Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action

Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.     

Physiological perspectives of therapy in bronchial hyperreactivity

Purpose

This paper reviews the literature on the aetiology and therapy of bronchial hyperreactivity to describe the underlying pathophysiology, identify patients at risk and update knowledge on new and existing therapies.

Source

Information was obtained from monograms on New Drugs for Asthma, Respiratory Medicine: recent advances, Agents and Actions Supplements, Pulmonary Pharmacology, Anesth Analg, the European Journal of Respiration and a Medline literature search.

Principal findings

Reduced airway calibre, increased bronchial contractility, altered permeability of the bronchial mucosa, humoral and cellular mediators, and dysfunctional neural regulation are critical factors for bronchial hyperreactivity, a characteristic feature of hyperreactive airways which results in bronchoconstriction after exposure to varied stimuli. Preoperative anaesthetic considerations in these patients include FEV₁ and PEFR testing to assess the severity and for optimal control of the condition. Bronchospasm causing hypoxaemia is the major intraoperative problem anticipated in these patients. Current therapeutic management of bronchoconstriction focusses on the β₂ agonists, theophylline and steroids. Besides relaxing the airway smooth muscle these agents are all capable of altering bronchial inflammatory responses. Future developments of therapy are directed towards the inflammatory components of the disease.

Conclusion

This review has presented background information on physiological mechanisms of smooth muscle contractility, pathophysiological alterations of bronchial contractility and the pharmacological basis of therapy in bronchoconstrictive disease. Information is presented to enable the prompt arrest and reversal of airway constriction, and to maintain prophylactic treatment during the perioperative period. Intraopera’tive bronchospasm is managed by adequate oxygenation and reversal of bronchoconstriction     

"Masked" Ph1 chromosome abnormalities in CML: a report of two unique cases

Two patients with chronic myeloid leukemia (CML) showed previously undescribed variants of a "masked" Ph1 abnormality. The first patient had the karyotype 46,XY, + 21, -9, -22, +mar9,mar18 at presentation in the chronic phase. The dicentric marker 9 was interpreted as representing the usual translocation of 22q11 to 9q34, followed by translocation of the Ph1 chromosome (the deleted 22) to 9p and probable translocation of 9p to the distal long arm of the marker. The patient developed clones containing 2 and 3 copies of the "Ph1-containing" marker 9 concomitant with the metamorphosis of his disease to a more aggressive phase. The second case presented with the karyotype 46,XY,- 9,-22,+two D-group markers. A complex rearrangement of chromosomes 9 and 22 is postulated, with interstitial insertion of either 9p or distal 9q into chromosome 22q11. This patient is still in the chronic phase of his disease 9 mo after presentation. The common denominator in these unusual "masked" cases is the 22q11 breakpoint. The paucity of published reports of duplication of 9q + without concurrent duplication of the Ph1 chromosome, supported by the findings in our first case, leads us to conclude that the amplification of genes on the Ph1 chromosome are more important for the evolution of the abnormal stem cell in CML than the chromosome 9 derivative.     

Detrimental effect of neoadjuvant chemotherapy in patients with stage-iiib carcinoma of the cervix - results of a randomized trial

With the objective of testing the value of neoadjuvant chemotherapy in patients with stage III B carcinoma of the cervix, we began in 1984 a randomized, phase III trial comparing BOMP chemotherapy followed by pelvic radiotherapy versus pelvic radiotherapy alone. Patients were stratified by age, extension of parametrial involvement, and lymphangiographic findings. Despite a higher complete response rate, the overall 5-year survival was significantly inferior in the combined therapy group (39% vs 23%, P=0.02). Toxicity was more pronounced in the chemoradiation arm and 4 patients developed fatal pulmonary complications. Patterns of failure were similar in both groups. The use of primary chemotherapy in advanced carcinoma of the cervix was detrimental to the patients and its use outside a protocol setting is discouraged.     

Fatal neonatal pneumonia caused by adenovirus type 35. Report of one case and review of the literature.

