Ajoene in the topical short-term treatment of tinea cruris and tinea corporis in humans. Randomized comparative study with terbinafine.

Ajoene (CAS 92284-99-6), an organic trisulphur originally isolated from garlic, has an antimycotic activity which has been widely demonstrated both in vitro and in vivo. The objective of this work was to compare the safety and effectiveness of ajoene (0.6%, gel) with terbinafine (CAS 91161-71-6) (1%, cream) for the treatment of tinea corporis and tinea cruris. The patients selected were 60 soldiers with clinical and mycological diagnosis of either dermatophytosis. They were distributed at random in two treatment groups, one treated with ajoene at 0.6% and the other with terbinafine at 1%. All patients were evaluated clinically and mycologically 30 and 60 days after completion of the treatment, which was considered effective when clinical signs and symptoms had disappeared and the mycological cultures were negative. Thirty days after treatment, the percent healing rate was 77 and 75 for the groups treated with ajoene and terbinafine, respectively. Sixty days after treatment, the healing rate 73% and 71% for the groups treated with ajoene and terbinafine, respectively. These results and those obtained in previous studies confirm that ajoene is a new agent for the topic treatment of superficial mycoses, and for the first time show the therapeutic usefulness of an inhibitor of phospholipids biosynthesis in eukaryotes.     

Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action

Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.     

Time- and concentration-dependent induction of CYP1A1 and CYP1A2 in precision-cut rat liver slices incubated in dynamic organ culture in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin

In a previous 24-h study, precision-cut rat liver slices were validated as a useful in vitro model for assessing the dose-related induction of CYP1A1 and CYP1A2 in rat liver following exposure to 2, 3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Further assessment of the utility of this model was accomplished by initially exposing rat liver slices to medium containing TCDD (0.01 nM) for 24 h and incubating the slices up to an additional 72 h in TCDD-free medium. The slices remained viable throughout the incubation period with an intracellular potassium content varying from 45.2 +/- 2.3 micromol/g at 48 h to 50.0 +/- 1.6 micromol/g at 72 h. In TCDD-exposed slices, CYP1A1 protein and its respective enzymatic activity, the O-deethylation of ethoxyresorufin (EROD), significantly increased with time over the 96-h incubation period, with EROD activity increasing from 63.6 +/- 14.2 at 24 h to 905 +/- 291 pmol/mg/min at 96 h. Under identical incubation conditions, but in the absence of TCDD, the EROD activity for the control liver slices ranged from 14. 3 +/- 4.3 to 44.9 +/- 11.9 pmol/min/mg. Conversely, the level of CYP1A2 protein and its respective activity (acetanilide hydroxylation) transiently decreased from 24 to 96 h with no significant differences observed between the control (0 nM TCDD) and treatment group (0.01 nM TCDD). The concentration-effect relationship at 96 h was characterized by incubating rat liver slices for the initial 24 h in medium containing TCDD at concentrations ranging from 0.1 pM to 10 nM. Induction of CYP1A1 protein and EROD activity was observed for all treatment groups with the 10 nM TCDD treatment group displaying greater than 100-fold induction compared to control (0 nM TCDD). Immunohistochemical localization of CYP1A1 protein within liver slices supported the time- and concentration-dependent induction of EROD activity by TCDD. The induction of CYP1A1 was initially observed to be centrilobular, with increased expression due to both elevated CYP1A1 within cells and the recruitment of additional cells expressing CYP1A1 throughout the entire liver slice. Additionally, the immunohistochemical analysis of the liver slices demonstrated the conservation of tissue architecture following up to 96 h of incubation in dynamic organ culture and provided further evidence for maintenance of tissue viability. In comparison to CYP1A1, the induction of CYP1A2 at 96 h was a less sensitive response, with significant induction of CYP1A2 protein and its respective activity occurring at a medium concentration of 0.1 nM TCDD (686 pg/g liver). In general, increasing the incubation period from 24 to 96 h markedly increased TCDD-induced expression of CYP1A1 and minimally enhanced CYP1A2 expression. Moreover, extending the incubation period to 96 h resulted in in vitro induction profiles for CYP1A1 and CYP1A2 that were qualitatively and quantitatively similar to that previously observed following in vivo exposure to TCDD (Drahushuk et al., Toxicol. Appl. Pharmacol. 140, 393-403, 1996).     

