Compulsory admissions of patients with mental disorders: State of the art on ethical and legislative aspects in 40 European countries.

BACKGROUND: Compulsory admission procedures of patients with mental disorders vary between countries in Europe. The Ethics Committee of the European Psychiatric Association (EPA) launched a survey on involuntary admission procedures of patients with mental disorders in 40 countries to gather information from all National Psychiatric Associations that are members of the EPA to develop recommendations for improving involuntary admission processes and promote voluntary care. METHODS: The survey focused on legislation of involuntary admissions and key actors involved in the admission procedure as well as most common reasons for involuntary admissions. RESULTS: We analyzed the survey categorical data in themes, which highlight that both medical and legal actors are involved in involuntary admission procedures. CONCLUSIONS: We conclude that legal reasons for compulsory admission should be reworded in order to remove stigmatization of the patient, that raising awareness about involuntary admission procedures and patient rights with both patients and family advocacy groups is paramount, that communication about procedures should be widely available in lay-language for the general population, and that training sessions and guidance should be available for legal and medical practitioners. Finally, people working in the field need to be constantly aware about the ethical challenges surrounding compulsory admissions.

Cicletanine attenuates overdrive pacing-induced global myocardial ischemia in rabbits: possible role of cardiac cyclic nucleotides.

BACKGROUND: This study examined whether cicletanine, an antihypertensive drug with cGMP phosphodiesterase inhibitory effect, could alleviate ventricular overdrive pacing-induced myocardial ischemia in chronically instrumented rabbits. METHODS: An electrode-catheter implanted into the right ventricle was used for pacing (500 bpm over 5 min) and for measuring intracavital ST-segment elevation and ventricular effective refractory period (VERP). PQ and QT intervals were measured in the chest-lead ECG, and dP/dtmax as well as left ventricular end-diastolic pressure (LVEDP) were recorded through a left intraventricular catheter. In separate groups, mean arterial blood pressure (MABP) was monitored from the right carotid artery. Experiments were performed on conscious rabbits after a week of convalescence. In anesthetized, open-chest rabbits, samples were taken from the left ventricle before and after drug treatment and/or overdrive pacing for determination of cGMP and cAMP contents by radioimmunoassay. RESULTS: Intravenous cicletanine, 30 mg/kg body weight, did not change resting MABP, dP/dtmax, and LVEDP, but it did reduce heart rate and prolonged PQ and QT intervals and VERP. Overdrive pacing produced intracavital ST-segment elevation, increased LVEDP, and decreased dP/dtmax and MABP. Cicletanine administered 15 minutes before pacing significantly attenuated ST-segment elevation, increased LVEDP, and decreased dP/dtmax and MABP. In anesthetized animals, cicletanine itself slightly increased cardiac cGMP and cAMP contents. Overdrive pacing moderately increased cGMP and profoundly elevated cAMP, and in overpaced rabbits, cicletanine further increased cGMO and markedly attenuated cAMP content increased by overdrive pacing. CONCLUSIONS: These results suggest that in correlation with alterations of cardiac cycle nucleotide contents, cicletanine protects the heart against pacing-induced myocardial ischemia.

Vascular remodeling and antihypertensive therapy: the example of cicletanine.

Hypertension causes major structural vascular modifications including increase of wall:lumen ratio, vessel wall hypertrophy, and rarefaction of arterioles and small arteries. These structural alterations are accompanied with vascular dysfunctions. The stimuli responsible for this vascular remodeling are numerous and comprise physical, humoral, and locally synthetized factors. Among them, vasoactive substances such as vasoconstrictors (e.g., angiotensin II and endothelin) or vasodilating substances (e.g., prostacyclin and nitric oxide) may play a role as important as those of growth factors. The vascular protection afforded by antihypertensive drugs depends on their mode and their site of action and probably on their direct interference with the local hemodynamic and growth-affecting factors. This is well illustrated by cicletanine, a new antihypertensive agent that provides a good example of protection of the vasculature. This also emphasizes that vascular remodeling is important in hypertension and must be considered as an essential property of any new antihypertensive drug.

Cicletanine sulfate: inhibition of anion transport systems and natriuretic activity.

