Drugs under experimental and clinical research最新文献

The mevalonate pathway is relevant in bone cells. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme of this route, stimulating osteoblast differentiation and activity. Pravastatin increases bone formation markers in postmenopausal women and bone density in diabetics. D-003 is a mixture of high-molecular-weight acids purified from sugarcane wax which inhibits cholesterol biosynthesis through HMG-CoA reductase regulation, preventing bone loss in osteoporosis induced with ovariectomy and prednisolone in rats. We investigated the effects of D-003 (50 mg/kg) and pravastatin (20 mg/kg) orally administered for 12 weeks to ovariectomized rats. Female rats were randomized in four groups (10 rats/group): two control groups treated with the vehicle, one false-operated (sham) and another ovariectomized (positive control), while two other groups received D-003 or pravastatin. Bone resorption and formation was studied through histomorphometry and apoptosis through immunohistochemistry. D-003 and pravastatin significantly (p < 0.001) prevented the changes of trabecular bone versus ovariectomized rats and (p < 0.001) the increase of the surface and number of osteoclasts versus ovariectomized controls. D-003 and pravastatin, however, did not modify osteoblast surfaces, a bone formation marker D-003 and pravastatin increased osteoclast apoptosis and reduced (p < 0.05) osteoblast and osteocyte apoptosis versus ovariectomized controls; D-003 was more effective (p < 0.05) than pravastatin. In conclusion, D-003 (50 mg/kg) orally administered for 12 weeks prevented bone loss and bone resorption in ovariectomized rats, increasing osteoclast apoptosis. The preventive effects of D-003 on bone loss and resorption in ovariectomized rats are comparable to those of pravastatin. Both drugs inhibited osteoblast apoptosis but failed to change osteoblast surface. The effects of D-003 on bone cell apoptosis were greater than those of pravastatin. Therefore, D-003 could be used to prevent or treat bone loss in postmenopausal women, but further animal studies and clinical trials are required to confirm the clinical relevance of this potential effect.

Rheumatoid arthritis (RA) is a disease that is still insufficiently controlled by current treatments. Methotrexate (M7X), a small molecular weight compound, has been the gold standard in the treatment of RA. It has several anti-inflammatory activities, but their contribution to its antiarthritic effects has not yet been established. We conducted a rat adjuvant arthritis study, in which we investigated the effect of MTX on local cytokine and chemokine production in arthritic paws. Our data demonstrate that MTX was able to significantly suppress cytokine and chemokine release in the inflamed joints in a dose-dependent fashion, accompanied by amelioration of the disease as indicated by reduced paw swelling and arthritic scores. These findings prompt further studies to clarify whether these suppressive effects of MTX on local cytokine and chemokine release are direct or whether they are a result of other preceding anti-inflammatory activities of the compound.

Chondroitin sulfate (CS) and 500-730 kDa hyaluronic acid (HA) are symptomatic slow-acting drugs for the treatment of osteoarthritis (OA). In addition, a growing body of evidence suggests a role for CS and this specific HA as modifiers of the course of OA. The therapeutic efficacy of CS and HA lies in their different mechanisms of action. Stromelysin-1 (metalloprotease-3 [MMP-3]) is a cartilage proteolytic enzyme, which induces cartilage destruction and acts as a mediator of the inflammatory response. However, there are few studies evaluating the in vitro effect of CS and HA on MMP-3 synthesis in human chondrocyte cultures from OA patients. Thus, the aim of the present study was to analyze the effect of CS and HA (500-730 kDa) on MMP-3 synthesis induced by interleukin-1beta (IL-1beta) in chondrocytes from patients with hip OA. Chondrocyte cultures were incubated for 48 h with IL-1beta (2.5 ng/ml) in the absence or presence of different HA 500-730 kDa (Hyalgan, Bioibérica Farma, Barcelona, Spain) concentrations, or alternatively, CS (Condro.san, Bioibérica Farma) at concentrations of 10, 50, 100, 150, 200 and 1,000 microg/ml. The results revealed that both CS and HA (500-730 kDa) inhibited MMP-3 synthesis induced by IL-1beta in human OA chondrocytes. Specifically, CS and HA (500-730 kDa) reduced MMP-3 expression levels at all tested concentrations. Therefore, our study provides new data on the mechanism of action of these drugs, which could help to explain their clinical efficacy in OA patients.

