Excretion of tolbutamide metabolites in young and old subjects

Summary Tolbutamide (1 g/70 kg) was administered as a single intravenous dose to 31 healthy, non-smoking, drug-free males between 23 and 87 years old and the total amounts of hydroxy and carboxytolbutamide excreted in 24 h were measured. There was a significant decrease in the urinary recovery of both metabolites with age. The reason for these findings is not known at the present time and may be associated with the decrease in creatinine clearance observed in these subjects or other changes in the pharmacokinetics of tolbutamide which are currently being investigated.     

Pharmacokinetics of bretylium in man after intravenous administration

The pharmacokinetic profile of bretylium was studied in four normal male volunteers using a new sensitive EC-GC procedure for its quantitation in biological fluids. The plasma concentrations and urinary excretion rates following the constant i.v. infusion of a single 4mg/kg dose of bretylium tosylate declined biexponentially and the data were fitted to a two-compartment model with a renal and a nonrenal route of elimination. The drug had a mean half-life (t_1/2)of 7.8 hr and apparent volume of distribution (V_d,)of 8.18 liters/kg. The renal clearance, which was 6 times that of the glomerular filtration rate, accounted for almost 84% of the total body clearance and correlated linearly with the subjects' creatinine clearance. The observed side effects of bretylium were mild and similar to those of other adrenergic blocking agents.This work was supported in part by a grant from Arnar-Stone Laboratories, Inc., McGaw Park, Illinois.     

Engineering of an alternative electron transfer path in photosystem II

The initial steps of oxygenic photosynthetic electron transfer occur within photosystem II, an intricate pigment/protein transmembrane complex. Light-driven electron transfer occurs within a multistep pathway that is efficiently insulated from competing electron transfer pathways. The heart of the electron transfer system, composed of six linearly coupled redox active cofactors that enable electron transfer from water to the secondary quinone acceptor Q_B, is mainly embedded within two proteins called D1 and D2. We have identified a site in silico, poised in the vicinity of the Q_A intermediate quinone acceptor, which could serve as a potential binding site for redox active proteins. Here we show that modification of Lysine 238 of the D1 protein to glutamic acid (Glu) in the cyanobacterium Synechocystis sp. PCC 6803, results in a strain that grows photautotrophically. The Glu thylakoid membranes are able to perform light-dependent reduction of exogenous cytochrome c with water as the electron donor. Cytochrome c photoreduction by the Glu mutant was also shown to significantly protect the D1 protein from photodamage when isolated thylakoid membranes were illuminated. We have therefore engineered a novel electron transfer pathway from water to a soluble protein electron carrier without harming the normal function of photosystem II.     

Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice

Mild traumatic brain injury (mTBI) represents a major and increasing public health concern and is both the most frequent cause of mortality and disability in young adults and a chief cause of morbidity in the elderly. Albeit mTBI patients do not show clear structural brain defects and, generally, do not require hospitalization, they frequently suffer from long-lasting cognitive, behavioral, and emotional problems. No effective pharmaceutical therapy is available, and existing treatment chiefly involves intensive care management after injury. The diffuse neural cell death evident after mTBI is considered mediated by oxidative stress and glutamate-induced excitotoxicity. Prior studies of the long-acting GLP-1 receptor agonist, exendin-4 (Ex-4), an incretin mimetic approved for type 2 diabetes mellitus treatment, demonstrated its neurotrophic/protective activity in cellular and animal models of stroke, Alzheimer’s and Parkinson’s diseases, and, consequent to commonalities in mechanisms underpinning these disorders, Ex-4 was assessed in a mouse mTBI model. In neuronal cultures in this study, Ex-4 ameliorated H₂O₂-induced oxidative stress and glutamate toxicity. To evaluate in vivo translation, we administered steady-state Ex-4 (3.5 pM/kg/min) or saline to control and mTBI mice over 7 days starting 48 h prior to or 1 h post-sham or mTBI (30 g weight drop under anesthesia). Ex-4 proved well-tolerated and fully ameliorated mTBI-induced deficits in novel object recognition 7 and 30 days post-trauma. Less mTBI-induced impairment was evident in Y-maze, elevated plus maze, and passive avoidance paradigms, but when impairment was apparent Ex-4 induced amelioration. Together, these results suggest that Ex-4 may act as a neurotrophic/neuroprotective drug to minimize mTBI impairment.     

