Anti-inflammatory 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes: a new class of airway selective steroids for the treatment of asthma.

The synthesis and anti-inflammatory potencies of a new class of 17beta-thioalkyl-16alpha,17alpha-ketal and -acetal androstanes are described. This new class of steroids was made by fragmentation of 2-thioxo-1,2-dihydropyrid-1-yl esters of the corresponding 17-acids to the 17-radical. The radical generated was trapped using a variety of radicophilic disulfides, giving a steroidal D-ring having acetal or ketal functionality at C-16 and C-17, together with a sulfide link at C-17. Compounds from this series bind to the glucocorticoid receptor with high potency and are functional agonists as measured by their ability to induce tyrosine aminotransferase activity in a rat hepatic cell line in vitro. These 17beta-thioalkyl androstanes potently inhibit Sephadex-induced rat lung inflammation when administered directly into the airways. The high topical potency, together with a low propensity to induce systemic glucocorticoid-like side effects (rat thymus involution), provides the present compounds with a high degree of airway selectivity compared with currently available inhaled glucocorticoids. The presently described 17beta-thioalkyl-16alpha,17alpha-ketal androstanes may be useful for therapies for inflammatory diseases such as asthma.

Mycotic pseudoaneurysm complicating flap closure of an infected median sternotomy.

False aneurysm, or pseudoaneurysm, formation is a well-recognized complication of cardiac surgery that can occur in the setting of postoperative mediastinitis. We present the first case report of a pseudoaneurysm involving flap closure of the infected mediastinum and discuss the presentation and diagnosis of this life-threatening complication.

Acyl-CoA:cholesterol O-acyl transferase (ACAT) inhibitors. 1. 2-(Alkylthio)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT.

A potent, bioavailable ACAT inhibitor may have beneficial effects in the treatment of atherosclerosis by (i) reducing the absorption of dietary cholesterol, (ii) reducing the secretion of very low density lipoproteins into plasma from the liver, and (iii) preventing the transformation of arterial macrophages into foam cells. We have found that a mevalonate derivative 2, which contains a 4,5-diphenyl-1H-imidazol-2-yl moiety, inhibits rat hepatic microsomal ACAT in vitro and produces a significant hypocholesterolemic effect in the cholesterol-fed rat. Structure-activity relationships for analogues of 2 demonstrate that the 4,5-diphenyl-1H-imidazole moiety is a pharmacophore for inhibition of rat microsomal ACAT.

Antitumor imidazotetrazines. 20. Preparation of the 8-acid derivative of mitozolomide and its utility in the preparation of active antitumor agents.

The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted preferentially with nucleophiles at the 8-position rather than at the reactive 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide (including an amide derived from an amino acid), hydroxamic acid, hydrazide and sulfoximide, azide and diazoacetyl derivatives. The in vivo activity is presented of a range of these compounds against TLX5 lymphoma and L1210 leukemia cell lines.

Hypolipidemic 2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-ones. Structure-activity relationships of a novel series of high-density lipoprotein elevators.

The preparation and plasma lipid altering characteristics of a series of 4H-3,1-benzoxazin-4-ones are described. Hypocholesterolemic, hypotriglyceridemic, and high-density-lipoprotein elevating properties are found for derivatives bearing a 4-(1,1-dimethylethyl)phenyl group at the 2-position, and this activity is displayed in both hypercholesterolemic and in normolipidemic rats when the ring system is substituted at position 6 with hydrogen, methyl, chloro, or iodo groups, and is optimal when the 6-position is substituted by a bromine atom. Evidence is presented suggesting that a metabolite or degradation product is responsible for the changes in lipoprotein concentration observed with active molecules of this type. Synthesis of anticipated degradation products of the active molecules gave products displaying the expected in vivo activity, but no improvement in the narrow therapeutic margin of the best compound, 6-bromo-2-[4-(1,1-dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-one, was obtained.

The effects of D and L isomers of menthol upon nasal sensation of airflow.

Objective and subjective measurements of nasal airflow were made before and after inhalation of Vanilla, D-Menthol and L-Menthol separately. Despite the fact that the menthol isomers were mirror images of one another, only L-Menthol produced the sensation of increased nasal airway patency. No objective change in resistance was found after inhaling either D-Menthol, L-Menthol or the vanilla control. These findings demonstrate that L-Menthol exerts a specific action upon nasal sensory nerve endings, which are responsible for the subjective appreciation of nasal airflow.

The effects of menthol isomers on nasal sensation of airflow.

The effects of inhalation of L-menthol, D-isomenthol and D-neomenthol, upon nasal resistance and sensation to airflow were investigated in 40 subjects. L-menthol caused a highly significant enhancement of nasal sensation of airflow but despite their great similarity in structure and a similar peppermint smell the isomers D-isomenthol and D-neomenthol had no effect on nasal sensation of airflow. These findings show that L-menthol has a specific pharmacological action on nasal sensory nerve endings which is not related to its peppermint smell.

