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Paget's disease of bone is a chronic disorder of unknown etiology that can result in enlarged and misshapen bones. The excessive breakdown and formation of bone tissue cause affected bones to weaken, resulting in pain, misshapen bones, fractures, and arthritis in the joints. In most cases the diagnosis is achieved casually, as only 5% of patients develop burning pain at the level of affected bones. As regards therapy, the use of anti-reabsorbing drugs, such as bisphosphonates and calcitonin, appears reasonable. Given the disease pathogenesis, the administration of denosumab and tocilizumab may be a valuable alternative to inhibit RANK expression, and thus osteoclast formation, and interleukin-6 production.

Serenoa repens (SeR) is frequently associated with other natural compounds, such as lycopene (Ly), a carotenoid, and selenium (Se), an essential trace element, to increase its therapeutic activity in benign prostatic hyperplasia (BPH). The LY-Se-SeR association has a greater and stronger anti-inflammatory activity than SeR alone. In addition, the LY-Se-SeR combination is more effective than SeR alone in reducing prostate weight and hyperplasia, augmenting apoptosis, and reducing cell proliferation and growth factor expression. This experimental evidence suggests that Ly-Se-SeR association is superior to SeR alone in reducing benign prostate growth.

In recent years, new technologies have become available for imaging small animals. The use of animal models in basic and preclinical sciences, for example, offers the possibility of testing diagnostic markers and drugs, which is becoming crucial in the success and timeliness of research and is allowing a more efficient approach in defining study objectives and providing many advantages for both clinical research and the pharmaceutical industry. The use of these instruments offers data that are more predictive of the distribution and efficacy of a compound. The mouse, in particular, has become a key animal model system for studying human disease. It offers the possibility of manipulating its genome and producing accurate models for many human disorders, thus resulting in significant progress in understanding pathologenic mechanisms. In neurobiology, the possibility of simulating neurodegenerative diseases has enabled the development and validation of new treatment strategies based on gene therapy or cell grafting. Noninvasive imaging in small living animal models has gained increasing importance in preclinical research, itself becoming an independent specialty. The aim of this article is to review the characteristics of these systems and illustrate their main applications.

It was the purpose of the study to evaluate morcellized bone with cement and antibiotic release mixed with vancomycin and methylmethacrylate cement (PMMA). The aim of the study is part of a wider one aimed at verifying the possibility of using this composite for the treatment of chronic septic pathologies of the bone. Five cylinders 1 cm in height by 1 cm in diameter, formed by morcellized bone with cement and vancomycin were immersed in plasma and 5 in physiological solution. Three cylinders equal in size but formed by cement and antibiotic alone were immersed in plasma and 3 in physiological solution. All of the cylinders remained in immersion for 28 days at a temperature of 37 degrees C. The immersion fluids were changed every day during the first week and on days 14, 21 and 28. The quantity of vancomycin released was dosed in each specimen. The greatest and most constant release of antibiotic took place in the cylinders of morcellized bone, cement and antibiotic immersed in plasma.

The repellent and anti-feeding effect of garlic oil was evaluated in laboratory conditions against the bite of Phlebotomus papatasi females. The effectiveness was evaluated by two different laboratory procedures: (i) topical application of garlic oil on five human volunteers, using the "standard cage test", and (ii) feeding sandflies on artificial membranes treated with the compound. Garlic oil showed a significant protection by topical application on the skin of volunteers, being the protection 97% and 40%, respectively at 1% and 0.005% dilution. Garlic oil showed also an anti-feeding effect when tested on the artificial membrane feeding apparatus; the anti-feeding effect was dose dependent, being 100% at 1%. The results of the present study confirm previous observations on the repellent effect of garlic oil against haematophagous arthropods.

Plant kingdom has a wider biochemical diversity than animals and at least four-fifths of secondary metabolites come from vegetable world. This is probably due to the link between soil and plants, therefore these have to develop numerous adaptation mechanisms. To date, about 40% of modern monomolecular drugs derives directly or indirectly from plants. The phytotherapy today constitutes the most popular medical practice of complementary medicine, and in many countries its increase is continuous. Some vegetable preparations are marked as pharmaceutical regulation. However in the most cases, in absence of clinical tests, the empiric experience matured in a long period can be considered acceptable testimony of their efficacy. The vegetable products, that are used to cure smaller indications, are based on the Directive 2004/24/EC of March 2004.

