Absorption, Metabolism, and Excretion of N,N-Diethyl-m-toluamide Following Dermal Application to Human Volunteers

The absorption, metabolism, and excretion of N,N-diethyl-m-toluamide(DEET) in male human volunteers following dermal applicationof |¹⁴C|DEET was studied. DEET was applied to two groups ofsix volunteers either as the undiluted technical grade materialor as a 15% solution in ethanol. The material was applied overa 4 x 6-cm area on the volar surface of the forearm and wasleft in contact with the skin for 8 hr, then rinsed off theskin. Application sites also were tape stripped at 1, 23, and45 hr after rinsing. Serial blood samples and all urine andfeces were collected for 5 days after application. Aliquotsof these materials were analyzed for total radioactivity inorder to define absorption and excretion patterns. Urine samplesalso were analyzed by HPLC to characterize the metabolic profileand/or to identify metabolites. Absorption of DEET as evidencedby plasma radioactivity occurred within 2 hr after dose application.Elimination of radioactivity from plasma was rapid and quantifiablelevels of radioactivity were observed in plasma for only 4 hrafter the end of the 8-hr exposure period. Urine was the principalroute of excretion of radioactivity and accounted for an averageof 5.61 and 8.33/ of the applied dose in the undiluted DEETand 15/ DEET in ethanol groups, respectively. Excretion of radioactivityin the feces was less than 0.08/ of the applied dose in bothgroups. DEET did not accumulate in the superficial layers ofthe skin as evidenced by low amounts of radioactivity in thetape strippings. The major fraction of the applied radioactivitywas recovered in the skin rinses. Absorbed DEET was completelymetabolized and six major metabolites were observed in urine.Two major urinary metabolites tenta tively were identified.Based upon the percentage of applied dose recovered in the excreta,dermal absorption of DEET ranged from 3 to 8% with a mean of5.6/ in the volunteers applied undiluted technical grade DEET.The corresponding values for the volunteers applied 15/ DEETin ethanol were 4 to 14/ and 8.4/, respectively.     

The Myocardial Lesions Produced by the Potassium Channel Opener Aprikalim in Monkeys and Rats Are Prevented by Blockade of Cardiac {beta}-Adrenoceptors

Aprikalim is a potent, specific, and selective opener of ATP-sensitiveK⁺ (K_ATP) channels. By virtue of this pharmacological property,aprikalim affords cardioprotection in experimental models ofischemia/reperfusion injury, and, at higher doses, also causesperipheral or coronary vasodilatation. Direct-acting peripheralvasodilators can cause myocardial lesions, particularly in ratsand dogs. However, unexpectedly, aprikalim produced this effectalso in monkeys. Thus, the primary aim of this investigationwas to assess whether in monkeys these myocardial lesions werethe direct or indirect consequence of the vascular effects ofaprikalim. Cyno-mologus monkeys were given the ß-adrenoceptorantagonist nado-lol (2 mg/kg po, twice daily) for 4 consecutivedays. On the third and fourth day of the experiment, they receivedaprikalim (1 mg/kg po). In another series, two monkeys carryingtelemetry transmitters for blood pressure and heart rate measurementswere also given aprikalim or its vehicle. Finally, aprikalim(1 mg/kg po for 2 days) or its vehicle was administered to ratswhich were concurrently treated with the ß-adrenoceptorantagonist atenolol (5 mg/ kg sc) or its vehicle. In cynomologusmonkeys, aprikalim produced focal and multifocal myocardialnecrosis of minimal to moderate intensity in or near the papillarymuscles of the left ventricle. These effects were abrogatedby nadolol. Similarly, necrotic lesions were caused by aprikalimonly in those rats which had not been pretreated with atenolol.In monkeys, aprikalim produced a marked and long-lasting decreasein aortic blood pressure, accompanied by an even more prolongedtachycardia. These results demonstrate that aprikalim can producemyocardial necrosis not only in rats but also in monkeys. Toour knowledge, this is the first time that such adverse effectsare reported for a vasodilator in monkeys. More importantly,these effects were prevented by blocking cardiac ß-adrenoceptors.Thus, the myocardial lesions produced by aprikalim may be attributedto its profound and prolonged hemodynamic effects.     

