Studies on the pharmacokinetics and metabolism of 4-chlorodiphenyl ether in rats

The metabolic disposition of 14C-labeled 4-chlorodiphenyl ether ([14C]4-CDE) was examined in rats following iv administration of a single dose (850 nmol/kg). [14C]4-CDE decayed rapidly from the blood since no unchanged [14C]4-CDE was detected in the blood beyond 2 hr after [14C]4-CDE administration. The dispositional kinetics of [14C]4-CDE in rats were best described by a two-compartment open pharmacokinetic model. Total radioactivity was excreted slowly from rats; about 41% and 33% of the administered dose were excreted into the urine and feces, respectively, within 1 week after chemical administration. About 5% of the total radioactivity administered to rats was excreted into the bile in 1 hr. The bulk of the radioactivity in the excreta was due to the presence of [14C]4-CDE metabolites. 14C-labeled 4'-hydroxy-4-CDE was the major metabolite and accounted for at least 90% of the radioactivity in the urine. The metabolic conversion of [14C]4-CDE to 14C-labeled 4'-hydroxy-4-CDE was corroborated by in vitro studies with liver microsomes of rats. In addition, [14C]4-CDE was converted by liver microsomes to reactive metabolites which bound irreversibly to microsomal protein. An arene oxide is suggested as the intermediate metabolite in the biotransformation of [14C]4-CDE by rats.     

Aspiration cytology in the management of breast lesions

In a group of patients with breast lumps, diagnosis made by pre-operative aspiration cytology was compared with that obtained by histological section of excised specimens. Results showed that aspiration cytology correctly diagnosed 89% of malignant lesions and 92.6% of benign lesions based upon histological diagnosis. Cytological diagnosis of benign disease had a false negative rate of 6% while cytological diagnosis of malignant disease had a 2.7% false positive rate. Only 3.5% of cytologies returned an inadequate diagnosis. This study shows that aspiration cytology should be useful in allowing a better psychological preparation of patients before surgery as well as better utilization of operation theatre facilities.     

Characterization and opioid modulation of inflammatory temporomandibular joint pain in the rat.

PURPOSE: Experimental inflammation of the rat temporomandibular joint (TMJ) is commonly used to study trigeminal nociceptive processing. This study describes spontaneous pain-related behaviors following TMJ inflammation in the rat. The ability of preemptive systemic morphine to attenuate behaviors as well as immediate-early gene expression in the trigeminal nucleus is described. MATERIALS AND METHODS: Adult male Sprague-Dawley rats received an intra-articular injection of mustard oil (0% to 20%, 50 microL) and were observed for behavioral changes. Morphine sulfate (0 to 10 mg/kg SC) was given 30 minutes before mustard oil; this was reversed in one group with naltrexone hydrochloride (5 mg/kg SC). Two hours after injection rats were killed and perfused. Immunohistochemistry for the protein product of the immediate-early gene c-fos was performed, and brain stem sections including the trigeminal subnucleus caudalis were examined for positive nuclei. RESULTS: Mustard oil inflammation of the rat TMJ induces dose-dependent, morphine-sensitive behaviors. Behaviors observed included excessive grooming of the region, a chewing-like behavior, and head shaking. Fos expression in the trigeminal subnucleus caudalis parallels changes in behaviors. Morphine dose dependently attenuates the number of behaviors, as well as Fos expression; this effect is reversed by the micro-opioid receptor antagonist naltrexone. CONCLUSIONS: Mustard oil inflammation of the rat TMJ causes reliable behavioral changes, which may be quantified and, together with Fos expression, used to assess various experimental TMJ treatment modalities.     

Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985: overall survival and patterns of failure.