Constitutive nitric oxide (NO) is generated by constitutively expressed types of NO-synthase enzymes (NOS-I and -III), being involved in physiological processes such as nervous transmission and vasodilatation. Inducible NO, synthesized by the NO-synthase isoform NOS-II, is an anti-pathogen and tumoricidal agent. However, inducible NO production requires a tight control because of cytotoxic and immune-modulation activity. NO produced by human and canine macrophages has long been demonstrated to be involved in the intracellular killing of Leishmania. Mechanisms of parasite survival and persistence in the host have been throughly investigated, and include suppression of NOS-II and the parasite entry into NOS-II negative cells. Both intracellular and extracellular morphotypes of Trypanosoma cruzi are killed by NO in vitro and in vivo, although a role of NO in the pathogenesis of heart disease has been reported. Killing of extracellular protozoa such as Trichomonas vaginalis and Naegleria fowleri by activated macrophages is also mediated by NO. The main control of Plasmodium spp infection in human and murine hepatocytes, and in human monocytes is achieved by NO-mediated mechanisms. Protection from severe malaria in African children has been found associated with polymorphisms of the NOS-II promoter; however, a pathogenic role of endogenous NO has been documented in cerebral malaria. Although several macromolecules are putative NO targets, recent experimental work has shown that NO-releasing compounds inhibit cysteine proteases (CP) of P. falciparum, T. cruzi and L. infantum in a dose-dependent manner. CPs are present in a wide range of parasitic protozoa and appear to be relevant in several aspects of the life cycle and of the parasite-host relationships. Comparative analysis of 3-D amino acid sequence models of CPs from a broad range of living organisms, from viruses to mammals, suggests that the Sy atom of the Cys catalytic residue undergoes NO-dependent chemical modification (S-nytrosilation and disulfide bridge formation), with the concomitant loss of enzyme activity. The NO-donor S-nitroso-N-acetilpenicillamine (SNAP) was shown to kill T. cruzi epimastigotes and L. infantum promastigotes in culture, while a combination of nitrite plus acid organic salts was highly effective against L. major amastigotes in mouse macrophages. A parasitostatic effect--with both encystation and excystation inhibition--of S-nitrosoglutathione and spermine-NONOate was documented in trophozoite cultures of Giardia duodenalis. Recently, a novel formulation of metronidazole bearing a NO-releasing group was found to enhance significantly the in vitro killing of Entamoeba histolytica trophozoites, compared to metronidazole. So far, only two clinical studies were performed on human patients, suffering from cutaneous leishmaniasis. In one study, 16 Ecuadorean patients were treated with a SNAP cream administered on lesions for 10 days. All lesions were parasitologically cured and clinically healed by day 30. In the second study, a different NO-producing cream (basically nitrite in acidic environment) was employed to treat 40 Syrian patients. Only 28% of them showed improvement and 12% were cured by day 60. In conclusion, despite the wide evidence that NO can be regarded as a natural anti-protozoal weapon, little efforts have been made to develop and test NO-based drugs in human medicine. This is mainly due to the difficulty in designing suitable chemical carriers able to release the right amount of NO, in the right place and in the right time, to avoid toxic effects against non-target host cells.

Surgery is still the first line of therapy for endometriosis. At present, medical therapy is mostly indicated for treatment and prevention of recurrences. Current pharmacological regimens induce a hypoestrogenic state; this effect tends, on one hand, to inhibit the growth of endometriotic implants while, on the other hand, it significantly interferes with the integrity of the hypothalamus-pituitary-ovarian axis. The aim of this study is to review current knowledge on the new experimental therapeutic approaches to the disease. English articles on this topic have been searched by Medline. A particular attention has been paid to experimental therapeutic interventions supported by in vivo results. Three different novel strategies have been identified: 1) To act on estrogenic dependence of endometriosis using new drugs such as aromatase inhibitors and raloxifene. These drugs may have the advantage to act more specifically on the disease. 2) To treat the disease with immuno-modulators and anti-inflammatory drugs. These compounds may be helpful in both limiting the growth of endometriotic implants and in controlling the symptoms of the disease. 3) To prevent adhesion reformation after surgical lysis. Adhesions are an important hallmark of endometriosis which cannot be adequately eliminated by surgery. The use of barrier and fluid agents after surgical lysis seems to be effective in this regard. Results from studies aimed to investigate the effectiveness of these approaches are appealing. However, controlled clinical trials are now required to appropriately determine their real benefits and their specific indications.

Background: Aging (O) rats have a greater susceptibility to renal ischemia than young (Y) rats due to an endothelial dysfunction partially reversed by exogenous administration of L-Arginine. Since statins are able to increase nitric oxide (NO) production, aim of the study was to evaluate whether pre-treatment with atorvastatin (ATO, 10 mg/kg/day for 12 days), had positive effects on ischemic acute renal failure (ARF) of aging rats., Methods: Renal clearance studies (inulin) were performed 24 hours after ischemia in 6 Groups (n=6 in each Group) of both Y- and O-rats: control rats (CON), untreated rats with ARF (Groups IRA), and rats with ARF but pretreated with ATO (Groups ATO+IRA)., Results: Renal ischemia determined a sharper decrease in GFR of Group O-IRA than Y-IRA (-80% and -63% vs respective CON, both p<0.001). In both Groups the fall in GFR was secondary to renal vasoconstriction and the consequent reduction in renal plasma flow. Pre-treatment with ATO did not modify GFR in Group Y-ATO+IRA, but was able to determine a marked rise in GFR of rats of O-ATO+IRA Group (+100% vs O-IRA), through a reduction in renal vascular resistances. Induction of ARF greatly enhanced nitrate excretion in Group Y-IRA, but slightly affected Group O-ARF. Administration of ATO did not modify nitrite excretion in Y rats, whereas it was able to increase nitrate excretion in O-ATO+ARF rats (+111% vs O-IRA)., Conclusions: Pre-treatment with ATO is able to improve the renal response to ischemia in aging rats, through a mechanism which likely is NO-dependent.

