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The role of heart rate (HR) as an independent predictor of cardiovascular morbidity and mortality remains controversial. Direct evidence supporting a causal association between HR and prognosis is still lacking even if such relation appears plausible and may be inferred from epidemiological studies and clinical trials with HR lowering agents. The introduction of If current blocking agents, namely ivabradine, has offered the novel and unique opportunity to directly and exclusively interfere with HR and, thus, to validate the presence of a causal relationship between HR and prognosis. The BEAUTIFUL trial has recently confirmed that HR is a powerful negative prognostic predictor in patients with coronary artery disease and left ventricular systolic dysfunction. Particularly, subjects with a resting HR >70 b/min showed an increased risk of major adverse cardiovascular events. In these patients, HR reduction with ivabradine was associated with a reduction in major cardiac ischemic events, though not mortality. Further data will become available with the SHIFT trial in which patients with heart failure and HR > or =70 b/min are included and reduction in cardiovascular mortality and heart failure hospitalizations is the primary endpoint.

Aim: Levobupivacaine, a new local anaesthetic, has been recently introduced into clinical practice because of its lower toxic effects for heart and central nervous system. It has been already investigated in epidural and loco-regional techniques, but more has to be known regarding its characteristics in spinal anaesthesia. The aim of our study was to compare clinical and anaesthetic features of levobupivacaine and racemic bupivacaine when intrathecally administered in 60 patients undergoing major orthopaedic surgical procedures., Methods: Three ml of glucose-free levobupivacaine 0.5% (group L) or 3 ml of isobaric bupivacaine 0.5% (group B) were administered in 30 patients each. Sensory and motor blockades were evaluated by the pinprick test and a modified Bromage score, respectively. Vital parameters, postoperative VAS and rescue analgesia were recorded as well., Results: No statistically significant differences between groups were observed either in anaesthetic potencies or postoperative pain. Either heart rate or mean arterial pressure slightly decreased in both groups, with no preoperative significant differences. Nevertheless, spinal puncture was accompanied by severe hypotension and bradycardia in 2 patients of group B. In both cases, hemodynamics were promptly and successfully treated, with no sequelae., Conclusions: In conclusion, levobupivacaine results a valid alternative to racemic bupivacaine for spinal anaesthesia, the latter remaining a cheap and effective local anaesthetic yet. Notwithstanding the complete absence of any significant hemodynamic complications in the patients of group L, further and larger studies are needed in order to assess if levobupivacaine is preferable to bupivacaine for minimizing the possible cardiovascular impact of spinal anaesthesia.

Background: To compare clinical profiles of levobupivacaine, racemic bupivacaine and ropivacaine at equipotent doses in axillary brachial plexus block in the orthopaedic surgery of wrist and hand., Methods: For this prospective, open randomised study we took on 45 patients of both sexes, ASA I-III, subdivided into three groups in which, respectively, axillary brachial plexus block was performed, with ENS, using levobupivacaine 0.50% (1 mg/kg), racemic bupivacaine 0.50% (1 mg/kg) and ropivacaine 0.75% (1.4 mg/kg). The onset of sensory and motor block, their duration, onset of surgical block, anaesthetic plane and possible adverse events were recorded., Results: The duration of sensory block was longer in group of patients treated with levobupivacaine than in two other groups. Surgical onset was similar for levobupivacaine and ropivacaine, but it was delayed for racemic bupivacaine. In group of patients who received racemic bupivacaine, two episodes of reduction in heart rate without significant hypotension have been observed. The anaesthetic plan was satisfactory in the all three groups of patients., Conclusions: In our experience levobupivacaine has been demonstrated to be a good substitute for racemic bupivacaine. Compared to ropivacaine, levobupivacaine induces a longer duration of postsurgery analgesia and, in our opinion, this datum seems to be the most significant.

The rate and extent of passive pharmacokinetic processes, such as passive gastrointestinal absorption, tissue distribution and glomerular filtration, depend on the physical-chemical properties of a drug. In the case of chiral drugs, since enantiomers have the same properties, in general we would not expect passive processes to be stereoselective. On the contrary, enantioselectivity would occur for processes involving a drug interaction with a chiral macromolecule (e.g. receptors, enzymes, transport proteins), like the carrier-mediated absorption, protein binding, active renal and biliary secretion, metabolism. However, a few exceptions aside, the degree of stereoselectivity of these processes is relatively modest. In this paper we reviewed several examples of stereoselective kinetic processes and discussed the limits of the interpretation of pharmacokinetic data resulting from the application of non-stereospecific analytical methods.

