Formulating octyl methoxycinnamate in hybrid lipid-silica nanoparticles: An innovative approach for UV skin protection.

Sunscreens have been employed on daily skin care for centuries. Their role in protecting the skin from sun damage, avoiding accelerated photoaging and even limiting the risk of development of skin cancer is unquestionable. Although several chemical and physical filters are approved as sunscreens for human use, their safety profile is dependent on their concentration in the formulation which governs their acceptance by the regulatory agencies. A strategic delivery of such molecules should provide a UV protection and limit the skin penetration. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) may offer an alternative approach to achieve a synergistic effect on the UV protection when loaded with sunscreens as particles themselves also have a UV light scattering effect. Besides, the lipid character of SLN and NLC improves the encapsulation of lipophilic compounds, with enhanced loading capacity. Silica nanoparticles have also been employed in sunscreen formulations. Due to the formed sol-gel complexes, which covalently entrap sunscreen molecules, a controlled release is also achieved. In the present work, we have developed a new sunscreen formulation composed of hybrid SLN-Silica particles loaded with octyl methoxycinnamate (Parsol®MCX), and their further incorporation into a hydrogel for skin administration. Hybrid SLN-silica particles of 210.0 ± 3.341 nm of mean size, polydispersity below 0.3, zeta potential of ca. |7| mV, loading capacity of 19.9% and encapsulation efficiency of 98.3% have been produced. Despite the slight negative surface charge, the developed hybrid nanoparticles remained physicochemically stable over the study period. Turbiscan transmission profiles confirmed the colloidal stability of the formulations under stress conditions. The texture profile analysis of Parsol-SLN and Parsol-SLN-Si revealed semi-solid properties (e.g. adhesiveness, hardness, cohesiveness, springiness, gumminess, chewiness, resilience) suitable for topical application, together with the bioadhesiveness in the skin of pig ears. The non-irritation profile of the hybrid nanoparticles before and after dispersion into Carbopol hydrogels was confirmed by HET-CAM test.

d-α-tocopherol nanoemulsions: Size properties, rheological behavior, surface tension, osmolarity and cytotoxicity.

The aim of this study was the assessment of the physicochemical stability of d-α-tocopherol formulated in medium chain triglyceride nanoemulsions, stabilized with Tween®80 and Lipoid®S75 as surfactant and co-surfactant, respectively. d-α-tocopherol was selected as active ingredient because of its well-recognized interesting anti-oxidant properties (such as radical scavenger) for food and pharmaceutical industries. A series of nanoemulsions of mean droplet size below 90 nm (polydispersity index < 0.15) have been produced by high-pressure homogenization, and their surface electrical charge (zeta potential), pH, surface tension, osmolarity, and rheological behavior, were characterized as a function of the d-α-tocopherol loading. In vitro studies in Caco-2 cell lines confirmed the safety profile of the developed nanoemulsions with percentage of cell viability above 90% for all formulations.

Toxicological impact of cadmium-based quantum dots towards aquatic biota: Effect of natural sunlight exposure.

Cadmium-based quantum dots (QDs) are increasingly applied in existent and emerging technologies, especially in biological applications due to their exceptional photophysical and functionalization properties. However, they are very toxic compounds due to the high reactive and toxic cadmium core. The present study aimed to determine the toxicity of three different QDs (CdS 380, CdS 480 and CdSeS/ZnS) before and after the exposure of suspensions to sunlight, in order to assess the effect of environmentally relevant irradiation levels in their toxicity, which will act after their release to the environment. Therefore, a battery of ecotoxicological tests was performed with organisms that cover different functional and trophic levels, such as Vibrio fischeri, Raphidocelis subcapitata, Chlorella vulgaris and Daphnia magna. The results showed that core-shell type QDs showed lower toxic effects to V. fischeri in comparison to core type QDs before sunlight exposure. However, after sunlight exposure, there was a decrease of CdS 380 and CdS 480 QD toxicity to bacterium. Also, after sunlight exposure, an effective decrease of CdSeS/ZnS and CdS 480 toxicity for D. magna and R. subcapitata, and an evident increase in CdS 380 QD toxicity, at least for D. magna, were observed. The results of this study suggest that sunlight exposure has an effect in the aggregation and precipitation reactions of larger QDs, causing the degradation of functional groups and formation of larger bulks which may be less prone to photo-oxidation due to their diminished surface area. The same aggregation behaviour after sunlight exposure was observed for bare QDs. These results further emphasize that the shell of QDs seems to make them less harmful to aquatic biota, both under standard environmental conditions and after the exposure to a relevant abiotic factor like sunlight.

Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems.

Tramadol hydrochloride (TrHC) is a synthetic analgesic drug exhibiting opioid and non-opioid properties, acting mainly on the central nervous system. It has been mostly used to treat pain, although its use to treat anxiety and depression has also been documented. These properties arise from the fact that they inhibit serotonin (5-HT) reuptake augmenting 5-HT concentration on the synaptic cleft. Despite this, TrHC has also been described to have several side effects which are mainly due to its fast metabolization and excretion which in turn requires multiple doses per day. To surpass this limitation, new pharmaceutical formulations are being developed intending the protection, target and sustained delivery as well as a reduction on daily dose aiming a reduction on the side effects. In the present work we have revised the efficacy, safety, biological and adverse effects of TrHC, and the added value of developing a novel drug delivery system for topical administration.

Sequential treatment with lamivudine and interferon monotherapies in patients with chronic hepatitis B not responding to interferon alone: results of a pilot study.

Sustained viral suppression using monotherapy with interferon alfa (IFN-alpha) or lamivudine can only be achieved in a small percentage of patients with chronic hepatitis B. The concomitant administration of lamivudine and IFN-alpha does not enhance efficacy. We postulated that the optimal timing of therapy might be sequential treatment with lamivudine and IFN-alpha. The aim of this study was therefore to assess the efficacy of sequential treatment in patients resistant to IFN-alpha alone. Fourteen male patients, with a median age of 40 years, nonresponders to IFN-alpha with hepatitis B virus (HBV) DNA > 100 pg/mL (branched DNA [bDNA] Chiron) and positive hepatitis B e antigen (HBeAg) in 11 of 14 patients, were treated with lamivudine 100 mg/d alone for 20 weeks, then with both IFN-alpha2b 5 MU 3 times per week and lamivudine for 4 weeks, and lastly with IFN-alpha alone for 24 weeks. At the end of lamivudine therapy, all patients had undetectable serum HBV DNA, and none exhibited an emergence of HBV polymerase mutant or breakthrough. Sustained serum HBV-DNA clearance 6 months after the end of sequential treatment was achieved in 8 of 14 patients, HBeAg-to-anti-HBe seroconversion in 5 of 11 patients, and HBeAg and hepatitis B surface antigen (HBsAg) seroconversions in 3 of 14 patients (anti-HBs > 100 IU/mL). All sustained responders had normalized their alanine transaminase (ALT) values and exhibited histologic improvements. In conclusion, the results of this pilot study suggest that sequential treatment with lamivudine and IFN-alpha can induce a sustained virologic response, including HBs seroconversion, in patients with chronic hepatitis B not responding to IFN-alpha alone, without the selection of drug-resistant mutants. This therapeutic schedule warrants further evaluation in clinical trials.

Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C.

BACKGROUND/AIMS: Steatosis could be the result of HCV (hepatitis C virus)-induced hypobetalipoproteinemia in patients with chronic hepatitis C. The aim of this study was to assess serum levels of main constituents of betalipoproteins and their relationship with steatosis in patients with chronic hepatitis C without known risk factors for steatosis. PATIENTS: One-hundred male patients with untreated biopsy proven non-cirrhotic chronic hepatitis C were included. Twenty-nine of these patients were further treated with interferon. RESULTS: Cholesterol concentration was significantly lower in patients compared to three control groups: reference male population, patients with chronic hepatitis B or with non-alcoholic fatty liver. In multivariate analysis, low apolipoprotein B concentration was an independent factor related with the degree of steatosis. Hypobetalipoproteinemia and degree of steatosis were significantly associated with infection with genotype 3. Among treated patients, only sustained virological responders had a significant increase of cholesterol (5.6 +/- 1 vs. 4.7 +/- 1.3 mmol/l; P = 0.03) and apolipoprotein B concentrations (113 +/- 19 vs. 75 +/- 14 mg/dl; P = 0.05). CONCLUSION: In chronic hepatitis C, hypobetalipoproteinemia is prevalent and associated with steatosis, especially in patients infected with genotype 3. The correction of hypobetalipoproteinemia following HCV eradication suggests that HCV itself could induce hypobetalipoproteinemia and steatosis.

Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons.