A 3680-g term male neonate developed bilateral bronchopneumonia at 9 days of age. The labor, delivery, and immediate postnatal period had been unremarkable. Despite standard antibiotic therapy, the patient progressed to respiratory failure and died 4 days later. Adenovirus particles were found in oropharyngeal secretions 1 day prior to death. Autopsy revealed an extensive necrotizing bronchiolitis and alveolitis with frequent "smudge cells." Adenovirus was identified by culture, electron microscopy, and in situ DNA hybridization. The adenovirus was serotyped as type 35, which, to our knowledge, has not been previously described in neonatal adenovirus pneumonia.     

Dense cystic craniopharyngiomas

Characteristic computed tomographic (CT) findings of craniopharyngioma include calcification, contrast enhancement, and cyst formation. Sharp margins associated with a hypodense centrum usually characterize the CT appearance of a cystic tumor. The appearance of "dense" cysts in craniopharyngiomas has not been emphasized. Four cases of craniopharyngiomas with isodense to hyperdense cysts are reported. Comparative biochemical and in vitro CT analysis of cyst aspirates taken from these lesions demonstrate that high intracystic protein concentration accounts for the greater part of the hyperdensity. Various mechanisms for intracystic protein accumulation are discussed. Lesion characteristics, and not necessarily attenuation coefficients, are stressed in differentiating "dense" cystic from solid craniopharyngiomas.     

Trends in stomach carcinoma. A statistical analysis of 1204 cases

The authors report a retrospective analysis of their experience of gastric cancer. One thousand two hundred and four patients, observed between 1977 and 1994, of whom 1,094 underwent surgery, were studied. Data analysis was performed, dividing this period as follows: 1977-1982, 1983-1988, 1989-1994. The results reveal that, over time, substantial changes occurred both in tumor characteristics and surgical approach. With regards to tumor characteristics, the disease weighs heavily, even if it is less frequent than in the past (25% reduction), striking younger subjects and presenting in increasingly more aggressive forms [higher frequency of proximal (+11.4%) and diffuse forms (+18.1%), reduction of advanced forms (-11.6%) not proportional to the increase of early forms (+64.5%), as well as increase of cases with a short clinical history (+15.2%)]. In terms of surgical approach, while the use of conservative surgery was reduced during the study period, extensive procedures were more widely used, particularly in the curative treatment of advanced tumors (subtotal gastrectomies: reduction of 39.5%; total gastrectomies: increase of 106%). The increasing use of extended surgery is linked to the modifications occurred in tumor characteristics and in pre and post-operative management rather then to changes in surgical approach. It must be noted, however, that such technical advances have not yielded an improvement in survival (p = n.s.); as such, it is likely that gastric cancer has became a more aggressive disease and, therefore, has counterbalanced the benefits of early diagnosis and extended exeresis.     

Factors influencing outcome in gastric cancer involving muscularis and subserosal layer.

AIMS: The prognostic factors for advanced gastric carcinoma without serosal invasion (pT2 AGC) are not clear. In terms of prognosis, pT2 AGC is considered intermediate between early gastric cancer (EGC) and gastric carcinoma with serosal invasion. METHODS: From January 1985 to December 2000, 182 patients with pT2 AGC underwent curative gastric resection in our Department. Prognostic factors were evaluated by univariate and multivariate analyses. RESULTS: Univariate analysis demonstrated that gender, tumour location, lymph node involvement, Borrmann type, number of lymph nodes involved, venous infiltration and extent of lymphadenectomy were significantly related to the prognosis. Multivariate analysis revealed that extent of lymph node metastasis (N1 vs N0 relative risk (RR) of recurrences=3.96, p<0.05; N2 vs N0 RR=6.55, p<0.05), and extent of lymphadenectomy (D1 vs D2 RR=3.2, p<0.01) were independent prognostic factors. In a subset of patients in which venous infiltration was analysed, this factor was also significant (RR=3.9, p<0.05). CONCLUSIONS: Our study shows that lymph node involvement and venous infiltration are important prognostic factors for pT2 AGC and, as such, adjuvant chemotherapy could be useful in this group of patients. An extensive lymph node dissection, minimum D2, should always be performed in order to reduce the risk of recurrence.