1-[(2R)-2-([[(1S,2S)-1-amino-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl]amino)-3-(4-chlorophenyl)propanoyl]-N-(tert-butyl)-4-cyclohexylpiperidine-4-carboxamide (1) is a potent melanocortin-4 receptor agonist that exhibited time-dependent inhibition of cytochrome P450 (P450) 3A in incubations with human liver microsomes. In incubations fortified with potassium cyanide, a cyano adduct was identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis as a cyanonitrosotetrahydronaphthalenyl derivative. The detection of this adduct suggested that a nitroso species was involved in the formation of a metabolite intermediate (MI) complex that led to the observed P450 inactivation. Further evidence supporting this hypothesis derived from incubations of 1 with recombinant P450 3A4, which exhibited a lambda(max) at approximately 450 nm. The species responsible for this absorbance required the presence of beta-nicotinamide adenine dinucleotide phosphate reduced form (NADPH), increased with increasing incubation time and decreased following the addition of potassium ferricyanide to the incubation mixture, suggestive of an MI complex. Similar results were obtained with rat liver microsomes and with recombinant P450 3A1. When rats were dosed with indinavir as a P450 3A probe substrate, plasma exposure to indinavir increased three-fold following pretreatment with 1, consistent with drug-drug interaction projections based on the k(inact) and K(I) parameters for 1 in rat liver microsomes. A similar approach was used to predict the magnitude of the corresponding drug-drug interaction potential in humans dosed with a drug metabolized predominantly by P450 3A, and the forecast area under the curve (AUC) increase ranged from four- to ten-fold. These data prompted a decision to terminate further evaluation of 1 as a development candidate, and led to the synthesis of the methyl analogue 2. Methyl substitution alpha to the amino group in 2 was designed to reduce the propensity for formation of a nitroso intermediate and, indeed, 2 failed to exhibit time-dependent inhibition of P450 3A in human liver microsomal incubations. This case study highlights the importance of mechanistic studies in support of drug-discovery and decision-making processes.

We reported a 31 year-old man with repeated episodes of migraine at a frequency of about once a week on and after January, 2000. In January 2001, scintillating scotoma and pulsating headache appeared followed by left hemianopsia. His platelet count decreased to 80,000/microliter and high intensity areas were observed in the right occipital lobe and hippocampal gyrus on the FLAIR image of brain MRI. Subsequently performed brain MRA and vertebral angiography revealed segmental stenosis and obstruction in the right posterior cerebral artery. Under the diagnosis of migrainous infarction, sodium ozagrel and lomerizine hydrochloride were administered. Idiopathic thrombocytopenic purpura was additionally diagnosed based on the decreased platelet count which was then treated with predonisolone. After these treatment, his migraine attack disappeared. In this patient, platelet destruction due to idiopathic thrombocytopinic purpura and subsequent release of serotonin seemed to have involved in the occurrence of migrainous infarction.

During her third pregnancy, a woman becomes preoccupied with illness and death. When the dysphoria continues after her child is born, how would you evaluate and manage the problem?

We report a patient with a parkinsonian syndrome induced by sertraline (Zoloft), an SSRI antidepressant, whose symptoms resolved after the drug was discontinued. This case prompted us to investigate the effect of sertraline on dopamine metabolism in animals. Sertraline (30 mg/kg, i.p.) or placebo (vehicle) was administered to two groups of six normal, anesthetized rats and using cerebral microdyalisis extracellular striatal levels of dopamine, the dopamine metabolites (HVA and DOPAC), as well as the serotonin metabolite 5-HIIA were monitored. In animals pre-treated with sertraline, DOPAC, HVA, and 5-HIAA levels were significantly decreased compared to control animals (p < 0.01). These data indicate that sertraline has an effect on dopamine metabolism, which may alter function in the striatum and induce a parkinsonian syndrome.

Parental anger can have detrimental effects on children and can contribute to physical abuse. Ego-dystonic anger attacks are an underrecognized psychiatric symptom that occurs in associated with depression, with other psychiatric disorders, and in the absence of comorbid disorders. They are characterized by overwhelming anger and autonomic arousal occurring upon provocation viewed as trivial by the individual, and they respond well to treatment with serotonergic antidepressants. Consequently, they represent a readily treatable problem. Four cases of anger attacks in mothers of young children are described to illustrate the importance of recognizing and treating anger attacks.