Clodronic acid is a non-aminate bisphosphonate capable of inhibiting bone resorption. Pharmacological and clinical trials have shown the efficacy of clodronic acid in the treatment of post-menopausal osteoporosis and in all conditions of excess bone resorption, such as Paget's disease, malignant tumoral hypercalcemia and osteolytic metastases. Clodronic acid is the only bisphosphonate currently on the market available for both oral and parenteral administration. Intramuscular therapy with clodronic acid at a dose of 100 mg/week has shown significant effects on bone mineral density after 6 months treatment in patients with postmenopausal osteoporosis and these effects were maintained 3 years after the start of treatment. Increased bone mass is associated with a reduced risk of the onset of vertebral fractures. In a recent three-year study a significant increase was observed in bone mineral density associated with a 46% reduction in the incidence of vertebral fractures. The reduction in bone pain after parenteral treatment with clodronic acid is an important added value in the use of this molecule in osteopenic pathologies. Moreover the costs of parenteral clodronic acid treatment is certainly competitive compared to other drugs. Oral and parenteral clodronic acid was well tolerated in clinical trials. Gastrointestinal adverse effects were described only with high oral doses. These effects were transient and generally resolved without interrupting the treatment. Clodronic acid is an effective and well tolerated drug able to inhibit bone resorption. The low incidence of undesired effects at a gastroenteric level, the possibility of formulas for parenteral administration, the antalgic effect and low costs make clodronic acid an extremely interesting molecule for the prevention and treatment of postmenopausal osteoporosis and all conditions of excessive bone resorption, such as Paget's disease, malignant tumoral hypercalcemia, osteolytic metastasis and hyperparathyroidism.

A rat model was used to investigate the efficacy of levofloxacin, cefazolin and teicoplanin in the prevention of vascular prosthetic graft infection. Graft infections were established in the subcutaneous tissue of 300 male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with methicillin-susceptible and methicillin-resistant S. epidermidis. The study included a group without contamination, two contaminated groups without prophylaxis, two contaminated groups with intraperitoneal levofloxacin prophylaxis (10 mg/kg), two contaminated groups with intraperitoneal cefazolin prophylaxis (30 mg/kg), two contaminated groups with intraperitoneal teicoplanin prophylaxis (10 mg/kg) and six contaminated groups with rifampin-soaked graft and intraperitoneal levofloxacin, cefazolin or te- icoplanin prophylaxis. The grafts were removed after 7 days and evaluated by quantitative culture. The efficacy of levofloxacin against the methicillin- susceptible strain did not differ from that of cefazolin or teicoplanin. Levofloxacin showed slight less efficacy than teicoplanin against the methicillin-resistant strain. The levofloxacin-rifampin combination proved to be similarly effective to the rifampin-teicoplanin combination and more effective than the rifampin-cefazolin combination against both strains. The rifampin-levofloxacin combination may be useful for the prevention of late-appearing vascular graft infections caused by S. epidermidis because it takes advantage of the good anti-staphylococcal activity of both drugs.

Background: The aim of this paper is to study the properties of innovative materials based on defective calcium phosphates produced by physical methods in the therapy of dentin hypersensitivity., Methods: In particular, the effects of gels, aqueous solutions and toothpastes containing the above mentioned materials on dentinal permeability measured as dentin hydraulic conductance have been studied. The calcium phosphates have been characterized by X-ray powder diffraction (Rietveld analysis) and Fourier transform infra-red analysis. In addition, scanning electron microscopy has been performed to study the surface of dentin and enamel after treatment with the phosphates. In particular sound occlusal dentin, sound cervical dentin, carious occlusal dentin, sound buccal enamel and carious buccal enamel have been observed., Results: The results have shown that these biocompatible materials can be produced with chemical and physical characteristics very similar to dentin and/or enamel. By forming a protective layer inside and outside the dentin tubuli, the calcium phosphates significantly reduce the dentinal hypersensitivity., Conclusions: These phosphates seem to be a promising material for clinical application.

Oxygen free-radical reperfusion products play a critical role in postischemic tissues injury. In this study we used deferoxamine, an iron ligand that seems to inhibit hydroxyl radicals production, in renal normothermic acute ischemia in the rat. Our results demonstrated a significant protective effect of deferoxamine on kidneys subjected to normothermic acute ischemia.

Recent studies have suggested that simvastatin may exert endothelial-protective and anti-ischemic effects via nitric oxide (NO) mechanisms. The aim of this study was to evaluate, in isolated working rat hearts, the effect of acute simvastatin administration on endothelial and inducible NO-synthase (eNOS and iNOS) mRNA and on myocytic apoptosis after ischemia-reperfusion. We used isolated working rat hearts submitted to 15 min global, no-flow, normothermic ischemia and 180 min reperfusion. To detect myocytic apoptosis we used DNA agarose gel electrophoresis and Tunel technique; eNOS and iNOS expression were evaluated by multiplex reverse transcriptase-polymerase chain reaction; glyceraldehyde-3-phosphate dehydrogenase (G3PDH) was used as standard. The eNOS and iNOS mRNAs were expressed as G3PDH/eNOS and G3PDH/iNOS densitometric ratio (BioRad Gel Doc 1000). Hearts were divided into four groups: A) hearts excised and used as histological controls; B) untreated hearts submitted to ischemia and reperfusion; C) actinomicin D-treated (1.5 mg/kg) hearts, perfused with 25 microM simvastatin, subjected to ischemia and reperfusion; D) hearts treated with simvastatin 25 microM and submitted to ischemia and reperfusion. In Group B we evidenced a significant myocytic apoptotic damage, reduced in groups C and D. In Group B an increase in G3PDH/eNOS ratio vs Group A was detected; in Group D a reduction in G3PDH/eNOS ratio vs Group B occurred; no significant changes were observed between groups C and D. As for G3PDH/iNOS ratio, it was significantly increased in Group D with respect to groups A and B. Our data suggest that simvastatin in acute may modulate NO-synthase mRNA expression (induction of eNOS mRNA by means of post-transcriptional mechanisms and inhibition of iNOS postischemic overexpression) and reduce myocytic apoptosis.