Chronic lymphoproliferative disorders are extremely heterogeneous from a clinical, morphological and immunological point of view. The paper reports the case of a woman with chronic prolymphocytic leukemia. The neoplastic clone revealed the typical immunological features of pre-B lymphocytes, which are at an earlier stage of differentiation in respect to prolymphocytes. After polychemotherapy (CEOP) the phenotype of the neoplastic cells shifted to an immunological pattern typical of B lymphocytes.

Thirty out-patients, age ranging from 22 to 64 years (mean 49.20 +/- 1.71 SE) diagnosed according to DSM III-R, were studied to evaluate clinical efficacy and tolerability of L-sulpiride (L-SLP) vs racemic sulpiride (SLP) in the treatment of somatoform disorders. After one week of placebo treatment, not responders were treated under double blind conditions with L-SLP (150 mg po/die) (group 1) or with SLP (300 mg po/die) (group 2) for three weeks. A placebo week followed the treatment. Clinical picture and side-effects were evaluated at the beginning of the study and then weekly using the Lipman scale for somatoform disorders (SCL), the Hamilton rating scale for anxiety (HRS-A), the EPSE for extrapyramidal side-effects and a check list for anticholinergic side-effects (ACS). Haematochemical routine, ECG and EEG were controlled at the beginning and at the end of the study. All patients showed a significant improvement (p less than 0.01 for group 1, p less than 0.05 for group 2) at the SCL from the first week of treatment. Patients treated with L-SLP showed a significant improvement (p less than 0.01) of HRS-A since the first week of treatment, while group 2 showed it since the second week. Extrapyramidal and anticholinergic side-effects were more frequent in group 2. This study seems to confirm the useful use of L-SLP in somatoform disorders; clinical and tolerability data point out that this isomer is more potent than the racemic compound, with less side-effects.

The use of loratadine was compared to dexchlorpheniramine in the treatment of children affected by perennial allergic rhinitis in order to assess its clinical efficacy and tolerability. Children were randomly assigned to two groups: 15 were treated with loratadine and 16 with dexchlorpheniramine. Loratadine was administered in a single daily dose of 5 mg (2.5 mg for children under 20 kg) and dexchlorpheniramine at a dose of 1 mg every 8 hours (0.5 mg for the youngest children). Clinical symptoms were recorded before and during the study using a score of 0.3 (from absent to severe). Symptoms were markedly reduced by both drugs. Eye burning was reduced more by loratadine (p less than 0.05) than the control drug. Rhinoscopic investigations revealed that both groups reacted favourably to the drugs used. Overall clinical assessment showed similar and revealed the good efficacy of both drugs. Tolerability was satisfactory and there were no signs of drowsiness. Hematological and hematochemical parameters showed no clinically significant changes and body weight remained constant. On the basis of these results, loratadine is preferable to dexchlorpheniramine thanks to its once-a-day dosing.

Baclofen (Lioresal), a muscle relaxant, exerts a specific action on the trigeminal system by depressing excitatory synaptic transmission in the spinal trigeminal nucleus. To evaluate the effects of racemic and L-baclofen on the human trigeminal reflexes, the area of the blink reflex was measured in seven normal subjects, before and after i.v. administration of racemic baclofen (25 mg.) and oral administration of L-baclofen (15 mg.). The blink reflex is a trigeminal facial reflex consisting of two components (R1 and R2): R1 has a shorter latency and is mediated by an oligosynaptic pontine circuit; R2 has a longer latency and is believed to be relayed via a polysynaptic circuit through the lateral bulbar reticular system. Whereas the R1 response was scarcely affected by administration of racemic baclofen, it was significantly reduced by L-baclofen (P less than 0.01). R2 was depressed by both drugs (P less than 0.01). These results indicate that both racemic and L-baclofen inhibit trigeminal transmission in man, probably because they interfere with excitatory transmission through the interneurons of the lateral reticular formation. In addition, since L-baclofen reduced both R1 and R2 this form of the drug presumably has a more powerful effect than its racemic counterpart, on the few interneurons of the short latency component.