Attention-deficit hyperactivity disorder (ADHD) and major depression are common ailments that can cause significant dysfunction throughout the life cycle. These two disorders may occur comorbidly. This case series describes 7 pediatric patients (aged 10-16 years) and 4 adults (aged 38-44 years) whose ADHD and comorbid major depression were treated in a naturalistic open clinical fashion. For all 11 patients, symptoms of major depression appeared to respond well to either fluoxetine or sertraline monotherapy. Using starting doses of fluoxetine 10 mg or sertraline 25 mg daily, we did not observe any adverse behavioral activation or clinical deterioration. However, no improvement in ADHD symptoms was observed in any patient during fluoxetine or sertraline monotherapy. Adjunctive treatment with a psychostimulant seemed necessary for chronic ADHD symptoms to be effectively addressed. The psychostimulants did not appear to provide observable antidepressant effects. With the exception of one adult who had a 20 mm Hg increase in diastolic pressure on methylphenidate monotherapy at 22.5 mg daily, the administration and coadministration of these agents were not associated with significant changes in blood pressure or heart rate. No patient developed suicidality, increased aggressiveness, mania, or other problematic side effects. This combination therapy was well tolerated and appeared to be effective in ameliorating both ADHD and depressive symptoms. These cases support previous suggestions that adjunctive treatment with psychostimulants might be a safe and effective intervention for children treated with fluoxetine or sertraline who have persistent ADHD symptoms and suggests that such combined treatment may be suitable for adults as well.

Sertraline and other SSRIs have a relatively favorable side-effect profile and are widely prescribed. We report the emergence of psychotic symptoms during treatment with sertraline in four patients. Three of these patients had a history of psychotic illness and were on antipsychotic medication, when sertraline was added. The psychotic symptoms emerged within 3 days-7 weeks of starting sertraline and resolved on its discontinuation. We wish to alert clinicians to the possibility that sertraline may provoke or exacerbate positive psychotic symptoms, particularly in patients on neuroleptics, with a previous history of psychosis.

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We describe a patient with chronic depression who was treated with the selective serotonin-reuptake-inhibitor sertraline. Following surgery, the patient developed severe nausea and vomiting, necessitating an efficient antiemetic treatment, possibly including the 5-HT3-receptor antagonist ondansetrone. Because both drugs, sertraline and ondansetrone, interact with the serotonin system at the synapsis, a possible interaction was discussed. Since the effect of the selective serotonin-reuptake inhibitors mainly depends on 5-HT1 and 5-HT2-receptors, a pharmacodynamic interaction between an 5-HT3-antagonist and a serotonin-reuptake-inhibitor at the synapsis leading to the relapse of depression seems to be very unlikely. There exist also no conclusive data suggesting a clinically relevant pharmacokinetic interaction between the two drugs. A treatment with ondansetrone was considered to be safe in this patient.

OBJECTIVE: To study the adverse drug reaction (ADR) profile of selective serotonin re-uptake inhibitors (SSRI) in Belgium and the Netherlands.
METHODS: Descriptive study.
METHODS: The Belgian Pharmacovigilance Centre and the Dutch Drug Safety Unit.
METHODS: All adverse reactions of fluoxetine, fluvoxamine, paroxetine and sertraline, reported between the moment of registration of these drugs and January 1st 1995, were assessed for causality. Possible, probable and certain adverse reactions were counted per drug and per country.
RESULTS: At the national monitoring centres of Belgium and of the Netherlands adverse reactions were reported 78 and 537 times, respectively. Approximately 30% of the adverse reactions were well-established. Approximately 60% of the reactions were poorly documented or not serious. Less than 1% of the adverse reactions reported in Belgium and approximately 13% of the reactions reported in the Netherlands, were less established and/or serious. These reactions were: movement disorders and extrapyramidal reactions, convulsions, galactorrhoea, hyponatraemia and syndrome of inappropriate antidiuretic hormone secretion, and purpura.
CONCLUSIONS: The ADR profile was compatible with the ADR profile in the medical literature, but not all ADR were similarly represented in the product information of the different SSRI. More adverse reactions were reported in the Netherlands than in Belgium.