Synthesis of Novel Cationic Photosensitizers Derived from Chlorin for Application in Photodynamic Therapy of Cancer.

BACKGROUND: Chlorins (dihydroporphyrins) are tetrapyrrole-based compounds that are more effective in photodynamic therapy than porphyrins. The instability of the compounds and their oxidation to porphyrin limits the use of these compounds. However, the design and synthesis of new stable chlorin-based cationic photosensitizers with the potential for use in cancer photodynamic therapy can be interesting. METHODS: In this research, new tetracationic meso substituted chlorins were designed, synthesized, and characterized. After determining the chemical structure and spectroscopic properties of five new photosensitizers, their phototoxicity on breast cancer cell lines (MCF-7) was investigated under optimized conditions in terms of factors such as photosensitizer concentrations and light intensity. RESULTS: The results of cytotoxicity assayed by the MTT method showed that the synthesized compounds, even up to the concentration of 50 µM had very low toxicity in the absence of light, which indicates their safety under dark conditions. Compounds A1 and A3 with the best physicochemical properties such as solubility, high absorption intensity in the effective range of photodynamic therapy, and the high quantum yield of singlet oxygen, had a good toxic effect (IC50 = 0.5 µM) on the cancer cells (MCF-7) in the presence of laser light. CONCLUSION: According to the obtained results, compounds A1 and A3 have the potential to continue research on PDT for confirmation and use in treatment.

Molecular Epidemiology of Candida Auris Outbreak in a Major Secondary-Care Hospital in Kuwait.

The emerging, often multidrug-resistant Candida auris is increasingly being associated with outbreaks in healthcare facilities. Here we describe the molecular epidemiology of a C. auris outbreak during 18 months, which started in 2018 in the high dependency unit (HDU) of a secondary-care hospital in Kuwait. Demographic and clinical data for candidemia and colonized patients were prospectively recorded. Clinical and environmental isolates were subjected to phenotypic and molecular identification; antifungal susceptibility testing by broth microdilution method; PCR-sequencing of ERG11 and FKS1 for resistance mechanisms to triazoles and echinocandins, respectively; and molecular fingerprinting by short tandem repeat (STR) analyses. Seventy-one (17 candidemic and 54 colonized) patients including 26 with candiduria and seven environmental samples yielded C. auris. All isolates were identified as C. auris by Vitek2, MALDI-TOF MS, PCR amplification and/or PCR-sequencing of rDNA. Twelve candidemia and 26 colonized patients were admitted or exposed to HDU. Following outbreak recognition, an intensive screening program was instituted for new patients. Despite treatment of all candidemia and 36 colonized patients, 9 of 17 candidemia and 27 of 54 colonized patients died with an overall crude mortality rate of ~50%. Nearly all isolates were resistant to fluconazole and contained the Y132F mutation in ERG11 except one patient's isolates, which were also distinct by STR typing. Only urine isolates from two patients developed echinocandin resistance with concomitant FKS1 mutations. The transmission of C. auris in this outbreak was linked to infected/colonized patients and the hospital environment. However, despite continuous surveillance and enforcement of infection control measures, sporadic new cases continued to occur, challenging the containment efforts.

Hypouricemic and antioxidant activities of Allium cepa Lilliaceae and quercetin in normal and hyperuricemic rats.

OBJECTIVE: To evaluate the hypouricemic and antioxidant effects of Allium cepa Lilliaceae (Allium cepa L.) and quercetin in normal and hyperuricemic rats. METHODS: The following study was conducted in the Department of Nutrition and Biochemistry, Tehran University of Medical Science, Iran, between May 2007 and March 2008. A total of 48 male Wistar rats (body weights: 180-200 g) were randomly divided into 8 equal groups including normal; normal + Allium cepa L. (5g/kg); normal + quercetin (5mg/kg); normal + allopurinol (5mg/kg); hyperuricemic; hyperuricemic + Allium cepa L. (5g/kg); hyperuricemic + quercetin (5mg/kg); hyperuricemic + allopurinol (5mg/kg) once a day for 14 days. Experimentally, hyperuricemia in rats was induced by intraperitoneal injection of potassium oxonate (250mg/kg). RESULTS: Allium cepa L. and quercetin treatments for 14 days significantly reduced (p=0.000) the serum uric acid levels of hyperuricemic rats in a time-dependent manner. All treatments significantly inhibited hepatic xanthine oxidase/xanthine dehydrogenase activity. Allium cepa L. and quercetin treatments led also to a significant improvement in biomarkers of oxidative stress in hyperuricemic rats (p=0.000). Although the hypouricemic effect of allopurinol was much higher than that of Allium cepa L. and quercetin, it could not significantly change oxidative stress biomarkers. CONCLUSION: These results may be responsible partly for the beneficial effects of Allium cepa L. and its major flavonoid on hyperuricemia and oxidative stress.