This is a retrospective analysis of 5037 patients with squamous cell carcinoma of the nasopharynx treated during the years 1976-1985. The stage distribution according to Ho's classification was 9% Stage I, 13% II, 50% III, 22% IV, and 6% Stage V. Only 4488 (89%) patients had a full course of megavoltage radiation therapy. The median equivalent dose to the nasopharyngeal region was 65 Gy and cervical region in node-positive patients 53 Gy. Seventy percent (906/1290) of the node-negative patients had no prophylactic neck irradiation. The overall actuarial 10-year survival rate was 43%, and the corresponding failure-free survival 34%. Altogether, 4157 (83%) patients achieved complete remission lasting more than 6 months, but 53% (2205/4157) of them relapsed after a median interval of 1.4 years. The 10-year actuarial local, regional, and distant failure-free rates were 61%, 64%, and 59%, respectively. Thirty-eight percent (338/891) of all patients with local recurrence achieved second local remission. The local complete remission rate with aggressive re-irradiation alone was 47% (333/706). But 37% (124/338) of the responders recurred the second time. The incidence of distant failure correlated significantly with both the N-stage and the T-stage, with the highest (57%) occurring in patients with N3 disease. The incidence of nodal relapse in node-negative patients was 11% (44/384) among those given prophylactic neck irradiation, but 40% (362/906) among those without. Therapeutic irradiation achieved a complete regional remission rate of 90% (306/339). However, despite successful salvage, these patients had a significantly higher distant failure rate than those without nodal relapse, even if they remained local-failure-free (21% vs 6%). Patients treated during 1981-1985 achieved significantly better treatment results than those treated during 1976-1980, especially in terms of the overall survival (57% vs 47% at 5-year), the overall failure-free survival (42% vs 35% at 5-year), and the local failure-free rate (70% vs 63% at 5-year). The possible contributing factors are discussed.     

Anticipatory nausea and emesis, and psychological morbidity: assessment of prevalence among out-patients on mild to moderate chemotherapy regimens.

The prevalence of nausea and emesis among a series of out-patients (n = 95) receiving mainly mild-to moderately-emetic cytotoxics, was assessed, along with levels of psychological morbidity. Particular focus was given to the rates of psychologically-based (anticipatory) nausea and emesis. Results indicated that 23% of patients experienced anticipatory nausea and the majority reported that this occurred before at least half of the previous treatment cycles. Both emetic challenge of chemotherapy regimen and younger age were linked to this anticipatory effect. The data clearly indicated that nausea and emesis, both post-treatment and in anticipation of treatment, carried a psychological cost with anxiety being highest in those experiencing anticipatory nausea and/or emesis. The role of anxiety in the aetiology of psychologically-based nausea and emesis was not evaluated and it is considered that a prospective study is needed to clarify the exact contribution of psychological factors in the incidence of both post-treatment and anticipatory side-effects.     

An immunohistochemical investigation of diagnostic biopsy material taken from short and long term survivors with small cell lung cancer.

An immunohistochemical study has been carried out on fibre optic-biopsy specimens from patients with small cell lung cancer (SCLC) who had either died within 3 months, or who had survived more than 2 years. Long term survivors (LTS) were identified from completed clinical trials at major UK centres and were matched for age and sex within the trial with short term survivors (STS). The panel of immunohistochemical markers included those previously reported to be associated with prognosis, and reagents representative of both neuroendocrine and epithelial differentiation. A preliminary screen of 17 antibodies identified 11 as consistently reactive on paraffin-embedded material using streptavadin-biotin immunoperoxidase. Of 186 identified patients, 110 biopsy samples were retrieved. Of these, 70 gave sufficient material for analysis. All sections were scored by three observers without knowledge of the prognosis. The analysis failed to identify any antigen whose expression was correlated with prognosis. We conclude that, in fibre-optic biopsy specimens, immunohistochemical analysis does not add prognostic information in SCLC.     

