Changing trends in anti-coagulant therapies. Are heparins and oral anti-coagulants challenged?

The conventional management of thrombotic and cardiovascular disorders is based on the use of heparin, oral anticoagulants and aspirin. Despite progress in the sciences, these drugs still remain a challenge and mystery. The development of low molecular weight heparins (LMWHS) and the synthesis of heparinomimetics represent a refined use of heparin. Additional drugs will continue to develop. However, none of these drugs will ever match the polypharmacology of heparin. Aspirin still remains the leading drug in the management of thrombotic and cardiovascular disorders. The newer antiplatelet drugs such as adenosine diphosphate receptor inhibitors, GPIIb/IIIa inhibitors and other specific inhibitors have limited effects and have been tested in patients who have already been treated with aspirin. Warfarin provides a convenient and affordable approach in the long-term outpatient management of thrombotic disorders. The optimized use of these drugs still remains the approach of choice to manage thrombotic disorders. The new anticoagulant targets, such as tissue factor, individual clotting factors, recombinant forms of serpins (antithrombin, heparin co-factor II and tissue factor pathway inhibitors), recombinant activated protein C, thrombomodulin and site specific serine proteases inhibitors complexes have also been developed. There is a major thrust on the development of orally bioavailable anti-Xa and IIa agents, which are slated to replace oral anticoagulants. Both the anti-factor Xa and anti-IIa agents have been developed for oral use and have provided impressive clinical results. However, safety concerns related to liver enzyme elevations and thrombosis rebound have been reported with their use. For these reasons, the US Food and Drug Administration did not approve the orally active antithrombin agent Ximelagatran for several indications. The synthetic pentasaccharide (Fondaparinux) has undergone clinical development. Unexpectedly, Fondaparinux also produced major bleeding problems at minimal dosages. Fondaparinux represents only one of the multiple pharmacologic effects of heparins. Thus, its therapeutic index will be proportionately narrower. The newer antiplatelet drugs have added a new dimension in the management of thrombotic disorders. The favorable clinical outcomes with aspirin and clopidogrel have validated COX-1 and P2Y12 receptors as targets for new drug development. Prasugrel, a novel thienopyridine, Cangrelor and AZD 6140 represent newer P2Y12 antagonists. Cangrelor and AZD 6140 are direct inhibitors, whereas Prasugrel requires metabolic activation. While clinically effective, recent results have prompted a closure of a clinical trial with Prasugrel due to bleeding. The newer anticoagulant and antiplatelet drugs are attractive, however, none of these are expected to replace the conventional drugs in polytherapeutic approaches. Heparins, warfarin and aspirin will continue to play a major role in the management of thrombotic and cardiovascular disorders for years to come.

Adsorption of cadmium on anatase nanoparticles-effect of crystal size and pH.

The adsorption and desorption of Cd(2+) to large and nanometer-scale anatase crystals have been studied to determine the relationship between heavy metal adsorption properties and anatase particle size. A solvothermal method was used to synthesize very fine anatase nanocrystals with average grain sizes ranging from 8 to 20 nm. On a surface area basis, it was found that large and nanometer-scale anatase particles had similar maximum Cd(2+) adsorption capacities, while their adsorption slopes differed by more than 1 order of magnitude. The particle-size effect on adsorption is constant over a pH range of 4-7.5. The desorption of Cd(2+) from both particle sizes is completely reversible. The adsorption data have been modeled by the Basic Stern model using three monodentate surface complexes. It is proposed that intraparticle electrostatic repulsion may reduce the adsorption free energy significantly for nanometer-sized particles.

Effect of film thickness on the performance of photopolymers as holographic recording materials.

An important issue in developing applications for photopolymers in holography is the effect of film thickness on recording properties. Now it is possible to create these samples with a much wider range of thickness (d = 20-1400 mum) than was previously available. We exploit these recent advances in photopolymer processing to systematically evaluate how the dynamic range of a photopolymer depends on its thickness. The results illustrate that sample performance increases linearly with thickness as predicted by standard models of volume holography. However, above a critical thickness sample performance degrades, and the angular response of recorded plane-wave holograms shows evidence of grating curvature. These distortions are likely the result of photopolymer shrinkage, which in thicker samples occurs in a nonuniform fashion. This problem limits the performance of these photopolymers and is likely to be an issue for any photopolymer that undergoes comparable polymerization shrinkage.

Aortic valvoplasty for traumatic aortic insufficiency: a 2-year follow-up.

A 23-year-old man sustained acute rupture of an aortic valve cusp in a motorcycle accident. We repaired the valve using an autologous pericardial patch. A 2-year follow-up two-dimensional echocardiogram and Doppler study show completely normal appearance and function.

