Perilla ketone: a potent lung toxin from the mint plant, Perilla frutescens Britton.

Perilla ketone, from the essential oil of Perilla frutescens, is a potent pulmonary edemagenic agent for laboratory animals and livestock. This finding would account for reported effects of the plant on grazing cattle. The use of perilla in oriental foods and medicinal preparations suggests possible hazards to human health as well.

Combination of flavor enhancement and chemosensory education improves nutritional status in older cancer patients.

BACKGROUND: Abnormalities in taste and smell functioning occur with elevated frequency in both older adults and patients with cancer. With the predicted increase in both of these populations in the coming decades, it is imperative to evaluate potential interventions that are designed to help older cancer patients compensate for the additive burden of this disease and its treatment on age-related taste and smell losses. OBJECTIVE: The purpose of the current study was to determine if providing instruction and products for flavor enhancement of foods to elderly cancer patients in addition to nutritional information would improve their nutritional status, and, by extension, functional and immune status as well as quality of life. DESIGN: One hundred and seven subjects enrolled in the study. Fifty-four subjects were in the experimental group that received flavor enhancement plus nutritional information; fifty-three control subjects received only nutritional information. Subjects were evaluated 1 month, 3 months, and 8 months after beginning chemotherapy. At every session, subjects completed taste and smell assessments as well as questionnaires related to nutritional status, activities of daily living, and quality of life. Blood samples were also obtained to determine immune parameters. RESULTS: At the eight-month time point, experimental subjects had better scores on the mini nutritional assessment (MNA) and the physical function assessment of the quality of life questionnaire. Also at eight months, self-reported taste and smell perception for experimental subjects was better than that of controls as well as better than at earlier time points. Tests that assessed quantity and quality of food intake, as well as a number of immune parameters declined over time and did not differ significantly between groups. CONCLUSION: The combination of flavor enhancement, chemosensory education, and nutritional information for elderly cancer patients improved their nutritional assessment on the MNA and physical function over time. On the whole, experimental subjects perceived themselves to be better functioning at eight months than did their control counterparts.

Sustaining diabetes prevention and care interventions: A multiple case study of translational research projects.

BACKGROUND: This study identifies the barriers and enablers for sustainability of interventions in primary and secondary prevention of diabetes. In the context of translational research, sustainability is defined as the continued use of program components and activities for the continued achievement of desirable program and population outcomes. METHODS: In this study, eleven translational research projects, supported by the BRIDGES program of the International Diabetes Federation, were investigated. By theoretically-informed semi-structured interviews and analyses of project reports, qualitative data was collected on the sustainability outcomes and the barriers and enablers. RESULTS: The sustainability outcomes can be grouped in three main areas: (1) sustainability at the intervention site(s); (2) diffusion to the wider community; and (3) replication of the intervention at other site(s). Each of the outcomes has their own set of enablers and barriers, and thus requires consideration for a different sustainability strategy. CONCLUSIONS: This study is the first international study that relates the sustainability outcomes of translational research project to specific barriers and enablers, and develops an evidence-based framework which provides practical advice on how to ensure the sustainability of health interventions.

Using plasma transforming growth factor beta-1 during radiotherapy to select patients for dose escalation.

PURPOSE: The ability to prescribe treatment based on relative risks for normal tissue injury has important implications for oncologists. In non-small-cell lung cancer, increasing the dose of radiation may improve local control and survival. Changes in plasma transforming growth factor beta (TGFbeta) levels during radiotherapy (RT) may identify patients at low risk for complications in whom higher doses of radiation could be safely delivered. PATIENT AND METHODS: Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved nodes to a dose of 73.6 Gy (1.6 Gy twice daily). If the plasma TGFbeta level was normal after 73.6 Gy, additional twice daily RT was delivered to successively higher total doses. The maximum-tolerated dose was defined as the highest radiation dose at which < or = one grade 4 (life-threatening) late toxicity and < or = two grade 3 to 4 (severe life-threatening) late toxicities occurred. RESULTS: Thirty-eight patients were enrolled. Median follow-up was 16 months. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGFbeta levels. Fourteen patients whose TGFbeta levels were normal after 73.6 Gy were escalated to 80 Gy (n = 8) and 86.4 Gy (n = 6). In the 86.4-Gy group, dose-limiting toxicity was reached because there were two (33%) grade 3 late toxicities. CONCLUSION: It is feasible to use plasma TGFbeta levels to select patients for RT dose escalation for non-small-cell lung cancer. The maximum-tolerated dose using this approach is 86.4 Gy.