A clinical trial to evaluate the safety and tolerability of a new influenza adjuvanted vaccine (FLUAD, Chiron Vaccines), compared with a conventional non adjuvanted influenza vaccine, was conducted in elderly ambulatory patients. Subjects were vaccinated with one dose of either vaccine each year for three consecutive years; 92 subjects received the first immunization, 74 subjects received the second and 67 subjects received the third. The primary objective of this study was to evaluate the safety of repetitive injections of the adjuvanted vaccine in elderly subjects. There were no reports of any vaccine-related serious adverse event or of safety concerns related to study vaccines after the first, second or third immunization. The adjuvanted vaccine induced more local reactions than the conventional vaccine; however, the reactions were normally mild and limited to the first 2-3 days after immunization. No statistically significant difference between groups in systemic postimmunization reactions was reported except for a mild, transient malaise after the first immunization. Compared with the first immunization, no increase in postimmunization reactions was seen after the second and third immunizations. Despite the small sample size of the trial, which was not powered to test immunogenicity differences, the antibody response was tested and resulted higher in the adjuvanted vaccine recipients, not only against the current season's vaccine strains, but also against heterologous vaccine strains.

Interferon alfa therapy in patients with chronic hepatitis C and persistently normal aminotransferase activity.

BACKGROUND & AIMS: Chronic hepatitis C virus carriers may have repeatedly normal aminotransferase activity despite detectable viremia and histological hepatitis. The aim of this study was to determine the effect of interferon in this population. METHODS: Three million units of interferon alfa was administered 3 times weekly for 6 months in 10 patients with chronic hepatitis C virus infection, repeatedly normal alanine aminotransferase activity, and chronic hepatitis on liver biopsy. Serum hepatitis C virus RNA was detected by polymerase chain reaction and quantified by branched DNA before, at the end, and 1 year after treatment. A liver biopsy was performed 1 year after treatment withdrawal. RESULTS: At treatment withdrawal, hepatitis C virus RNA levels had significantly decreased, but RNA was still detectable by polymerase chain reaction in 8 of 10 patients. During the 1-year follow-up period, 6 of 9 patients had elevated aminotransferase activity on at least one occasion. One year after treatment withdrawal, RNA levels had returned to pretreatment values and no significant histological improvement was observed in the 7 patients who underwent liver biopsy. CONCLUSIONS: In patients with chronic hepatitis C and repeatedly normal aminotransferase activity, standard interferon therapy does not lead to sustained virological or histological responses despite a transient effect on hepatitis C virus replication.

[Association of Gougerot-Sjögren syndrome and viral hepatitis C. Apropos of 6 cases]. / Association d'un syndrome de Gougerot-Sjögren et d'une hépatite virale C. A propos de 6 observations.

Hepatitis C virus (HCV) has been found in the serum of 3 out of 109 patients with Sjögren's syndrome, whereas Sjögren's syndrome has been demonstrated in 3 out of 7 HCV-positive patients. The six HCV-positive Sjögren's syndrome patients were compared with 95 HCV-negative Sjögren's syndrome patients. Anti-smooth muscle antibodies were detected in 1 of the former group and 6 of the latter. Cryoglobulin existed in 1 and 6, respectively. The levels of circulating IgA and IgA-containing immune complexes were lower in the HCV-positive than in the HCV-negative patients.

Factors predictive of the response to interferon in patients with chronic hepatitis C.

Factors predictive of the response to interferon in patients with chronic hepatitis C remain to be identified. In this study, we investigated factors predictive of the short-term response, defined as a return to normal alanine aminotransferase activity after treatment, and the long-term response defined as normal alanine aminotransferase activity 1 year after completing treatment, in 75 patients with chronic hepatitis C virus treated with recombinant alpha interferon (either 6 MU x 3/week for 3 months then 3 MU x 3/week for 3 months (n = 27) or 3 MU x 3/week for 6 months (n = 48)). At the end of treatment, 42 patients (56%) had normal alanine aminotransferase activity ("responders") and 33 (44%) had high alanine aminotransferase activity ("non-responders"). Twenty (48%) of the 42 responders had normal alanine aminotransferase activity 1 year after treatment ("sustained responders"), while 22 (52%) had high alanine aminotransferase activity ("transient responders"). The dosage of interferon was not predictive of the short-term and the long-term response to treatment. The responders differed significantly from the non-responders in terms of age, i.v. drug abuse, aspartate aminotransferase, gammaglutamyltranspeptidase and alkaline phosphatase activities, bilirubinemia, serum bile acid concentrations, prothrombin time, platelet count, ferritinemia, hyaluronic acid levels, positivity for the antibody to 5.1.1 of the recombinant immunoblot assay band and the histological fibrosis score. The following parameters were independently correlated with the short-term response in a multivariate analysis: gammaglutamyltranspeptidase activity, serum bile acid concentrations and positivity for the antibody to 5.1.1 of the recombinant immunoblot assay band.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of screening donor blood for alanine aminotransferase and antibody to hepatitis B core antigen on the risk of hepatitis C virus transmission.