Background: The well-known soft tissue healing properties in some rat models as well as the modulating fibroblasts activity of heterologous collagen led us to the hypothesis that it is possible to prevent the peritoneal adhesions in the rat by interposition of the collagen after peritoneal surgery., Methods: In this study, the use of Type I heterologous collagen in different physical forms (1% gel, lyophilized sponge, dehydrated film) for the postoperative peritoneal adhesions prevention has been evaluated. In the second part of the experiment; the 1% gel heterologous collagen including the recombinant tissue plasminogen activator (rtPA) has been applied., Results: The results of both the experiments don't show any improvement in the number and the quality of the adhesions., Conclusions: It is cannot be excluded that, increasing the rtPA concentration it is possible to obtain better results, but the great cost and its potential systemic toxicity are limiting factors for its widespread use in order to prevent peritoneal adhesions.

Background: Recent studies have demonstrated that IGF-I has several biological activities that correlate with the GH axis, by acting as a cell protecting factor and a promoting compound in different tissues and organs. Our latest findings have demonstrated a potential application of IGF-I in the treatment of postischemic renal injury, which frequently appears after a kidney transplant. The beneficial effect of the renal postoperative recovery probably correlates with the regulation of the vascular tone, in which IGF-I plays a role with other cytokines. However, this rises the question whether IGF-I has any effect on the general hemodynamic status. This study was designed to underline the intraoperative hemodynamic effect of exogenous IGF-I in an experimental setting of renal transplantation in swine., Methods: Twelve female swine underwent a left renal autotransplantation. At the reperfusion the animals were separated in two groups. Group one served as control. Group two received 400 micrograms of IGF-I (added to the flushing solution). The animals were kept under complete hemodynamic monitoring over the operation., Results: Among the different parameters studied (mean arterial pressure, mean pulmonary arterial pressure, pulmonary wedge pressure, central venous pressure, cardiac output, oxygen extraction ratio, systemic vascular resistance, oxygen delivery and oxygen consumption), any statistically significant difference between group one and two were observed., Conclusions: While the clinical administration of IGF-I requires further studies, the in vivo administration of this peptide is apparently well tolerated, and does not cause any hemodynamic instability to the operation.

The efficaciousness of ACE inhibitors in arterial blood hypertension is well known. These drugs decreased the incidence of hypertension and myocardial infarction in population. However, they increase tissue levels of some kinines, that may be responsible of some adverse reactions (cough, etc.). Angiotensin-receptor antagonists can minimize the adverse reactions due to kinine accumulation and may increase the safety of the antihypertensive drug-treatment. Pharmacological and clinical aspects of angiotensin-receptor antagonists are discussed.

The extrinsic coagulation pathway is activated when tissue factor (TF) is exposed as a consequence of arterial damage. TF binds to factor VII (FVII) or activated FVII (FVIIa), generating a complex that activates both FX and FIX, ultimately leading to thrombin formation. To determine whether inhibition of FVII binding to TF would result in antithrombotic effects, active site-blocked FVIIa (FVIIai) was used in a rabbit model of intravascular thrombus formation. In addition, to study the interaction between extrinsic coagulation pathway activation and platelet aggregation, in the same model of intravascular thrombus formation, recombinant human FVIIa was administered in antiplatelet-treated rabbits. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were initiated by placing an external constrictor around the endothelially-injured rabbit carotid arteries (Folt's model). Carotid blood flow was measured continuously by a Doppler flow probe placed proximally to the constrictor. CFVs were induced in 29 New Zealand White rabbits. After CFVs were observed for 30 min, the animals were randomly divided in four groups: 5 animals received via a small catheter (26G) placed proximally to the stenosis, an intra-arterial infusion of human recombinant FVIIai (0.1 mg/kg/min for 10 min); 9 animals received AP-1, a monoclonal antibody against rabbit TF (0.1 mg/kg i.v. bolus); 7 animals received ridogrel, a dual thromboxane A2 synthetase inhibitor and thromboxane A2 receptor antagonist (10 mg/kg i.v. bolus); finally, 8 rabbits received aurintrycarboxilic acid (ATA), an inhibitor of platelet glycoprotein Ib/von Willebrand factor interaction (10 mg/kg i.v. bolus). FVIIai abolished CFVs in 5 of 5 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 106 +/- 9% of the baseline values; NS vs baseline). AP-1 abolished CFVs in 7 of 9 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 58 +/- 35% of the baseline values; NS vs baseline). Finally, in all the animals receiving ridogrel or ATA CFVs were abolished (CFV frequency 0 cycles/hour; p < 0.05 in both groups; carotid blood flow velocity, respectively 62 +/- 32 and 66 +/- 40% of the baseline values; NS vs baseline in both groups). Thirty minutes following inhibition of CFVs, in the FVIIai treated rabbits, human recombinant FVIIa was infused, via the small catheter placed proximally to the stenosis, at the dose of 0.1 mg/kg/min for 10 min. In the other three groups, FVIIa, at the same dose, was infused i.v. Infusion of FVIIa restored CFVs in all FVIIai treated animals and in 6 of 7 AP-1 treated animals, thus indicating that AP-1 and FVIIai bindings to TF was competitive and was replaced by FVIIa. Infusion of FVIIa failed to restore CFVs in ridogrel e ATA treated rabbits (1 of 7 and 0 of 8 rabbits, respectively), showing that activation of extrinsic coagulation by FVIIa was overcome by inhibition of platelet function. Activated partial thromboplastin time, and ex vivo platelet aggregation in response to ADP and thrombin, were not different after FVIIai infusion, while prothrombin time was slightly but significantly prolonged as compared to baseline values. Thus, FVII-VIIa plays an important role in initiating thrombus formation in vivo. Administration of FVIIai exerts a potent antithrombotic effects in this model without affecting systemic coagulation. In addition, in this model platelets exert an important role in arterial thrombosis, since in the presence of inhibition of platelet function, activation of the extrinsic coagulation pathway failed to restore thrombus formation.

