furthermore, the analgesic and rewarding (euphoric?) properties of morphine have been related inter alea to interactions with dopaminergic systems. An attempt has been made to analyse molecular mechanisms involved in the action of morphine on dopaminergic neurons in different brain areas and to analyse the relation of both these actions and behavioural responses to acute morphine administration

Dose-dependent effects of intravenous lorazepam on cardiovascular activity, plasma catecholamines and psychological function during rest and mental stress

Dose-dependent effects of intravenously administered lorazepam on psychophysiological activity during rest and mental stress were studied in order to examine differential responses to doses which may induce anxiolysis or sedation. In a double-blind randomized cross-over study, nine male volunteers participated in a placebo and a lorazepam session, during which the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.06, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). Heart rate showed a dose-dependent decrease during rest with an ED50 of 0.13 mg lorazepam, while lorazepam had no effect on the cardiovascular and plasma catecholamine response magnitudes to the CWT. Subjective fatigue and reaction time increased significantly after 0.94 mg lorazepam, while at the same dose vigor decreased; state anxiety after the CWT was not influenced by lorazepam. These data show differential effects of lorazepam on cardiovascular, biochemical and psychological function. While heart rate was suppressed at low doses during rest and reaction time and subjective fatigue increased at doses which induced sedation, state anxiety and physiological response patterns to the CWT were not influenced by lorazepam

Functional Locomotor Consequences of Uneven Forefeet for Trot Symmetry in Individual Riding Horses

ABSTRACT: Left-right symmetrical distal limb conformation can be an important prerequisite for a successful performance, and it is often hypothesized that asymmetric or uneven feet are important enhancing factors for the development of lameness. On a population level, it has been demonstrated that uneven footed horses are retiring earlier from elite level competition, but the biomechanical consequences are not yet known. The objectives of this study were to compare the functional locomotor asymmetries of horses with uneven to those with even feet. Hoof kinetics and distal limb kinematics were collected from horses (n = 34) at trot. Dorsal hoof wall angle was used to classify horses as even or uneven (1.5° difference between forefeet respectively) and individual feet as flat (55°). Functional kinetic parameters were compared between even and uneven forefeet using MANOVA followed by ANOVA. The relative influences of differences in hoof angle between the forefeet and of absolute hoof angle on functional parameters were analysed using multiple regression analysis (P<0.05). In horses with uneven feet, the side with the flatter foot showed a significantly larger maximal horizontal braking and vertical ground reaction force, a larger vertical fetlock displacement and a suppler fetlock spring. The foot with a steeper hoof angle was linearly correlated with an earlier braking-propulsion transition. The conformational differences between both forefeet were more important for loading characteristics than the individual foot conformation of each individual horse. The differences in vertical force and braking force between uneven forefeet could imply either an asymmetrical loading pattern without a pathological component or a subclinical lameness as a result of a pathological development in the steeper foot

A double blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients

Antidepressant effects of mirtazapine and imipramine were compared in a randomized, double blind, fixed blood-level study with in-patients in a single centre. Patients with a DSM-III-R diagnosis of major depression and a Hamilton (17-item) score of ≤ 18 were selected. After a drug-free and a placebo-washout period of 7 days in total, 107 patients still fulfilling the HRSD criterion of ≤ 18, started on active treatment. The dose was adjusted to a predefined fixed blood level to avoid suboptimal dosing of imipramine. Concomitant psychotropic medication was administered only in a few cases because of intolerable anxiety or intolerable psychotic symptoms. Eight patients dropped out and two were excluded from analyses because of non-compliance; 97 completed the study. According to the main response criterion (50% or more reduction on the HRSD score) 11/51 (21.6%) patients responded on mirtazapine and 23/46 (50%) on imipramine after 4 weeks' treatment on the predefined blood level. Such a dramatic difference in efficacy between antidepressants has not often been reported before. The selection of (severely ill) in-patients, including those with suicidal or psychotic features, may have significance in this respect. Optimization of treatment with the reference drug imipramine through blood level control, exclusion of non-compliance for both drugs, exclusion of most concomitant medication and a low drop-out rate may also have contributed. It is concluded that imipramine is superior to mirtazapine in the patient population studied

