Infusion of docosahexaenoic acid protects against myocardial infarction.

Most of the cardioprotective effects of long-chain omega 3 fatty acids, namely docosahexaenoic (DHA; 22:6n-3) and eicosapentaenoic (EPA; 20:5n-3), are due to their hypotriglyceridemic and anti-inflammatory effects, which lower the risk for cardiovascular disease and myocardial infarction. Little is known on the direct preventive activities of DHA and EPA on heart function. In isolated hearts, we studied (1) whether infused DHA is able to protect the heart from ischemia/reperfusion damage and (2) the role played by Notch-mediated signal transduction pathways in myocardial infarction. Perfusion with DHA before and before/after induction of ischemia reperfusion significantly diminished cardiac damage and afforded antioxidant protection. Mechanistically, infusion of DHA before and before/after the induction of ischemia differentially modulated the expression of Notch2 and 3 target genes. In particular, DHA increased the expression of Hey1 when infused pre- and pre/post-ischemia; Jagged 1 and the Notch2 receptors increased with DHA pre-ischemia, but not pre/post; Notch2 and 3 receptors as well as Delta increased following DHA administration pre- and (especially) pre/post-ischemia. In conclusion, while the precise nature of the Notch-mediated protection from ischemia/reperfusion afforded by DHA is as yet to be fully elucidated, our data add to the growing body of literature that indicates how systemic administration of DHA provides cardiovascular protection.

Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis.

AIMS: To develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis. METHODS: Children were treated with PYR (1.25 mg kg(-1)) and SDX (25 mg kg(-1)) (Fansidar) plus folinic acid (Lederfoline) 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model. RESULTS: Eighty-nine children, aged 1 week to 14 years and weighing 2.9-59 kg, were available for evaluation. Both PYR and SDX concentration-time profiles were best described by a one-compartment open model. Volume of plasma distribution (V) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day(-1) and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day(-1) and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half-lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX. CONCLUSION: This study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low-wight children are probably appropriate.

[Development of antidepressant drugs. Experience and prospects]. / Développement des antidépresseurs. Acquis et perspectives.

THE FIRST ROUTES OF RESEARCH: The first antidepressants were developed after the discovery of the existence during depression of a perturbation in the synaptic transmission of the principle monoamines: noradrenalin, serotonin and dopamine. The pharmacological effect of the various molecules developed is mainly on the metabolisation routes of neurotransmitters, but may also concern the different receptors present on synaptic level. THE AWARENESS OF NEW MEDIATORS: The progress in research on antidepressants has widened the scope of the development of such medicinal products to the domain of endocrinology (hypothalamo-pituitary-adrenal axis, progestogen hormones, thyreotropic axis) and studies on neuropeptides (substance P, neuropeptide Y). The complexity of the physiopathological mechanisms of depression hence appears enhanced.

Bromism from daily over intake of bromide salt.

Bromide intoxication today is an infrequent disease, but preparations containing bromide are still available in nonprescription compounds, on the French market. We report a casewith bromide intoxication due to daily over intake (approximately 20 tablets per day; i.e. total elemental bromide intake approximately 6 g/day) of calcium bromo-galactogluconate (Calcibronat) for 1.5 months. A 30-year-old woman with a long history of psychotropic drug abuse was hospitalized in a psychiatric department for neuropsychological manifestations. She presented a seriously disturbed mental status with confusion, disorientation, auditory and visual hallucinations, and loss of short-time memory. A markedly increased serum bromide level of 1717 mg/L (21.5 mEq/L) measured on the first day after her admission confirmed the diagnosis of chronic bromism suspected based on her symptomatology. During her hospitalization, bromide plasma concentrations were measured and monitored using inductively coupled plasma mass spectrometry, a sensitive and very specific method. After withdrawal of the drug, the symptoms improved within 8 days. Serial bromide concentrations gradually declined throughout nearly 2 months of monitoring, until she was discharged from the hospital. We found an elimination half-life of bromide in blood of approximately of 10 days. This case demonstrates that, while today bromism occurs infrequently, it should still be included in the differential diagnosis of neuropsychiatric symptoms.

