An efficient synthesis of [13C6]‐3,5‐dichloroaniline

3,5‐Dichloroaniline is commonly found in many compounds with pharmacological and other biological activities. [¹³C₆]‐Aniline or its hydrochloride salt was converted in three steps to [¹³C₆]‐3,5‐dichloroaniline, which can be incorporated in compounds of interest and used as internal standards in drug metabolism and pharmacokinetics (DMPK) studies. Copyright © 2008 John Wiley & Sons, Ltd.     

Vocal cord paralysis with Ebstein's anomaly

Left recurrent laryngeal nerve runs a long intrathoracic course in close relationship to the aortic arch and adjacent heart structures and, hence, is liable to be injured by diseases affecting the heart and its great vessels. We report a case of Ebstein's anomaly causing left recurrent laryngeal nerve paralysis in a neonate. To our knowledge, this is the first reported case of vocal cord paralysis associated with this condition.     

Chronic suppression of testicular function by constant infusion of gonadotropin-releasing hormone agonist and testosterone supplementation in the bonnet monkey (Macaca radiata).

OBJECTIVE: To study the efficacy of long-term buserelin acetate infusion to desensitize pituitary and block testicular function in adult male monkeys (Macaca radiata). ANIMALS: Proven fertile male monkeys exhibiting normal testicular function. PROTOCOL: Each of the control (n = 5) and experimental monkeys (n = 10) received a fresh miniosmotic pump every 21 days, whereas pumps in controls delivered vehicle of experimentals released 50 micrograms buserelin acetate every 24 hours. On day 170 (renewed every 60 days) a silastic capsule containing crystalline testosterone (T) was implanted in the experimental monkeys. At the end of 3 years, treatment was stopped, and recovery of testicular function and fertility monitored. RESULTS: (1) Treatment resulted in marked reduction of nocturnal but not basal serum T; (2) the pituitary remained desensitized to buserelin acetate throughout the 3-year period; (3) animals were largely azoospermic with occasional oligospermia exhibited by two monkeys; and (4) withdrawal of treatment restored testicular function, with 70% of animals regaining fertility. CONCLUSION: Long-term infertility (but restorable) can be induced in male monkeys by constant infusion of buserelin acetate and T.     

Intraoperative touch imprint of sentinel lymph nodes in breast carcinoma patients

BACKGROUND: Sentinel lymph node examination in patients with breast carcinoma has been gaining in popularity. Currently, there is no standard intraoperative assessment of sentinel lymph nodes. To assess the utility of an intraoperative touch imprint (TI) evaluation, the authors compared TI cytology with surface hematoxylin and eosin (H&E) histology in sentinel lymph nodes from patients with breast carcinoma. METHODS: Sixty five sentinel lymph node biopsy cases were identified. Diagnoses from TI and surface H&E histologic sections were compared. RESULTS: Touch imprint had a specificity of 100%, a negative predictive value of 88%, a sensitivity of 65%, and a false negative rate of 9% per sentinel lymph node biopsy case. Eighty three percent of the false negative TI cases were due to micrometastasis. Preoperative chemotherapy, primary tumor type, and primary tumor size did not significantly contribute to false negative events. Touch imprint identified 67% of the cases that required completion axillary dissection. CONCLUSIONS: Touch imprint is a reliable and accurate intraoperative technique, with the potential to save a significant number of patients morbidity and the cost of a second surgical procedure to remove axillary lymph nodes. The difficulty of identifying micrometastases appeared to be the major source of false negative events, a problem that is not unique to TI cytology.     

CT-guided percutaneous fine-needle aspiration biopsy of small (< or =1-cm) pulmonary lesions

PURPOSE: To determine the accuracy of percutaneous computed tomography (CT)-guided fine-needle aspiration biopsy (FNAB) of small (< or =1.0-cm in diameter) pulmonary lesions. MATERIALS AND METHODS: Sixty-one patients (34 men and 27 women) 21-89 years old (mean age, 61.3 years) with lung nodules 1.0 cm or smaller underwent CT-guided transthoracic FNAB. Fifty-seven of the 61 patients had an underlying primary malignancy. Maximum nodule diameters were 0.5-0.7 cm in 10 patients and 0.8-1.0 cm in 51 patients. Cytopathologic evaluation of FNAB samples was immediate in all patients. Sensitivity and accuracy were calculated, and each case was reviewed for complications, including pneumothorax and thoracostomy tube insertion. Four patients were not included in our statistical analysis because of a lack of follow-up information. RESULTS: FNAB samples were adequate for diagnosis in 47 (77%) of 61 patients. Diagnoses were malignancy (n = 29) or suspected malignancy (n = 3) in 52% (n = 32) and benign or atypical findings in 25% (n = 15). Findings were nondiagnostic in 23% (n = 14). Of the 29 patients without evidence of malignancy, 25 had follow-up findings available. Follow-up included chest CT in 16 patients and surgical resection in nine. Four patients were not included in statistical analysis because of a lack of follow-up information. Overall sensitivity was 82% (32 of 39); specificity, 100% (18 of 18); and diagnostic accuracy, 88% (50 of 57) on the basis of 57 patients being evaluable. Results for 47 0.8-1.0-cm lesions were considerably better (sensitivity, 88%; accuracy, 92%) than those for 10 0.5-0.7-cm lesions (sensitivity, 50%; accuracy, 70%). Sensitivity (75% vs 87%) and accuracy (87% vs 89%) also improved when comparing subpleural (< or =1.0 cm from pleural surface, n = 30) with deeper (>1 cm from pleural surface, n = 27) pulmonary lesions, but the improvement did not indicate statistical significance. Core biopsy did not reveal malignancy in any of the nine patients in whom preliminary cytologic results were inconclusive and did not improve diagnostic yield. Thirty-eight (62%) patients had pneumothorax, with 19 (31%) requiring thoracostomy tube placement. CONCLUSION: CT-guided FNAB of pulmonary lesions 1.0 cm or smaller can yield high diagnostic accuracy rates approaching those of larger lesions; FNAB of 0.8-1.0-cm lesions that are not subpleural offers the best opportunity for success.     