Cotton honeydew extract is composed of a unique combination of oligosaccharides, including fructose, glucose, inositol, melezitose, saccharose, trehalose and trehalulose. Studies have shown that these oligosaccharides exhibit a protective effect. Therefore, we were interested in studying the effect of these oligosaccharides on normal and damaged human hair. Both clinical and scanning electron microscopy (SEM) studies were performed. Standardized human hair samples were used to determine the effect of a rinse-off mask with 1% cotton honeydew extract on the ultrastructure of hair. In addition, hair samples were submitted to different aggressions, following various experimental protocols. SEM showed that, without extra aggression, the cuticle scales appeared to lie more smoothly in the hair in cotton honeydew extract-treated samples than in untreated samples. The extract-treated hair samples were also less prone to chipping. In contrast, the control, untreated hair samples retained a dry and damaged appearance and were prone to chipping and progressive splitting. In a clinical study, 15 volunteers had half of their hair treated with a formula with 1% honeydew extract and the other half was left untreated as a control. Pictures and visual evaluation of the hair showed that the honeydew extract formula left the hair with a smoothness that was far superior to the control side and this result was confirmed by SEM. In addition, mRNA studies on epidermal cells were performed and confirmed the stimulating effect of honeydew extract on keratin synthesis. These results demonstrate that cotton honeydew extract can be of great use in hair care products and cosmetics.

Loracarbef is an oral synthetic beta-lactam antibiotic of the carbacephem class. The aim of this study was to compare the efficacy and safety of loracarbef 15 mg/kg versus 30 mg/kg in children with acute sinusitis. A randomized, parallel-group, clinical study was conducted. Fifty-eight children aged 5-12 years with acute sinusitis were divided into two groups, which received either loracarbef 15 mg/kg/day or 30 mg/kg/day orally, divided in two doses for 10 days. Clinical examination, anterior rhinoscopy and sinus radiographs were performed at the beginning of treatment. Clinical evaluation was repeated in a second session, 0-2 days after the final dose, and in a third session, 30 days after the beginning of the treatment. Sinus X-rays were repeated selectively in the second session and in all patients in the third session. Nineteen of 29 (65.5%) patients in the 15 mg/kg/day group and 26 of 29 (89.6%) in the 30 mg/kg/day group were characterized as completely or clinically cured at the end of the study. In conclusion, a statistically significant difference between the two treatment groups was shown with better results in the 30 mg/kg group. Despite the slight difference in adverse events between the two groups (with fewer adverse events in the 15 mg/kg group), we recommend that if loracarbef is chosen as initial therapy in acute sinusitis, a regimen of 30 mg/kg/day in two doses is followed.

Otitis media with effusion (OME) is a common pediatric disease and there is great controversy concerning its management. Mechanical, medical and surgical treatments have not proven adequate in resolving the disease and serve mainly to manage complications. Leukotriene inhibitors are new drugs that have been approved recently for the treatment of asthma in children. The aim of this study was to evaluate the impact of leukotriene inhibitor therapy for asthma on the clinical course of OME in children with co-existing disease. Fifty children with bilateral OME and asthma, divided equally into two groups, were studied. The children in the first group were treated with budesonide and terbutaline inhalers together with the leukotriene inhibitor montelukast, whereas the children in the second group were treated with the inhalers alone. Duration of treatment was 30 days. Pneumatic otoscopy, tympanometry and pure-tone audiometry were performed at the beginning and at the end of treatment. Fifteen (60%) of the children receiving inhalers and montelukast and nine (36%) of those receiving only inhalers were found free of OME after 30 days of therapy. Thus, it may be concluded that a statistically significant beneficial effect on the clinical course of OME resulted from the addition of montelukast to the treatment of children with co-existing asthma and OME. Given that no medication has been shown to be effective in OME therapy, further investigation of the possible effects of leukotriene inhibitors is warranted.