Randomized, dose-escalation study of SD/01 compared with daily filgrastim in patients receiving chemotherapy.

PURPOSE: To explore the use of SD/01 (a polyethylene glycol-conjugated filgrastim shown in preclinical studies to have a prolonged half-life) in patients with chemotherapy-induced neutropenia. PATIENTS AND METHODS: Thirteen patients with non-small-cell lung cancer were randomized to receive daily filgrastim (5 microg/kg/d) or a single injection of SD/01 (30, 100, or 300 microg/kg) 2 weeks before chemotherapy and again 24 hours after administration of carboplatin and paclitaxel. Pharmacodynamic, pharmacokinetic, and safety analyses were performed. RESULTS: Peak serum concentrations of SD/01 and the duration of increased serum concentrations were dependent on the SD/01 dose. SD/01 concentrations remained increased longer in patients with chemotherapy-induced neutropenia. Prechemotherapy median absolute neutrophil counts (ANCs) in patients receiving SD/01 were increased in a dose-dependent fashion, with the duration of this effect also being dose dependent. After chemotherapy, median ANC nadirs were similar in the filgrastim cohort and the cohort receiving SD/01 30 microg/kg, with higher nadirs seen in the cohorts receiving SD/01 100 or 300 microg/kg. Dose-limiting toxicities were not noted. CD34(+) cells were mobilized in all cohorts. CONCLUSION: A single dose of SD/01 increases the serum concentration of SD/01 for several days in a dose-dependent fashion and is not associated with significant toxicity. The effects of SD/01 on ANC and CD34(+) cell mobilization are comparable or greater than those achieved with daily filgrastim. The self-regulation of this molecule provides a potential therapeutic advantage in a variety of clinical settings associated with neutropenia.

Phase II study of irinotecan plus cisplatin in patients with advanced non-small-cell lung cancer.

PURPOSE: To evaluate the antitumor efficacy and safety of a combination of irinotecan (CPT-11) and cisplatin in patients with inoperable non-small-cell lung cancer (NSCLC). A secondary objective was to characterize the pharmacokinetics and pharmacodynamics of CPT-11 and its active metabolite, SN-38. PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were treated with repeated 4-week courses comprising CPT-11 (60 mg/m(2)) administered on days 1, 8, and 15, and a single dose of cisplatin (80 mg/m(2)) after CPT-11 administration on day 1. RESULTS: Fifty-two patients were enrolled, including 33 men and 19 women. The median age was 61 years (range, 29 to 79 years). Southwest Oncology Group performance status was 0 in 12 patients, 1 in 32 patients, and 2 in eight patients. Eleven and 41 patients had stage IIIB and IV disease, respectively. Objective responses occurred in 28.8% of patients (15 of 52; 95% confidence interval, 16.5% to 41.2%). The median survival duration was 9.9 months (range, 1.6 to 30.8 months). The 1-year survival rate was 37%. Grade 3/4 adverse events consisted primarily of nausea (32. 7% ) or vomiting (13.5%), late-onset diarrhea (17.3%), and neutropenia (46.1%). The study design led to preferential modification of CPT-11 doses, resulting in CPT-11 dose attenuations to < or = 40 mg/m(2) in the majority of patients (31 of 52; 60%), whereas dose reductions of cisplatin were uncommon. CPT-11 pharmacokinetic parameters were comparable to those reported previously in single-agent studies. CONCLUSION: CPT-11/cisplatin is an active combination regimen with manageable toxicity in the therapy of stage IIIB/IV NSCLC. Future studies should be designed with schedules and dose modification provisions that avoid unnecessary CPT-11 dose reductions to exploit more directly the therapeutic synergy of these agents.

Urinary sodium, potassium and aldosterone in Duchenne muscular dystrophy.

Four adolescent boys with Duchenne (progressive) muscular dystrophy (DMD) of 10-11 years duration and six normal boys of similar age were studied on a metabolism ward for 22 days. Sodium and potassium intake was as follows: Period I, Na 60 mEq, K 60 mEq; Period II, Na 10, K 60; Period III, Na 10, K 95-150; Period IV, Na 60, K 60. The differences between the DMD group and the group of normal boys for sodium and potassium in serum and urine and for urinary aldosterone were not significant. These findings show that the pathologically elevated sodium-potassium ratio in skeletal muscle of patients with DMD is not due to increased aldosterone or other causes of renal wastage of potassium.