The transfusion-related risk of transmission of hepatitis C virus (HCV) was evaluated in France for the periods before and after exclusion of donor blood units with the surrogate markers elevated alanine aminotransferase (ALT) levels and antibody to hepatitis B core antigen (anti-HBc). A total of 1,412 blood recipients undergoing surgery were followed up prospectively in the period from 1986 to 1989. The stored serum samples were tested for antibodies to HCV by an enzyme immunoassay (EIA) and the result in reactive sera confirmed by a recombinant immunoblot assay (RIBA). The risk of HCV transmission was estimated by the maximum likelihood method for a subpopulation of 892 recipients divided into three groups. Of 55 (3.9%) EIA positive patients, 56.4% were found to be positive prior to transfusion. HCV seroconversion (positive RIBA) occurred in 22 patients (1.6%). The risk of HCV transmission per 1,000 transfused blood units decreased significantly from 4.11 in Group 1 (receiving non-screened blood) to 3.43 in Group II (receiving ALT screened blood) and to 1.40 in Group III (receiving ALT and anti-HBc screened blood). These results demonstrate that screening of donors for surrogate markers had reduced the risk of HCV transmission before the introduction of a systematic anti-HCV screening policy in France in March 1990.

Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: results of a controlled trial comparing propranolol, endoscopic sclerotherapy and placebo.

Propranolol and endoscopic sclerosis of esophageal varices are the two approaches currently used in prophylaxis of the first gastrointestinal hemorrhage in the cirrhotic patient. One hundred twenty-six cirrhotic patients with esophageal varices and no histories of bleeding were included in the trial regardless of the gravity of the cirrhosis or the size of the esophageal varices. Patients with hepatocarcinomas or other cancers, clearly impossible follow-up, previous treatment for portal hypertension or contraindication to beta-blockers were excluded. After randomization, 43 patients received propranolol twice daily at a dose reducing the heart rate by 25%; 42 patients were treated with intravariceal and extravariceal injections of Polidocanol; 41 control patients received vitamin K orally as placebo. The patients were seen at 3-mo intervals for 2 yr. On entry to the trial the three groups were comparable in terms of clinical and biological parameters, including size of esophageal varices (grade I = 51, grade II = 54, grade III = 17), Child-Pugh classification (A = 29, B = 61, C = 32) and the origin of cirrhosis (alcoholic in 79% of cases). Twenty-four patients bled (two bled in the propranolol group, nine bled in the endoscopic sclerosis of esophageal varices group and 13 bled in the placebo group). Actuarial estimates (Kaplan-Meier) of the time of onset of first bleeding showed that the differences were significant between propranolol and placebo (p less than 0.004) and between propranolol and sclerotherapy (p less than 0.03) but not between sclerotherapy and placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

[Ascites disclosing systemic lupus erythematosus]. / Ascite révélatrice d'un lupus érythémateux disséminé.

We report the case of a 38-year old woman with massive ascites. No cause could be demonstrated despite multiple investigations. The patient was febrile and had an elevated erythrocyte sedimentation rate. Systemic lupus erythematosus was subsequently diagnosed, when malar rash, arthritis, leucopenia, anti-native DNA and anti-Sm antibodies appeared. Ascites and lupus manifestations resolved simultaneously on steroid therapy. This unusual cause of ascites should be recognized, since it responds favorably to steroid therapy.

[Nodular regenerative hyperplasia of the liver and primary biliary cirrhosis. A fortuitous association?]. / Hyperplasie nodulaire régénérative du foie et cirrhose biliaire primitive. Une association fortuite?

We report here in a case of primary biliary cirrhosis associated with nodular regenerative hyperplasia of the liver in a white woman revealed by digestive hemorrhage due to ruptured esophageal varices. The diagnosis of primary biliary cirrhosis was based on the following: elevated serum IgM, high titer of antimitochondrial antibody (anti M2), typical histopathological picture of stage I/II disease. The diagnosis of nodular regenerative hyperplasia was supported by the demonstration of disseminated small hepatic nodules without perinodular fibrosis. This association may be a supplementary argument in favor of a possible autoimmune origin of nodular regenerative hyperplasia of the liver.