Efficiency of amifostine as a protection against doxorubicin toxicity in rats during a 12-day treatment.

BACKGROUND: Our purpose was to determine the effects of amifostine, a cytoprotective agent, on doxorubicin tolerance and cardiotoxicity in rats. MATERIALS AND METHODS: Male Wistar rats were treated every other day with an intraperitoneal injection of amifostine or saline 30 minutes before intraperitoneal injection of doxorubicin or saline. Weight change was recorded, and contractile function was evaluated after 11 injections by means of the isolated heart. RESULTS: Weight evolution and cardiac function were significantly improved by 7 and 20 mg/kg amifostine (p < 0.001) but not by 50 mg/kg. The final weight were: controls 349 +/- 16 g; doxorubicin alone 258 +/- 54 g; with amifostine: 7 mg/kg 314 + 28 g; 20 mg/kg 312 +/- 32 g; 50 mg/kg 250 +/- 34 g. Left ventricular developed pressure were: controls 137 +/- 15 mmHg; doxorubicin alone 119 +/- 20 mmHg; with amifostine: 7 mg/kg 140 +/- 20 mmHg; 20 mg/kg 137 +/- 25 mmHg; 50 mg/kg 124 +/- 20 mmHg. CONCLUSION: Seven and 20 mg/kg amifostine protected rats from the toxicity of doxorubicin at the cumulative dose of 18 mg/kg during a 12-day treatment, with regard to weight loss and heart contraction.

[Utilization of methylphenidate(Ritalin) in France]. / L'utilisation du méthylphénidate (Ritaline) en France.

Methylphenidate (Ritalin) is the only psychostimulant approved in France and indicated in attention deficit hyperactivity disorder in children over 6 years. It is under restricted prescription and distribution conditions. As such, it requires a hospital initiated prescription from either a neurology, psychiatry or pediatric specialist and it is covered by the "narcotics" schedule. The French Pharmacovigilance database spontaneous adverse drug reactions reporting, since it was approved in 1995, were analyzed. 21 adverse drug reactions were reported. In 16 cases, methylphenidate was suspected. They were generally non-serious, mild side effects and in most cases promptly resolved. These results do not suggest methylphenidate misuse in France or an overuse in between 1300 and 4000 treated children, to date. Until more information is available concerning the long-term effects of methylphenidate, and in order to limit misuse, inappropriate or overuse, the current prescription and dispensing regulation should be maintained in France, and could well be developed in other countries.

Reports of withdrawal syndrome with the use of SSRIs: a case/non-case study in the French Pharmacovigilance database.

The SSRIs can be associated with withdrawal reactions and the objective of this study is to test the existence of an association between reports of withdrawal syndromes with the selective serotonin re-uptake inhibitors in the French spontaneous reports database. All reactions are coded according to the WHO ART dictionary. Cases are reports of reactions of interest (withdrawal syndrome). Non-cases are all reports of reactions other than those being studied. We calculated the odds ratio (OR) as the ratio of the odds of the association of reports of withdrawal syndrome with SSRIs in cases and non-cases. SSRIs are clearly associated with a higher risk of withdrawal syndrome (OR: 5.05, 95% CI: 3.81-6.68) and in particular with venlafaxine and paroxetine (OR: 12.16, 95% CI: 6.17-23.35 and OR: 8.47, 95% CI: 5.63-12.65, respectively). The risk of withdrawal reactions appears to be greater with short half-life drugs such as paroxetine and venlafaxine. The precise mechanisms have not been identified.

Pharmacokinetics of gacyclidine enantiomers in plasma and spinal cord after single enantiomer administration in rats.