Influence of poly(ethylene glycol)-alpha-cyclodextrin complexes on stabilization and transdermal permeation of ascorbic acid.

The present study was conducted to investigate the effect of poly(ethylene glycol)-alpha-cyclodextrin (alpha-CD) complexes on stabilization and cutaneous permeation of ascorbic acid from specially prepared transdermal patches. Poly(ethylene glycol) citrate (6-armPEG) and its inclusion complex with alpha-CD were prepared and used for preparation of the transdermal patches. Duro-Tak 87-2979 was taken as an adhesive matrix in combination with ascorbic acid. A diffusion cell with an artificial membrane was used to evaluate the absorption of ascorbic acid from the patches. The influence of drug release of alpha-CD and two types of its PEG complexes (as the novel permeation enhancers) was tested. The 6-armPEG-alpha-CD complex consisting of a PEG-citric acid ester at a concentration of 0.08-0.1% (w/v) is a suitable stabilizer for ascorbic acid during UV assay. The release studies showed that the type of enhancer is important in diffusion of the drug across membrane. Furthermore, the diffusion of ascorbic acid was considerably enhanced in the presence of 6-armPEG-alpha-CD complex. Inclusion complexes of 6-armPEG with alpha-CD at a concentration of 0.08-0.1% (w/v) is a suitable stabilizer for UV method of assay. The present data suggest that 6-armPEG-alpha-CD complex is also useful in enhancing the release of ascorbic acid from the acrylic type pressure sensitive adhesives.

Synthesis and hydrolytic behaviour of 2-mercaptoethyl ibuprofenate-polyethylene glycol conjugate as a novel transdermal prodrug.

Thiolated derivatives of ibuprofen and its polyethylene glycol ester were synthesized via condensation of 2-mercaptoethyl ibuprofenate with carboxy-terminated polyethylene glycol. The release of ibuprofen from this polymeric prodrug has been studied under conditions simulating those encountered in the skin. The polymeric prodrug of ibuprofen was found to undergo pH-dependent hydrolysis, ranging from negligible hydrolysis at pH 4 to 23.9% hydrolysis at pH 8.5 (15% at pH 7.4) after 48 h at 37 degrees C. The polymer-drug conjugate was subjected to enzymatic hydrolysis in human plasma. The polymer showed considerable enzymatic hydrolysis (68% after 48 h). The results showed that the polymeric prodrug model of non-steroidal anti-inflammatory drugs (NSAIDs) described here can be used in topical formulations of NSAIDs. It is expected that the novel thiol derivative will have both enhanced transdermal penetration and stability to oxidation which make it a suitable candidate for transdermal formulations.

Effects of nibbling and gorging on lipid profiles, blood glucose and insulin levels in healthy subjects.