Inhibition of separated forms of cyclic nucleotide phosphodiesterase from pig coronary arteries by 1,3-disubstituted and 1,3,8-trisubstituted xanthines.

A series of xanthines with varied substituents in the 1, 3, and 8 positions were prepared in an attempt to understand the structure--activity relationship for alkylxanthines as inhibitors of two different forms of cyclic nucleotide phosphodiesterase. Polar substituents on the 1 or 3 position of the xanthine reduced the potency of the xanthines to inhibit both the calmodulin-sensitive and the "cyclic AMP specific" forms of phosphodiesterase. Polar substituents on the 8 position of the xanthine, other than a carboxylic acid, increased the potency to inhibit the calmodulin-sensitive form of phosphodiesterase, if they were capable of donating electrons to the xanthine nucleus. On the other hand, any substituent in the 8 position larger than H reduced the potency of the xanthines to inhibit the cyclic AMP specific form of phosphodiesterase. Topographical maps of the active sites of the two forms of phosphodiesterase are presented in summary.

Inhibition of separated forms of phosphodiesterases from pig coronary arteries by uracils and by 7-substituted derivatives of 1-methyl-3-isobutylxanthine.

A series of 7-substituted 1-methyl-3-isobutylxanthines was designed in an attempt to increade the specificity of the 1-methyl-3-isobutylxanthine (MIX) structure for one of the two cyclic nucleotide phosphodiesterase peaks isolated by DEAE-cellulose chromatography of the soluble fraction of the intima + media layer of pig coronary arteries. A series of 1,3-dialkyluracils was of low potency as inhibitors of either peak I or peak II. The 7-substituted xanthines were prepared by alkylation of MIX with the corresponding alkyl or aralkyl halide in DMF containing K2CO3. These compounds were, in general, much less potent inhibitors of peak II activity than was MIX, but some of them retained the potency of MIX as inhibitors of peak I and, therefore, were relatively specific for inhibition of peak I. 7-Bzl-MIX was the most selective compound tested; it was a potent inhibitor of peak I activity but was much less effective as an inhibitor of peak II activity. Substitution of either electron-withdrawing (nitro) or electron-donating (methoxy) groups on the 7-benzyl moiety reduced the effectiveness of the 7-benzyl compounds as inhibitors of peak I. Chlorobenzyl substitution increased the potency slightly over the benzyl but not the selectivity between peaks.

In Grignard reagent formation from cyclopropyl bromide in diethyl ether, trapping by DCPH is consistent with diffusing cyclopropyl radical intermediates.

[reaction: see text] For reactions of magnesium with cyclopropyl bromide in diethyl ether, added DCPH decreases the yield of cyclopropylmagnesium bromide by as much as 75%, while solvent-derived products disappear and cyclopropylcyclohexylphosphine and tetracyclohexyldiphosphine appear. These changes reflect trapping of diffusing intermediate cyclopropyl radicals.

Growth inhibition of a human lung adenocarcinoma cell line by genetic complementation with chromosome 11.

Two regions on chromosome segment 11p15.5 have frequent allele loss in lung cancer. LOH11A is centromeric between loci D11S1758 and D11S12, and LOH11B is telomeric between HRAS and D11S1363. We studied the biological significance of this allele loss using microcell-mediated transfer of human chromosomes 11, 11p, and two radiation-reduced fragments of 11p into human lung adenocarcinoma cell lines. Chromosome 12, which has not been implicated in lung carcinogenesis, was used as a control. All four chromosome 11-containing hybrid clones showed significantly reduced tumorigenicity in nude mice and growth in liquid culture. These findings support the notion of a tumor suppressor gene located in the LOH11A region on chromosome segment 11p15.5.

Accurate, wide-range, automated, high-performance liquid chromatographic method for the estimation of octanol/water partition coefficients II: Equilibrium in partition coefficient measurements, additivity of substituent constants, and correlation of biological data.