The purpose of this study was to determine the pharmacokinetics of gacyclidine, a non-competitive NMDA antagonist, in plasma and spinal cord extracellular fluid (ECF) after IV administration of single enantiomers in rats. After implantation of microdialysis probes in spinal cord, concentrations in plasma and ECF dialysates were determined by a chiral GC/MS assay over 5 h after administration of either (+)-gacyclidine or (-)-gacyclidine (1.25 mg/kg). Plasma protein binding was estimated in vitro by equilibrium dialysis. Plasma concentrations decayed in parallel in a biphasic manner (t(1/2)alpha approximately 9 min; t(1/2)beta approximately 90 min) with no significant difference between the two enantiomers. Clearance of (+)-gacyclidine and (-)-gacyclidine (291 versus 275 ml/min per kg, respectively), volume of distribution (Vdbeta: 38 versus 40 l/kg), and protein binding (90 versus 89%) were not stereoselective. Both gacyclidine enantiomers were quantifiable in spinal cord ECF 10 min after drug administration and their concentrations remained stable over the duration of the experiment in spite of changing blood concentrations. Penetration of the two enantiomers in spinal cord ECF was similar although highly variable between animals. Exposure of spinal cord ECF was comparable for both enantiomers, and not correlated with plasma AUCs. This study showed the absence of any pharmacokinetic difference between the two enantiomers when administered individually, and no enantiomeric inversion. Both gacyclidine enantiomers penetrate rapidly and extensively into spinal cord ECF, and their distribution may involve an active transport system.

Seizure induced by ropivacaine.

OBJECTIVE: To report development of a seizure after administration of ropivacaine. CASE SUMMARY: A 26-year-old woman was scheduled for a cesarean section because of a stagnation of the uterine neck dilatation after 4.5 hours. After peridural administration of 279 mg of ropivacaine (total dose) over five hours, she presented with oculogyric movements and slurred speech that preceded convulsions of the face and of the upper limbs. DISCUSSION: Convulsions are well-known complications of local anesthetics. Ropivacaine, a relatively new agent, is considered safer for the central nervous system. Currently, there are only four published reports that implicate ropivacaine as being associated with convulsions. The likelihood that ropivacaine caused the seizure in our patient was possible based on the Naranjo probability scale. CONCLUSIONS: Clinicians should be aware of the possibility of seizures as an adverse effect of ropivacaine.

[Iatrogenic risk of self-medication by the pregnant patient]. / Risques iatrogènes de l'automédication chez la femme enceinte.

REALITY OF SELF-MEDICATION IN PREGNANCY: Pregnant women use self-medication readily. Such behavior must not be overlooked by physicians and midwives during pregnancy. More epidemiology data would be useful. IATROGENIC RISKS: Drug toxicity, generally related to the advancement of somatic development of the embryo and fetus, can appear at variable stages during pregnancy. Moreover, the pharmacokinetic properties of drugs are different during pregnancy. These facts must be taken into account when assessing the risk of uncontrolled drug use by pregnant women. RECOMMENDATIONS FOR PREGNANT WOMEN: Obstetricians, midwives and primary care physicians caring for pregnant women should explain the risks of self-medication. The specific features of disease during pregnancy should be considered when giving relevant information.

Distribution of gacyclidine enantiomers after experimental spinal cord injury in rats: possible involvement of an active transport system.

