The effect of pH and concentration on alpha-methyldopa absorption in man

An open crossover study of the absorption of alpha-methyldopa has been conducted in normal healthy adult male volunteers in whom a triple lumen perfusion tube had been placed. Three volunteers were perfused on separate occasions with 0.1 mM alpha-methyldopa at pH 4.5, 6.0 and 7.4. Three other volunteers were perfused on separate occasions with 0.1, 1.0 and 10 mM alpha-methyldopa at pH 6.0. Two additional subjects were perfused with 0.1 mM alpha-methyldopa at pH 6.0. Absorption was not a linear function of concentration above 1 mM alpha-methyldopa. There was also a weak trend toward greater absorption near pH 6.0. At higher concentrations of drug in the perfusion solution (10 vs 1 mM), the free fraction of alpha-methyldopa in plasma samples was increased significantly. Thus, although absorption of alpha-methyldopa is more efficient at lower concentrations, bioavailability may not be substantially enhanced due to increased sulphation in the gut wall. Comparison of permeabilities with previous results from our laboratories suggests the rat is a good model for predicting the behaviour of alpha-methyldopa after its oral administration to man.     

Humoral immune function in pediatric patients treated with autologous bone marrow transplantation for B cell non-Hodgkin's lymphoma. The influence of ex vivo marrow decontamination with anti-Y 29/55 monoclonal antibody and complement

Elimination of neoplastic B cell populations from autologous bone marrow grafts also removes normal B lymphocytes. This is potentially hazardous for the reconstitution of the immune system in patients undergoing high-dose chemotherapy and total body irradiation followed by autologous marrow rescue. Five pediatric patients with B cell non- Hodgkin's lymphoma in first remission undergoing such a regimen were studied. They received bone marrow pretreated with anti-Y 29/55 monoclonal antibody and complement. B and T lymphocyte subpopulations reached normal levels within 6 months after autologous bone marrow transplantation (ABMT), and serum immunoglobulin levels became normal within 4 to 9 months. Vaccination with diphtheria and tetanus toxoid, trivalent poliomyelitis vaccine of the Salk type, and pneumococcal capsular antigens (38 to 54 months after transplantation) gave rise to specific antibody production. ABO isoagglutinins could be demonstrated in all patients. The response pattern was similar to that of patients who received unmanipulated autologous bone marrow. It is concluded that ex vivo anti-Y 29/55 depletion of the marrow graft does not induce relevant disturbances of humoral immune functions.     

The blood-brain barrier models to study apolipoprotein E genotypes in Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative disease that is characterized by an age-dependent progressive decline of memory,impairment of cognitive functions and changes in personality and behavior.Despite the improvement in understanding of the mechanisms underlying the disease,AD remains an incurable complex disorder with multifaceted pathophysiology to date.Apolipoprotein E(ApoE)is the main cholesterol carrier in the brain that supports lipid transport between brain cells.The individuals carrying the APOE4 allele are known to be at increased risk of developing AD compared with those carrying the more common APOE3 allele.     

Cogrinding enhances the oral bioavailability of EMD 57033, a poorly water soluble drug, in dogs.

The oral bioavailability of EMD 57033, a calcium sensitizing agent with poor solubility, was compared in dogs using four solid dosage form formulation approaches: a physical blend of the drug with excipients, micronization of the drug, preparation of coground mixtures and spray-drying of the drug from a nanocrystalline suspension. The formulations contained generally accepted excipients such as lactose, hydroxypropylmethyl cellulose and sodium lauryl sulphate in usual quantities. Drug micronization and cogrinding was realized by a jet-milling technique. Nanoparticles were created by media milling using a bead mill. All formulations were administered orally as dry powders in hard gelatine capsules. While micronization increased the absolute bioavailability of the solid drug significantly compared to crude material (from nondetectable to 20%), cogrinding with specific excipients was able to almost double this improvement (up to 39%). With an absolute bioavailability of 26%, spray-dried nanoparticular EMD 57033 failed to show the superior bioavailability that had been anticipated from in vitro data. The control solution prepared with cyclodextrin was shown to have an absolute bioavailability of 57% (vs. i.v. infusion). It was concluded that cogrinding can be a useful tool to improve the bioavailability of poorly soluble drugs from a solid dosage form format.     

Biorelevant dissolution testing of St John's wort products

In contrast to chemically defined drugs, most herbal medicinal products (HMPs) are poorly characterized in terms of their pharmaceutical properties. In many cases it is assumed that the plant extract as a whole is the active moiety, since it is often difficult to identify the individual components responsible for the pharmacological activity and even more difficult to assess synergies among the various components. However, where the active components have been identified, it should be possible to compare products with respect not only to content uniformity but also to their biopharmaceutical properties. The aim of this study was to investigate and compare the dissolution characteristics of several St John's wort products under biorelevant conditions. Components of St John's wort known, or suspected, to play a role in its antidepressant activity include phloroglucines, naphthodianthrones and the flavonoids. Since these groups have a broad spectrum of polarity and solubility, dissolution was studied for representative compounds from each group. Although the labelling indicates that several of the products studied should be pharmaceutically equivalent, dissolution under biorelevant conditions revealed that they have quite different release profiles and cannot be considered switchable. It was concluded that biorelevant dissolution testing can be a powerful tool for comparing HMPs as well as synthetically produced drug products.     

Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY- 14,643

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4- chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643.      

Ketoacidosis at the diagnosis of type 1 (insulin dependent) diabetes mellitus is related to poor residual beta cell function. Childhood Diabetes in Finland Study Group

The determinants of the degree of metabolic decompensation at the diagnosis of type 1 (insulin dependent) diabetes mellitus (IDDM) and the possible role of diabetic ketoacidosis in the preservation and recovery of residual beta cell function were examined in 745 Finnish children and adolescents. Children younger than 2 years or older than 10 years of age were found to be more susceptible to diabetic ketoacidosis than children between 2 and 10 years of age (< 2 years: 53.3%; 2-10 years: 16.9%; > 10 years: 33.3%). Children from families with poor parental educational level had ketoacidosis more often than those from families with high parental educational level (24.4% v 16.9%). A serum C peptide concentration of 0.10 nmol/l or more was associated with a favourable metabolic situation. Low serum C peptide concentrations, high requirement of exogenous insulin, low prevalence of remission, and high glycated haemoglobin concentrations were observed during the follow up in the group of probands having diabetic ketoacidosis at the diagnosis of IDDM. Thus diabetic ketoacidosis at diagnosis is related to a decreased capacity for beta cell recovery after the clinical manifestation of IDDM in children.     

Standards for total body fat and fat-free mass in infants

Data on body composition in conjunction with reference centiles are helpful in identifying the severity of growth and nutritional disorders in infancy and for evaluating the adequacy of treatment given during this important period of rapid growth. Total body fat (TBF) and fat-free mass (FFM) were estimated from total body electrical conductivity (TBEC) measurements in 423 healthy term Caucasian infants, aged 14-379 days. Cross sectional age, weight, and length related centile standards are presented for TBF and FFM. Centiles were calculated using Altman's method, based on polynomial regression and modelling of the residual variation. The TBF percentage steeply increased during the first half year of life, and slowly declined beyond this age. Various simple TBEC derived anthropometric prediction equations for TBF and FFM are available to be used in conjunction with these standards. Regression equations for the P50 and the residual SD, depending on age, weight, or length, are provided for constructing centile charts and calculating standard deviation scores.