Diabetic macular edema: review and update

Impairment in the visual acuity and quality of life of diabetic patients with macular edema can undeniably be decreased with systemic and ocular therapeutic intervention, as shown by numerous controlled studies. Such interventions, with early screening and periodic examination, are even more crucial given the increasing survival of patients with diabetic retinopathy. In the 1950s, adjusted 5-year survival rates for patients with PDR were less than 30%, whereas by the end of the century age- and sex-adjusted 5-year survival rates approached 90% for patients with early-onset diabetes and 60% for patients with late-onset diabetes [83]. Furthermore, advances in our understanding of diabetic retinopathy have led to biochemical adjuncts that offer the potential for further reduction of visual loss caused by diabetic macular edema. Despite such advances, the implementation of effective treatments has been hampered by concerns over hypoglycemia after intensive insulin regimens, poor physician compliance regarding guidelines for dilated ophthalmic examinations, and economic barriers to access [84]. Therefore, it is imperative for the ophthalmologist not only to discuss the progression and treatment of diabetic macular edema and the importance of routine examination with patients but also to work with other health care professionals to ensure the evaluation and treatment of associated cardiovascular and neurologic disease. Educational programs, such as those created by the National Eye Health and Education Program [85], may also assist the ophthalmologist in providing patients with the optimal care available in the 21st century.     

Downregulated expression of ADAM9 in anterior polar cataracts

PURPOSE: To determine whether ADAM (a disintegrin and metalloproteinase) is regulated in lens epithelial cells (LECs) of patients with anterior polar cataracts and by transforming growth factor (TGF)-beta 1 in cultured LECs. SETTING: Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Korea. METHODS: Lens epithelial cells attached to the anterior capsules of human cataractous lenses with nuclear and anterior subcapsular cataracts and noncataractous lenses were analyzed by reverse transcribed-polymerase chain reaction for the expression of ADAMs. The effect of TGF-beta 1 on ADAM gene expression was also tested in mouse lens epithelial explants and cultured LEC lines (alpha TN-4 and HLE B-3). RESULTS: Significantly reduced expression of mRNA for ADAM9 was observed in LECs from patients with anterior polar cataracts. The expression of mRNA for ADAM9 was downregulated by TGF-beta 1 in cultured human LECs. Treatment of cultured mouse LECs with TGF-beta 1 led to a reduction in ADAM1 mRNA. CONCLUSIONS: ADAMs are expressed and regulated in LECs. The downregulated expression of ADAM9 may serve as a marker for anterior polar cataracts in addition to previously known proteins, fibronectin, alpha-SMA, and beta ig-h3. The functions of this protein in lens pathology require further investigation.     

Metabolism of a new neuroprotective agent for ischemia-rep-erfusion damage,KR-31543 in the rats using liquid chroma-tography/electrospray mass spectrometry

KR-31543, (2S,3R,4S)-6-amino-4-[N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amino]-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-2H-1-benzopyran is a new neuroprotective agent for ischemia-reperfusion damage. The in vitro and in vivo metabolism of KR-31543 in rats has been studied by LC-electrospray mass spectrometry. Rat liver microsomal incubation of KR-31543 in the presence of NADPH resulted in the formation of a metabolite M1. M1 was identified as N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine on the basis of LC-MS/MS analysis with the synthesized authentic standard. Rat CYP3A1 and 3A2 are the major CYP isozymes involved in the formation of M1.     

Grapefruit juice reduces the oral bioavailability of fexofenadine but not desloratadine

BACKGROUND: Certain foods, such as grapefruit juice, are known to substantially alter the bioavailability of some drugs. These effects may be mediated by interactions with enzyme systems, such as cytochrome P450, or with active transporter systems, such as P-glycoprotein and organic anion transporting polypeptides. OBJECTIVE: To assess the effect of consumption of grapefruit juice on the oral bioavailability of two nonsedating antihistamines, fexofenadine and desloratadine. DESIGN: Non-blinded, randomised, single-dose, four-way crossover study. PARTICIPANTS: Twenty-four healthy adult volunteers. INTERVENTIONS: Single oral doses of desloratadine 5mg and fexofenadine 60mg taken without and with grapefruit juice (pretreatment with 240ml of double-strength juice three times daily for 2 days prior to administration of study drug, plus the same amount simultaneously with, and 2 hours after, the drug dose). Each treatment was separated by at least 10 days. MAIN OUTCOME MEASURES: Log-transformed pharmacokinetic parameters [peak plasma concentration (C(max)) and area under the curve (AUC)], time to maximum concentration, elimination half-life and electrocardiographic (ECG) parameters. RESULTS: Comparing the ratio of the pharmacokinetic parameter means (C(max) and AUC) with and without grapefruit juice (expressed as a percentage), the rate (C(max)) and extent (AUC) of absorption of fexofenadine were reduced by 30% by consumption of grapefruit juice. In contrast, the bioavailability of desloratadine was unaffected by grapefruit juice. No clinically significant changes in ECG parameters were observed following coadministration of grapefruit juice with desloratadine or fexofenadine compared with either antihistamine given alone. CONCLUSION: The bioavailability of drugs that do not undergo significant intestinal or hepatic metabolism, such as fexofenadine, may be altered when administered with agents that influence drug transport mechanisms.     

