Increased tumor cures using combined radiosurgery and BCNU in the treatment of 9l glioma in the rat brain.

PURPOSE: Radiosurgery refers to the delivery of high, single focused beams of ionizing radiation to defined intracranial lesions. 1,3 Bis[2-chloroethyl]-1-nitrosourea (BCNU) and cis-diammine-1, 1-cyclobutane-dicarboxylate platinum (II) (carboplatin) are commonly used cytotoxic agents for the treatment of malignant gliomas of the brain. Drug therapies have exhibited a modest enhanced cell killing when combined with radiation in experimental animal tumor systems. The purpose of the present study was to investigate the role of cytotoxic drugs, such as BCNU and carboplatin, in combination with a single high dose of radiosurgery on the tumor control rates of 9L tumors in the rat brain. METHODS AND MATERIALS: Combined radiosurgery (25 Gy single dose) and/or chemotherapy (a single dose of BCNU, 7 mg/kg, i.p. 1.5 or 16 h prior to or 16 h after irradiation or a single dose of carboplatin, 30 mg/kg, administered either 1 h or 4 h prior to irradiation) was delivered 12 days after stereotactic tumor implantation. For dose escalation study, 4-10 mg/kg of BCNU was used. RESULTS: The radiation alone group showed a dose-dependent survival. A single dose of 25 Gy to the control group resulted in an increase of the median survival time from 20 days to 42 days, but all animals died of the tumor in 50 days. A significant prolongation of the median survival time of animals was more than 100 days, resulting in animal cures of 50% or more when combined with radiosurgery (25 Gy) and BCNU (7 mg/kg). BCNU alone did not prolong the median survival time of the animal with the 9L brain tumor. In contrast, there was no survival improvement when the animals were treated with combined radiosurgery and carboplatin. None of the long-term surviving animals showed any significant brain tissue damage as evaluated by histopathology and clinical observations. CONCLUSION: The data clearly suggest that the combined modalities of radiosurgery and concomitant BCNU represent an effective therapeutic regimen in the treatment of radioresistant human malignant gliomas of the brain. This study represents the first experimental report of the effectiveness of combined chemotherapy and radiosurgery.

DSM-IV antisocial personality disorder field trial.

The development of the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994) included 12 field trials to assess proposed revisions. This article provides results from the antisocial personality disorder (APD) field trial that was conducted to obtain data of relevance to the proposals for simplification and for the inclusion of more traditional traits of psychopathy. Provided herein are the results from 4 sites that had sampled from populations of particular relevance to the diagnosis of APD (i.e., prison inmates, psychiatric inpatients, outpatients with substance use disorders, and homeless persons). The results indicated that some items from the 3rd revised Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1987) could be deleted without affecting the diagnosis. The field trial provided mixed support for the proposal to include more traditional traits of psychopathy.

Interrelationship between buffer systems and particle sizes of TCPL drug delivery system.

The specific objective of this investigation is to study the effect of tricalcium phosphate delivery system (TCPL) particle sizes on the final density as well as the delivery profiles of various organic compounds in three different buffer environments. Each TCPL matrices were fabricated using three different particle sizes ranges between 1-38, 45-63 and 63-75 microns. The sintered microcrystal material was impregnated with either progesterone (P, 100 mg each) or bovine serum albumin (BSA, 100 mg each). In phase I of the study, each device was suspended in a serum bottle containing 100 mls of ethanol solution (50% wt/vol.) for P release or 100 mls of PBS (pH 7.4) for BSA release. In phase II, similar capsules were suspended in human plasma instead of standard buffers. The vials were agitated at 100 cycle per minute in a water bath set at 37 degrees C. The amount of P or BSA released from the devices into the buffered medium was measured spectrophotometrically. The results of this investigation revealed that a significant difference in the densities of the devices made from the range of individual particle sizes. The rate of steroid hormone and protein released from the devices made from 1-38 micron particle sizes was slower (p < 0.05) than the rate of delivery of P and BSA released from devices fabricated from either 45-63 or 63-75 micron particles. Regardless of the particle sizes effect the results show that the delivery profiles of BSA was higher than the rate of P. This observation could be attributed to the molecular structure as well as the physiochemical characteristics of the drug. In conclusion the data obtained from this study suggest that: (1) Particle sizes variations influence the density of the TCPL delivery system, (2) the rate of release of organic compounds from the ceramic devices is considerably affected by the physiochemical characteristics of medium or buffer system, and (3) the delivery rate of drugs from TCPL devices is directly proportional to the size of the device initial particles and macropores, and inversely proportional to the number of micropores within each device.

Hemifacial spasm. Occurrence in multiple sclerosis.

We present six patients with hemifacial spasm and multiple sclerosis. To our knowledge, this association has not been described previously in the North American literature. Magnetic resonance imaging was obtained in all the patients and plaques consistent with multiple sclerosis were identified. In two patients the plaques were seen in the area of the facial nucleus on the involved side. We suggest that hemifacial spasm can be a manifestation of multiple sclerosis. These cases illustrate the utility of magnetic resonance imaging in the investigation of hemifacial spasm. Our findings also support a central (nuclear) origin in multiple sclerosis associated with hemifacial spasm.

An NMR study of the interaction of daunomycin with dinucleotides and dinucleoside phosphates.

The mode of action of the widely used anticancer drug daunomycin was studied by 360 MHz and 100 MHz proton NMR. Information obtained from scalar coupling constants indicates that the conformation of the A ring of the aglycone moiety of daunomycin is maintained upon binding to dinucleotides but that the conformation of the daunosamine ring moiety is altered upon binding. Ring-current-induced chemical shifts of the drug protons were observed as the drug was titrated with deoxydinucleotides. The chemical shift results that daunomycin forms 1 : 1 complexes with deoxydinucleotides and that the strength of the drug-nucleotide interaction is dependent upon the base composition of the dinucleotide. On the basis of the NMR data, a model for the drug/deoxydinucleotide complex is presented featuring intercalation of the drug between the bases of the dinucleoside.

Production, isolation, and properties of azetomycins.

Streptomyces antibioticus synthesizes five actinomycins that differ in the "proline site" of the molecule. When cultured in the presence of azetidine-2-carboxylic acid (AzC), antibiotic synthesis was stimulated 40 to 50%, synthesis of actinomycin IV was inhibited, and one or both prolines were replaced by AzC. AzC incorporation could not be reversed by concomitant supplementation with proline or sarcosine, and only pipecolic acid affected a minor reversal of AzC incorporation. AzC-containing actinomycins were isolated and designated azet-I and azet-II; a third unresolved component or mixture was called azet-III. The molar ratio of AzC to proline was: azet-I, 1:1; azet-II, 2:0. Azet-III was equivocal. These azetidine actinomycins (azetomycins) were found to be potently inhibitory to the growth of selected gram-positive but not as potent to the growth of gram-negative organisms. The relative inhibitory affect against growth and ribonucleic acid synthesis in Bacillus subtilis was: actinomycin IV =/> azet-I > azet-II >>> azet-III. Protein synthesis was affected similarly; however, kinetic studies with B. subtilis revealed that ribonucleic acid synthesis was inhibited rapidly followed by an inhibition of protein synthesis. At concentrations less than 1 mug/ml, deoxyribonucleic acid synthesis was stimulated by these actinomycins.