5-HT 2C receptor sensitivity during treatment with selective serotonin re-uptake inhibitors

We studied the effect of repeated treatment with selective serotonin re-uptake inhibitors (SSRIs) on the sensitivity of brain 5-HT(2C) receptors, by measuring the decrease in slow wave sleep (SWS) that follows administration of meta-chlorophenylpiperazine (mCPP) (7.5 mg orally). mCPP significantly lowered SWS both in patients taking SSRIs and in a group of healthy controls. There was, however, no difference in the response between the two groups. The results do not support the suggestion that repeated SSRI treatment alters the sensitivity of 5-HT(2C) receptors in the human brain. The present study, however, cannot exclude the possibility that a decrease in 5-HT(2C) receptor sensitivity was offset by higher plasma levels of mCPP in the SSRI-treated group.     

Treatment of systemic and renal-limited vasculitic disorders with pooled human intravenous immune globulin

Idiopathic crescentic glomerulonephritis is characterized by an absence of immunohistological evidence of immune deposits, often with evidence of segmental glomerular necrosis. Such pauciimmune crescentic glomerulonephritis is the most common renal manifestation seen in patients with Wegener's granulomatosis, polyarteritis nodosa, and glomerulonephritis associated with other systemic vasculitic disorders (i.e., Churg-Strauss syndrome). Recently, the idiopathic crescentic glomerulonephritides, either in renal-limited form or in association with other systemic vasculitic disorders, were found to have in common a serologic marker, antineutrophil cytoplasmic autoantibodies. These cytoplasmic and perinuclear antineutrophil cytoplasmic autoantibodies are specific for constituents of neutrophil primary granules and monocyte lysosomes. As serologic markers for vasculitic disorders, they are also felt to be directly involved in the pathogenesis of necrotizing vascular injury.In vitro, both perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies are capable of causing cytokineprimed neutrophils to undergo degranulation and respiratory burst, releasing toxic oxygen species and lytic enzymes. Antiidiotype antibodies which inhibit antineutrophil cytoplasmic autoantibodiesin vitro, in a V region-dependent manner, are found in pooled humanγ-globulin preparations. Intravenous immune globulin infusionsin vivo have produced dramatic improvements in the necrotizing vascular injury produced by antineutrophil cytoplasmic autoantibodies, and a rapid reduction in these autoantibody levels is seen post-intravenous immune globulin infusion in most patients. The proposed mechanisms of action of intravenous immune globulin in vasculitic disorders include Fc-dependent mechanisms, and F(ab′)₂-dependent mechanisms are likely important. Intravenous immune globulin infusions appear to have an important place in the management of the necrotizing vascular injury. Blinded, randomized, placebo-controlled trials will be necessary to establish definitively intravenous immune globulin as a therapeutic option in vasculitic disorders.     

The Influence of Dirithromycin on the Pharmacokinetics of Cyclosporine in Healthy Subjects and in Renal Transplant Patients

The effect of a standard regimen of the investigational macrolide antibiotic, dirithromycin, on the single-dose kinetics of orally administered cyclosporine (CSA) was investigated in healthy young males and on the steady-state disposition kinetics of cyclosporine in a panel of renal transplant patients. Eight male volunteers participated after giving informed consent. CSA was administered in three single doses (15 mg kg(minus sign1) p.o. each) in each of three phases: (1) prior to a 14-day regimen of dirithromycin; (2) at the end of a 14-day regimen of dirithromycin (500 mg p.o. qAM); and (3) 2 weeks after the last dose of a 14-day regimen of dirithromycin. Pharmacokinetic parameters of CSA were estimated, and the differences among treatments were assessed by analysis of variation. No significant differences among treatment (phase) means were detected (p < 0.05). We conclude that a typical 14-day regimen of dirithromycin failed to alter the disposition kinetics of CSA when taken orally healthy young adult males. The effect of a standard regimen of dirithromycin on the steady-state disposition kinetics of orally administered CSA was investigated in a panel of 15 stable renal transplant patients. Pharmacokinetic parameters for CSA were evaluated prior to, during, and 2 weeks after discontinuing a 14-day (500 mg day(minus sign1)) oral regimen of dirithromycin. Dirithromycin elicited small but significant changes in the following parameters: C(av) was increased by 16% during dirithromycin treatment, and the changes in normalized C(av) were comparable. Likewise, C(SS,min) and normalized C(SS,min) were increased by 19% and 20%, respectively, during dirithromycin treatment. CSA oral clearance, CL/F(SS), decreased by 17% during dirithromycin treatment. C(SS,max) and normalized C(SS,max) were increased by 13% and 17%, respectively, during dirithromycin treatment but were not significantly different from those either before or after dirithromycin. The magnitude of the pharmacokinetic changes for CSA during dirithromycin treatment (<15% in normal subjects and 15--20% in renal transplant patients) when considered in the context of the therapeutic range of cyclosporine concentrations was relatively small, and not likely to warrant special attention to the dosing of CSA in such patients beyond routine whole-blood CSA and serum creatinine monitoring.     

