Drugs under experimental and clinical research最新文献

Adult rats were treated subcutaneously for 10 days with capsaicin, and their food intake and body weight were recorded for almost 6 weeks after stopping the treatment. The animals were exposed to different ambient temperatures: Ta (22, 32, 35, 10 and 22 degrees C). In the capsaicin-treated group a persistent increase in food intake and a reduction of body weight were observed when the animals were exposed to the lowest Ta of 10 degrees C. Starting from this temperature, food intake remained significantly higher than in controls until the end of the experiment at a Ta of 22 degrees C. The discrepancy between body weight increase and food intake especially at low temperature (10 degrees C) suggests that capsaicin could prevent suppression of food intake through the mediation of capsaicin-sensitive vagal afferent fibers by activation of cold-temperature-sensitive receptors.

The pool of different carnitine derivatives is formed by carnitine, acetylcarnitine, propionylcarnitine and isovalerylcarnitine. Isovalerylcarnitine is a compound performing activities that differ from those of the other carnitine esters. Its activity on proteolytic enzymes and on the calpain system has been demonstrated in the past. Both the calpain and the caspase systems belong to the protease family and lead to cytochrome activation and apoptosis. The two systems can interact to promote apoptosis. In view of this proapoptotic activity of isovalerylcarnitine, studies were carried out to ascertain whether this carnitine derivative influences cell-reaction processes associated with apoptosis. U937 leukemic cells were selected for these studies because they are a well-established model for the assessment of cellular immune responses. In addition to nuclear morphologic alterations produced by apoptosis that can be detected by specific histochemical and microscopic methods, we also took other cell functions into consideration, such as phagocytosis, cell killing and cell growth, which are indices of immune function related to apoptosis. Unlike reference carnitine forms, isovalerylcarnitine produced an early and marked increase in phagocytosis and also an increase in cell killing. Cell proliferation was reduced. The hypothesis is set forth that isovalerylcarnitine may be a caspase-activating, proapoptotic factor that resembles various anticancer agents, which induce early apoptosis that coincides with early activation of caspase. This hypothesis is supported by the ability of isovalerylcarnitine to induce early phagocytosis and cell killing.

The metabolic syndrome is strongly associated with insulin resistance and has been recognized as a cluster of risk factors for cardiovascular diseases such as visceral obesity, hypertension, diabetes and dyslipidemia. Recently, insulin resistance in the absence of overt diabetes or the metabolic syndrome itself has been shown to be associated with endothelial dysfunction, one of the initial steps in the process of atherosclerosis. In the present article we review the molecular mechanisms by which the metabolic syndrome causes endothelial dysfunction and subsequently promotes atherosclerosis. We also discuss promising therapeutic strategies that specifically target the mechanisms responsible for vascular alterations in the metabolic syndrome.

Recently, it has become indispensable for anti-aging active ingredients to provide a visible and immediate smoothing antiwrinkle effect. In Quercus suber, suberin is the most important structural component of cork cell walls. Studies have shown that suberin is made up mostly of hydroxycarboxylic acids and that it is endowed with many special mechanical and chemical properties that evoke a possible smoothing effect on the surface of the skin. Therefore, we were interested in investigating the effect of this cork extract on the skin's surface in a double-blind clinical study. The study was conducted in 15 healthy volunteers, aged 22 to 52 years. The volunteers applied a gel formula with 3% of cork extract, or placebo gel, on each forearm. Skin surface roughness was evaluated visually by pictures and by silicone replicas 1 and 2 h after application, followed by statistical analysis using the matched-pairs McNemar statistical test. McNemar analysis of the pictures revealed that application of cork extract on the skin resulted in a highly significant reduction of roughness 1 h after application. This effect was observed in 73.3% of volunteers. Two hours after cork extract application, a highly significant improvement of skin roughness was found in 78.6% of volunteers. Moreover, silicone replica treatment confirmed significant improvement in average of roughness at 2 h. These results demonstrate that cork extract provides a remarkable and highly significant tensor and smoothing effect on the skin, which could be of great use in anti-aging skin care products.