This study aimed to define the pharmacokinetics of nifedipine following oral administration of a new extended-release formulation. Twelve healthy volunteers of both sexes, aged 39 +/- 4 years, were treated with a single oral tablet of a new extended-release formulation containing 40 mg of nifedipine. Samples of venous blood were taken before dosing, after 30 min and at 1, 2, 4, 8, 12, 16, 20 and 24 h after administration. Nifedipine concentration was measured by means of a high-performance liquid chromatography method. Noncompartmental pharmacokinetics parameters were then calculated. The plasma concentration of nifedipine increased slowly and in seven subjects biphasic peaks occurred. The mean values were as follows: t(max): 8.5 +/- 1.2 h; C(max): 36.55 +/- 6.76 ng/ml; AUC: 347.06 +/- 51.61 ng/h/ml; AUC 409.99 +/- 61.08 ng/h/ml; A(half-life): 2.26 +/- 0.36 h; D(half-life): 2.43 +/- 0.44 h; E(half-life): 4.62 +/- 0.79 h. Twenty-four hours after administration nifedipine was still detectable (3.17 +/- 0.67 ng/ml). Arterial blood pressure decreased and heart rate increased concurrently and proportionally to the increase in nifedipine concentration. Extended-release nifedipine formulations have better tolerability profiles than immediate-release formulations, which are at present not recommended in the treatment of hypertension, hypertensive crises or myocardial infarction. This new extended-release formulation has interesting pharmacokinetic parameters and may be effective in conditions in which dihydropyridine calcium channel blockers are indicated.

It is well known that topical tacrolimus is safe and effective in the treatment of atopic dermatitis (AD) patients. Tacrolimus is primarily an immunosuppressive agent without any antistaphylococcal effects. Thus colonization of Staphylococcus aureus on the skin of patients treated with this agent might be increased. The purpose of this study was to determine the effect of tacrolimus on S. aureus colonization in patients with AD and to compare the results with clinical severity and skin barrier function. We enrolled 65 patients with moderate to severe AD. They were treated with 0.03% tacrolimus ointment twice daily for 4 weeks. Clinical severity was assessed by the eczema area and severity index (EASI). S. aureus colonization was measured by the tape method. Skin barrier function was checked by measuring transepidermal water loss (TEWL). Evaluations were performed at weeks 0 (baseline), 1, 2 and 4. The results were compared and statistical analysis was performed. S. aureus colonization was significantly decreased with tacrolimus treatment at week 1 compared with baseline. However, there were no differences among weeks 1, 2 and 4. EASI and TEWL showed a decreasing tendency in a time-dependent fashion. The correlations between data were variable.

HESA-A, a marine compound, has been shown to exhibit antihepatic cancer, antitumor and anti-Parkinson effects. The hepatoprotective potential of HESA-A pretreatment at doses of 125 mg and 250 mg per day orally for a period of 40 days was evaluated against thioacetamide-induced liver damage in rabbits. Biochemical parameters such as serum glutamate oxaloacetate transaminase and lactate dehydrogenase in serum were estimated to assess liver function and lipid peroxidation products (malondialdehyde [MDA]) and the antierythrocyte lysis effect of plasma for measurement of antioxidant potential capacity. Data on the hepatic biochemical parameters revealed the hepatoprotective potential of HESA-A pretreatment against thioacetamide-induced hepatotoxicity in rabbits. There was an increase in total antioxidant and antierythrocyte lysis and a decrease in MDA in plasma after HESA-A treatment. These results strongly suggest that HESA-A has a protective action against preoperative damage to biomembranes.

There is a growing body of evidence that dihydropyridine-based calcium antagonists (DHPs) improve endothelial function, thus slowing the development and progression of atherosclerosis. We have previously shown that nifedipine, one of the most popular DHPs, inhibits tumor necrosis factor-alpha (TNF-alpha)-induced reactive oxygen species generation and subsequent monocyte chemoattractant protein-1 (MCP-1) expression in human umbilical vein endothelial cells (HUVEC). However, the molecular mechanism underlying this phenomenon remains to be elucidated. CD40, a cell surface receptor that belongs to TNF-alpha receptor, has been associated with the pathogenesis of chronic inflammatory diseases such as atherosclerosis. In this study, we investigated the involvement of CD40 in MCP-1 suppression by nifedipine in TNF-alpha-exposed HUVEC. Nifedipine completely inhibited TNF-alpha-induced upregulation of CD40 mRNA levels in HUVEC. Furthermore, antibody against human CD40 was found to significantly inhibit upregulation of MCP-1 mRNA levels in TNF-alpha-exposed HUVEC. These results demonstrate that nifedipine could inhibit the TNF-alpha-induced upregulation of MCP-1 mRNA levels via suppression of CD40 expression in HUVEC. Our present study suggests that blockade of CD40 signaling in endothelial cells may be a molecular target for the vasculoprotective property of nifedipine.