Erythromycin coadministration increases plasma atorvastatin concentrations

The effect of erythromycin on the pharmacokinetics of atorvastatin, an inhibitor of HMG-CoA reductase, was investigated in 12 healthy volunteers. Each subject received a single 10 mg dose of atorvastatin on two separate occasions, separated by 2 weeks. Erythromycin (500 mg qid) was given from 7 days before through 4 days after the second atorvastatin dose. Atorvastatin concentrations were determined by an enzyme inhibition assay, which measured both atorvastatin and active metabolites. When erythromycin was coadministered with atorvastatin, mean Cmax and AUC(0-infinity) increased by 37.7% and 32.5%, respectively. Mean terminal half-life was similar following each atorvastatin dose. Possible mechanisms for this interaction include erythromycin inhibition of first-pass conversion of atorvastatin to inactive metabolites and erythromycin inhibition of P-glycoprotein-mediated intestinal or biliary secretion.     

In vivo neutralization of vascular endothelial growth factor (VEGF) vascular permeability factor (VPF) inhibits ovarian carcinoma-associated ascites formation and tumor growth

Vascular endothelial growth factor (VEGF)/ vascular permeability factor (VPF) is emerging as an important growth factor in a variety of tumor types. As a potent endothelial cell mitogen and vascular permeabilizing agent, VEGF/VPF has the unique functional capacity to mediate the component events of solid tumor neovascularization and ascites tumor growth. In the present series of investigations, our experimental hypothesis was that VEGF/VPF is a critical mediator of ovarian carcinoma-associated ascites formation and solid tumor growth. Athymic nude mice xenotransplanted with human ovarian carcinoma cell lines received either a preimmune rabbit serum or VEGF/VPF antiserum. Compared with the control group receiving the preimmune serum, the antiserum-treated animals displayed a 10- and 12-fold reduction in ascites accumulation and solid tumor growth, respectively. The administration of a neutralizing antiserum to VEGF/VPF conferred a modest survival advantage to animals harboring intraperitoneal tumors. These data demonstrate the significance of VEGF/VPF in the pathogenesis of ovarian carcinoma and suggest that interventions targeting this growth factor and/or its receptor may be of therapeutic value in the management of ovarian cancer.     

Measures implemented to project personal privacy for an on-line national patient index: a case study

Increasing use of electronic data storage and exchange is inevitable. Although of considerable benefit to all concerned, they pose a potential threat to personal privacy. Measures to protect personal privacy in national information networks are essential. These and related security issues require the highest priority in strategic planning because experience shows that poor handling of security is the single factor most likely to lead to rejection of a system. It is increasingly important to be able to identify individuals uniquely for health-related purposes, and implementation of an on-line master index is the approach that has been adopted in New Zealand to address this need. Such an index, however, contains personal information, the privacy of which must be respected. Substituting the unique identifier for all personal details in electronic messages can provide a degree of security as long as access to the index is controlled and usage is monitored. The article outlines the measures, technical and otherwise, implemented to manage security concerns successfully in that context.     

Use of resident physicians: an evaluation of the effects of a significant increase

Medical school graduates have become increasingly dependent on former community hospitals for residency programs because charitable institutions attached to medical schools are disappearing. It is not known what impact residencies have on hospitals that were community hospitals. We interviewed private practice physicians, residents, nurses, patients, and other groups in a large former community hospital. Overall, the interviews indicated good support for the hospital's new teaching function. Furthermore, the residents were viewed in very favorable terms by all groups. There were two problem areas. One, some residents seem less sensitive to human relations than private practice physicians and other hospital groups. Two, many private practice physicians are concerned over the number of hospital-salaried physicians and the outpatient care offered by residents supervised by hospital-salaried physicians. This research suggested several recommendations that, if followed, would serve to increase the value of the residency in meeting patient needs in the most effective manner.     

RTOG Phase I study on fast neutron teletherapy for squamous cell carcinoma of the esophagus

From August, 1977, through January, 1981, the Radiation Therapy Oncology Group sponsored a Phase I study (RTOG 77-09) on the use of fast neutrons for treating inoperable squamous cell carcinomas of the esophagus. A total of 39 evaluable patients were treated with curative intent using either fast neutrons alone or in combination with low LET irradiation as part of a mixed beam fractionation scheme. Actuarial survival curves are presented for both the "neutrons alone" and the "mixed beam" treatment groups. There was no significant survival difference between these groups of patients. The projected survival at two years is less than 10%, which is comparable with megavoltage photon results for an unselected series of patients. The size of the primary lesion and the initial Karnofsky performance status were found to be the most important prognostic indications for prolonged survival. Sixteen of 39 patients were felt to have achieved local clearance of their tumor at some time during their follow-up with the median time until a local recurrence being 17 months. Treatment related complications and patterns of metastatic spread are discussed. In general, it appeared that the response of large tumors to neutron irradiation resulted in necrosis and fistula formation. In many cases this was accompanied by persistent/recurrent tumor within the high dose radiation volume.