With the increasing knowledge on the pathogenesis of atherosclerosis, it appears that the prevention of cardiovascular disease in the future will involve, besides risk factor correction, direct pharmacological control of processes occurring in the arterial wall. Among them, a pivotal role is played by smooth muscle cell migration and proliferation that, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates (isoprenoids) of cholesterol synthesis are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently we provided evidence that fluvastatin, simvastatin, lovastatin, but not pravastatin, dose-dependently decrease smooth muscle cell migration and proliferation, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was completely prevented by the addition of mevalonate and partially (80%) by farnesol and geranylgeraniol, confirming the specific role of isoprenoid metabolites--probably through prenylated proteins--in regulating these cellular events. The present results provide evidence that HMG-CoA reductase inhibitors interfere directly with processes involved in atherogenesis--beyond their effects on plasma lipids--partially through local inhibition of isoprenoid biosynthesis.

The onset and progression of long-term complications in diabetes mellitus appear to be related to the degree of hyperglycemia and the overall metabolic control. Therefore, an important goal in the therapy of subjects with diabetes is to avoid wide fluctuations in blood glucose concentrations and increases in lipid levels. The first therapeutic maneuver to achieve glycemic control is to establish a correct diet containing complex carbohydrates and an adequate amount of dietary fibers. Dietary fibers are capable of reducing the intestinal uptake of carbohydrates. An additional strategy to reduce the uptake of carbohydrates across the intestine has recently been proposed by Puls et al. This strategy involves the use of inhibitors of alpha-glucosidase, an intestinal enzyme that participates in the breakdown of polysaccharides into disaccharides and monosaccharides. The inhibition of alpha-glucosidase by these agents is competitive and reversible and results in delayed and reduced uptake of carbohydrates across the intestine. This effect attenuates the post-prandial hyperglycemia and subsequent insulin secretory response particularly in subjects with hyperinsulinemia. The compound acarbose is a member of first generation alpha-glucosidase inhibitors. The administration of high doses of acarbose can be associated with side effects such as flatulence, meteorism, abdominal pain, and diarrhea due to the fermentation of non-absorbed carbohydrates in the intestinal lumen. Usually, these effects subside following a few days of therapy and/or reduction of the initial dose. Acarbose has been effectively used to treat type 2 diabetic patients either as a first choice drug or in association with sulfonylurea agents and in type 1 diabetics in association with insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Intimal hyperplasia is one of the main risk factors for the patency of small diameter bypass grafts. The standard unfractioned heparin (UH) is able to control this phenomenon but the clinical use is not fit for long term treatment; on the other hand the antiplatelet drugs have an anti-thrombotic effect but they seem to be unable to control intimal hyperplasia. Low molecular weight heparins (LMWH) have an anti-thrombotic effect superimposable to that of UH with minimal side-effects and might inhibit intimal hyperplasia too. Based on these criteria, we carried out an experimental study on sheep with the aim of evaluating the efficacy of postoperative treatment with LMWH versus an anti-platelet drug in controlling intimal hyperplasia and growth of true endothelial cells in small prosthetic ePTFE grafts (4 mm) interposed in the carotid artery. At the operation, 30 sheep were randomly located in 3 groups: A = control group, no treatment; B = Ticlopidine hydrochloride 250 mg/bid by mouth for 4 weeks; C = LMWH 3.075 IU AXa (0.3 ml) sc preoperatively and then once a day for the same period. Complete thrombosis of the graft occurred in 7 sheep of group A, 5 in B and 2 partial in group C. The intimal hyperplasia was moderate-severe in group A, mild-moderate in group B and no-mild in group C. True endothelial cells were found mainly in the LMWH group; in the other groups and in other portions of the grafts the cellular coverage was accomplished almost completely by fibroblasts. The study is still in progress with 6 further sheep treated with LMWH.

