ENEA extremity dosemeter based on LiF(Mg,Cu,P) to evaluate Hp(3,alpha).

Recent epidemiological studies suggest a rather low-dose threshold (<0.5 Gy) for the induction of a cataract of the eye lens. Some other studies even assume that there is no threshold at all. Therefore, protection measures have to be optimised and current dose limits for the eye lens may be reduced in the future. ICRP Publication 103 on H(p)(d), in §(136), reads that '… a depth d = 3 mm has been proposed for the rare case of monitoring the dose to the lens of the eye. In practice, however, H(p)(3) has rarely been monitored and H(p)(0.07) can be used for the same monitoring purpose… '. As recommended on the EU 'Technical recommendations for monitoring individuals occupationally exposed to external radiation', a test on the ENEA TL extremity dosemeter is herein reported. The results within the actual EU founded Optimization of RAdiation protection for MEDical staff (ORAMED) Project, whose WP2 is aimed at the quantity H(p)(3) and eye lens dosimetry in practice, are taken into account. The paper summarises the main aspects of the study carried out at ENEA-Radiation Protection Institute (Bologna, Italy) to provide practical solutions (in the use and the design) to evaluate the response of the ENEA TL extremity dosemeter in terms of H(p)(3).

Conformational search of antisense nucleotides.

A preliminary MMFF implementation of selenium atom parameters necessary to model the nucleoside 1 is reported. X-ray structures of two compounds 1 and 2 have been used as references. Ab initio methods have been adopted for checking torsional energy profile and charge distribution. Monte Carlo calculations and energy minimization in solvation complete the conformational search.

Novel hypotensive agents from Verbesina caracasana. 8. Synthesis and pharmacology of (3,4-dimethoxycinnamoyl)-N(1)-agmatine and synthetic analogues.

The more polar metabolites from the Venezuelan plant Verbesina caracasana, i.e., N(3)-prenylagmatine, (3,4-dimethoxycinnamoyl)-N(1)-agmatine, agmatine, and galegine (prenylguanidine), previously reported (Delle Monache, G.; et al. BioMed. Chem. Lett. 1999, 9, 3249-3254), have been synthesized following a biosynthetic strategy. The pharmacologic profiles of various synthetic analogues of (3,4-dimethoxycinnamoyl)-N(1)-agmatine (G5) were also analyzed, to shed some light on the structure-activity relationship of these compounds. Derivatives with the (E)-configuration and/or with a p-methoxybenzoyl moiety were found to be responsible for higher hypotensive effects, which were associated with a slight and, in some cases, not dose-related increase of cardiac inotropism, with variable and not significant chronotopic responses, and, only at higher doses, with effects of respiratory depression. Either an increase (to six) or a decrease (to two) of the number of methylene groups in the alkyl chain of (E)-G5 did not change blood pressure responses, while slightly increasing the positive inotropic ones. At pharmacological doses, all the studied compounds showed hypotensive and slight positive inotropic effects without relevant chronotropic and respiratory actions.

Phase II study of vinorelbine with protracted fluorouracil infusion as a second- or third-line approach for advanced breast cancer patients previously treated with anthracyclines.

PURPOSE: To evaluate the feasibility and activity of vinorelbine in association with protracted infusional fluorouracil in patients with advanced breast cancer who were previously treated with anthracycline-containing regimens. PATIENTS AND METHODS: Eighty-three consecutive patients were entered onto the study. Forty-three patients experienced treatment failure or relapse after anthracycline-based, first-line chemotherapy for advanced disease and 29 experienced treatment failure or relapse after first- and second-line approaches; 11 patients experienced progressive disease within 6 months of completion of adjuvant anthracycline therapy. Sites of involvement were as follows: liver involvement, 42 patients (50.6%); lung 24 (28.9%); bone, 49 (59.0%); and skin/lymph nodes, 21 (25.3%). Treatment consisted of vinorelbine 30 mg/m(2) administered on days 1 and 15 every 28 days and fluorouracil 200 mg/m(2)/d given continuously over a 24-hour period. RESULTS: Toxicity was recorded for 441 cycles. The scheme was well tolerated: grade 1/2 nausea/vomiting occurred in 13 patients (15.6%), grade 1/2 diarrhea in nine (10.8%), and grade 2/3 stomatitis in six (7.2%). Three patients (3.6%) experienced grade 3/4 leukopenia and four (4.8%) experienced grade 2/3 anemia. Grade 2/3 neurologic toxicity was observed in three cases (3.6%), and grade 2/3 hand-foot syndrome was observed in three (3.6%). The median relative dose-intensity was 92% and 100% for vinorelbine and fluorouracil, respectively. Six patients (7.2%) attained a complete clinical response and 45 (54.2%) attained a partial response, for an overall response rate of 61.4% (95% confidence interval, 50.9% to 71.9%). Twenty-one patients (25.3%) obtained disease stabilization, and 11 (13.3%) experienced disease progression. Median time to progression in responding patients was 15 months; median overall survival of the entire population was 22 months. CONCLUSION: Vinorelbine associated with protracted infusional fluorouracil is an active and manageable scheme in advanced breast cancer patients previously treated with anthracyclines. The response obtained is durable.

