A novel in vitro release method for submicron-sized dispersed systems

Sink conditions are often violated when using conventional release methods for dispersed systems. A novel reverse dialysis bag method was designed to overcome this problem. Model drug transport rates from submicron emulsions obtained using the conventional diffusion cell method and this novel method were compared. In the side-by-side diffusion cell method, emulsions were placed in the donor chamber and surfactant/buffer solutions in the receiver chamber. In the novel dialysis bag method, emulsions were diluted infinitely in the donor phase and surfactant/buffer solutions were placed in the receiver phase (dialysis bags). Slow release rates and linear release profiles were obtained using the side-by-side diffusion cell method apparently due to limited model drug solubility in the donor chamber resulting in violation of sink conditions. Biphasic release profiles were obtained using the dialysis bag method apparently due to an initial rapid release of free and micellar solubilized model drug from the donor to the receiver chambers followed by slow release from the oil droplets. Using both release methods, an initial increase and latter decrease in release rates were observed with increase in surfactant concentration. The initial increase was considered to be due to a decrease in the model drug oil-in-water partition coefficients and the subsequent decrease in release rates was due to micellar shape change (spheres to rods) causing a decrease in diffusion rates. Sink conditions were violated using the side-by-side diffusion cell method but were maintained in the dialysis bag method since emulsions were diluted infinitely in the donor phase.     

Pregnancy recency and risk of ovarian cancer

Objective: A recent analysis suggested that ovarian cancer risk increased with time since last birth, possibly because of some aspect of pregnancy that affects the clearance of cells that have undergone malignant transformation. We analyzed data from four case–control studies pertaining to ovarian cancer risk in relation to age at first pregnancy, age at last pregnancy, and years since last pregnancy: 628 cases and 3432 neighborhood or population controls, ages 18–79, were included.>Methods: We used logistic regression to analyze associations between ovarian cancer risk, controlling for study, age (at diagnosis or corresponding reference age for controls), race, parity, oral contraceptive use, tubal ligation, family history of ovarian or breast cancer, and excluding women with a history of infertility.Results: An early age at first pregnancy was associated with an increased risk of ovarian cancer (odds ratio 1.4, 95% confidence interval (1.1–1.8) for ages 19 compared to 25). Years since last pregnancy was also associated with increased ovarian cancer risk, with odds ratios of 1.4, 1.4, 1.8, and 2.1 for 10–14, 15–19, 20–24, and 25 years compared to 0–9 years (trend test p = 0.004), respectively.Conclusion: These observations support the results from the previous study, and raise additional questions about the role of pregnancy in the etiology of ovarian cancer.     

Mast cell tryptase as a target for drug design

Human mast cell tryptase-beta, a tryptic serine protease with a unique structure, is an interesting therapeutic target that several companies and institutions have targeted for drug discovery. The catalytic activity of this tryptic enzyme has been linked to many disease states and proinflammatory events; however, the physical and physiological differences of tryptase across various species have made animal model data difficult to interpret, particularly in the context of human disease. Still, both protein and small-molecule tryptase inhibitors have been reported and the X-ray crystal structure of the enzyme aids in understanding how these compounds might bind. Three modes of inhibition exist: monofunctional inhibition, bifunctional inhibition and tetramer disruption. Many of these inhibitors have demonstrated activity in animal models. Human clinical studies have been conducted or are under way with certain tryptase inhibitors.     

Malignant melanoma in patients with multiple endocrine neoplasia type 1 and involvement of the MEN1 gene in sporadic melanoma

Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome associated primarily with endocrine tumors of the parathyroids, enteropancreas and anterior pituitary. However, tumors of mesenchymal origin such as angiofibroma and collagenoma of the skin have also been associated with the syndrome. This highlights the possibility of an association between MEN 1 and some other types of tumors. Here we report 7 cases of primary malignant melanoma occurring in 7 MEN 1 families, all patients exhibiting classic features of MEN 1. Based on these findings and the previous implication of multiple melanoma tumor suppressor(s) in 11q, including the MEN1 region, we have investigated the involvement of the MEN1 gene in melanoma tumorigenesis. Mutation analysis was performed on a panel of 39 sporadic metastatic melanomas, 13 melanoma cell lines and 20 melanoma families without CDKN2A or CDK4 germline mutations. In addition, 19 sporadic metastatic tumors were screened for loss of heterozygosity (LOH) in 11q13. LOH was detected in 6 tumors (32%), and in 4 of the tumors the pattern of LOH suggested that the deletion included the MEN1 gene locus. A novel somatic nonsense mutation in exon 7 (Q349X) was identified in 1 sporadic tumor which also showed loss of the wild-type allele. We conclude that the MEN1 gene plays a role in the tumorigenesis of a small subgroup of melanoma.     