Dapsone in the treatment of lupus erythematosus

Dapsone yielded excellent therapeutic results in certain forms of lupus erythematosus (LE), whereas discoid lesions and the maculo-papular rash of the systemic and disseminated chronic forms of discoid LE remained uninfluenced by the drug. On the basis of these observations, we suggest the following indications for dapsone treatment in LE:

• 1 Vasculitic urticaria
• 2 Oral ulceratino
• 3 Non-scarring form of chronic LE
• 4 Chloroquine intolerance.

     

Pulmonary Bioavailability and Fine Particle Enrichment of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Respirable Soil Particles

The pulmonary bioavailability of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) and the enrichment of polychlorinated dioxins (PCDDs)and furans (PCDFs) in fine particles were evaluated to assessthe implications that these factors have on risk and exposureassessments. Respirable subfractions of PCDD-contaminated soilfrom a former 2,4,5-trichlorophenoxyacetic acid manufacturingsite were isolated by chemical dispersion and gravity sedimentation.Analysis of the subfractions revealed that there was a size-dependentenrichment of PCDDs and PCDFs, with smaller particles more highlycontaminated. TCDD was enriched up to 33-fold as compared tounfractionated soil. Soil and laboratory-recontaminated galliumoxide, which served as the positive control, were administeredby intratracheal instillation to female Sprague-Dawley rats.Animals were terminated up to 28 days following treatment andpulmonary bioavailability of TCDD was assessed by hepatic enzymeinduction and TCDD concentration. Enzyme induction was dependenton the duration of exposure with up to 56 and 918% increasesin cytochrome P450 and aryl hydrocarbon hydroxylase (AHH) activity,respectively, following exposure to PCDD-contaminated soil.There was no significant difference in AHH induction betweenanimals which received contaminated soil and those treated withthe positive control. Hepatic concentration of TCDD in soil-exposedrats was 115, 101, and 179% of positive controls at 1, 7, and28 days post-treatment, suggesting that the soil or co-contaminantsinfluenced retention of TCDD in the liver. These data indicatethat the relative pulmonary bioavailability of TCDD on respirablesoil particles is 100% as compared to laboratory-recontaminatedgallium oxide and that PCDDs and PCDFs are highly enriched onrespirable particles. Utilization of these results will reducethe uncertainty and improve the accuracy of envi ronmental riskassessments of PCDDs and PCDFs.     

Prognostic value of serial CA125 measurements during chemotherapy for patients with advanced ovarian cancer

Serum CA125 concentrations measured before and during chemotherapy may provide additional information for prognostic assessment of patients with epithelial ovarian cancer (EOC), and enable discrimination between patients who are likely to benefit from further therapy and those who will not. Medical records of 40 patients with advanced EOC, treated at the Department of Obstetrics and Gynecology of the University Hospital Nijmegen between July 1984 and April 1993, were examined. All patients had primary cytoreductive surgery followed by platinum-based chemotherapy. Serum samples were obtained before surgery and during chemotherapy. Follow-up information and patient and tumor characteristics were abstracted from medical records until December 1, 1994. By using multivariate Cox proportional hazards models for disease-free and overall survival it was evaluated whether outcome prediction was improved by inclusion of serum CA125 quantitations.
  Only FIGO stage and extent of residual tumor were significant independent prognostic factors before the start of chemotherapy. When such regression models were constructed after subsequent courses of chemotherapy, serum CA125 measurements conducted after each of the first three chemotherapy courses improved the prediction of disease-free survival. Prediction of overall survival was improved by inclusion of serum CA125 measurements after courses 1–6. Inclusion of serum CA125 measurements during chemotherapy improved prognostic assessment of patients with advanced EOC.     

