Didanosine extended-release matrix tablets: optimization of formulation variables using statistical experimental design

Statistical experimental design was applied to evaluate the influence of some process and formulation variables and possible interactions among such variables, on didanosine release from directly-compressed matrix tablets based on blends of two insoluble polymers, Eudragit RS-PM and Ethocel 100, with the final goal of drug release behavior optimization. The considered responses were the percent of drug released at three determined times, the dissolution efficiency at 6 h and the time to dissolve 10% of drug. Four independent variables were considered: tablet compression force, ratio between the polymers and their particle size, and drug content. The preliminary screening step, carried out by means of a 12-run asymmetric screening matrix according to a D-optimal design strategy, allowed evaluation of the effects of different levels of each variable. The drug content and the polymers ratio had the most important effect on drug release, which, moreover, was favored by greater polymers particle size; on the contrary the compression force did not have a significant effect. The Doehlert design was then applied for a response-surface study, in order to study in depth the effects of the most important variables. The desirability function was used to simultaneously optimize the five considered responses, each having a different target. This procedure allowed selection, in the studied experimental domain, of the best formulation conditions to optimize drug release rate. The experimental values obtained from the optimized formulation highly agreed with the predicted values. The results demonstrated the reliability of the model in the preparation of extended-release matrix tablets with predictable drug release profiles.     

Biomechanical comparison of effects of supraspinatus tendon detachments,tendon defects,and muscle retractions

BACKGROUND: Rotator cuff ruptures are frequently associated with loss of strength of the shoulder. However, the characteristics of the rotator cuff tear that are responsible for the loss of force generation and transmission have not yet been identified. The purpose of this study was to compare the effects of supraspinatus tendon detachments, tendon defects, and muscle retractions on in vitro force transmission by the rotator cuff to the humerus. METHODS: The rotator cuff tendons from ten cadaver shoulders were loaded proportionally to the respective cross-sectional areas of their muscles. A fiberglass rod was cemented into the medullary canal of the humerus and connected to a three-component load cell for the measurement of the forces transmitted by the rotator cuff to the humerus. This study was performed with the humerus in a hanging arm position and with various sizes of supraspinatus tendon detachments, tendon defects, and muscle retractions. RESULTS: Detachment or creation of a defect involving one-third or two-thirds of the supraspinatus tendon resulted in a minor reduction in the force transmitted by the rotator cuff (< or =5%), while detachment or creation of a defect involving the whole tendon resulted in a moderate reduction (11% and 17%, respectively). Simulated muscle retraction involving one-third, two-thirds, and the whole tendon resulted in losses of torque measuring 19%, 36%, and 58%, respectively. Side-to-side repair of the one-third and two-thirds defects nearly restored the force transmission capability, whereas a deficit remained after side-to-side repair following complete resection. CONCLUSIONS: Our results support the rotator cable concept and correspond to the clinical observation that patients with a small rupture of the rotator cuff may present without a loss of shoulder strength. Muscle retraction is potentially an important factor responsible for loss of shoulder strength following large rotator cuff ruptures. Clinical Relevance: Supraspinatus muscle retraction diminishes glenohumeral abduction torque significantly more than either a defect in the tendon or a simple detachment of the tendon from the tuberosity. In cases of irreparable defects, side-to-side repair may be worthwhile to restore muscle tension and the integrity of the rotator cable.     

Helicobacter infection in patients with HCV-related chronic hepatitis,cirrhosis, and hepatocellular carcinoma

Chronic hepatitis may progress to cirrhosis and hepatocellular carcinoma (HCC). HCC represents one of the most common human cancers. Incidence rates for this tumor vary widely on a worldwide, suggesting that environmental factors such as infectious microorganisms, carcinogens, or nutrition play a role in its pathogenesis. Several Helicobacter spp. colonize the liver of animals and induce hepatitis. The aim of this study was to determine whether Helicobacter infection was associated with HCV-related liver diseases in humans. Liver tissue samples, including biopsy and surgically excised tissues, were collected from patients positive for hepatitis C viruses (HCV) RNA in the serum. Genomic DNA was extracted from sections of formalin-fixed paraffin-embedded tissues by using the QIAamp Tissue Kit and subjected to polymerase chain reaction (PCR) analysis using two sets of Helicobacter-specific 16S ribosomal RNA primers. To identify positive samples for H. pylori, a set of primers specific for a conserved region in the H. pylori vacA gene were also used. The patients' H. pylori status was determined by ELISA. Forty-one patients (mean age 54.9, range 19–78 years; 24 men) were studied. Thirty patients had chronic viral hepatitis (CH) without (N = 18) or with (N = 12) cirrhosis (CIR), and 11 patients had HCC. Anti-H. pylori IgG was detected in 54%. The expected 422- and 210-bp fragments of Helicobacter 16S rRNA were amplified from 27% of liver samples, including 17% of CH-CIR and 55% of HCC (P = 0.004). The vacA sequence was amplified in 10 of 41(24%) samples (27% of those with HCC).: These data confirm the presence of H. pylori DNA sequences in human liver and suggest an association of Helicobacter spp. with HCV-related chronic liver diseases. Further studies are needed to ascertain whether Helicobacter spp. infection plays a role in the development of HCC.     

Study of formulation variables influencing the drug release rate from matrix tablets by experimental design.