Synthesis and preliminary biological evaluation of 4,6-disubstituted 3-cyanopyridin-2(1H)-ones, a new class of calcium entry blockers.

The preparation of 3-cyano-4,6-diaryl-pyridin-2(1H)-ones 4a-h, calcium entry blockers related to diltiazem, is described starting from 1,3-diaryl-2-propen-1-ones 5. On preliminary pharmacological tests all compounds are active and some of them show calcium antagonistic activity superior or comparable to diltiazem.

Novel hypotensive agents from Verbesina caracasana. 6. Synthesis and pharmacology of caracasandiamide.

Caracasandiamide, a second hypotensive agent isolated from Verbesina caracasana, is the cyclobutane dimer (truxinic type) of the previously reported 1-[(3, 4-dimethoxycinnamoyl)amino]-4-[(3-methyl-2-butenyl)guanidino]butane (caracasanamide) (Delle Monache, G.; et al. BioMed. Chem. Lett. 1992, 25, 415-418). The structure was confirmed by synthesis starting from beta-truxinic acid obtained by photoaddition of 3, 4-dimethoxycinnamic acid. The dimer was coupled with 2 mol of prenylagmatine to give caracasandiamide in satisfactory yield. By contrast, the direct photodimerization of caracasanamide was unsuccessful. Caracasandiamide, assayed by the iv route in anesthetized rats at doses ranging from 50 to 3200 microgram/kg of body weight, was found to have no appreciable effect on heart rate. At lower doses, the drug stimulates breathing and increases cardiac inotropism, stroke volume, and cardiac output, thus augmenting blood pressure and aortic flow. At higher doses, caracasandiamide depresses breathing likely through central neurogenic mechanisms (not involved in the cardiovascular effects), continues to stimulate cardiac inotropism, and induces, by reducing peripheral vascular resistance, arterial hypotension with reduction of both aortic flow and stroke volume. These cardiovascular effects appear to involve complex interactions at the level of the peripheral beta(1)-, beta(2)-, and alpha(2)-adrenoreceptor-dependent as well as M(2)- and M(4)-cholinergic receptor-dependent transductional pathways both in cardiovascular myocells and at the level of the postganglionic sympathetic endings (with reserpine- and guanethidine-like mechanisms). The cardiovascular effects of caracasandiamide, different from those of caracasanamide, do not depend on significant actions on the central nervous system and on baroreflex pathways. In a similar manner and more effective than caracasanamide, caracasandiamide may be considered a hypotensive and antihypertensive drug. It is devoid of some of the negative side effects, e.g., reflex tachycardia and decreased cardiac inotropism, which are shown by the majority of the most common antihypertensive and vasodilator drugs.

Novel hypotensive agents from Verbesina caracasana. 2. Synthesis and pharmacology of caracasanamide.

Caracasanamide, one of the hypotensive agents isolated from Verbesina caracasana, is a mixture of (Z)-1a and (E)-1b forms of 1-[(3,4-dimethoxycinnamoyl)amino]-4- [(3-methyl-2-butenyl)-guanidino]butane. The structure of (E)-caracasanamide (1b) was confirmed by high-yielding synthesis starting from N,N'-bis(tert-butoxycarbonyl)-S-methylisothiourea. The water-soluble Z-form of 1a, assayed by i.v. route in anesthetized rats at doses ranging from 50 to 1600 micrograms/kg body weight, was found to decrease blood pressure, to increase cardiac inotropism, respiratory frequency, and tidal volume, and to induce a very slight and not significant tachycardia. Higher doses determined respiratory depression and, in some cases, consequent cardiac arrest. The compound was shown to affect cardiovascular function by acting at the vascular level in inducing arterial vasodilation, by determining sympathetic hypotone through central neurogenic mechanisms, and by interacting with the cardiac beta 1-adrenoreceptors. The respiratory effects were independent of the cardiovascular ones. In lowering blood pressure, the compound was more potent than guanethidine and not less potent than reserpine and papaverine. (Z)-Caracasanamide may therefore be useful in the treatment of arterial hypertension of moderate degree.

Inhibition of adenosine 3',5'-cyclic monophosphate phosphodiesterase by flavonoids from licorice roots and 4-arylcoumarins.

Isoliquiritigenin, glabridin, licoarylcoumarin and licoricidin were identified as strong inhibitors of adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase in waste materials which were obtained during the industrial extraction of glycyrrhizin from licorice roots. The structure-activity relationships of 12 flavonoids from licorice roots and 34 4-arylcoumarins were studied. In 4-arylcoumarins, 5,7-dihydroxy derivatives were generally highly inhibitory towards cAMP phosphodiesterase.

[Clinical observations on the treatment of ischemic cardiac disease with a calcium antagonist: nifedipine]. / Osservazioni cliniche sul trattamento della cardiopatia ischemica con un calcio-antagonista: la Nifedipina.

Results obtained wih Nifedipine in 146 coronary patients, 85 of them suffering from coronaro-sclerosis with rest and effort stenocardic attacks, and 61 with post-infarctual stenocardic signs, are reported. In 76% of patients in the first group and in 85% of those in the second, pain symptomatology disappeared rapidly; ECGs also showed attenuation and modification, particularly among angina patients. The drug also led to a reduction in hypertension.