Risk analysis in resection of squamous cell carcinoma of the esophagus

A study of risk factors that affect morbidity and mortality in 523 patients with squamous cell cancer of the esophagus who had one-stage resection was undertaken. The 30-day and hospital mortality rates were 5.0% and 15.5%, respectively. Pulmonary complications, malignant cachexia, and surgical complications accounted for 42%, 25%, and 21% of hospital deaths, respectively. Major pulmonary complications occurred in 23% of patients. Multivariate analysis identified six factors that predicted major pulmonary complications: age, mid-arm circumference, percent of predicted FEV₁, abnormal chest radiograph, amount of blood loss, and palliative resection. Three risk groups of pulmonary complications were identified: low, median, and high risk group with complications in 3%, 17%, and 43% of patients, respectively. Significantly, patients with curative resection had a lower hospital mortality rate (9%) than those with palliative resection (20%), p=0.001. Patients with stage I, IIa, or IIb disease had a lower hospital mortality rate (9%) than those with stage III or IV disease (18%), p=0.026. Multivariate analysis identified six factors that predicted hospital death: age, mid-arm circumference, history of smoking, incentive spirometry, number of stairs climbed, and amount of blood loss. Three risk groups of hospital death were identified: low, median, and high risk groups with death in 7%, 30%, and 38%, respectively. Anastomotic leakage rate was 4%. Technical faults were identified in 53% of patients with leakage. Together with other surgical complications, a presumed or apparent technical error was noted in 63% of patients. The identification of high-risk patients and prevention of technical faults can help improve surgical outcome.

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Resumen Se emprendió un estudio sobre los factores de riesgo que afectaron la mortalidad en 523 pacientes con carcinoma escamocelular del esófago sometidos a resección en una etapa en nuestra institución.Las tasas de mortalidad a 30 días y de mortalidad hospitalaria fueron 5% y 15%. Las complicaciones pulmonares, caquexia maligna y quirúrgica representaron 42%, 25% y 21% de las muertes hospitalarias, respectivamente. Complicaciones pulmonares mayores fueron registradas en 23% de los pacientes.El análisis multivariado identificó seis factores que predicen complicaciones pulmonares mayores: edad, circunferencia del brazo, porcentaje del FEV1 predecible, radiografía de tórax anormal, pérdida de sangre durante la operación y resección de tipo paliativo. Se identificaron tres grupos de riesgo de desarrollar complicaciones pulmonares: bajo, medio y alto, con tasas de 3%, 17% y 43% de los pacientes, respectivamente. Los pacientes que recibieron resección curative exhibieron una significativamente menor tasa de mortalidad hospitalaria (9%) en comparación con los que recibieron resección paliativa (20%), p=0.001. Los pacientes con enfermedad en estados I, IIa, IIb exhibieron menor mortalidad hospitalaria (9%) en comparación con los estados III o IV (18%), p=0.026. El análisis multivariado identificó seis factores que predicen mortalidad hospitalaria: edad, circunferencia del brazo, historia de tabaquismo, espirometría de incentivo, número de escalones que puede ascender y pérdida de sangre durante la operación. Se identificaron tres grupos de riesgo de mortalidad hospitalaria: bajo, medio y alto, con tasas de 7%, 30% y 38% respectivamente.La tasa de fuga anastomótica fue 4% y se identificaron defectos técnicos en 53% de los pacientes. Junto con otras complicaciones quirúrgicas, se observó un error técnico presumible o aparente en 63% de los pacientes.La identificación de los pacientes de alto riesgo y la prevención de los errores técnicos pueden ayudar a mejorar el pronóstico.