Experimental work from our laboratory has confirmed the protective power of vanadium compounds on hyperglycemia and glycosuria in streptozotocin (STZ) diabetes. Furthermore, the diabetic cataract too has been partially prevented. The protection slightly increased, when vanadium was administered in combination with vitamin E. This investigation has introduced a combination of Na3VO4 plus the lazaroid U-83836E, a liposoluble antioxidant much more efficacious than tocopherol, in order to improve the insufficient protection when vitamin E was used. Male Wistar rats, rendered diabetic with STZ, were treated for 12 weeks with Na3VO4 in drinking water, U-83836E carried by the food, or both. The most significant metabolic parameters (food and fluid intake, diuresis and excreted feces) were studied monthly by means of metabolic cages. Body weight, glycemia, glycosuria and proteinuria were also recorded. At week 6 and 12 of the treatment, the opaqueness of the eye lenses was controlled. Circulation glycosylated hemoglobin (HbA1c), fructosamine, N-acetyl-beta-D-glucosaminidase (NAG) and fluorescent peroxides were evaluated at the end of the experiment. After the first month of treatment U-83836E improved significantly the protective effect of vanadate alone on polydipsia and polyuria, but more efficiently on hyperglycemia and glycosuria. The further ameliorating effect of the lazaroid was observed also on HbA1c, NAG and, most important, on the cataract. In conclusion, these findings demonstrate that the lazaroid U-83836E succeeds in further protecting the most important symptoms of diabetes treated with vanadate, and that this antioxidant acts effectively even when it is administered per os, in a non invasive manner.

Changes in liver membrane fluidity constitute one of the most important factors in the pathogenesis of experimental and human cholestasis. These alterations could partly be correlated with a defect in the methylation of membrane phospholipids and with a modification in the cholesterol/phospholipids ratio, which in turn may result from a decrease in the ademethionine hepatic levels and from a dysfunction of the enzymes involved in the ademethionine synthesis or in methylation processes, where ademethionine is a crucial factor. On the basis of these considerations, several trials have proved the protective effect of ademethionine in cholestasis and in hepatic disease with different etiology. As regard human pathology the efficacy of ademethionine was demonstrated firstly in intrahepatic cholestasis of pregnancy or estrogen-induced and later on in hepatic diseases with different etiology. These results are particularly encouraging since very few are the drugs effective in the treatment of intrahepatic cholestasis, which represents indeed a crucial element in hepatic diseases.

Clinical and experimental studies have markedly expanded our understanding of the causes of renal disease. Although they have not resulted in comparable therapeutic advances, new lines of treatment have emerged which cannot be underestimated. The prognosis of lipoid nephrosis has been substantially modified. The treatment of membranous glomerulonephropathy with steroids and immunosuppressive drugs may modify the course of the disease, at least in a subset of patients with decreased and deteriorating renal function. Encouraging results have been reported after the use of inhibitors of platelet aggregation in mesangiocapillary glomerulonephritis. We have demonstrated that a receptor antagonist of thromboxane can significantly influence the renal functional parameters in patients with lupus nephritis. ACE-inhibitors, cyclosporine and NSAID's have proved useful in reducing nephrotic proteinuria. Lipid lowering agents are able to ameliorate the glomerular lesions in experimental models of renal injuries. Since systemic hypertension may initiate the development of renal disease or accelerate loss of function in the kidney in which parenchymal disease is already established, controlling hypertension by any effective means helps to slow the progression of renal failure. Preliminary reports have suggested that there may be advantages to using ACE-inhibitors and/or calcium entry blockers.

Cyclosporin A (CsA) is an immunosuppressive drug, but it has also a marked action on carbohydrate metabolism. This study was designed to define the role of a single CsA administration in glucose load distribution. Results show that CsA seems to modify glucose load distribution; in fact it influences considerably glycemia and hepatic, cardiac and muscular glycogen levels, particularly after glucose load. The present experiments suggest that CsA has an antagonist action on insulin release elicited by glucose. This effect may be due to a modification of Ca2+ cellular levels in pancreatic beta-cells. Reduction of insulin release may develop a "pharmacologic diabetes" with metabolism deviated towards gluconeogenesis.

The protective effects of captopril were evaluated in vitro on isolated perfused rat hearts after a global ischemia of 20 min. The hearts were randomly allocated in 2 groups. In the first one (n = 6) captopril was added at a concentration of 270 microM. The second one was utilized as control (n = 6). Aortic flow and minute work respectively decreased on reperfusion by 35% and 49% in captopril group and by 65% and 71% in controls (p < 0.001). No changes occurred in heart rate. Aortic systolic pressure and coronary flow decreased in the 2 groups, but not significantly. Myocardial enzyme release during reperfusion showed significant lower levels of CPK and LDH in the captopril group as compared to controls (p < 0.001 after 41 min). The occurrence of serious ventricular arrhythmias was considerably higher in controls with respect to the captopril group. Irreversible ventricular fibrillation occurred only in control hearts (50%). These data indicate that captopril exerts a protective effect during myocardial ischemia and reperfusion by preventing serious ventricular arrhythmias, reducing enzymatic release and a lower decrease in cardiac performance, without an increase in heart rate.