OBJECTIVE: Although there is some evidence indicative of some beneficial effects of an increased meal frequency on the lipid profiles, the results published are controversial. The aim of the present study is to investigate the effects of feeding frequency on blood lipids, glucose and insulin. METHODS: The subjects of this study were 15 healthy non-smoker males aged 27.2 +/- 6.4 years. All subjects were placed on 2 identical diets in which they consumed the same food either as 3 meals at 7-hours intervals (gorging diet) or as 9 snacks at 2 hours intervals (nibbling diet). Each diet was of 2 week's duration and was separated from each other by a period of 3 weeks. At the end of both diets, the plasma was obtained from fasting blood samples and its lipid levels were determined. The study was carried out in Tabriz University of Medical Sciences, Tabriz, Iran between 30 October 1998 and 19 December 1998. RESULTS: The nibbling diet was associated with an increased level of glucose (p<0.01) and a decreased level of insulin (p<0.05). The plasma levels of total cholesterol, triglyceride, low-density lipoprotein, and lipoprotein (a) were found to be lower in the end of nibbling diet compared with the gorging diet, however, only for the last parameter this reduction was significant (p<0.02). The nibbling diet resulted in an insignificant increase in the high-density lipoprotein concentration. CONCLUSION: Taking into account, the difficulty in following the nibbling diet with a fear of weight gain, there would be no advantages in recommending the nibbling dietary pattern for normal free-living subjects, although its metabolic benefits in obese people could be the subject for further studies.

Synthesis of chemically cross-linked hydroxypropyl methyl cellulose hydrogels and their application in controlled release of 5-amino salicylic acid.

The objective of this study was to achieve the colon-specific delivery of an anti-ulcerative colitis drug using hydroxypropyl methyl cellulose (HPMC) hydrogels. HPMC hydrogels containing poly ethylene glycol (PEG) as cross-links have been prepared by reacting HPMC sodium salt with polyethylene glycol dichloride. The effect of cross-linking agent on swelling behavior of HPMC-PEG hydrogels, were investigated. Swelling parameters such as equilibrium degree of swelling, swelling ratio and network parameter such as molecular mass between cross-links (M(c)) were determined. The cross-linking concentrations were 0.5%, 1%, 1.5%, and 2% (based on weight of HPMC). The equilibrium swelling ratio (Q) of cross-linked HPMC hydrogels increases from 13.2 to 27.1 as the cross-linker percentage increases from 0.5% to 2%. 5-Aminosalicylic acid (5-ASA) was used as a model of an anti-inflammatory drug. Cross-linked HPMC hydrogels were found to be a promising drug delivery system for the drugs to be delivered to the colon.

Adriamycin release from poly(lactide-coglycolide)-polyethylene glycol nanoparticles: synthesis, and in vitro characterization.

The preparation, properties, and application in adriamycin delivery ofbiocompatible and biodegradable poly(lactide-co-glycolide)-polyethylene glycol (PLGA-PEG) nanoparticles are discussed. PLGA-PEG copolymers were synthesized by ring opening polymerization of the dl-lactide and glycolide in the presence of PEG1000. 1H-NMR and FT-IR spectrum were consistent with the structure of PLGA-PEG copolymers. The adriamycin-loaded nanoparticles could be prepared using a precipitation-solvent evaporation technique. The nanoparticles have been produced by a precipitation-solvent evaporation technique. The physical characteristics and drug loading efficiency of the PLGA-PEG nanoparticles were influenced by the composition of the PLGA-PEG copolymers used to prepare the nanoparticles. Particle sizes were between 65 and 100 nm for different compositions of PLGA-PEG copolymers. PLGA-PEG nanoparticles prepared from copolymers having relatively high PLGA/PEG ratios were smaller. Entrapment efficiency was 25%-33%. Adriamycin release from the nanoparticles at pH 7.4 showed an initial burst release and then sustained release phase. These results showed that PLGA-PEG nanoparticles could be an effective carrier for cancer therapy.

Development of a novel prolonged-release nicotine transdermal patch.

A transdermal patch for delivering nicotine for periods of 12-48h was designed. An inclusion complex formed between the nicotine and beta-cyclodextrine (beta-CD) was used in drug depot. The usefulness of a specially cross-linked polyvinyl alcohol (cross-PVA) membrane was investigated as a rate controlling membrane. The influence of carbopol polymers, type C-934P and C-940 and propylene glycol on transdermal permeation of nicotine through the rat skin was investigated. The results indicated a maximum flux of 42 microgcm(-2)h(-1) after 48 h from the patches made from C-934P when the propylene glycol concentration was 15% and the nicotine-beta-CD mole ratio in the inclusion complex was 3:1. These nicotine transdermal patches can be fabricated to obtain a controlled release, zero order systems.