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Résumé Dans cette étude, on a étudié les facteurs de risque influençant la morbidité et la mortalité chez 523 patients ayant un cancer épidermoïde de l'oesophage et ayant eu une résection en un seul temps. La mortalité à 30 jours et la mortalité hospitalière ont été respectivement de 5% et de 15.5%. Les complications pulmonaires, la cachexie maligne et les complications chirurgicales ont été responsable respectivement de 42%, 25% et 21% des décès hospitaliers. Une analyse multifactorielle a permis d'identifier six facteurs prédictifs des complications pulmonaires: l'âge, la circonférence brachiale, la prévision du volume expiratoire forcé en une seconde, les anomalies de la radiographie thoracique, la quantité de sang perdu, et le caractère palliatif de la résection. Trois groupes, dont le risque de complications pulmonaires a été classé faible, moyen et élevé, ont été identifiés. Le taux de complications dans ces groupes ont été respectivement de 3%, 17% et 43%. Les patients ayant eu une résection à visée curative avaient une mortalité hospitalière significativement plus basse (9%) comparée à celle des patients ayant eu une résection à visée palliative (20%) (p=0.001). Les patients ayant des maladies de stades I, IIa, IIb avaient une mortalité plus basse (9%) que ceux qui avaient des stades III ou IV (18%), (p=0.026). L'analyse multifactorielle a permis d'identifier six facteurs prédictifs de la mortalité hospitalière: l'âge, la circonférence brachial, des antécédents de consommation excessive du tabac, la spirométrie, le nombre d'escaliers que le patient peut monter, et la quantité de sang perdu. Trois groupes de patients, dont le risque de mortalité hospitalière a été classé faible, moyen, et élevé, ont eu des décès dans respectivement 7%, 30% et 38% des cas. Le taux de fistule a été de 4%. Une faute technique a été identifiée chez 53% des patients ayant eu une fistule. Une faute technique apparente ou présumée a été identifie chez 63% des patients ayant eu soit une fistule soit une complication chirurgicale. L'identification des patients à haut risque et la prévention des fautes techniques peuvent contribuer à améliorer le pronostic après chirurgie.

     

Developing policy in the provision of parenting programmes: integrating a review of reviews with the perspectives of both parents and professionals

Background   Parenting programmes are a key component of the delivery of children's services, but evidence-based policy has often proved difficult to implement.
Methods   The present review addressed this issue by integrating a review of systematic reviews of parenting programmes and a series of focus groups with parents and professionals involved in parenting across three agencies in a regional area (health, education and social work). The review summarizes parenting interventions targeting infant mental health, emotional and behavioural difficulties, autism spectrum disorder and attention deficit hyperactivity disorder, abuse/neglect, alcohol/substance abuse and 'vulnerable' parents. The focus groups discussed topics such as the range of parenting services across the three agencies, accessibility, gaps in the service and future directions.
Results and conclusions   Twenty systematic reviews were summarized. These reviews demonstrated that there is a wide range of parenting programmes available that have the potential to benefit families who are affected by problems ranging from emotional and behavioural difficulties to adolescent substance abuse. However, the findings of the focus groups reveal that the success of these programmes will depend in part on how they can be tailored to meet the social context of the families targeted. These integrated findings are discussed in terms of their implications for policy and practice.     

Pharmacokinetic and pharmacodynamic studies with mitoxantrone in the treatment of patients with nasopharyngeal carcinoma.

The pharmacokinetics and pharmacodynamics of mitoxantrone were studied in 15 patients with advanced nasopharyngeal carcinoma (NPC) after single intravenous rapid infusion (12 to 14 mg/m2). Mitoxantrone plasma concentrations and urinary excretion were measured specifically with the use of a high-performance liquid chromatographic method with ultraviolet detection at 242 and 658 nm. The pharmacokinetic parameters are described adequately by a three-compartment model with a terminal half-life of 71.5 +/- 40.1 hours and a volume of distribution of 5037 +/- 2377 l. The total plasma clearance was 743 +/- 462 ml/minute, and the renal clearance was 18.8 +/- 8.49 ml/minute. Within 72 hours, 1.8 +/- 0.6% of the administration dose was excreted in urine as mitoxantrone parent compound. From the urinary excretion rate data, glomerular filtration and possible tubular reabsorption were the mechanisms involved in the urinary excretion of mitoxantrone. The values for unbound fraction (%) in plasma at time 0 and 5 minutes were 2.88 +/- 0.91% and 3.25 +/- 1.19%, with an average of 3.04 +/- 1.01%. The degree of protein binding of mitoxantrone was not affected by concentration (P greater than 0.05) in Chinese patients with NPC. The response rate for mitoxantrone was poor in this study. Clinical studies have demonstrated that mitoxantrone was generally well tolerated. Only very low incidences of nausea, vomiting, and alopecia were observed. The mild and rapidly reversible dose-limiting hematologic toxic effects have proven leukopenia. Although the toxicities reported here were tolerated for most patients, other combination regimens including mitoxantrone or other administration routes may be considered and need to be evaluated carefully.