In contrast with cicletanine, its urinary sulfoconjugate metabolite (cicletanine sulfate) was active on membrane ion transport in human red blood cells. Cicletanine sulfate was a more potent inhibitor of the Na+ dependent [Cl-/HCO3-] exchanger (IC50 = 9 +/- 3 x 10(-5) mol/l; mean +/- SD of 4 experiments) than cicletanine (IC50 = 10(-3) mol/l). This inhibitory potency was intermediate between that of xipamide (IC50 = 2 x 10(-5) mol/l) and that of furosemide (IC50 = 2 x 10(-4) mol/l). Moreover, cicletanine sulfate exhibited modest inhibitory potency against the [Na+,K+,Cl-]-cotransport system (IC50 = 1 +/- 0.3 x 10(-3) mol/l; mean +/- SD of 4 experiments) and poor inhibitory activity against the [K+,Cl-]-cotransport system. Cicletanine sulfate was unable to modify the activity of Cl(-)-independent membrane carriers (Na+:H+ exchanger, Ca2+ pump, Na+:Li+ countertransport system and Na+,K+ pump). Following renal intraarterial administration in rats, cicletanine sulfate and not cicletanine, exhibited salidiuretic activity. In conclusion, the urinary sulfo-conjugate of cicletanine is an active anion transport inhibitor and natriuretic metabolite. In fact, this metabolite may be responsible for the salidiuretic action of cicletanine.

Effect of cicletanine on reperfusion-induced arrhythmias and myocardial ion contents: a comparison with furosemide.

We studied the effects of cicletanine, a furopyridine antihypertensive drug, and furosemide, a loop diuretic, on ventricular arrhythmias, such as sustained ventricular fibrillation (VF) and ventricular tachycardia (VT), and myocardial ion content in Langendorff rat hearts subjected to 30 min global ischaemia then 10 min reperfusion. Myocardial Na+, K+, Ca2+ and Mg2+ concentrations were measured by washout technique and atomic absorption spectrophotometry before and after ischaemia and reperfusion. Drugs were either perfused (acute treatment) or orally gavaged daily to the rats for 14 days before isolation of their hearts (chronic treatment). Under in vitro conditions 10(-5), 3 x 10(-5), 10(-4) or 3 x 10(-4) M of cicletanine reduced the incidence of sustained VF and VT from the control values of 91% and 100% to 83% and 100%, 50% (P less than 0.05) and 67%, 33% (P less than 0.01) and 50% (P less than 0.05), 25% (P less than 0.01) and 41% (P less than 0.05), respectively. Chronic treatment with 3, 10, 30 or 100 mg.kg-1.day-1 of cicletanine also resulted in a dose-dependent anti-arrhythmic effect. Neither acute (10(-5), 3 x 10(-5) and 10(-4) M) nor chronic furosemide treatment (3, 10 and 30 mg.kg-1.day-1) influenced the incidence of arrhythmias. Acute treatment with cicletanine or furosemide did not change myocardial ion concentrations, in non-ischaemic hearts, while chronic treatment with 30 mg.kg-1.day-1 furosemide significantly reduced myocardial Na+, K+ and Mg2+ content and increased Ca2+ concentration. Both acute and chronic cicletanine treatments attenuated ischaemia/reperfusion-induced myocardial Na+ and Ca2+ gains and K+ loss, while furosemide did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Cicletanine improves myocardial function deteriorated by ischemia/reperfusion in isolated working rat hearts.

The effect of cicletanine, a novel furopyridine antihypertensive drug was compared with that of nitrendipine, a dihydropyridine slow calcium channel blocker, on cardiac function and reperfusion-induced ventricular arrhythmias in isolated working rat hearts subjected to 10-min ischemia induced by ligation of the left main coronary artery followed by 10-min reperfusion. Before ischemia, cicletanine and nitrendipine, perfused at concentrations of 3 x 10(-5), 6 x 10(-5), 10(-4), and 2 x 10(-4) or 10(-8) M, respectively, did not influence heart rate (HR), LV developed pressure (LVDP), its first derivative (LVdP/dtmax), and LV end-diastolic pressure (LVEDP), whereas aortic flow (AF) was decreased by 2 x 10(-4) M cicletanine only. Coronary flow (CF) remained unchanged by various cicletanine concentrations but was slightly increased by nitrendipine. In the concentration range of 3 x 10(-5)-10(-4) M, cicletanine improved AF either in ischemia or during reperfusion, whereas 2 x 10(-4) M had no such effect. Nitrendipine slightly attenuated ischemia/reperfusion-induced decrease in AF. Cicletanine and nitrendipine enhanced LVDP during ischemia. Ischemia-induced deterioration of LVdP/dtmax was reduced by cicletanine, during reperfusion, but this parameter was reduced by nitrendipine and the highest cicletanine concentration. Cicletanine decreased LVEDP significantly during ischemia and reperfusion, but nitrendipine had no such effect. All cicletanine concentrations reduced the incidence of irreversible ventricular fibrillation (VF) during reperfusion, an effect roughly concentration dependent in the range of 3 x 10(-5)-10(-4) M, whereas nitrendipine had no influence on arrhythmias.

