ABSTRACT
Infectious purpura fulminans is associated with high mortality and morbidity despite standard antimicrobial therapy. We report satisfactory clinical outcome in two children with sepsis associated purpura fulminans who were treated with activated protein C (APC). There is need for proper evaluation of the efficacy of this extremely expensive therapeutic modality by randomized controlled trials before it is made standard of care in childhood infectious purpura fulminans.
Subject(s)
Acute Disease , Anticoagulants/therapeutic use , Blood Coagulation Factors/drug effects , Child, Preschool , Humans , Infant , Male , Protein C/therapeutic use , IgA Vasculitis/drug therapy , Receptors, Cell Surface/drug effects , Treatment OutcomeABSTRACT
Smooth muscle contraction has a characteristic step-response with successive additions of stimulating compounds, and instant reversal on withdrawing the stimulus, indicative of an equilibrium situation wherein continuous, rapid reactions are occurring. Vanadium compounds, ortho- and meta-vanadates, decavanadate and peroxovanadate, were found to contract a variety of smooth muscles. Their actions were analyzed with respect to activation of receptors, increase in the intracellular calcium concentration, and increase in calmodulin-dependent myosin light chain phosphorylation leading to contraction. A new perspective of smooth muscle contractility has emerged from the studies with vanadium compounds suggesting control mechanisms involving phosphorylation for contraction and redox for relaxation.
Subject(s)
Animals , Ion Channels/drug effects , Membrane Potentials/drug effects , Muscle Contraction/drug effects , Muscle Proteins/metabolism , Muscle, Smooth/drug effects , Oxidation-Reduction , Phosphorylation , Receptors, Cell Surface/drug effects , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Vanadium Compounds/chemistryABSTRACT
Either in vivo or in vitro quantitatives comparisons of drugs based on the dose-response relations were known for a long time. For therapeutically targeted molecular structure activity studies, agonists are simply compared on the basis of concentrations eliciting half-maximum response (EC50) and per cent maximum response elicited by drugs in the given system. For partial agonists the receptor affinity determined as the dissociation constant (KA) in homogenates corresponds to that in the organ system. However, due to the presence of spare receptors the EC50 of potent agonists does not represent the KA. If a fraction of receptors are irreversibly inactivated in the tissue, KA as well as relative intrinsic efficacy of the potent agonists can be obtained. Although quantitation of irreversible antagonists is quite complex, the competitive reversible blockers can be accurately compared on the basis of equilibrium dissociation constant (KB) values. Along with the relative order of potency of agonists and KB values of antagonists, receptors can be characterized and subclassified. Preclinical Therapeutic Index of drugs and Toxicity Index of pesticides require determinations of mean lethal dose (LD50) and the mean effective dose (ED50) in laboratory animals, so that a relatively safe drug can be promoted for human use. The understanding of pharmacokinetics is essential to explain drug action in the target organs. Drug combinations are investigated by isobolorographic analysis.
Subject(s)
Animals , Dose-Response Relationship, Drug , Drug Tolerance , Humans , Lethal Dose 50 , Pharmacology/statistics & numerical data , Receptors, Cell Surface/drug effectsABSTRACT
Melanin concentrating hormone (MCH: 5 x 10(-12)-5 x 10(-8) M) induced a concentration related, rapid and reversible pigment aggregation in innervated melanophores of Labeo rohita. In inducing melanosome aggregation MCH was found to be 10(4) times more potent than norepinephrine. Experiments employing phentolamine and propranolol suggest that MCH acts through its own specific receptors on the melanophores unrelated to adrenoceptors. MCH was able to aggregate the melanosomes even in the absence of extracellular Ca2+.
Subject(s)
Animals , Calcium/physiology , Carps/physiology , Cell Aggregation/drug effects , Hypothalamic Hormones , Melanins/metabolism , Melanocytes/drug effects , Melanophores/drug effects , Nerve Endings/drug effects , Norepinephrine/pharmacology , Phentolamine/pharmacology , Pituitary Hormones/metabolism , Propranolol/pharmacology , Receptors, Cell Surface/drug effects , Skin/cytologyABSTRACT
Con el objeto de conocer los mecanismos por los cuales el sistema opioíde endógeno (SOE) modula la actividad de la unidad hipotálamo-hipofisiaria, se analizaron los efectos de la administración de clorhidrato de naloxona (NAL) sobre la dinámica gonadotrópica de la hipófisis anterior de la rata macho y hembra durante diferentes estadios de la maduración sexual. A ratas Wistar de ambos sexos (de 5 a 50 días de edad) se les administró NAL por vía subcutánea (10 mg/Kg peso) en 0.05 ml de solución salina. Se utilizaron de 5 a 10 animales por grupo de edad incluyéndose igual número de grupos control los cuales recibieron únicamente 0.05 ml de solución salina. Posterior a una hora de la administración de la NAL, los animales fueron sacrificado colectándose la sangre, así como el hipotálamo y las glándulas hipofisiarias. Las concentraciones en suero y contenido hipofisiario de LH y FSH se determinaron por radioinmunoanálisis específicos. El contenido de receptores hipofisiarios de la hormona liberadora de las gonadotropinas (GnRH) se determinó utilizando el análogo sintético del GnRH, D-Ser(TBu6) -des- Gli10 -GnRH-N- etilamida, el cual fue marcado radiactivamente con I-25 utilizando la técnica enzimática de Lactoperoxidasa. Los cambios producidos por la administración de NAL sobre el procesamiento (cambios post-traduccionales) de FSH hipofisiaria fueron estudiados por cromatografía en concanavalina-A obteniéndose la relación libre y unida de FSH a la lectina. Los resultados demostraron que la inhibición del SOE durante etapas prepuberales induce el incremento de las concentraciones en suero de LH y FSH. Este efecto fue estadísticamente significativo únicamente para el caso de las ratas hembras no observándose efectos importantes en ratas del sexo masculino. El incremento de ambas gonadotropinas estuvo acompañado de la depleción de receptores hipofisiarios para GnRh y del incremento de la fracción libre de la hormona folículo estumulante a nivel hipofisiario...