Synthesis, structure, and antitumor activity of a novel tetranuclear titanium complex

The coordination complex cyclo-tetrakis[bis(1-phenyl-3-methyl-4-benzoylpyrazolon-5-ato++ +)mu-o xotitanium(IV)] has been synthesized and characterized with IR and NMR spectroscopies and X-ray diffraction. The core of this species consists of an eight-membered Ti-mu-oxo ring with alternate short-long Ti-O bond lengths. Besides these two O ligands, each metal is bound octahedrally to four O atoms from two chelating 1-phenyl-3-methyl-4-benzoylpyrazolon-5-ato anions. Several sets of Ti-O bond lengths are present: the shortest are the two Ti-O(oxo) (which are cis to each other), the longest are the two Ti-O(acyl) (cis to each other), and the two Ti-O(pyrazolonato) (trans to each other) are intermediate. The beta-diketonate ligand asymmetry, a feature considered essential in other antitumor Ti compounds, induces the short-long Ti-O(oxo) sequence of bond lengths. The antitumor activity of this compound, encapsulated in a dipalmitoylphosphatidylcholine liposome, has been studied in vitro using TA-3 (mouse mammary adenocarcinoma), HEP-2 (human epithelial larynx carcinoma), and VERO (African green monkey kidney) cell lines and in vivo in CF-1 and AJ female mice ip inoculated with TA-3. In vitro cytotoxicity is greater for TA-3 than for HEP-2 and null for VERO cell lines. In vivo results show a marked increase in survival time (T/C = 293% for AJ and 208% for CF-1), whereas tumor weight decrease was observed for CF-1-treated mice. These results suggest the Ti complex-liposome system may be promising as an antitumor drug.     

Otologic and otoneurologic injuries in divers: Clinical Studies On Nine Commercial and Two Sport Divers

In the past two decades, we have seen a great increase in the number of injuries from commercial and sport diving. During this time, our knowledge of the physiology and pathophysiology of diving has also increased. As a result, we now can accurately diagnose and successfully treat many of these injuries. Of the commercial and sport divers examined as patients in the Department of Otolaryngology at the University of Texas Medical Branch in Galveston, Tex., between September, 1974, and May, 1975, 11 showed positive otologic and otoneurologic findings which are reported herein. One patient was surgically explored for an oval window fistula. In localizing and classifying these injuries, we have utilized extensive and broad-based test batteries, which include complete history, otologic and otoneurologic physical examination, audiometry, a central auditory test battery, and a vestibular test battery. These tests are described. The findings in each of the divers are illustrated and analyzed. This article further describes the use of these test batteries, which were employed to localize otoneurologic pathology in this sample of injured divers. Based on these cases, we have expanded and modified Edmonds' classification of the etiology of vertigo related to diving. We feel that the test batteries which we describe, or similar tests, should be part of the otologic and otoneurologic workup of injured divers. Index terms are: 1. central auditory tests; -2. oval window rupture; 3. diving injuries; and 4. vestibular test battery     

Synthesis of new [1,3,4]thiadiazolo[3,2-a]thieno[2,3-d]pyrimidinone derivatives with antiinflammatory activity

New thiadiazolothienopyrimidinones were synthesized in continuation of efforts to prepare thienopyrimidine derivatives with analgesic and antiinflammatory activities. In this study, the effect of various substituents in the thiophene ring on the pharmacological activity of the compounds was investigated.     

Voice onset time, frication, and aspiration during stutterers' fluent speech

The purpose of this study was to investigate voice onset time (VOT) and durations of frication and aspiration in stutterers' fluent speech. Broadband wound spectrograms were used to measure five adult stutterers' and five adult normally fluent controls' VOT, frication and aspiration durations during fluent productions of 18 word-initial sounds or sound clusters. Results indicate that stutterers' mean VOT for six of the 18 sounds/sound clusters (/p b br pr tw bl/) was significantly different from that of normally fluent speakers. VOT values for four of these 18 sounds/sound clusters (/b bl p tw/) could, to a moderate degree, be predicted from knowledge of whether a subject is a stutterer or a normally fluent speaker. With one exception, aspiration duration for /tw/, stutterers were not significantly different from normally fluent speakers in terms of frication and aspiration durations. These results suggest that stutterers' VOT during fluency is within normal limits and as such is of small assitance in distinguishing between stutterers and normally fluent speakers.     

Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel

The focus of this paper is a case study of a woman in the first trimester of pregnancy who presented with metastatic breast cancer. The bony spread of the metastases was rapid and it was necessary to treat the patient as soon as possible after the period of organogenesis (days 18–60 of human gestation). This stage is the phase of greatest sensitivity of teratogens and the malformations are observed most often. Yet, the choice of third-line chemotherapy was difficult because of anthracycline-resistant metastatic breast cancer. The world literature reported cytotoxic combinated regimens as the standard of care for the management of the metastases. The development of new antitumoral strategies with less toxicity and their encouraging results led us to the approval of docetaxel for the treatment of the patient even though it had never been tested in pregnancy. Docetaxel is a potent inhibitor of microtubule depolymerization and has a unique ability to alter certain classes of microtubules. The monochemotherapy was administered once every 3 weeks for a total of three cycles until 30 weeks of gestation. During the 32nd week of pregnancy the patient delivered a female infant whose birthweight and Apgar score were normal. The infant did not have any anomalies. The woman finished her treatment in puerperium and she received three cycles of docetaxel. The patient has been receiving vinorelbine (one cycle every 2 weeks) for 2 years; her last follow-up was good and showed that the progression of the metastases had stopped. The daughter's psychophysical development was normal.     

Effect of celioscopic ovarian resection in patients with polycystic ovaries

Ovarian resection was performed by means of celioscopy in 12 patients with polycystic ovaries (PCO), who had not responded to clomiphene + HCG therapy. This therapy had induced ovulation in only 14% of 56 therapeutic cycles. Ovarian resection through celioscopy induced ovulation in 45% of cycles. Clomiphene + HCG therapy after resection in patients with no spontaneous ovulation induced ovulation in 44% of cycles. Seven pregnancies followed in 5 women, equal to 41% of patients. Hormonal patterns (FSH, LH, E2, progesterone, dehydroepiandrosterone sulfate, testosterone) before and after resection showed no significant variation. The authors emphasize other advantages of this technique, such as fewer surgical injuries than laparotomy, relative harmlessness of the treatment, the possibility of repeating it and of performing subsequent laparotomy.     

Adenosine signalling in airways

Current research endeavours indicate that adenosine elicits strong inflammatory responses in the lung and might be involved in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and chronic obstructive pulmonary disease (COPD). The contribution of adenosine-associated effector mechanisms to the initiation, persistence and progression of the inflammatory response is highly heterogeneous and is dictated by the expression pattern of four different adenosine receptors. Selective activation or blockade of these sites can therefore be exploited in an attempt to generate novel therapies for asthma and COPD. In addition, an important development is the use of adenosine (or AMP) as a diagnostic test for discriminating asthma from COPD, and as an accurate biomarker to monitor corticosteroid requirements in asthma. It is likely that therapies interfering with adenosine signalling in the airways will offer a considerable advance in the management of asthma and COPD.     

Effect of homocysteine lowering by 5-methyltetrahydrofolate on redox status in hyperhomocysteinemia

The endothelial dysfunction induced by hyperhomocysteinemia can be reversed by 5-methyltetrahydrofolate (5-MTHF) via homocysteine (Hcy) lowering. An additive antioxidant action of 5-MTHF has been suggested to ameliorate endothelial dysfunction through increased nitric oxide production and superoxide radical scavenging, independent of Hcy lowering. The aim of the study was to assess whether 5-MTHF affects the redox state in hyperhomocysteinemia. We examined the effect of 3 months of oral 5-MTHF treatment (15 mg/day) on the redox pattern in 48 hyperhomocysteinemic subjects compared to 24 untreated hyperhomocysteinemic subjects. By analysis of variance with repeated measures in the 72 subjects, 5-MTHF markedly decreased plasma total Hcy (p-tHcy; P = 0.0001) and blood-total glutathione (GSH; b-tGSH; P = 0.002). By multivariate linear regression in the treated subjects, p-tHcy changes from baseline to 3 months (adjusted by baseline p-tHcy levels) correlated only with changes in reduced cysteinylglycine (P = 0.001). The effects of treatment on Hcy lowering and GSH metabolism were greater in medium than in moderate hyperhomocysteinemia. In conclusion, high-dose 5-MTHF treatment for 3 months ensures marked Hcy lowering to normal values even in subjects with high Hcy levels, and should be the treatment of choice in medium hyperhomocysteinemia. Furthermore, 5-MTHF shows a favorable interaction with GSH metabolism.