The pharmacokinetics of gacyclidine enantiomers, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, were studied in plasma and spinal cord extracellular fluid (ECF) after experimental spinal cord injury in rats. Spinal cord trauma was produced by introducing an inflatable balloon in the dorsal subdural space. Upon implantation of microdialysis probes in spinal cord (T9) and intravenous (iv) bolus administration of (+/-)-gacyclidine (2.5 mg/kg), concentrations in plasma and ECF were monitored over 5 h and analyzed by a stereospecific gas chromatography-mass spectrometry (GC-MS) assay. In plasma, concentrations of (+)-gacyclidine were approximately 25% higher than those of (-)-gacyclidine over the duration of the experiment and decayed in parallel (t(1/2 alpha) approximately 7 min; t(1/2 beta) approximately 90 min) with no significant difference between the two enantiomers. Clearance (CL) and volume of distribution (Vd) of (-)-gacyclidine were approximately 20% higher than those of its optical antipode (CL: 285 versus 236 mL. kg(-1). min(-1); Vd(beta): 39.3 versus 31.2 l/kg). Protein binding (approximately 91%) was not stereoselective. In spinal cord ECF, both enantiomers were quantifiable within 10 min after drug administration, and their concentration remained stable over the duration of the experiment in spite of changing blood concentrations. Repeated iv bolus injections of gacyclidine did not modify these profiles. Areas under the curves (AUCs) of concentration in ECF versus time were similar for both enantiomers and not correlated with AUCs in plasma. Penetration of (-)-gacyclidine was, however, significantly higher (approximately 30%) than that of (+)-gacyclidine. In summary, the disposition of gacyclidine enantiomers is stereoselective. Both enantiomers exhibit a high affinity for spinal cord tissue, and the drug exchange between plasma and spinal cord ECF involves an active transport system. These findings contribute to the explanation of the discrepancy between drug concentrations in plasma and spinal cord ECF.

Effects of 7-hydroxycoumarin (umbelliferone) on isolated perfused and ischemic-reperfused rat heart

7-Hydroxycoumarin (CAS 93-35-6, 7-HC) is the main coumarin (1,2-benzopyrone) metabolite and the therapeutic active molecule. It exhibits antioxidant properties in vitro and may share with other coumarin derivatives vasodilator effects. The aim of the study was to assess the effects of 7-HC on isolated perfused and ischemic-reperfused rat heart. After a 10-min perfusion, an increase in the coronary flow was observed with 7-HC at 10(-4) mol/l (p = 0.002) as well as an increase in left ventricular developed pressure with 7-HC at 10(-5) mol/l (p = 0.038). The increase in coronary flow is not solely explained by the increase in inotropism. It appears to be also induced through a direct vasodilator effect which, however, does not involve the release of vasodilator prostaglandins since it was not inhibited by indometacin. After the 30-min global ischemia and the 45-min reperfusion period, 7-HC at 10(-5) mol/l induced an increase in left ventricular developed pressure (p = 0.042) and in the ratio of heart rate x left ventricular developed pressure over oxygen consumption (p = 0.036).

Influence of in vivo hemoglobin carbamylation on HbA1c measurements by various methods.

Increased carbamylated hemoglobin formed in erythrocytes during uremia may interfere with HbA1c assays, but few studies compared directly both parameters. We measured carbamylated hemoglobin by HPLC in 45 non-diabetic uremic patients (16 with acute and two with chronic renal failure, 27 with transplant recipients) as 57.8 +/- 22.3 microg carbamylvaline/g Hb (mean +/- standard deviation) vs. 31.6 +/- 5.1 in 15 controls (+83%, p < 0.001). In these samples, HbA1c was evaluated by three ion-exchange HPLC methods, 1: Diamat (BioRad), 2: A1c2.2 (Tosoh) and 3: HA8140 (Menarini), and one immunoassay method (Tinaquant II Roche). Whichever the method, mean HbA1c values obtained increased in patients with high (> 60 microg carbamylvaline/g Hb) vs. low (< 45) carbamylated hemoglobin values (+0.08 to 0.25% of total Hb), but differences were not significant. Minor peaks on the chromatograms were however increased in parallel to carbamylated hemoglobin. HbA1c values over 6% were found in 4, 1, 2 and 0 samples, with HPLC 1, 2, 3 and immunoassay, respectively. Fructosamine values were not significantly altered. Our results show that Hb adducts, whether due to carbamylation or to other chemical reactions, interfere to a variable extent with different HbA1c assay methods, and confirm that HbA1c values should be interpreted with caution in uremic patients.

