Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.     

Retinoids inhibit the respiratory burst and degranulation of stimulated human polymorphonuclear leukocytes

Retinoids exhibit a wide spectrum of activities, including antiinflammatory properties. We have investigated the effect of retinoic acid (RA) and retinyl acetate (RAc) on the production of reactive oxygen metabolites and the release of lysosomal enzymes by human polymorphonuclear leukocytes (PMN). Incubation of PMN with RAc or RA (1–100 μM) caused a dose-dependent inhibition (upto 90%) in O ₂ ^? production and chemiluminescence induced by phorbol myristate acetate (PMA), N-formyl-methionylleucyl-phenylanaline (fMLP), opsonized zymosan or ionophore A23187. Both retinoids (1–100 μM) also inhibited, in a dose-dependent way, degranulation induced by fMLP (upto 85% at the highest concentration of RA). These inhibitory effects appear irreversible, since they persist after the drugs are removed and the cells washed before stimulation. Inhibitors of cyclo-oxygenase activity such as acetylsalicylic acid and indomethacin did not influence the effects of RAc. In contrast, BW755, an inhibitor of both cyclooxygenase and lipoxygenase, reversed the inhibitory action of RAc, suggesting that the effect of retinoids occurs possibly through the mediation of lipoxygenase products. The modulation of PMN oxidative metabolism and degranulation might help explain the antiinflammatory properties of retinoids.     

Occurrence of disseminated intravascular coagulation in rat BNML leukaemia despite lack of leucocyte procoagulant activity.

Signs of disseminated intravascular clotting were observed during the development of BNML myelomonocytic leukaemia in rats, when the peripheral leucocyte count exceeded 20,000/microliters and more than 50% blasts were present in the circulation. BNML cells, harvested from blood and tested in appropriate systems, were found devoid of any procoagulant activity (PCA) even following prolonged in vitro incubation with endotoxin. Thus, it appears that these rat leukaemic cells share the same inability to express PCA which had been previously described in peripheral blood mononuclear cells from normal rats. Conceivably, in this rat model, leucocyte PCA does not represent a major trigger of intravascular coagulation and blood clotting is initiated by other, mainly plasmatic, pathways.     

Basismaßnahmen zur Wiederbelebung Erwachsener (Basic Life Support)

Notfall + Rettungsmedizin - Der Europäische Rat für Wiederbelebung hat diese Leitlinie – Basismaßnahmen zur Wiederbelebung – auf Grundlage des...     

Increased resting lipid oxidation in Crohn's disease

Resting energy expenditure (REE) was measured by indirect calorimetry and body composition was assessed by both direct (bioimpedance) and indirect (anthropometry) methods in 20 hospitalized patients with biopsy-proven ileal Crohn's disease and in a group of 16 healthy volunteers matched for sex, age, and height with the patient group. The Crohn's disease activity index was below 120 in all patients studied. who were treated with a low dose of corticosteroids (0.2–0.3 mg/kg body wt of prednisone). The average weight of Crohn's patients was signficantly lower than that of controls (55.70 vs 70.50 kg,P<0.001) due to both lower fat mass (9.97 vs 18.30 kg,P<0.001) and lower lean body mass (45.72 vs 52.20 kg,P<0.02). The average REE was significantly higher in the control group (1785.42±7.503 vs 1559.1±48.39 kcal/day,P<0.001). However, these differences disappeared when REE was normalized by lean body mass (LBM) (34.49±2.56 vs 34.704±3.75 kcal/kg LBMP=NS). The nonprotein respiratory quotient was significantly lower in the patient group (0.823±0.031 vs 0.882±0.012.P<0.025), indicating an increased lipid oxidation. This increased lipid oxidation might explain the reduced fat stores found in the group of Crohn's patients, suggesting also that a sufficiently lipid-rich diet could be useful in their nutritional management.     

Obesity in celiac sprue

Celiac sprue usually results in biochemical and clinical signs of malabsorption, nutrient loss, and resulting growth failure. We report a child with celiac sprue diagnosed at 1 year of age who was initially cachectic but who eventually developed obesity while taking a gluten-containing diet.     

Endothelial cells in the bone marrow of patients with multiple myeloma

Endothelial cells (EC) were extracted through a lectin-based method from bone marrow of 57 patients with active multiple myeloma (MM) and compared with their healthy quiescent counterpart, human umbilical vein EC (HUVEC). MMECs exhibit specific antigens that indicate ongoing angiogenesis and embryo vasculogenesis; solid intercellular connections, hence stability of MM neovessels; and frequent interactions with plasma cells, hence tumor dissemination. They show heterogeneous antigen expression, hence existence of subsets. Their main genetic markers are indicative of a vascular phase. They show intrinsic angiogenic ability, because they rapidly form a capillary network in vitro, and extrinsic ability, because they generate numerous new vessels in vivo. They vividly secrete growth and invasive factors for plasma cells. They signal through kinases mandatory for development of neovascularization. Ultrastructurally, they are abnormal and show metabolic activation, like tumor ECs. Thalidomide heavily interferes with their functions. Vasculogenesis and angiogenesis might contribute to the MM vascular tree and progression, in the form of growth, invasion, and dissemination. In view of the heterogeneity of the antigenic phenotype of MMECs, a mixture (or a sequence) of antiangiogenic agents coupled with thalidomide would seem plausible for the biologic management of MM.     

Selective Serotonin Reuptake Inhibitors: A Review of its Effects on Intraocular Pressure

The increase in serotonin (5-HT) neurotransmission is considered to be one of the most efficacious medical approach to depression and its related disorders. The selective serotonin reuptake inhibitors (SSRIs) represent the most widely antidepressive drugs utilized in the medical treatment of depressed patients. Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. The primary SSRIs pharmacological action’s mechanism consists in the presynaptic inhibition on the serotonin reuptake, with an increased availability of this amine into the synaptic cleft. Serotonin produces its effects as a consequence of interactions with appropriate receptors. Seven distinct families of 5-HT receptors have been identified (5-HT₁ to 5-HT₇), and subpopulations have been described for several of these. The interaction between serotonin and post-synaptic receptors mediates a wide range of functions. The SSRIs have a very favorable safety profile, although clinical signs of several unexpected pathologic events are often misdiagnosed, in particular, those regarding the eye. In all cases reported in the literature the angle-closure glaucoma represents the most important SSRIs-related ocular adverse event. Thus, it is not quite hazardous to hypothesize that also the other reported and unspecified visual disturbances could be attributed - at least in some cases - to IOP modifications. The knowledge of SSRIs individual tolerability, angle-closure predisposition and critical IOP could be important goals able to avoid further and more dangerous ocular side effects.     

Middle ear neoplasms showing adenomatous and neuroendocrine components

Middle ear adenomas are rare epithelial tumours. Reports indicate that neuroendocrine (carcinoid) tumours may also occur at this site, often in association with an adenomatous component. The clinico-pathological findings (including C.T. scan appearances) of such a 'mixed' neoplasm are presented together with a brief review of the few previously described cases. The importance of immuno-histochemistry and electron microscopy for accurate pathological diagnosis of these neoplasms is confirmed.