PAF-acether induced arterial thrombosis and the effect of specific antagonists.

Platelet-vessel wall interactions and local thrombosis are investigated in vivo in a branch of the mesenteric artery of the guinea pig, using optoelectronic registration and ultrastructural control. Following an electrical challenge resulting in changes of cell membrane polarization, subsequent superfusion by PAF-acether or a stable analogue, (1-O-alkyl-2-N-methylcarbamyl-sn-glycero-3-phosphocholine, 10(-8) M focal concentration (f.c.)) for a restricted period results in endothelial cell retraction and bleb formation followed by platelet adhesion and the development of a thrombus which over time becomes invaded by leukocytes and eventually occludes the vascular lumen. It was demonstrated in a previous investigation that these phenomena are triggered by the generation of endogenous PAF-acether by the endothelial cells. Specific PAF-acether-antagonists, such as BN 52021 a ginkgolide, but also synthetic molecules, derivatives of the triazolo-pyridino-diazepine group (BN 50727, BN 50755 and BN 50789), significantly inhibit platelet-vessel wall interactions and thrombosis, but not the formation of blebs in the endothelial cells. Hydrogen peroxide (10(-5)M f.c.) not only primes the effect of PAF-acether, but is by itself capable of inducing thrombosis through a PAF-acether-mediated mechanism. Inhibition of acetyl hydrolase by PMSF (phenyl-methyl-sulfonyl-fluoride, 10(-5)M f.c.) invariably results in a significant enhancement of thrombosis, while conversely, inhibition of acetyl transferase by 27584 RP (4-(naphtylvinyl)pyridine hydrochloride, 10(-6)M f.c.) inhibits thromboformation indicating that the remodeling pathway is involved.

Platelet activating factor (PAF). A review of its effects, antagonists and possible future clinical implications (Part I).

This review is an attempt to summarise recent data on platelet activating factor (PAF) and PAF antagonists from 1988 to the present. This period saw a burst in research activity focused predominantly on the effect of PAF in various organs. The effect of PAF and its antagonists was further intensively studied in vitro on isolated platelets, leucocytes, macrophages and endothelial cells. From these and earlier data, based on the catastrophe theory of Thom and Zeeman, a new concept on the interaction between PAF and various cytokines could be recognised as an important mechanism of action of the phospholipid mediator, suggesting the existence of an autocatalytic feedback network through which PAF can influence cellular function under certain pathophysiological conditions. This mechanism can be regarded as the culmination of our recent knowledge on the role of PAF, and may influence the possible clinical implications of PAF antagonists in the near future. It is recognised that PAF is released in shock and ischaemic states, and that PAF antagonists can protect the heart and brain against ischaemic injury. Therefore, in contrast to the previous period, which was predominantly devoted to the elucidation of the role of PAF in immediate hypersensitivity reactions, studies performed on cerebral, myocardial and intestinal ischaemia as well as in various shock conditions have concentrated on entirely new aspects of the effect of PAF antagonists, emphasising the significance of the inflammatory process and cell-to-cell interactions in these pathophysiological states. This has led to a re-evaluation of the experimental data previously accumulated. At the same time, these new trends in PAF and PAF antagonist research have explored further possibilities for the application of PAF antagonists in clinical practice. Attention has been focused on the physiological role of PAF as a signal molecule, especially between the neuroendocrine system and related sensory organs. The recognition of the significance of PAF in mammalian reproduction is fascinating and may lead to new clinical applications of PAF antagonists. It appears probable that, like eicosanoids, PAF is involved in a great variety of membrane-dependent processes that play a fundamental role in the maintenance of homeostasis. PAF research has provided several potent natural and synthetic antagonists which may facilitate the clinical application of these drugs in the near future.

Effect of BN 50739, a new platelet activating factor antagonist, on ischaemia induced ventricular arrhythmias in isolated working rat hearts.