Kinetics of carbamylated haemoglobin in acute renal failure.

BACKGROUND: Carbamylation of proteins by isocyanic acid, the reactive form of cyanate derived from urea, is increased in uraemia and may contribute to uraemic toxicity. Kinetics of carbamylation that may reflect uraemic toxicity is not clearly defined in acute renal failure (ARF). METHODS: Twenty-eight patients with ARF and 13 with chronic renal failure (CRF) were included in the study in order to determine changes in carbamylated haemoglobin concentration (CarHb) in ARF. The usefulness of this parameter for differentiating ARF from CRF was also investigated. CarHb was measured by high-performance liquid chromatography after acid hydrolysis. RESULTS: Mean CarHb level (expressed as microg carbamyl valine per gram (CV/g) Hb) was significantly higher in ARF (54.3+/-5.2) than in normal subjects (31.6+/-1.3). On admission, CarHb level was correlated with duration of ARF prior to hospitalization in the intensive care unit (r(2)=0.723, P<0.001). CarHb was significantly higher at recovery in the subgroup of patients requiring haemodialysis than in the subgroup not requiring haemodialysis (82. 4+/-11.3 vs 46.7+/-5.2, P<0.01). Similarly dialysis patients lost more weight (8.6+/-1.4 vs 2.7+/-0.5 kg, P<0.005) and had higher averaged blood urea levels in the 20 days prior to recovery (17. 6+/-1.9 vs 11.3+/-1.8 mol/l, P<0.05). After recovery, CarHb level decreased at a rate of 0.219 microg CV/g Hb per day in patients with reversible renal insufficiency. CarHb concentration was higher in patients with CRF. A cut-off CarHb value of 100 microg CV/g Hb had a sensitivity of 94% and a positive predictive value of 94% for differentiating ARF from CRF. CONCLUSIONS: Kinetics of CarHb showed a near normal red blood cell life span in ARF. Changes in CarHb enabled, with a good sensitivity, the distinction to be made between patients who recovered from ARF and those with sustained renal impairment, whether due to prior CRF or resulting from parenchymal sequelae. Measurement of CarHb is valuable at clinical presentation of ARF in patients with an unknown medical history of renal disease.

Distribution of gacyclidine enantiomers in spinal cord extracellular fluid.

PURPOSE: Determination of the pharmacokinetics of gacyclidine enantiomers, a non-competitive NMDA antagonist, in plasma and spinal cord extracellular fluid (ECF) of rats. METHODS: Implantation of microdialysis probes in spinal cord (T9). Serial collection of plasma samples and ECF dialysates over 5 hours after IV bolus administration of (+/-)-gacyclidine (2.5 mg/kg). Plasma protein binding determined in vivo by equilibrium dialysis. Chiral GC/ MS assay. RESULTS: Plasma concentrations of (+)-gacyclidine were approximately 25% higher than those of (-)-gacyclidine over the duration of the experiment in all animals. Plasma concentrations decayed in parallel in a biphasic manner (t1/2alpha approximately 9 min; t1/2beta approximately 90 min) with no significant difference between enantiomers. Clearance and volume of distribution of (-)-gacyclidine were approximately 20% higher than those of its optical antipode (CL: 248 vs 197 ml.kg(-1)x min(-1); Vdbeta: 31.6 vs 23.5 1/kg). Protein binding (approximately 90%) was not stereoselective. Both gacyclidine enantiomers were quantifiable in spinal cord ECF 10 min after drug administration and remained stable over the duration of the experiment in spite of changing blood concentrations. Penetration of (-)-gacyclidine was significantly higher (approximately 40%) than that of (+)-gacyclidine in all animals. Yet, exposure of spinal cord ECF was similar for both enantiomers, and not correlated with plasma AUCs. CONCLUSIONS: The disposition of gacyclidine enantiomers is stereoselective. Both enantiomers exhibit a high affinity for spinal cord tissue and their distribution may involve a stereoselective and active transport system. This hypothesis could also explain the discrepancy between drug concentrations in plasma and spinal cord ECE

Modified gas chromatographic-mass spectrometric assay for the determination of gacyclidine enantiomers in human plasma.