Intrahepatic absorbable fine mesh packing of hepatic injuries: Preliminary clinical report

A previous report from the authors' institution reported the effectiveness of hepatic packing with absorbable fine mesh (AFMP) for the control of hemorrhage in an animal model with an otherwise lethal hepatic injury. The technique has subsequently been applied to 12 abdominal trauma patients with hemodynamic instability and actively hemorrhaging hepatic injuries. Two patients expired in the operating room owing to uncontrolled hemorrhage from hepatic and associated injuries for a mortality of 16.7%. AFMP was successful in controlling hemorrhage in the remaining 10 patients. Hepatic injuries ranged from grade II to grade V, and all were actively hemorrhaging at the time of exploration. None of the surviving 10 patients experienced early or late recurrent bleeding attributable to the hepatic injuries, and there were no intraabdominal abscesses or late deaths. Liver function studies returned to normal prior to discharge in all surviving patients. Follow-up included serial computed tomographic scans, which demonstrated fibrosis incorporating the mesh packing. Complete resolution of injury and mesh appears to proceed over approximately a 6-month period. AFMP is a safe, effective method for controlling hepatic hemorrhage. It is easy to perform in the operating room, offers an excellent matrix for hemostasis, provides tamponade of bleeding sites, and does not require reoperation for removal of packing material, as is necessary with conventional, nonabsorbable packing techniques.

---

Resumen En una publicación previa se informó la eficacia del empaquetamiento hepático con una fina malla absorbible en el control de la hemorragia en un modelo animal experimental sometido a lesión hepática letal. Desde entonces la técnica ha sido aplicada en 12 pacientes con trauma abdominal e inestabilidad hemodinámica y lesiones hepáticas sangrantes. Dos pacientes expiraron en la mesa de operaciones por hemorragia no controlada proveniente de la arteria hepática y de otras lesiones asociadas, con una tasa de mortalidad de 16.7%. La malla fue eficaz en cuanto a controlar la hemorragia en el resto de los pacientes. Las lesiones hepáticas variaron en cuanto a severidad entre los Grados II a V y todas exhibían hemorragia activa en el momento de la exploración. Ninguno de los 10 sobrevivientes desarrolló sangrado recurrente temprano o tardío que pudiera ser atribuible a las lesiones hepáticas y no se observaron abscesos intraabdominales o muertes tardías. Las pruebas de función hepática retornaron a valores normales con anterioridad al egreso, en la totalidad de los sobrevivientes. El seguimiento incluyó tomografías computadorizadas seriadas, que demostraron fibrosis del área de empaquetamiento con la malla; la resolución completa de la lesión y de la malla parece tener lugar en el curso de seis meses, aproximadamente. La malla representa un método seguro y eficaz de control de la hemorragia hepática, es fácil de aplicar en el quirófano, ofrece una excelente matriz para la hemostasia, produce taponamiento de los sitos sangrantes y no requiere reoperación para remover el material de empaquetamiento, como sí lo requieren las técnicas convencionales de empaquetamiento con materiales no absorbibles.

---

Résumé Nous avons déjà rapporté l'efficacité du packing périhépatique par un filet fin résorbable (FFA) pour contrôler l'hémorragic autrement mortelle provenant d'une lésion hépatique chez l'animal. Cette même technique a été utilisée utilisée chez 12 patients ayant un traumatisme sévère du foie avec une hémodynamique instable. Deux patients sont décédés en salle d'opération des lésions hépatiques et des structures avoisinantes soit une mortalité de 16.7%. La technique de FFA a été couronnée de succès chez les 10 autres patients. Les lésions ont été classées selon leur sévérité du grade II au grade V et toutes saignaient activement au moment de l'opération. Aueun des patients survivants n'a eu de récidive hémorragique attribuable à la lésion hépatique et il n'y a eu aucun abcès intra-abdominal ni de mortalité tardive. La fonction hépatique est redevenue normale avant la sortie chez tous les autres patients. La surveillance du suivi a comporté une tomodensitométrie montrant une fibrose autour du filet. La résolution complète de la lésion et la résorption du filet évoluent en général sur six mois. La technique de FFA est sûre et efficace dans le contrôle de l'hémoragie provenant des traumatismes du foie. La méthode est facile à appliquer en salle d'opération, procure une hémostase excellent par tamponnade et ne nécessite pas de réintervention pour enlever le packing comme quand on utilise le matériel traditionnel non résorbable.

     

Effect of dietary sodium on airways responsiveness and its importance in the epidemiology of asthma: an evaluation in three areas of northern England.

BACKGROUND--Although several investigations have shown a relationship between asthma (or its surrogate, airways responsiveness) and dietary or urinary sodium, others have not, and the matter remains controversial. This "salt effect" has been investigated during two recent epidemiological surveys of men in northern England. The first assessed the possible effect on airways responsiveness of occupational exposure to welding fumes, and the second characterised airways responsiveness in two geographically distinct residential areas. Thus, three separate study areas/populations were involved. METHODS--Investigation 1 involved 1059 shipyard workers aged 16-27 years who were exposed variously to welding fumes, and Investigation 2 involved 587 men aged 20-44 years who lived in rural West Cumbria or in urban Newcastle upon Tyne. In Investigation 1, a 24 hour urine specimen was requested from each subject with quantifiable airways responsiveness (PD20 < or = 6400 micrograms methacholine) and from an equal number of subjects without measurable airways responsiveness from the same occupational subgroup. In Investigation 2, every subject was asked to provide a 24 hour urine specimen. RESULTS--Of the men undergoing methacholine tests, satisfactory 24 hour urine specimens were obtained from 234 (22.1%) in Investigation 1 and 232 (39.5%) in Investigation 2. Analysis using multiple linear regression, multiple linear logistic regression, and multiple regression for censored data produced consistent results within each study population but conflicting results between them, such that there was no hint of a relationship between airways responsiveness and 24 hour urinary sodium excretion in the shipyard workers of Investigation 1 nor in the rural West Cumbrian population of Investigation 2, but an association was found in the urban Newcastle population of Investigation 2. All study populations were sufficiently large to demonstrate anticipated relationships between airways responsiveness and atopy, baseline FEV1, and (Newcastle only) age. CONCLUSIONS--If airways responsiveness is related to dietary sodium the relationship is not likely to be strong.