The role of tumor necrosis factor (TNF-alpha) was investigated in an anaesthetized rat model of coronary artery ligation (60 min) followed by reperfusion (60 min; MI/R). Sham operated rats were used as controls (Sham MI/R). Myocardial necrosis, myocardial myeloperoxidase activity (MPO; investigated as an index of leukocyte adhesion and accumulation), serum creatinphosphokinase (CPK) activity and serum and macrophage TNF-alpha were studied. Ischemia and reperfusion produced a marked myocardial injury, with enhancement of serum CPK levels and myocardial MPO activity in the area at risk and in the necrotic area. Furthermore, serum TNF-alpha was undetectable during the occlusion period, but increased significantly after release of the coronary artery. At the end of reperfusion, macrophage TNF-alpha was also enhanced. A passive immunization with a hyperimmune serum containing antibodies against murine TNF-alpha or administration of an inhibitor of TNF-alpha synthesis, such as cloricromene, significantly lowered myocardial necrosis, reduced the increase in serum CPK and decreased MPO activity in the area at risk and in the necrotic area. Finally, the administration of the specific anti-TNF-alpha antibodies neutralized the serum levels of TNF-alpha and the injection of cloricromene reduced both serum and macrophage TNF-alpha. These data are consistent with an involvement of TNF-alpha in myocardial ischemia-reperfusion injury and suggest that drugs capable of reducing TNF-alpha might represent a novel therapeutic approach to the treatment of myocardial reperfusion injury.

The periodontal pack is often used to cover the surgical site after surgery, even when associated with local applications of preparations containing chlorexidine, in order to obtain an antiseptic protection. However many people question whether the drug effectively succeeds in penetrating the pack, or if the presence of the pack itself doesn't obstruct the action of the medication. The aim of this work is to evaluate the efficiency of the clorexidine in the surgical area with and without a periodontal pack. In a first stage, a case was chosen and contemporary operated on in two different but anatomically similar sites at the same time. One of the two sites was covered with a chlorexidine gel for the following week, whilst the other was left without medication. After seven days the stitches removed from the two different sites were placed in culture mediums to number and classify the bacterial strains present. In the second stage of the experiment, another eight patients were operated on in the same way, and the two sites covered with periodontal packs. In one of the two sites a layer of chlorexidine gel was positioned under the pack, and the chlorexidine above and on the sides of the pack was continually renewed throughout the week following the operation. The other site was not treated. The results obtained show that the pack partially reduces the action of the drug medication, probably because an insufficient amount reaches the site. The activity and efficiency of chlorexidine against the strains of bacteria found in vivo were tested in vitro. The chlorexidine destroyed all of them.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of reperfusion with L-propionyl-carnitine-taurinammide 1 mM was evaluated on the metabolic recovery of the isolated postischemic rat heart. Data referring to the tissue concentration of the high-energy phosphates, oxypurines, nucleosides, nicotinic coenzymes, lactate and pyruvate indicate that L-propionyl-carnitine-taurinammide significantly improves the metabolism of the reperfused myocardium. In particular, ATP, creatinphosphate, GTP, sum of adenine nucleotides and the energy charge resulted 1.80, 1.83, 3.47, 1.47 and 1.20 times higher respectively than the corresponding values recorded in control reperfused heart (p < 0.01 all). These data, out of supplying the necessary biochemical support to the beneficial effects of L-propionyl-carnitine-taurinammide on hemodynamics obtained in previous studies, suggest that L-propionyl-carnitine-taurinammide might represent a useful tool for the pharmacological treatment of myocardial infarction.

It is clearly settled that the management of overt heart failure offers poor prognostic impact due to the advanced setting of the disease. Relief of symptoms, objective benefits, as testified by short-term hemodynamic improvements, are as a matter of fact not reliable prognostic markers. Myocardial dysfunction starts early in the natural history of many cardiac diseases, and runs through the steps of progressive wall remodeling, witnessed by quantitative and qualitative changes in cells, interstitium and connective tissue. Experimental studies offered keys to interventions modulated to oppose the pathophysiological changes present in early myocardial dysfunction. At present, medical therapy has made great strides in testing early myocardial dysfunction. Angiotensin-converting enzyme inhibitors, which retard ventricular dilatation and thus may lower myocardial oxygen consumption requirements seem to offer a unique prognostic profile. Preliminary pilot studies on them and some of many large-scale multicentre trials still in progress reached evidence that this class of drugs is by this time a cornerstone of medical therapy, useful to lower cardiac events-rate in patients with heart failure.

We have investigated (multivariate Cox's model) the relative risk of stable excitation-conduction block (ECB) in right ventricular myocardial strips (2 x 5 x 1 mm) from 26 female guinea-pigs, bathed in a 2-compartment chamber (3 ml) on the anterior side of which modified Tyrode's solution (K+ 12 mM, HCO3- 9 mM, pH 7 +/- 0.05, pO2 80 +/- 10 mmHg and absence of glucose) is supraperfused (stimulation rate: 450 ms; wire in the posterior compartment), thus enabling simulation of electrophysiologic changes seen during acute myocardial ischemia. Using glass microelectrodes, action potential amplitude (APA), durations (APD50 and 90%), resting membrane potential (RMP) and upstroke velocity (Vmax) are investigated. The hypothesis was tested of prostacyclin and histamine involvement in the genesis of ischemia-induced ECB in this model. Either a weak prostacyclin stimulator (cicletanine 10(-5) M, IPSEN, Paris, F, in DMSO 1:100; n = 16) or a potent prostacyclin generation blocker (indomethacin 10(-5) M, Sigma, in DMSO 1:100; n = 10) and either DMSO alone (1:100; n = 16) or a specific histaminergic H1 receptor antagonist (terfenadine 10(-5) M, Sigma, in DMSO 1:100; n = 10) were supraperfused using a randomization scheme. Each animal was used twice and either a first or a second occlusion (supraperfusing the modified Tyrode's solution for 30 min) period was performed and the randomized substances were supraperfused, thus enabling obtention of n = 52 experiments for analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