Some results on the chiroptical properties of 2,4-dinitrophenylaminoacids reported in the literature, have been re-examined since they were in disagreement with our earlier research. Extension of this research to several sympathomimetic amines, demonstrates that the chiroptical properties of these derivatives show coherent behaviour; as a consequence the absolute configuration of the amino compounds condensed with Sanger reagent can be correlated to the sign of their higher wavelength Cotton effect.

The effects of d-Sulpiride (25 mg i.v.) and 1-Sulpiride (25 mg i.v.) administration in the control of arterial blood pressure (ABP) and PRL-GH secretion have been analyzed in five normal male volunteers. It was observed a quite different action on ABP, 1-Sulpiride causing a long lasting hypotension and d-Sulpiride a short-lived hypertension. The correlation between ABP, heart rate and PRL-GH levels suggests a probable central cation for 1-Sulpiride and a possible peripheral action for d-Sulpiride effects on ABP.

Among the biologically active metabolites produced by Streptomyces peucetius adriamycin (syn. doxorubicin) appeared the most effective anthracycline. Because of the low yield of the biosynthetic process, the chemical conversion of daunorubicin to adriamycin represent the key-step of the development of the drug. The therapeutic importance of adriamycin prompted us to begin since 1972 a research program aimed to the development of the second generation anthracyclines. The studies carried out during this research program allowed to discover three new synthetic anthracyclines, which, for the time being, are under clinical investigation: 4'- epidoxorubicin ( epirubicin ), 4-demethoxydaunorubicin ( idarubicin ) and 4'-deoxydoxorubicin ( esorubicin ). These compounds, like daunorubicin and doxorubicin, show affinity to DNA, but some of their pharmacological properties and metabolism in animals as well as in humans are different in respect to those of the parent drugs. Herein the stages of the search for new analogs and the outlooks of further progress in the filed of the antitumor anthracyclines are shortly reported.

In DOCA-pretreated men during hypotonic polyuria Dopamine (DA) infusion in a subpressor dosage (0.1 microgram X kg -1 X min -1) produces renal hyperemia, inhibition of isosmotic sodium reabsorption, increase in sodium distal load (s. d.l.) and finally inhibition of anisosmotic sodium reabsorption as a percentage of s.d.l. Such DA effects are variously modified by sulpiride isomers. Sodium distal load increase is still apparent in the presence of racemic, but not in the presence of either d- or l-Sulpiride isomers. However DA inhibition of anisosmotic sodium reabsorption % s.d.l. is unaffected by either or both Sulpiride isomers. If the DA tubular inhibition was dependent on specific DA receptors these receptors, unlike vascular DA receptors, would bind in a weaker way both d- and l-Sulpiride isomers.

After a rapid examination of the international literature concerning human, animal, histological and epidemiological experimental data, the Authors state that the use of oral contraceptives considerably reduces the risk of benign disease of the breast. This risk reduction seems to be connected to the presence of progestin in this type of contraception. The Authors then expound the data regarding a group of patients (3527), who came to the center for the diagosis and prevention of cancer of the breast at the S. Martino hospital of Genoa during the years 1977-1980. The results of the study are comparable to those found in international literature, in that they confirm the protective effect of hormonal contraception on benign pathology of the breast. Finally we have shown the data of the retrospective and prospective studies conducted up till now on the effects of hormonal contraception on malignant breast pathology. In conclusion we have shown which lines of study should be taken in order to clarify once and for all the links existing between estroprogestins and cancer of the breast.

The effect of Adriamycin and 4-Eip-Adriamycin was studied on CFUs, CFUc, CFUe of murine bone marrow and spleen. Differences among the bone marrow stem cells and the spleen stem cells have been observed. It seems possible to explain some of these differences admitting a process of redistribution from the bone marrow to the spleen.

In the present study some observations about the effects of stereochemically different fatty acids on cholesterolaemia are reported. It is well known that high in EFA diets are useful for cholesterol metabolism: in fact cholesterol is preferably esterificated by EFA. Because of the increasing intake of fats, as high in hydrogenated EFA margarines, it has been verified whether such a technological process, inducing structural modifications, affects or not the ipocholesterolemic effect of EFA, particularly linoleic acid. Actually this research has shown such an effect to fail in presence of trans fatty acids and has pointed out some implications of lipid metabolism which are related to the different stereochemical configurations.