STUDY OBJECTIVE: The aim was to investigate the role of platelet activating factor (PAF) in myocardial ischaemia by using BN 50739, a new specific PAF receptor antagonist with a hetrazepine framework. DESIGN: Isolated working rat hearts were subjected to regional ischaemia, induced by ligation of the left main coronary artery for 30 min, followed by reperfusion. BN 50739 was applied at concentrations of 10(-7), 10(-6), 10(-5) and 5 X 10(-5) M, and its effects on the incidence of ischaemia induced and reperfusion induced ventricular tachycardia and ventricular fibrillation and heart functions, such as heart rate, coronary flow, aortic flow, left ventricular developed pressure (LVDP), its first derivative (LVdP/dtmax), and left ventricular end diastolic pressure (LVEDP), were determined. EXPERIMENTAL MATERIAL: Studies were performed on isolated working hearts of male Sprague-Dawley rats weighing 300-360 g. Hearts were perfused with BN 50739 dissolved in dimethylsulphoxide. Control hearts were perfused with the vehicle. MEASUREMENTS AND MAIN RESULTS: Regional ischaemia triggered ventricular arrhythmias showing high incidence between 12 and 20 min with peak appearance at 16 min. BN 50739 induced dose dependent protection against ventricular tachycardia and fibrillation: incidences declined from their respective control values of 91% and 75% to 33% (p less than 0.05) and 8% (p less than 0.05) after exposure to 10(-5) M, and to 25% (p less than 0.05) and 8% (p less than 0.05) after exposure to 5 X 10(-5) M concentrations. Reperfusion of the ischaemic myocardium resulted in an immediate appearance of ventricular tachycardia and fibrillation, but these were not suppressed by the PAF antagonist. Regional ischaemia slightly reduced heart rate, markedly decreased coronary flow, aortic flow, LVDP and LVdP/dtmax, and increased LVEDP. With the exception of LVEDP, these variables were not influenced by the drug. BN 50739, applied at a concentration of 5 X 10(-5) M, reduced LVEDP significantly during the whole ischaemic period. CONCLUSIONS: Under in vitro conditions PAF is likely to be involved in the genesis of ischaemia induced ventricular arrhythmias since BN 50739, a specific PAF receptor antagonist, exerts a protective effect against these rhythm disturbances. This suggests that PAF antagonists may have benefit in the clinical management of acute myocardial ischaemia.

Recovery of postischemic brain metabolism and function following treatment with a free radical scavenger and platelet-activating factor antagonists.

We have studied the metabolic and functional effects of two new platelet-activating factor (PAF) antagonists (BN 50726 and BN 50739) and their diluent (dimethyl sulfoxide; DMSO) during reoxygenation of the 14-min ischemic isolated brain. Blood gases, EEG, auditory evoked potentials, cerebral metabolic rate for glucose (CMRglc), and cerebral metabolic rate for oxygen (CMRO2) were monitored throughout the study. Frozen brain samples were taken for measurement of brain tissue high-energy phosphates, carbohydrate content, and thiobarbituric acid-reactive material (TBAR, an indicator of lipid peroxidation) at the end of the study. Following 60 min of reoxygenation in the nontreated 14-min ischemic brains, lactate, AMP, creatine (Cr), intracellular hydrogen ion concentration [H+]i), and TBAR values were significantly higher and ATP, creatine phosphate (PCr), CMRglc, CMRO2, and energy charge (EC) values were significantly lower than the corresponding normoxic control values. PCr and CMRO2 values were significantly higher, and glycogen, AMP, and [H+]i values were significantly lower in the BN 50726-treated ischemic brains than in DMSO-treated ischemic brains. In brains treated with BN 50739, ATP, ADP, PCr, CMRO2, and EC values were significantly higher, and lactate, AMP, Cr, and [H+]i values were significantly lower than corresponding values in the DMSO-treated ischemic brains. TBAR values were near control levels in all brains exposed to DMSO. There was also marked recovery of EEG and auditory evoked potentials in brains treated with DMSO. Treatment with BN 50726 or BN 50739 in DMSO appeared to improve brain mitochondrial function and energy metabolism partly as the result of DMSO action as a free radical scavenger.(ABSTRACT TRUNCATED AT 250 WORDS)

[A brain abscess of mycotic origin due to Histoplasma capsulatum]. / Abces cerebral de origine micotica cu Histoplasma capsulatum.

The case here presented is one of the histoplasmosis cases occurring sporadically in Romania. It is the first case with cerebral site and with the aspect of an extensive intracranial process. The diagnosis was made by a careful microscopic examination of the intraoperative specimens.

Histamine H1-receptors mediate phosphoinositide and calcium response in cultured smooth muscle cells--interaction with cicletanine (CIC).