Occasionally, results from the highly reproducible automated log P(o/w) measurement (ALPM) differ from those determined by shake-flask methods. Several specific examples affording different values are presented. One source of these differences may be curvilinearity in plots of log (t - t0) versus percent methanol, which complicate accurate intercept determinations and, thus, estimates of log P(o/w). Other sources of these differences are presented and discussed, although their cause remains unclear. Equilibrium ALPM log P(o/w) measurements of various phenyl-, methyl-, fluoro-, chloro-, and bromobenzenes, suggest substituent constants are not strictly additive. Moreover, the higher values indicate that calculated values may not be accurate for those compounds having multiple substituents or high log P(o/w) values. ALPM gives better predictability of the in vivo concentration process of 8 or 12 toxicants in fish than the shake-flask method, another HPLC method, or even calculated log P(o/w) values. However, it equally correlates the binding to bovine serum albumin by 34 chemicals as predicted by a combination of shake-flask and calculated log P(o/w) values reported elsewhere.

Preparation and Baeyer-Villiger Reaction of certain 2-carbalkoxycyclopropyl methyl ketones.

Treatment of mixed anhydrides derived from cis- and trans-2-carbobenzyloxycyclopropanecarboxylic acids and ethyl chloroformate with ethoxymagnesio di-tert-butyl malonate and subsequent treatment of the resulting adducts with p-toluenesulfonic acid afforded cis- and trans-benzyl-2-acetylcyclopropanecarboxylates in good to excellent yields, with retention of the original stereochemistry of the systems. These methyl ketones and an open chain congener, benzyl levulinate, were inert toward m-chloroperbenzoic acid. The cis-isomer and benzyl levulinate underwent normal Baeyer-Villiger reactions mediated by trifluoroperacetic acid, forming moderate yields of the acetate ester insertion products.

Accurate, wide-range, automated, high-performance liquid chromatographic method for the estimation of octanol/water partition coefficients I: Effect of chromatographic conditions and procedure variables on accuracy and reproducibility of the method.

A high-performance liquid-chromatographic (HPLC) procedure is reported for estimation of the logarithm of the octanol/water partition coefficient, log P(o/w). This automated log P(o/w) measurement (ALPM) circumvents many inherent difficulties with the shake-flask method, yet gives high reproducibility and excellent overall correlation with shake-flask results. Partition coefficients for numerous structurally diverse chemicals, ranging from approximately 0 to approximately 8 log P(o/w) units, can be determined; however, values for zwitterionic compounds cannot be obtained. Additional advantages of ALPM include lower cost and greater safety when compared with other HPLC or shake-flask procedures. Chromatographic conditions (i.e., flow rate and temperature) and variables (i.e., column length and solvent composition) affecting this method are discussed in detail. ALPM may also find application in quality control of HPLC columns, qualitative-quantitative analysis, and in computer-controlled method development and analysis.

Tumor lysis syndrome and acute renal failure after treatment of non-small-cell lung carcinoma with combination irinotecan and cisplatin.

Tumor lysis syndrome, characterized by multiple metabolic abnormalities resulting from abrupt tumor cell death and release of intracellular constituents and metabolites, is most commonly associated with the treatment of highly chemotherapy-sensitive lymphoid and leukemic neoplasms. The authors report a case of tumor lysis syndrome accompanied by acute renal failure that occurred in a patient with stage IV non-small-cell lung cancer who was treated with topoisomerase I inhibitor, irinotecan, and cisplatin. Consistent with the rapid tumor lysis, an objective, marked, early clinical response was observed. Attention to adequate hydration, electrolytes, and renal function should be given to outpatients with non-small-cell lung cancer who receive newer chemotherapeutic agents that have greater efficacy toward this group of tumors.

Vascular injuries associated with elbow fractures and dislocations.

The association between elbow fractures and dislocations and vascular injury was reviewed at our institution over a ten year period from 1983 to 1993. A total of fifty-six cases of acute elbow fracture or dislocation which required operative treatment were reviewed and of these two had a concomitant vascular injury. In both these cases diagnostic imaging studies confirmed the clinical diagnosis and arterial reconstruction was done. These cases are reviewed along with the arterial anatomy about the elbow which allows for significant collateral circulation. The general principles of fracture or dislocation reduction followed by vascular reassessment and arterial reconstruction if needed are reviewed.

Diagnosis of posttransplant granulocytic sarcoma by fine-needle aspiration cytology and flow cytometry.