The antineoplastic efficacy of the prodrug Cloretazine is produced by the synergistic interaction of carbamoylating and alkylating products of its activation

Cloretazine {1,2-bis(methylsulfonyl)-1-[(2-chloroethyl)-2-(methylamino)carbonyl]hydrazine; VNP40101M; 101M} is a sulfonylhydrazine prodrug that possesses broad spectrum antitumor efficacy against transplanted murine and human tumor models and has shown activity in clinical trials against relapsed or refractory acute myeloid leukemia. Base catalyzed activation of this prodrug generates two different reactive intermediates: chloroethylating species that covalently interact with DNA at the O6-position of guanine residues that progress to a G-C interstrand cross-link, and a carbamoylating agent, methyl isocyanate. Previous findings from this laboratory have provided initial evidence that methyl isocyanate can contribute to the efficacy of Cloretazine by enhancing the cytotoxicity of the generated chloroethylating species. This action may be due in part to inhibition of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT); however, activity in cells devoid of AGT indicates that other actions are involved in the synergistic cytotoxicity. Herein we demonstrate that O6-benzylguanine can also produce synergistic cell kill with the alkylating component of Cloretazine but differs from methyl isocyanate in that the enhancement occurs in AGT-containing cells, but not in cells devoid of AGT. Methyl isocyanate generated by the decomposition of 1,2-bis(methylsulfonyl)-1-[methylaminocarbonyl]hydrazine also acts to enhance the activity of a variety of DNA cross-linking agents, while only producing additive cytotoxicity with methylating agents. Flow cytometric studies using annexin as a marker for apoptosis indicate that in Chinese hamster ovary cells and in human leukemia cells Cloretazine-induced apoptosis is primarily caused by the generated methyl isocyanate. Comet assays designed to detect DNA cross-links in intact cells indicate that the chloroethylating species generated by the activation of Cloretazine produce DNA cross-links, with the co-generated methyl isocyanate increasing the degree of cross-linking produced by the reactive chloroethylating species. These findings provide further evidence that the methyl isocyanate produced by the activation of Cloretazine can be a major contributor to the cytotoxicity produced by this antineoplastic agent.     

A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants

We compared the onset of clinical response and safety of two surfactants, poractant alfa (Curosurf, Chiesi Pharmaceuticals, Parma, Italy) and beractant (Survanta, Ross Laboratories, Columbus, OH), for treatment of respiratory distress syndrome (RDS) in preterm infants weighing 750 to 1750 g at birth and <35 weeks gestation. The study was performed as a 20-center prospective, randomized, masked comparison trial. Preterm infants (n = 293) with RDS were randomized to receive an initial dose of either 100 (n = 96) or 200 (n = 99) mg/kg of poractant alfa or 100 ( n = 98) mg/kg of beractant. All repeat dosing was given at 100 mg/kg. The onset of clinical response after the first dose was studied by comparing changes in the fraction of inspired oxygen (F IO(2)) between 0 and 6 hours measured using the area under the curve (F IO(2) AUC (0-6)); other outcomes were assessed for the entire cohort at 28 days and for infants born at < or = 32 weeks gestation at 36 weeks postconceptional age. We found that the mean F IO(2) AUC (0-6) values for the 100 and 200 mg/kg poractant alfa groups were both significantly lower than the mean F IO(2) AUC (0-6) values for the beractant group ( p < 0.005) but were not different from each other. Other outcomes were not different among the three groups for the entire cohort, but in infants born at < or = 32 weeks gestation, mortality up to 36 weeks postconceptional age was significantly less in the 200 mg/kg poractant alfa group than in either the beractant group (3% versus 11%; p = 0.034) or in the 100 mg/kg poractant alfa group (3% versus 11%; p = 0.046). Need for more than one dose of surfactant was significantly lower in infants treated with an initial dose of 200 mg/kg poractant alfa in comparison to the beractant-treated group ( p < 0.002). Treatment with poractant alfa (200 mg/kg initial dose) resulted in rapid reduction in supplemental oxygen with fewer additional doses of surfactant versus treatment with beractant in infants <35 weeks gestation with RDS, and significantly reduced mortality ( p <0.05) than either beractant or poractant alfa (100 mg/kg dosing) in infants < or =32 weeks gestation with RDS.