Smooth muscle cells were cultured from guinea-pig aorta and labelled with 45Ca++ and 32Pi to investigate the possible effect of cicletanine, a new antihypertensive drug, on the release of intracellular Ca++ and the metabolism of phosphoinositide induced by histamine. In 45Ca++ labelled cells, histamine increased in a dose-dependent manner the 45Ca++ efflux in the first two minutes. Stimulation of 45Ca++ release was observed with H1-agonist [2-pyridylethylamine dihydrochloride (2-PEA)] but not with H2-agonist (dimaprit). In addition, histamine- or 2-PEA- induced 45Ca++ efflux was inhibited by the H1-antagonists (mepyramine and terfenadine) whereas the H2-antagonist (cimetidine) was without effect. Similar results were obtained in 32Pi labelled cells; both H1-agonists (histamine and 2-PEA) increased the labelling of phosphoinositides. This effect was completely blocked by mepyramine. These results demonstrate that the histamine-induced stimulation of 45Ca++ efflux and phosphoinositide metabolism are mediated through H1-receptors. In the above systems, cicletanine was as effective as the H1-antagonist (mepyramine) with an IC50 of 10(-6) M for both 45Ca++ efflux and phosphoinositide metabolism. Blockade of these systems by cicletanine may be part of the mechanism by which this drug produces relaxation of blood vessels and may account for its in vivo antihypertensive action.

Gaps and perspectives of new fluoroquinolones.

The gaps in the present piperazinyl-substituted fluoroquinolones include: (a) gaps in their antibacterial spectrum, varying from one fluoroquinolone to another for streptococci-pneumococci-enterococci (SPE), some Gram-negative and Gram-positive anaerobes, Nocardia, Pseudomonas maltophilia, Ureaplasma urealyticum, slow-growing mycobacteria; (b) a pH dependence of their antibacterial activity (low activity at acidic pH for piperazinyl-substituted fluoroquinolones); (c) a rapid development of bacterial resistance for some bacteria (staphylococci, pseudomonas) in prolonged treatment of cystic fibrosis, intensive care units; (d) some gaps in the pharmacokinetic parameters such as incomplete oral bioavailability, short half-life, intensive biotransformation, unwanted interactions with other antibiotics or other drugs. The prospects for fluoroquinolones are trying to eliminate these gaps. The 7-piperazinyl or pyrrolidinyl, 1-cyclopropylfluoroquinolones have improved activity on SPE, anaerobes and pseudomonas-acinetobacter. Two categories can be distinguished: (i) with increased activity on SPE, but keeping also the activity on pseudomonas (A-62824, A-62254, A-65846, A-60969, AT-3295, AT-3765); (ii) with increased activity on SPE but with a loss of activity on pseudomonas (CI-934, PD-117558, S-25932). The pharmacokinetic parameters are modified by the N-methylation of the piperazine ring (bioavailability), modification of the hydrophilic or lipophilic character, conditioning half-life, metabolic biotransformation, diffusibility into the spinal fluid, crossing the blood-brain barrier, tubular reabsorption and neuropsychic adverse effects.

Endogenous lignans--a potential endogenous digitalis.

Lignans are natural products formed by oxidative dimerization of monomeric phenols. A few were recently discovered in human and animal urine, semen and blood plasma but their role has never been assessed. We investigated the actions of mammalian lignans obtained by total synthesis or extracted from the urine of pregnant women, on the Na+K+-pump in human red cells. Some of the tested lignans (enterolactone, prestegane B and 3-O-methylenterolactone) inhibited the Na+K+-pump activity with IC50 ranging from 5 to 9 X 10(-4) mol/l. The IC50 for ouabain (7 X 10(-7) mol/l) was not modified by addition of lignans suggesting a non-competitive inhibition.

Inhibition of the erythrocyte Na+, K+-pump by mammalian lignans.

Several mammalian lignans, particularly enterolactone, 3-oxy-methyl enterolactone and prestegane B are able to inhibit Na+, K+-pump activity in human red cells with IC50 of about 1 mM. The inhibition of Na+, K+-pump activity by mammalian lignans have the following properties: the IC50 for ouabain remains unchanged suggesting a noncompetitive inhibition. The apparent affinity for internal Na+ and maximal rate of cation translocation are both diminished. The above inhibition of the Na+, K+-pump was obtained at doses 2-3 orders of magnitude higher than those required for ouabain. However we cannot exclude that a glycosyl- (and/or butenolide)-derivative of enterolactone could be one endogenous ouabain-like factor.