We describe a patient who developed granulocytic sarcomas of the mesentery and breast approximately 4 yrs following an allogenic bone marrow transplantation for acute myeloblastic leukemia. The diagnosis was made by a combination of fine-needle aspiration cytology and flow cytometry. The differential diagnoses of localized masses in posttransplant patients and how the combination of fine-needle aspiration cytology and flow cytometry may be used are discussed.

The effects of selected bulky substituents on the pulmonary toxicity of 3-furyl ketones in mice.

Preliminary studies examined the toxicity of a series of simple alkyl 3-furyl ketone congeners of perilla ketone, 1-(3-furyl)-4-methylpentan-1-one (1), in mice, but little was known about how aromatic or bulky side chains might affect toxicity. Therefore, 3-furylphenyl ketone (2) 3-furylphenethyl ketone (3) and 1-3-furyl-4, 4-dimethylpentan-1-one (4) were synthesized to examine this problem. The 48-h LD50 (i.p.) in Notre Dame Swiss mice for each analog was greater than that of the parent toxicant, perilla ketone (1, 30 +/- 5; 2, 173 +/- 4; 3, 150 +/- 11; 4, 79 +/- 5 mumol/kg). Absorption and distribution of these compounds should be similar based on their lipophilicities. Preliminary evidence suggested that the reduced toxicities of 2, 3 and 4 compared with 1 cannot be explained on the basis of 13C-NMR (electron density) characteristics. Instead, the reduced potency likely is the result of steric hindrance of bioactivation by the bulky side chain substituents and(or) alternative metabolism on the phenyl ring rather than the furan ring of 2 and 3.

Arsenic-sulfur amino acid interactions in the chick.

Experiments were conducted with growing crossbred chicks to determine the reasons why cysteine exacerbates roxarsone (3-nitro-4-hydroxyphenylarsonic acid) toxicity. A fortified corn-soybean meal diet that met or exceeded all nutrient requirements of the young chick was fed. While cysteine enhanced roxarsone toxicity, it had little effect on the toxicity of the inorganic arsenicals As2O3 and As2O5. The toxicity of another pentavalent organic arsenical, phenylarsonic acid, was also exacerbated by cysteine. In contrast, the growth-depression resulting from feeding the trivalent form of phenylarsonic acid, i.e., phenylarsine oxide, was not affected by dietary addition of cysteine. Supplementation of the diet with cystine, methionine or K2SO4 did not exacerbate roxarsone toxicity. Reduced glutathione (GSH), however, slightly increased the gain/feed depression resulting from feeding 300 mg roxarsone/kg diet. When injected ip 1) roxarsone and cysteine, or 2) roxarsone and ascorbic acid killed 100 or 60% of the birds, respectively, within 48 h postinjection. Few (6.7%) deaths resulted from ip injections of the same level of roxarsone alone. Therefore, the potentiation of toxicity requires pentavalent organic arsenicals and compounds that can act as reducing agents. We concluded that cysteine exacerbates roxarsone toxicity by reducing it to the more toxic trivalent state.

Species susceptibility to the pulmonary toxicity of 3-furyl isoamyl ketone (perilla ketone): in vivo support for involvement of the lung monooxygenase system.

To explore a possible relationship between metabolism and lethality, the acute toxicity of naturally occurring perilla ketone (PK), 1-(3-furyl)-4-methyl-pentan-1-one, was examined in the uninduced mouse, hamster, rabbit, dog and pig. The LD50 (+/- SE), determined using intraperitoneal (ip) injection, for the mouse and hamster were low at 5.0 +/- .3 and 13.7 +/- .9 mg/kg, respectively. The rabbit died from an ip dosage of near 14 mg/kg and estimated ip LD50 dosages were quite high for the dog and pig, being 106 +/- 25 mg/kg and over 158 mg/kg, respectively. Dogs and the pig that died from ip injections of PK displayed varying degrees of midzonal and centrilobular liver damage and dogs also had elevated serum alkaline phosphatase and glutamic-pyruvic transaminase activities. In contrast, rodents and rabbits display only pulmonary toxicity from this agent. Cytochromes P-450 and b5 concentrations and NADPH-cytochrome c reductase activity were determined for the lung, liver and kidney of mice, hamsters, rabbits, dogs, swine, sheep and cattle. High correlation between lethality and enzyme concentration further supports the hypothesis that enzymatic bioactivation of PK is required for toxicity in all species.