Work and lifestyle factors associated with morbidity of electronic women workers in Selangor,Malaysia

The objective of this study was to identify sociodemographic, work, living arrangement and lifestyle factors associated with morbidity of electronics women workers in selected factories in Selangor, Malaysia. The research design was a cross-sectional questionnaire-based survey. Most of the 401 respondents were young single Malay women. Morbidity was high as 85.5% of the women reported experiencing at least one chronic health problem, and 25.7% said that an illness or injury prevented them from carrying out normal activities within the last two weeks. Major acute illness symptoms were the common cold, backache, and diarrhoea while chronic health problems such as persistent headache, eye problems, menstrual problems, and persistent backache were also reported. After logistic regression, chronic health problems was significantly associated with room sharing; while illness that prevented normal activities within the last two weeks was significantly associated with overtime work and exercise. Further research is recommended to understand the complex inter-relationship between morbidity and working and living conditions.     

Accuracy of minimum data set in identifying residents at risk for undernutrition: oral intake and food complaints

OBJECTIVE: to evaluate the accuracy of nursing home (NH) staff in documenting two Minimum Data Set (MDS) items that are used to identify residents at risk for undernutrition, low oral intake and food complaints, using standardized observation and interview assessment protocols implemented by research staff. DESIGN AND METHODS: MDS information related to low oral intake (item K4c: <75% of most meals) and complaints about the taste of food (item K4a) was compared to independent evaluations of low oral intake and food complaints for a random sample of 75 residents in two proprietary NHs within the same month that a complete MDS assessment was due for each participant. Direct observations were conducted by research staff during nine mealtime periods for 3 consecutive days according to a standardized mealtime observational protocol to estimate low oral intake; and, two one-on-one interviews with residents were conducted on two consecutive days using standardized questions to assess the stability of food complaints. RESULTS: Research staff documentation based on direct observation and resident interviews showed a significantly larger number of residents being identified as potentially at risk for undernutrition due to low oral intake (73%) and/or stable complaints about the taste of food (32%) as compared with NH staff documentation of MDS items K4c (44%) and K4a (0%), respectively, within the same month. A total of 47% of the participants expressed stable complaints about some aspect of the NH food service (eg, variety, appearance, temperature). CONCLUSION: The documentation of low oral intake and food complaints on the MDS was inaccurate and resulted in a significant underestimate of residents with either of these risk factors for undernutrition.     

Microemulsion formulation of clonixic acid: solubility enhancement and pain reduction

Clonixic acid is currently marketed as a salt form because of its poor water-solubility. However, the commercial dosage form causes severe pain after intramuscular or intravenous injection. To improve the solubility of clonixic acid and to reduce pain on injection, clonixic acid was incorporated into oil-in-water microemulsions prepared from pre-microemulsion concentrate composed of varying ratios of oil and surfactant mixture. As an oil phase for drug incorporation, up to 14% castor oil could be included in the pre-microemulsion concentrate without a significant increase in droplet size. Both drug contents and droplet size increased as the weight ratio of Tween 20 to Tween 85 decreased. Taken together, when microemulsions were prepared from pre-microemulsion concentrate composed of 5:12:18 weight ratio of castor oil:Tween 20:Tween 85, clonixic acid could be incorporated at 3.2 mg mL(-1) in the microemulsion with a droplet size of less than 120 nm. The osmotic pressure of this microemulsion was remarkably lower than the commercial formulation, irrespective of the dilution ratios. The rat paw-lick test was used to compare pain responses among formulations. The microemulsion formulation significantly reduced the number of rats licking their paws as well as the total licking time, suggesting less pain induction by the microemulsion formulation. The pharmacokinetic parameters of clonixic acid after intravenous administration of the clonixic acid microemulsion to rats were not significantly different from those of the commercial formulation, lysine clonixinate. The present study suggests that microemulsion is an alternative formulation for clonixic acid with improved characteristics.     

Current developments in LC-MS for pharmaceutical analysis

The current developments in liquid chromatography-mass spectrometry (LC-MS) and its applications to the analysis of pharmaceuticals are reviewed. Various mass spectrometric techniques, including electrospray and nanospray ionization, atmospheric pressure chemical ionization and photoionization and their interface with liquid chromatographic techniques are described. These include high performance liquid chromatography, capillary electrophoresis and capillary electrochromatography and the advantages and disadvantages of each technique are discussed. The applications of LC-MS to the studies of in vitro and in vivo drug metabolism, identification and characterization of impurities in pharmaceuticals, analysis of chiral impurities in drug substances and high-throughput LC-MS-MS systems for applications in the "accelerated drug discovery" process are described.     

Modulation of radioligand binding to the GABA(A)-benzodiazepine receptor complex by a new component from Cyperus rotundus

Four sesquiterpenes, beta-selinene, isocurcumenol, nootkatone and aristolone and one triterpene, oleanolic acid were isolated from the ethylacetate fraction of the rhizomes of Cyperus rotundus and tested for their ability to modulate gamma-aminobutyric acid (GABA(A))-benzodiazepine receptor function by radioligand binding assays using rat cerebrocortical membranes. Among these compounds, only isocurcumenol, one of the newly identified constituents of this plant, was found to inhibit [3H]Ro15-1788 binding and enhance [3H]flunitrazepam binding in the presence of GABA. These results suggest that isocurcumenol may serve as a benzodiazepine receptor agonist and allosterically modulate GABAergic neurotransmission via enhancement of endogenous receptor ligand binding.