A modified method for the determination of gacyclidine enantiomers in human plasma by GC-MS with selected-ion monitoring using the deuterated derivative of gacyclidine (d3-gacyclidine) as internal standard was developed. Following a single-step liquid-liquid extraction with hexane, drug enantiomers were separated on a chiral fused-silica capillary column (CP-Chirasil-Dex; Chrompack). The fragment ion, m/z 266, was selected for monitoring d3-gacyclidine (retention times of 35.2 and 35.6 min for the (+)- and (-)-enantiomer, respectively) whereas the fragment ion, m/z 263, was selected for quantitation of gacyclidine (retention times of 35.4 and 35.9 min for the (+)- and (-)-enantiomer, respectively). The limit of quantitation for each enantiomer was 0.3 ng/ml, using 1 ml of sample, with a relative standard deviation (RSD) < 14% and a signal-to-noise ratio of 5. The extraction recovery of both gacyclidine enantiomers from human plasma was about 75%. The calibration curves were linear (r2 > 0.996) over the working range of 0.312 to 20 ng/ml. Within- and between-day RSD were < 9% at 5, 10 and 20 ng/ml, and < 16% at 0.312, 0.625, 1.25 and 2.5 ng/ml. Intraday and interday bias were less than 11% for both enantiomers. The chromatographic behavior of d3-gacyclidine remained satisfactory even after more than 500 injections. Applicability of this specific and stereoselective assay is demonstrated for a clinical pharmacokinetic study with racemic gacyclidine.

Effects of amifostine on perfused isolated rat heart and on acute doxorubicin-induced cardiotoxicity.

PURPOSE: To determine the effects of amifostine on an isolated perfused rat-heart model and its protective activity with regard to cardiotoxic doxorubicin perfusion. METHODS: Langendorff constant-pressure isolated rat-heart preparations were used to analyze the effects of the drugs during a 40-min period of perfusion after a 20-min stabilization interval. The first study was conducted with amifostine alone (controls and 10(-6), 10(-5), and 10(-4) M amifostine; n=6 in each group). The second study was conducted with amifostine and doxorubicin (controls, 2.5 x 10(-5) M doxorubicin, 2.5 x 10(-5) M doxorubicin and 10(-5) M amifostine, and 2.5 x 10(-5) M doxorubicin and 10(-4) M amifostine; n=4 in each group). RESULTS: Amifostine had no significant effect on hemodynamic parameters at 10(-6), 10(-5), and 10(-4) M concentrations. However. amifostine increased the coronary flow expressed as a percentage+/-SEM of the baseline flow as follows: 82+/-4% for controls, 95+/-6% for 10(-6) M amifostine, (P=0.13), 111+/-4% for 10(-5) M amifostine (P < 0.01), and 104+/-3% for 10(-6) M amifostine (P < 0.01). When we commenced an amifostine perfusion 20 min in advance of and then during a 40-min perfusion with doxorubicin, at a cardiotoxic concentration of 2.5 x 10(-5) M the left ventricular pressures (LVDP, expressed as percentages +/-SEM of the baseline LVDP before doxorubicin) were 55+/-3% for the doxorubicin controls, 68+/-2% for doxorubicin with 10(-5) M amifostine (P=0.05), and 80+/-3% for doxorubicin with 10(-4) M amifostine (P < 0.01). Whether this protective effect might be related to the known free-radical-scavenging activity of amifostine remains to be determined. CONCLUSION: On a Langendorff-type model of rat heart, 10(-5) and 10(-4) M amifostine alone induced a coronary dilation and, when associated with a cardiotoxic concentration of 2.5 x 10(-5) M doxorubicin, 10(-5) and 10(-4) M amifostine displayed a cardioprotective effect.