Effectiveness of the Cough Reflex in Patients with Aspiration Following Radiation for Head and Neck Cancer

The effectiveness of the cough reflex in patients who aspirated following radiation for head and neck cancer was evaluated in 89 patients (49 chemoradiation, 33 postoperative radiation, and 7 radiation alone). All patients had modified barium swallow because of dysphagia. The cough reflex was graded as present and effective, ineffective, intermittently effective, or absent. All patients were cancer-free at the time of the swallowing study. The cough reflex was present and effective in 46 patients (52%), ineffective in 17 patients (19%), and absent in 26 patients (29%) on initial investigation. Among the 43 patients who had ineffective or absent cough reflex, their treatment was chemoradiation (26), postoperative radiation (13), and radiation alone (4). In 30 patients who had sequential modified barium swallow, the cough reflex was constantly effective, ineffective, or intermittently effective in 12 (40%), 13 (43%), and 5 (17%) patients, respectively. The cough reflex was frequently ineffective or absent in patients who aspirated following radiation for head and neck cancer. Cough may also be intermittently ineffective to protect the airways following radiation.     

Successful treatment with plasma exchange in life-threatening hyperhemolytic syndrome unrelated to sickle cell disease

Introduction

Hyperhemolytic syndrome (HHS) is a severe form of delayed transfusion reaction primarily described in sickle cell anemia patients which is characterized by a hemoglobin decrease to pre-transfusion levels or lower, often with reticulocytopenia and no evidence of auto- or allo-antibodies.

Case Presentation

We present two cases of severe HHS in patients without sickle cell anemia refractory to treatment with steroids, immunoglobulins, and rituximab. In one case, temporary relief was achieved with eculizumab. In both cases, plasma exchange resulted in a profound and immediate response allowing for splenectomy and resolution of hemolysis.

Discussion/Conclusion

We discuss the pathophysiology of HHS, its presentation and treatment and expand on the possible role of plasma exchange in this setting.     

Hospitalizations due to falls in Jewish and Arab children in northern Israel

In Israel, there are no epidemiological data regarding nonfatal childhood falls. A retrospective survey was conducted in order to find epidemiological characteristics of childhood falls among the different populations of northern Israel. During the years 1993 through 1995, 3082 children were hospitalized in Rambam Medical Center (RMC) due to injury. The children were subdivided into the four main populations: Jewish and Arab residents of Haifa region (the main metropolitan area) and Jewish and Arab residents of the Galilee region (the rural region). All of the children who suffered injury that required mechanical ventilation and careful assessment were admitted to the PICU. The charts of the children admitted to the PICU were then further studied. The demographic characteristics of all the cases of falls were statistically analyzed and the annual admission rates due to falls were calculated using the national statistical registrations of children in Israel. Falls were responsible for 1049 admissions due to injury, one third of the total number of children who were admitted due to an injury. Most of the children were five years of age or younger. Two thirds of the total childhood falls were of Arabs. The majority of the admissions were of two major sub-populations of northern Israel: Arab residents of Galilee region (66%) and Jewish residents of Haifa region (34%). Higher admission rate was found among Arab children of the Western Galilee district in comparison with Jewish children of the Haifa district. Most of the children who were admitted to the PICU were Arabs: nearly all of these children were from the rural region. More Arab than Jewish children who fell were admitted to the PICU and the majority of these cases were falls from buildings (private houses). Arab children of the rural region were responsible for 95% of the cases. These falls were mainly in staircases (46%) and from balconies (21%), roofs (11%) and windows (11%). The findings of the present study suggest that young Arab rural children in northern Israel are at high risk to a severe injury due to fall. Possible causes are discussed and a preventative intervention is suggested.