The production of oxygen free radicals during anthracycline therapy has been proposed as a determinant of the toxicity of anthracyclines. Oxygen radical generation might specifically affect the myocardium because of the low antioxidant defense systems in cardiac tissue. The aim of the present investigations was to evaluate the potential cardioprotective effect of superoxide dismutase (SOD) against the delayed cardiomyopathy induced by doxorubicin (DXR) in a rat model. Female Sprague Dawley rats received 3 mg/kg of DXR intravenously weekly for 4 weeks. SOD was administered intravenously at the dose of 10,000 U/Kg one minute before and 30 minutes after each DXR administration. Cardiac toxicity was monitored in vivo by means of electrocardiography (QaT interval), by determining the contractile properties of isolated atria, and by light and electron microscopy evaluation of left ventricle fragments excised 5 weeks after the last DXR administration. The degree of morphologic lesions was quantitated according to the score system proposed by E. Billingham. DXR treated rats showed, in comparison with control animals treated with saline a decrease of body weight gain, a progressive and irreversible prolongation of QaT, decrease of contractility of isolated atria, and significant morphologic lesions consisting in myocyte vacuolization and myofibrillar loss. SOD significantly prevented the impairment of body weight gain, QaT prolongation and the impairment of myocardial contractility. Moreover morphologic lesions were significantly reduced in rats receiving DXR + SOD. The present data indicate that SOD could represent an important issue in myocardial protection against DXR cardiotoxicity.

A-cyanoacrylate proves to be an advanced means of osteosynthesis. It is particularly indicated for short bone fragments in the articular and comminuted fractures, where a perfect anatomic reduction is required. It is shown to be non-toxic for bone and surrounding tissues and to be endowed with a remarkable chemical bond. It is easily applied and inexpensive. The results are very interesting and stimulate continuation of the studies. The authors think a-cyanoacrylate (or a derivative) is the future of biological osteosynthesis.

In this brief review, we outline the properties of the new macrolide immunosuppressant FK-506. This selective anti-T cell agent has a similar mode of action to cyclospirin A (CSA). It is, however, more powerful, has the capacity (unlike CSA) to reverse liver allograft rejection and appears to have a higher therapeutic index than CSA in patients receiving organ transplants. Preliminary data suggest that renal function is better in recipients of liver transplants given FK-506 as primary therapy compared with those given CSA. In addition, evidence has been presented that FK-506-treated patients have shorter hospital stay than those receiving treatment with CSA. Other factors require to be taken into account, but it may be that it will prove less expensive in the future to treat patients with FK-506 than with CSA. The potential of FK-506 for the control of autoimmune diseases has been demonstrated in rodent models of rheumatoid arthritis, type I diabetes, posterior uveitis, allergic encephalomyelitis and glomerulonephritis. In the clinical field, FK-506 has been used in two cases of nephrotic syndrome resulting from glomerulonephritis; there was improvement in proteinuria and no decline in renal function. Studies to date have been restricted to one clinical centre although many hundreds of organ graft recipients have been studied. Both longer term and multi-centre investigations are urgently required, but it appears that FK-506 may offer considerable potential as an immunotherapeutic agent.

A new lipophilic compound, Gd-BOPTA, presenting a high rate (38.6%) of biliary excretion was tested as an hepato-specific MR contrast agent. Its adequacy was compared to that of Gd-DTPA in laboratory animals. T1-weighted spin-echo sequences (TR 220 ms, TE 20 ms) both before and after the administration of the 2 contrast agents (doses: 0.25, 0.5, and 1.0 mmol/kg) showed better liver enhancement with Gd-BOPTA than with Gd-DTPA. Gd-BOPTA superiority was more evident at lower doses, while at 1.0 mmol/kg a comparable enhancement was achieved. Inversion recovery sequence at the T-null of liver parenchyma before contrast (TR 800 ms, TE 30 ms, TI 100 ms) was performed after the injection of 0.1 and 0.5 mmol/kg of Gd-DTPA and Gd-BOPTA. This sequence allowed the good and long-lasting liver enhancement achieved with Gd-BOPTA to be even better demonstrated, while Gd-DTPA provided only a slight and early enhancement with 0.1 mmol/kg and returned to baseline values 60' after the injection of the highest dose (0.5 mmol/kg). Gd-BOPTA proved to be a good contrast agent to obtain prolonged liver enhancement, thus providing the radiologist with the long time needed to acquire conventional T1-weighted pulse sequences.

The reaction of 1,8-naphthyridine azides with ethyl acrylate leads to the formation of 2-pyrazolines instead of 1,2,3-triazolines. Some of the compounds obtained have undergone pharmacological and microbiological (antibacterial) testing.