Antilymphocyte globulins (ALGs) are polyclonal antibodies used in organ transplantation to prevent or treat acute allograft rejection. ALGs are obtained by immunizing animals (rabbits or horses) with human lymphoid cells (lymphoblasts, lymphocytes or thymocytes). Although ALGs have been in use for several decades, the interindividual variability in patient response remains poorly understood. Monitoring of drug effect is based on lymphocyte numeration, because ALG doses may be decreased when lymphopenia is obtained or the drug readministered to maintain it. Although lymphocyte count is an established biomarker of ALG therapeutic effect, the study of its quantitative relationship with ALG concentrations has not been reported. Read more…
The three isoforms of nitric oxide synthase (NOS), neuronal NOS (nNOS, NOS 1), inducible NOS (iNOS, NOS 2) and endothelial (eNOS, NOS 3), convert l-arginine to nitric oxide (NO) and l-citrulline. NO is a vasoactive compound that induces vasodilation of arterial and venous blood vessels. In endothelial cells, l-arginine is transported via the cell membrane by cationic amino acid transporters that are colocalized with eNOS. The MichaelisâMenten constant (Km) for eNOS is 
3 µM l-arginine. This is at least one order of magnitude lower than the normal plasma concentrations of l-arginine, which are usually in the range 60â140 µM. Nevertheless, oral supplementation with l-arginine has been shown to enhance NO-mediated vasodilation in several clinical studies, but not in all. One possible explanation for this âarginine paradoxâ is the presence of an endogenous inhibitor of NOS, which may shift the steep part of the substrateâactivity curve of NOS towards higher l-arginine levels. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of all three isoforms of NOS and it is circulating at low µM concentrations in humans. The ratio of l-arginine over ADMA (arginine/ADMA ratio) is one determinant of NO production by NOS. Once produced, NO activates soluble guanylyl cyclase (sGC) in smooth muscle cells, which leads to elevated intracellular cyclic guanosine monophosphate (cGMP). In human blood vessels this mechanism results in vasodilation. This process is essential for endothelial function, and disturbed NO production in the human endothelium contributes to endothelial dysfunction. Read more…
In Canada, chronic obstructive pulmonary disease (COPD) affects 4.3% of adults aged â¥35 years, making it the fourth most common cause of illness and death. Worldwide, COPD is also the fourth leading cause of death and the 12th leading cause of disability. Acute exacerbations are the most frequent cause of hospital admissions and death among COPD patients.
Unfortunately, recent guidelines for the diagnosis, management and prevention of COPD report that none of the existing medications for COPD has been shown to modify the long-term decline in lung function. Although the goals of COPD management include the prevention of disease progression and the reduction of mortality, they also include symptom relief, treatment and prevention of exacerbations and the improvement of health status. The step care approach proposed by the Global Initiative for Chronic Obstructive Disease (GOLD) treatment guidelines recommends theophyllines as the third line of treatment when symptoms are still persistent despite treatment with short- and long-acting inhaled bronchodilators. The recommendation for inhaled corticosteroids (ICS) use is more restricted, being recommended only for patients with frequent exacerbations, as their efficacy to improve lung function has been shown to be limited, whereas they have been shown to reduce the risk of exacerbations. In the ISOLDE trial, the annual rate of exacerbations among moderate to severe COPD patients was 1.90 (SD 2.63) for placebo group and 1.43 (SD 1.93) for patients on ICS after 3 years of treatment. In this randomized controlled trial (RCT), an exacerbation was defined as worsening of respiratory symptoms that required treatment with oral corticosteroids or antibiotics, or both. Read more…
There are more than 4000 chemicals found in cigarette smoke. Cigarette smoking is associated with an increased incidence of both respiratory and cardiovascular disease, but the relationship of specific constituents with disease has not yet been established. Carbon monoxide (CO) is one of the cigarette smoke constituents that has a very high affinity for haemoglobin (Hb) relative to that for oxygen (approximately 200-fold). This results in an acute effect of decrease in oxygen-carrying capacity of Hb and a leftward shift of the oxyhaemoglobin dissociation curve, which reduces the release of oxygen to tissues. CO also binds with other haemoproteins such as myoglobin, which abounds in skeletal muscles, causing dysfunction by impairing its oxygen-carrying capacity and the transportation of oxygen from the blood to the mitochondria. Read more…
Reactive oxygen species (ROS), like superoxide anion (O2.â) and hydrogen peroxide (H2O2), play an important role in health and disease. They have been implicated in the pathophysiology of different disease states, including anthracyclin-induced cardiotoxicity (AIC), inflammatory bowel disease, ischaemia/reperfusion injury and neurodegenerative conditions. The hypothesis is that in these pathological conditions, relatively large amounts of ROS are produced which cause functional damage to many tissues and even apoptosis. The underlying mechanism for the deleterious effect of ROS on tissues is not fully understood, but includes cell membrane damage due to lipid peroxidation, and direct damage to proteins and DNA.