The synthesis of the (+/-) 3-(4-biphenylyl)-3-hydroxybutanoic, pentanoic, hexanoic and isohexanoic acids, and their resolution in to enantiomers are described. The latter were submitted to preliminary assay for antiinflammatory activity: interesting results were obtained above all for the isohexanoic acid derivative.

Renal effects of Dopamine (DA, subpressor dosage 0.1 microgram X kg -1 X min -1) during hypotonic polyuria in moderate hydro-saline retention are variously modified by either d- or l-Sulpiride isomers. In the presence of d-Sulpiride, DA effects, such as an increase in diuresis, free water clearance (CH20) and kaliuresis are suppressed, while increases of saluresis and natriuresis are significantly blunted. In the presence of l-Sulpiride no changes are observed in both saluresis and natriuresis, while decreases occur in diuresis, CH20 and kaliuresis. The inhibitory DA effects on isosmotic sodium reabsorption as a percentage of sodium filtered load are prevented by either isomer as well. A possible role of ineffective renal vascular DA action can be involved in such defective tubular inhibition. However is also suggested a pharmacological blockade of proximal tubular specific DA receptors.

The synthesis of some homologues of 2-(4-biphenylyl)-3-hydroxypropionic acid, the separation of related diastereoisomers, their attribution to erythro and threo series, and resolution of the optical antipodes are described. The antiinflammatory activity--initially tested by carrageenin assay--proves generally influenced by steric configuration and is interesting for the isohexanoic derivative.

The sterical requirements of dopamine (DA) receptors involved in the control of prolactin (PL) secretion have been analyzed by studying the effects of the administration of d- and l-sulpiride (25 mg i.v.) on PL serum levels in five normal male volunteers. Both d- and l-sulpiride cause a remarkable rise in PL serum levels, the only difference between the two drugs being the lower decay rate of hormone levels after the l-isomer. The results obtained are discussed in the frame of a possible low steric selectivity of DA receptors controlling PL secretion in the hyposthalamo-pituitary axis.

This communication deals with the evaluation of the muscarinic activity (rat jejunum) of eight heterocyclic (dioxolane, oxathiolane, tetrahydrofuran) derivatives which constitute four couples of cis-trans isomers. The data on the observed stereoselectivity are referred.

The synthesis, diastereoisomeric separation, attribution to erythro and threo series, and resolution of the enantiomers of 2-(4-biphenylyl)-3-oxybutyric acid are described. The four isomers were tested for anti-inflammatory activity: the preliminary results are interesting, particular those for the (--) erythro enantiomer.

Interaction of sulpiride - both 1- and d- isomers as well as racemic- - with Dopamine (DA, subpressor dosage 0.1 microgram X kg -1 X min -1), on the renal hemodynamic, was studied in DOCA-pretreated men during hypotonic polyuria. P.A.H. and creatinine clearance and renal vascular resistances were determined. In the presence of d-Sulpiride, DA - induced renal vasodilation is carried out gradually and finally reaches similar levels as in the absence of d-Sulpiride. However no glomerular filtration rate increase is produced by DA. In the presence of 1-Sulpiride, DA vasodilating effect is suppressed. On the contrary a trend toward ischemia and a reduction in glomerular filtration rate becomes finally apparent. Stronger binding of 1- than d-Sulpiride with vascular DA receptors in suggested. When both isomers are simultaneously administered (at the nearly total dosage) much less inhibitory effect on DA vasodilator action is observed: it seems that each isomer decreases the affinity on the other isomer for vascular DA receptors.

The synthesis and the resolution of the enantiomers of (+/-)2-(4-biphenylyl)-4-oxybutyric and (+/-)4-(4-biphenylyl)-2-oxybutyric acids and the resolution of the enantiomers of (+/-)2-(4-biphenylyl)-2-oxybutyric and (+/-)4-biphenylylglycolic acids are described. The potassium salts of each enantiomer were submitted to preliminary assays of antiphlogistic activity.