Clinical evaluation of asaley

Asaley is an L-leucine derivative of sarcolysin which is more active against some rodent tumors. Studies in the USSR demonstrated activity in patients with ovarian and breast carcinoma, Hodgkin's disease, and multiple myeloma. This study in 73 evaluable patients indicated that an appropriate oral dose for patients with adequate bone marrow is 800 mg/M²/day × 4 days at 5–6 week intervals. The most common toxicities were myelosuppression, nausea, and vomiting. Antitumor activity was observed in 2 of 24 evaluable patients with melanoma, and stabilization of previously progressive disease was observed in patients with adenocarcinoma of the colon, multiple myeloma, lymphoma, breast carcinoma, and thyroid carcinoma. Responses were minimal and of short duration but most of the patients had received extensive prior therapy.     

Alkamide levels in Echinacea purpurea: effects of processing, drying and storage

The effects of processing, drying, and storage time and temperature on alkamide levels in Echinacea purpurea roots are described. Chopping altered the levels of some alkamides slightly, whereas drying had no effect. Levels of all alkamides fell by over 80% during storage at 24 degrees C for 64 weeks. Alkamide levels also dropped significantly during storage at -18 degrees C.     

Sucrase-isomaltase deficiency. A follow-up report.

Nine children with sucrase-isomaltase deficiency were assessed up to 10 years after diagnosis. All children continued to have episodes of diarrhoea associated with sucrose ingestion. Sucrose tolerance tests showed that malabsorption of sucrose persists into adolescence. Three older patients were unaware of their condition and were eating normal diets with unrestricted amounts of sucrose. They complained of gastrointestinal symptoms which improved after sucrose restriction.     

Therapy of infections in neutropenic patients: Results with gentamicin in combination with cephalothin or chloramphenicol

Gentamicin in combination with cephalothin (Gent-Ceph) or with chloramphenicol (Gent-Chloro) was utilized in the treatment of 55 infections occurring in 49 cancer patients. Responses were obtained in 78% of the infections treated with Gent-Ceph and in 64% of those treated with Gent-Chloro. Pneumonia and septicemia were the most common infections in this study. Among the cases of pneumonia, 64% responded to Gent-Ceph and 67% to Gent-Chloro. Among the cases of septicemia, 88% responded to Gent-Ceph and 50% to Gent-Chloro. All of the identified organisms producing infection were gram-negative bacilli. Of these, E. coli was the most common. All organisms were resistant to cephalothin in vitro, and only 41% of them were resistant to chloramphenicol. However, resistant organisms responded significantly better to the Gent-Ceph combination (p < 0.025). Also, response to therapy among patients with severe neutropenia (< 100 neutrophils/mm³) was better for those patients treated with Gent-Ceph (p = 0.07). The combination of gentamicin with cephalothin or with chloramphenicol did not increase the frequency of side effects expected from gentamicin alone. No significant hematological toxicity was seen among those patients treated with chloramphenicol. Gentamicin in combination with cephalothin or chloramphenicol is an effective and safe antibiotic combination against gram-negative bacilli infections occurring in cancer patients. The efficacy of Gent-Ceph in patients with severe neutropenia is particularly advantageous.     

The developmental status of children undergoing the Kasai procedure for biliary atresia

Children with biliary atresia who have undergone the Kasai procedure suffer prolonged illness and recurrent hospitalizations, both of which may interfere with normal growth and development. The developmental status of 20 children with this disorder is described. The mean cognitive developmental quotient of the entire group of children was within the normal range. The mean motor developmental quotient was within the borderline normal range. The developmental test results suggested an interesting pattern of development including normal cognitive and motor development until the age of 6 to 8 months, followed by a decreasing rate of development between ages 8 and 24 months with the potential for improved developmental outcome at the age of school entry. The overall developmental status of these children was better than might be expected considering the numerous high-risk medical/surgical and social/emotional stresses that these children must face. The effort required in the care of children with this disorder certainly seems warranted by their subsequent developmental outcome.