There are different endogenous defence mechanisms against the ROS damage such as superoxide dismutase (SOD), catalase, peroxidases and vitamin A and E which all share free radical scavenger properties.
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Acute seizures are a frequent clinical feature of severe malaria (SM) and other infections in children. Over 80% of children presenting to hospital with cerebral malaria have a history of seizures and about 60% have clinical seizures after admission. Protracted and multiple convulsions are often refractory to treatment and are associated with an increased risk of death and/or neurological and cognitive deficits among survivors. Therefore, early, prompt and effective termination and prevention of convulsions may improve outcome in children with SM. Furthermore, rapid and sustained seizure control may avert the need for multiple anticonvulsant administration and prolonged hospitalization.
The ideal drug for treating acute seizures and status epilepticus (SE) should: (i) enter the brain rapidly; (ii) have an immediate onset of anticonvulsant action; (iii) have minimal depression of consciousness or cardiorespiratory function; (iv) have a sustained duration of anticonvulsant action to prevent seizure recurrence; and (v) be easily and safely administered at peripheral healthcare facilities. Benzodiazepines are considered the drugs of choice for rapid termination of acute seizures and SE. In resource-poor countries, diazepam (DZ) is frequently used as the standard first-line treatment for acute convulsions and SE, as it is widely available, cheap and rapidly acting. However, it has several disadvantages. Gaining intravenous (i.v.) access is often technically difficult in most peripheral healthcare settings (with limited resources and healthcare personnel), particularly in young children who are having generalized tonic-clonic convulsions. Following i.v. administration, DZ is rapidly redistributed to lipoid tissues, and consequently, plasma concentrations rapidly decline with breakthrough seizures occurring when the concentrations fall below threshold levels. Accordingly, repeated injections or continuous infusions are often required for sustained control of seizures. However, administration of multiple doses of DZ is undesirable, especially in children with SM, due to accumulation and increased risk of fatal respiratory depression. Moreover, rectal administration of DZ (which has been suggested as a practical alternative to i.v. administration under such settings) generally results in variable absorption, leading to rapid recurrence of seizures. The intramuscular (i.m.) route, which is frequently used in such settings, is not suitable for administration of DZ for termination of acute seizures and SE, since it results in incomplete and erratic absorption. Read more…
Recombinant activated factor VII (rFVIIa, NovoSeven®; Novo Nordisk A/S, Bagsværd, Denmark) is established for the treatment of bleeding episodes and for the prevention of bleeding during surgery or invasive procedures in patients with congenital haemophilia A and B with inhibitors to coagulation factors VIII (FVIII) or IX (FIX) or in those expected to have a high anamnestic response to FVIII or FIX, acquired haemophilia, congenital FVII deficiency or Glanzmann’s thrombasthenia refractory to platelet transfusions.
In addition to these indications, the therapeutic potential of rFVIIa has been explored for a number of critical bleeding situations. For example, rFVIIa successfully reversed coagulopathy in 75% (61/81) of patients with bleeding and coagulopathy resulting from a number of different causes, including acute traumatic haemorrhage and traumatic brain injury. In a multicentre, random ized, controlled Phase II trial, rFVIIa reduced red blood cell (RBC) transfusion requirements and the need for massive transfusion vs. placebo in patients with severe blunt trauma and a confirmatory Phase III trial evaluating rFVIIa for the treatment of traumatic haemorrhage is ongoing. In addition rFVIIa has been shown to reduce haematoma growth in intracerebral haemorrhage, although this reduction did not translate into improved long-term clinical outcome. A number of clinical guidelines on rFVIIa use in nonhaemophilia indications has been published.
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