Risk of pneumonia in the vicinity of goat farms: a comparative assessment of temporal variation based on longitudinal health data

BACKGROUND: Although the association between living in the vicinity of a goat farm and the occurrence of pneumonia is well-documented, it is unclear whether the higher risk of pneumonia in livestock dense areas is season-specific or not. This study explored the temporal variation of the association between exposure to goat farms and the occurrence of pneumonia. METHODS: A large population-based study was conducted in the Netherlands, based on electronic health records from 49 general practices, collected for a period of six consecutive years (2014-2019). Monthly incidence rates of pneumonia in a livestock dense area were compared with those of a control group (areas with low livestock density) both per individual year and cumulatively for the entire six-year period. Using individual estimates of livestock exposure, it was also examined whether incidence of pneumonia differed per month if someone lived within a certain radius from a goat farm, compared to residents who lived further away. RESULTS: Pneumonia was consistently more common in the livestock dense area throughout the year, compared to the control area. Analyses on the association between the individual livestock exposure estimates and monthly pneumonia incidence for the whole six-year period, yielded a generally higher risk for pneumonia among people living within 500 m from a goat farm, compared to those living further away. Significant associations were observed for March (IRR 1.68, 95% CI 1.02-2.78), August (IRR 2.67, 95% CI 1.45-4.90) and September (IRR 2.52, 95% CI 1.47-4.32). CONCLUSIONS: The increased occurrence of pneumonia in the vicinity of goat farms is not season-specific. Instead, pneumonia is more common in livestock dense areas throughout the year, including summer months

Pipamperone Population Pharmacokinetics Related to Effectiveness and Side Effects in Children and Adolescents

Background: Pipamperone is a frequently prescribed antipsychotic in children and adolescents in the Netherlands, Belgium, and Germany. However, pediatric pharmacokinetics and the relationship with side effects and efficacy are unknown. Currently, divergent pediatric dosing recommendations exist. Objectives: The objective of this study was to describe the population pharmacokinetics of pipamperone in children and adolescents; to correlate measured and predicted pipamperone trough concentrations and predicted 24-h area under the curves with effectiveness, extrapyramidal symptoms, and sedation; and to propose dose recommendations based on simulations. Methods: Pipamperone concentrations were collected from Dutch pediatric patients in a prospective naturalistic trial (n = 8), and German pediatric patients in a therapeutic drug monitoring service (n = 22). A total of 70 pipamperone concentrations were used to develop a population pharmacokinetic model with non-linear mixed-effects modeling (NONMEM®). Additionally, an additional random sample of 21 German patients with 33 pipamperone concentrations from the same therapeutic drug monitoring service was used for external validation. Pharmacokinetic parameters were related to clinical improvement, sedation, and extrapyramidal symptoms. Simulations were performed to determine optimal dosages. Results: In a one-compartment model, the apparent volume of distribution was 416 L/70 kg and the apparent clearance was 22.1 L/h/70 kg. Allometric scaling was used to correct for differences in bodyweight. The model was successfully externally validated. The median [25th–75th percentile] measured pipamperone trough concentrations were numerically higher in responders (98.0 µg/L [56.0–180.5 µg/L]) than in non-responders (58.0 µg/L [14.9–105.5 µg/L]), although non-significant (p = 0.14). A twice-daily 0.6-mg/kg dosage was better than a fixed dosage to attain the concentration range observed in responders. Conclusions: Our findings suggest that pipamperone therapeutic reference ranges may be lower for children with behavioral problems than recommended for adults with psychotic symptoms (100–400 µg/L). When dosing pipamperone in children and adolescents, bodyweight should be taken into account