We have previously shown that azelnidipine, a long-acting dihydropyridine-based calcium antagonist (DHP), inhibited tumor necrosis factor-alpha-induced endothelial cell (EC) activation through its antioxidative properties. However whether azelnidipine could also block the angiotensin II (Ang II)-signaling in ECs remains to be elucidated. Since Ang II-type 1 receptor interaction could contribute to exacerbation of diabetic retinopathy by downregulating pigment epithelium-derived factor (PEDF) gene expression in ECs, we examined here whether azelnidipine inhibited the Ang II-induced reactive oxygen species (ROS) generation and subsequent PEDF gene suppression in microvascular ECs. Azelnidipine, but not nitrendipine, the other popular DHFP completely inhibited the Ang II-induced ROS generation in ECs. Furthermore, azelnidipine, but not nitrendipine, was found to partially restore decreased PEDF mRNA levels in Ang II-exposed ECs. The present study suggests that azelnidipine could inhibit the Ang II-induced decrease in PEDF mRNA levels in ECs through its antioxidative properties. Upregulation of PEDF by azelnidipine may become a therapeutic target for the treatment of diabetic retinopathy associated with hypertension.

Juzen-Taiho-To (JTT) is a Japanese herbal medicine that has been administered mainly to patients weakened by long illness. Currently, it has also been used for cancer patients and showed antitumor effects that have been reported as phagocytosis enhancement, cytokine induction and antibody production. In this study, we examined the effect of oral administration of JTT in mice on the immunological restoration of the liver, especially focused on natural killer (NK) T-cell induction. Mice were grouped to receive JTT or placebo orally for a period of 1, 3 and 7 days. After sacrifice, the liver tissue was fixed, embedded and stained with hematoxylineosin and some antibodies by common staining methods. Transmission electron microscope (TEM) observation was also carried out. Although the JTT-treated mice had the same appearance as the non-JTT-treated mice, their livers were infiltrated by massive mononuclear cells, some of which were aggregated in clusters. Immunohistochemical staining revealed that there was abundant cytokine expression of interleukin (IL)-12 and massive infiltration of mononuclear cells with large granules in the liver of JTT-treated mice. Oral administration of JTT may induce the expression of IL-12 and be followed by immunological restoration such as NK T-cell induction in liver

Diabetic nephropathy is a leading cause of end-stage renal disease in industrialized countries. Although the molecular mechanisms for the development and progression of diabetic nephropathy are not fully understood, the formation of advanced glycation end products (AGEs) and activation of the renin-angiotensin system (RAS) have been considered to be the main factors participating in the pathogenesis of diabetic nephropathy. However, functional cross-talk between AGEs and the RAS remains to be elucidated. In this study, we examined the effects of oral administration of olmesartan medoxomil, a newly developed angiotensin II type 1 receptor antagonist, on renal damage in AGE-treated rats. Administration of olmesartan medoxomil significantly inhibited the increase of systolic and diastolic blood pressure levels and urinary N-acetyl-beta-D-glucosaminidase activity in exogenously AGE-injected rats. Furthermore, olmesartan medoxomil treatment also prevented glomerulosclerosis in AGE-treated rats. These results indicate that exogenous AGE treatment could induce renal damage via the activation of the RAS. Our study suggests that olmesartan medoxomil could be a valuable drug for the treatment of diabetic nephropathy by blocking the deleterious effects of AGEs.