Determinants of perioperative morbidity and mortality after pneumonectomy.

A total of 197 consecutive patients undergoing pneumonectomy at the M.D. Anderson Cancer Center from 1982 to 1987 were reviewed. Sixty-five variables were analyzed for the predictive value for perioperative risk. The operative mortality rate was 7% (14/197). Patients having a right pneumonectomy (n = 95) had a higher operative mortality rate (12%) than patients having a left pneumonectomy (1%, p less than 0.05). The extent of resection correlated with the operative mortality rate (chest wall resection or extrapleural pneumonectomy, n = 39, 15%; versus simple or intrapericardial pneumonectomy, n = 158, 5%; p less than 0.05). Patients whose predicted postoperative pulmonary function, by spirometry and xenon 133 regional pulmonary function studies, was a forced expiratory volume in 1 second greater than 1.65 L, forced expiratory volume in 1 second greater than 58% of the preoperative value, forced vital capacity greater than 2.5 L, or forced vital capacity greater than 60% of the preoperative value had a lower operative mortality rate (p less than 0.05). Atrial arrhythmia was the most common postoperative complication (23%). Xenon 133 regional pulmonary function studies are useful in predicting the risks of pneumonectomy.

Effect of graded doses of iodide on thyroid hormones in intact, thyroxine-treated and hypophysectomized rats.

480 albino rats were used in the present study to see the effect of graded doses of iodide (low dose 10 micrograms/kg B. W. and high dose 1 mg to 30 mg/kg B. W.). On thyroid hormone status in intact, T4 treated and hypophysectomized rats. Serum free thyroxine and resin T3 uptake were estimated to assess thyroid function. Serum free thyroxine was calculated by multiplying serum total thyroxine and percentage free thyroxine. Low dose of iodide in case of 1) intact rats did not produce any change in thyroid status; 2) T4 treated rats showed significantly lower levels of serum free T4 and resin T3 uptake; 3) hypophysectomized rats exhibited extremely low levels of thyroid hormones. High dose of iodide in intact rats produced a low level of thyroid hormones and high dose iodide in T4 treated rats produced a hyperthyroid state. The result showed that iodide inhibition or stimulation at thyroid level depends upon the state of thyroid and the dose of iodide used.

Oxytocin release and plasma anterior pituitary and gonadal hormones in women during lactation.

Serial plasma oxytocin (OT), PRL, TSH, FSH, LH, estrone, estradiol, and progesterone were measured by RIA in 12 women before and during a 30-min breast-feeding period on the third or fifth postpartum day. Plasma OT increased significantly from 10.8 +/- 3.4 to 22.4 +/- 3.5 pg/ml (mean +/- SE) within 2 min of suckling (P = less than 0.05) to reach the mean peak level of 53.2 pg/ml at 10 min. The increase in plasma OT was bimodal. Plasma PRL and TSH also increased significantly from baseline levels of 192 +/- 39 ng/ml and 16.9 +/- 5.6 microU/ml, respectively, to reach maximum levels of 427 +/- 91 ng PRL/ml at 10 min (P = less than 0.025) and 281.5 +/- 56.6 microU TSH/ml at 25 min (P = less than 0.005). Plasma FSH-beta (range of means, 3.5-4.6 ng/ml), LH (range of means, 1.7-2.6 mIU/ml), and estradiol (range of means, 29.8-38.2 pg/ml) were low and remained unchanged throughout breast feeding. Plasma progesterone was 6.0 +/- 0.4 ng/ml before breast feeding and did not alter significantly during breast feeding. The significance of these findings is discussed in relation to the milk let-down reflex and the relationship of TSH to PRL.

Normal levels of norepinephrine in short term hypothyroidism.

Plasma epinephrine and norepinephrine levels were measured in four cases of short term hypothyroidism which developed after parturition. For comparison, six patients with idiopathic hypothyroidism were included in the study. Hypothyroidism was confirmed by clinical evaluation and tests of thyroid function, viz. serum T3, T4, free T4, and TSH. In all patients with idiopathic hyperthyroidism, epinephrine levels were normal and norepinephrine levels were significantly elevated. In the four patients with short term hypothyroidism, normal levels of epinephrine as well as norepinephrine were observed. Circulating thyroid hormone levels start increasing after 6--9 months in patients with short term hypothyroidism reaching euthyroid levels after 1 yr. The present results indicate that plasma norepinephrine concentrations in hypothyroidism seem to be significantly increased only after a lag period of some 6--9 months.