Experimental design was utilized to simultaneously investigate the effect of varying the type of diluent (insoluble Calcium phosphate or water-soluble arabic gum) and the diluent/matrix ratio on the drug release behaviour from both lipophilic (glyceryl behenate, Compritol) or hydrophilic (hydroxypropylmethylcellulose) matrix tablets. Ketoprofen, theophylline and sodium sulphadiazine were selected as model drugs on the basis of their respectively very low, medium and high water-solubility, in order to evaluate the influence of this parameter as well. The selected response variables were the dissolution efficiency (i.e. the area under the dissolution curve) after one and six hours and the time necessary to dissolve 10% drug. Tablets obtained by direct compression of drug-diluent-matrix ternary mixtures prepared according to the experimental plan provided for by an asymmetric screening matrix, were tested for drug release properties using a USP paddle apparatus. Graphic analysis of the effects allowed identification, for each examined drug, of the formulation factors active on the selected responses and determination of the proper level of the variables to be selected for the response improvement. The different results obtained with the three examined drugs pointed out the role of the drug solubility in determining the influence of formulation parameters on drug release rate from matrix tablets.     

FOLFOX2 regimen in the treatment of advanced colorectal cancer: a comparison between elderly and young patients.

Colorectal cancers (CRC) are primarily disease of the sixth,seventh, and eighth decades of life. The probability of developingCRC increases from 0.06% in the first four decades of life to3–4% in the sixth and seventh decades in the Western world[1]. The prevalence of the disease and     

Iron-saturated lactoferrin as a comitogenic substance for neonatal rat hepatocytes in primary culture

We studied the effect of lactoferrin on DNA synthesis in neonatal rat hepatocytes in primary culture to determine if this agent acts as a mitogen in human milk. Thymidine incorporation into the DNA of cultured hepatocytes stimulated by lactoferrin in the presence of insulin and human epidermal growth factor was examined. Iron-saturated lactoferrin increased DNA synthesis of neonatal hepatocytes by 1.5 times and this potency was the same as that of insulin. It significantly enhanced the stimulatory effect of human epidermal growth factor plus insulin; DNA synthesis under these conditions was seven times that of control. Iron-free lactoferrin did not affect DNA synthesis, nor did the exogenous addition of ferric ions. The enhancement of DNA synthesis by iron-saturated lactoferrin was significant for neonatal hepatocytes, but not for adult hepatocytes. These results suggest that iron-saturated lactoferrin, which itself had low mitogenic activity, is a co-mitogenic substance for neonatal hepatocytes in vitro.     

Intrauterine undernutrition in rats interferes with leukocyte migration, decreasing adhesion molecule expression in leukocytes and endothelial cells

Experimental and epidemiologic data have shown that malnutrition predisposes individuals to infections. Immune responses are compromised, particularly in undernourished children. Therefore, we investigated the migratory capacity of leukocytes, using the intravital microscopy technique, in male Wistar rats (8-9 wk of age) that were undernourished in utero after their dams were fed 50% less food than the amount consumed by control dams. The number of leukocytes rolling along the venular endothelium, sticking after stimulation with leukotriene B4, tumor necrosis factor-alpha (TNF-alpha) or zymosan-activated plasma, or migrating after TNF-alpha stimulation was significantly reduced in the undernourished rat offspring. Compared with nourished rat offspring, undernourished offspring had significantly reduced numbers of circulating leukocytes, higher blood pressure, and higher leukocyte rolling velocity (V(WBC)), as well as a higher ratio between V(WBC) and RBC velocity (V(RBC)). Endothelial P-selectin and intercellular adhesion molecule-1 (ICAM-1) expression, analyzed by immunohistochemistry, and basal leukocyte L-selectin expression, analyzed by flow cytometry, were significantly reduced in the undernourished rat offspring. Because the groups did not differ in leukocyte CD11/18 expression, endothelial expression of platelet-endothelial cell adhesion molecule-1, or venular blood flow velocity and, consequently, venular shear rate, we conclude that intrauterine undernutrition in rats reduces leukocyte migration, downregulates endothelial expression of P-selectin and ICAM-1, as well as leukocyte expression of L-selectin, while reducing leukocyte counts. The higher V(WBC) and V(WBC)/V(RBC) ratio may also play a role in this reduced leukocyte migration. Our data suggest that this phenomenon is involved in the increased predisposition to infections in undernourished subjects.     

Behavioral and psychological symptoms in Alzheimer's disease: frequency and relationship with duration and severity of the disease

The occurrence of behavioral and psychological symptoms of dementia (BPSD) is currently recognized as an important aspect of Alzheimer's disease (AD). We evaluated the frequency and severity of BPSD with the Neuropsychiatric Inventory across the various degrees and phases of the disease in 50 consecutive AD outpatients. Apathy, aberrant motor activity, dysphoria and anxiety were the symptoms most frequently reported by the caregivers, ranging in the whole study sample from 46 to 74%. A clear trend towards increasing frequency with the severity of disease was found for delusions, hallucinations and aberrant motor activity. A major effect of the duration of the disease was found in the probability of developing hallucinations and aberrant motor activity. Apart from hallucinations, all BPSD were present starting from a mild degree of dementia. A better understanding of the global spectrum of BPSD in AD is warranted in order to improve the allocation of health resources toward the treatment of dementia.