Of 17 patients (10 men and 7 women) with psoriasis vulgaris, aged between 12 and 59 years, included in this study, 4 patients were excluded (3 because of a treatment follow-up irregularity and 1 due to severe irritation). Thirteen patients completed the 6-week treatment course where each patient was instructed to apply calcipotriol-betamethasone ointment on the right side and calcipotriol ointment on the left side. The treatment effect was assessed according to the psoriasis area severity index (PASI) changes, and complete blood count and serum calcium was done prior to and at the end of the treatment. Results showed that both sides had improved by 92.3%, with a marked reduction in the mean PASI (from 11.5 to 2.2); a better reduction was observed in the right side during the second and third visits. A marked improvement to complete clearance was seen in 84.6% in calcipotriol-betamethasone side and 76.9% in calcipotriol alone. Mild irritation was reported in the left side in 15.4% which was tolerated with the continuation of treatment application. No telangiectasia or atrophy was observed on the right side. In conclusion, calcipotriol-betamethasone may be recommended in the early weeks of the treatment of psoriasis vulgaris, and it is helpful in psoriasis patients with irritation to calcipotriol alone.

The main goal of hypercholesterolemia management for coronary prevention is to reduce serum low-density lipoprotein cholesterol (LDL-C) levels. D-003 is a mixture of high molecular weight aliphatic acids purified from sugarcane wax, while policosanol is a cholesterol-lowering drug purified from the same source, consisting in a mixture of higher aliphatic alcohols. No previous comparative study of both drugs in humans has been reported. This randomized, double-blind study compares the efficacy and tolerability of D-003 and policosanol (5 and 10 mg/day) in patients with type II hypercholesterolemia. After a baseline period, 100 patients were randomized to D-003 or policosanol both at 5 mg/day and 10 mg/day, for 8 weeks. D-003 and policosanol 5 mg/day reduced (p < 0.0001) LDL-C by 26.9% and 20.9%, respectively. These reductions increased with 10 mg/day (35.1% for D-003, 25.1% for policosanol. The reductions of LDL-C achieved with D-003 5 mg/day and 10 mg/day were greater (p < 0.05 and p < 0.001, respectively) than with policosanol. The frequency of patients treated with D-003 (5 mg/day) reaching LDL-C reductions > or = 15% (22/25, 88%) was greater (p < 0.01) than with policosanol (5 mg/day) (19/25, 76%), and the same was true for D-003 10 mg/day (25/25, 100%) and policosanol (22/25, 88%; p < 0.01). D-003 and policosanol (5 mg/day) also lowered (p < 0.001) total cholesterol (TC) (16.2% and 13.5%, respectively), and increased high-density lipoprotein cholesterol (HDL-C) by 15.3% (D-003) and 6.7% (policosanol). At 10 mg/day, D-003 and policosanol reduced (p < 0.001) TC (21.3% and 16.0%, respectively), while HDL-C was increased by 17.3% and 9.8%, respectively, D-003 being more effective than policosanol. Treatments did not affect triglycerides. Both drugs were well tolerated, with D-003 tolerated as well as policosanol. Three patients discontinued the study, none due to adverse events (AEs). Seven patients (three from the D-003 group and four from the policosanol group) experienced mild AEs. In conclusion, D-003 (5 and 10 mg/day) administered to patients with type II hypercholesterolemia was more effective than policosanol in lowering LDL-C and TC, and in increasing HDL-C. D-003 could be useful for treating type II hypercholesterolemia, but this subject deserves further clinical research.

The purpose of this study was to evaluate the efficacy of calcipotriol ointment as monotherapy versus calcipotriol in combination with narrow-band ultraviolet (UV)-B or UVA1 phototherapy and to determine whether calcipotriol in combination with UVA1 is an alternative to calcipotriol with narrow-band UVB phototherapy. Forty-five patients with plaque psoriasis were divided into three treatment groups with no significant differences in Psoriasis Area and Severity Index (PASI) scores, mean age, sex or skin type. The total duration of the treatment was 3 months. Regarding PASI score, psoriasis regression was statistically significant between the groups. The response to UVA1 and narrow band UVB with calcipotriol was superior to calcipotriol monotherapy. UVA1 phototherapy with calcipotriol could be an alternative to narrow-band UVB phototherapy with calcipotriol.