All change: cancer services in transition

The policy and health service background to this discussion are the radical changes in cancer services currently underway in the wake of the Calman-Hine Report and the wider changes ushered in by the NHS and Community Care Act 1990 (UK). Using the changing face of hospice care as the focus, the authors explore some of the potential issues and dilemmas involved in providing supportive care for cancer patients and their families. Three 'themes', or areas of concern, are highlighted: links between services, changing organizational factors, and increasing 'medical imperialism'. Potential benefits and drawbacks of the changing ethos and organizational structures are discussed. Interview data are used as 'triggers' for the presentation of the authors' own reflections on developments in the hospice and cancer services' arenas. The paper draws on interview data collected in the pilot phase of a 3-year study on the psycho-social needs of cancer patients and their informal carers in north-west England. Twenty-nine interviews were conducted with a range of professionals involved in the provision of cancer services in Lancaster and Kendal. In the spirit of 'gathering thoughts' and facilitating debate, a commentary on developments in the hospice sector is offered rather than any firm conclusion.     

Effects of perfluorochemical evaporative properties on oxygenation during partial liquid ventilation

BACKGROUND: The physical-chemical properties of perfluorochemical (PFC) liquids have been shown to influence physiological and cellular responses during partial liquid ventilation (PLV). The aim of this study is to compare the relationship between patho-physiological endpoints and the physical properties of three PFC liquids used in treating acute lung injury. METHODS: A total of 18 juvenile rabbits were randomized into conventional mechanical ventilation or PLV groups after lung saline lavages. Three PFC liquids, including Flutec perfluoro-1,3,5-trimethylcyclohexane (PP4; vapor pressure, 28.8 mmHg at 37 degrees C), Perfluorodecalin (PFD; vapor pressure, 13.6 mmHg at 37 degrees C), and Perflubron (PFB; vapor pressure, 10.4 mmHg at 37 degrees C) were used for PLV with no replacement for 4 h. A thermal detector was used to measure PFC loss rate. Physiological measurements and evaporative loss rate of PFC were done every 30 min, and lung histology was examined. RESULTS: The mean evaporative loss rate was significantly higher in the PP4 group (4.75 +/- 0.24 mL/kg per h) than in either the PFD (1.43 +/- 0.11 mL/kg per h) or the PFB (1.18 +/- 0.05 mL/kg per h) group (P < 0.05). The oxygenation of PFD and PFB was maintained good for 4 h, however, the PP4 group showed a fast deterioration since 2 h post-treatment due to fast dropping of the residual PP4 amount in lungs. Histology showed good alveolar integrity in the PFD and PFB groups. CONCLUSIONS: The effects of PLV are directly influenced by the evaporative property of the PFC liquid. With no replacement over 4 h, PLV effects could be maintained with utilizing a PFC liquid with low, rather than high, vapor pressure. PFC with high vapor pressure has a high loss rate and low residual volume that causes poor maintenance on oxygenation during PLV. Therefore, measuring PFC loss rate is important in future studies and clinical application of PLV.     

A new metric for quantifying performance impairment on the psychomotor vigilance test

We have developed a new psychomotor vigilance test (PVT) metric for quantifying the effects of sleep loss on performance impairment. The new metric quantifies performance impairment by estimating the probability density of response times (RTs) in a PVT session, and then considering deviations of the density relative to that of a baseline‐session density. Results from a controlled laboratory study involving 12 healthy adults subjected to 85 h of extended wakefulness, followed by 12 h of recovery sleep, revealed that the group performance variability based on the new metric remained relatively uniform throughout wakefulness. In contrast, the variability of PVT lapses, mean RT, median RT and (to a lesser extent) mean speed showed strong time‐of‐day effects, with the PVT lapse variability changing with time of day depending on the selected threshold. Our analysis suggests that the new metric captures more effectively the homeostatic and circadian process underlying sleep regulation than the other metrics, both directly in terms of larger effect sizes (4–61% larger) and indirectly through improved fits to the two‐process model (9–67% larger coefficient of determination). Although the trend of the mean speed results followed those of the new metric, we found that mean speed yields significantly smaller (～50%) intersubject performance variance than the other metrics. Based on these findings, and that the new metric considers performance changes based on the entire set of responses relative to a baseline, we conclude that it provides a number of potential advantages over the traditional PVT metrics.