Antitumor imidazotetrazines. 14. Synthesis and antitumor activity of 6- and 8-substituted imidazo[5,1-d]-1,2,3,5-tetrazinones and 8-substituted pyrazolo[5,1-d]-1,2,3,5-tetrazinones.

The systematic variation of the potent antitumor agent mitozolomide (1) is extended to cover alteration of substituents at positions 6 and 8 and to change the imidazo[5,1-d]-1,2,3,5-tetrazinone (1) skeleton to the isomeric pyrazolo-[5,1-d]-1,2,3,5-tetrazinone (17) skeleton. The series of eight 6-alkyl and 6-aralkyl derivatives of 1 showed optimal antitumor activity when the group was small or linear, but activity diminished as size and branching of this substituent increased. This may reflect altered transport characteristics, or failure of the enlarged derivatives to fit a binding site, or possibly a reduced tendency for the derivatives having bulky groups at position 6 to hydrolytically generate the putatively active triazenes (21). Testing of 14 derivatives of 1 differently substituted at position 8 revealed a complex structure-activity relationship, with good antitumor activity obtained for carbamoyl and sulfamoyl groups bearing small substituents. The 8-methylsulfonyl compound had noteworthy activity, but the 8-cyano, 8-nitro, and 8-phenyl derivatives were devoid of useful antitumor activity in these tests. From the limited number of pyrazolotetrazinones (17) reported here, it is suggested that the same conclusions as regards activity also hold true for this ring system.

Antitumor imidazotetrazines. 1. Synthesis and chemistry of 8-carbamoyl-3-(2-chloroethyl)imidazo[5,1-d]-1,2,3,5-tetrazin-4(3 H)-one , a novel broad-spectrum antitumor agent.

Interaction of 5-diazoimidazole-4-carboxamide and alkyl and aryl isocyanates in the dark affords 8-carbamoyl-3-substituted-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-on es. In cold methanol or ethanol, the 3-(2-chloroethyl) derivative 7a decomposes to afford 2-azahypoxanthine (14) and methyl and ethyl N-(2-chloroethyl)carbamates, respectively. Compound 7a has curative activity against L-1210 and P388 leukemia and may act as a prodrug modification of the acyclic triazene 5-[3-(2-chloroethyl)triazen-1-yl]imidazole-4-carboxamide (MCTIC), since it ring opens to form the triazene in aqueous sodium carbonate.

An appraisal of en bloc resection of peripheral bronchogenic carcinoma involving the thoracic wall.

Thirty-two patients with peripheral bronchogenic neoplasms adherent to the chest wall underwent en bloc pulmonary and thoracic wall resections. Presenting symptoms were thoracic wall pain (75 percent), hemoptysis (12.5 percent), and cough with weight loss (12.5 percent). Patients were selected for surgical resection only after a search for metastatic disease, including mediastinoscopy, showed negative results. A standard posterolateral thoracotomy incision was used which did not require skeletal reconstruction or prosthetic material for closure. There were nine major postoperative complications (28.8 percent), principally respiratory, and one operative death (3.1 percent). The five-year actuarial survival was 35 percent. None of the patients with regional lymph node involvement or positive chest wall margins lived more than two years after surgery. Preoperative irradiation performed in 12 patients (37.5 percent) improved operability, but did not significantly alter survival. These results indicate that patients with peripheral bronchogenic carcinoma involving the thoracic wall may be successfully managed with en bloc pulmonary and chest wall resection, particularly if surgery is performed in the early stage of the disease.

Unsuspected intraperitoneal perforation of the urinary bladder as an iatrogenic disorder.

Perforation of the urinary bladder associated with long-term indwelling catheter drainage is a rare and lethal iatrogenic disorder. Moreover, bladder perforation can occur in a variety of surgical settings. We report here several unusual situations: one in which a fibroid uterus probably played a role in pressure necrosis of a bladder with an indwelling catheter, one in which carcinoma of the prostate and faulty catheter drainage was present, and one in which pelvic radiation therapy was followed by bladder perforation. These three cases illustrate the clinical acumen required to recognize intraperitoneal perforation. The variety of presentations is suggested by the fact that one case was diagnosed preoperatively by cystogram, one was unexpectedly found at laparotomy for acute peritonitis, and one was discovered only at autopsy. One of the patients was diabetic, two had been treated for miliary tuberculosis, and all had a history of long-term urinary bladder catheterization. Bladder perforation can be prevented by several alternative methods of chronic bladder drainage. The diagnosis of the problem requires a high degree of clinical suspicion, aided by definitive cystograms. The treatment is surgical, including prompt repair of the perforation and drainage of the bladder.