Volume 4, Number 10

Monday, March 8, 2004

In this issue: (click heading to view article)
		Editorial: The Science of Medical Research
		Associations Between Serum Lipoproteins and Severity of Diabetic Retinopathy
		Vitreous, Aqueous and Plasma Concentration of Orally Administered Voriconazole
		Protease IV Activity in P. aeruginosa Strains
		Orbital Radiotherapy for Mild Graves’ Ophthalmopathy
		Briefly

Editorial: The Science of Medical Research When I was in residency, the program I attended had a monthly journal club, as many teaching programs do. Typically, we were required to read three to five recent papers from peer-reviewed journals. Our professors made certain that the subject of each journal was thoroughly discussed. They considered it equally important that residents learned the skills required to judge whether the paper, subject matter and attendant research adhered to sound scientific principles. In other words, not only did we learn the subject matter of each paper, but we also assessed whether or not the paper itself was a sound work of research and reporting. At the time, the multitudes of short subject inserts on focused topics that we see today were uncommon, and the Internet was years from becoming an avenue for colleagues to learn, share information and glean advice. Today, we are deluged with tremendous amounts of information making one claim or another. In many instances the information is packaged in a clear and concise fashion and can be quite useful. Let us never forget, however, that these "packets" of information should never replace the work that still appears in major peer-reviewed journals. We also need to be diligent in remaining objective about what we read. We must judge the relevance, accuracy and importance of each research study and assess the validity of its conclusions. It is equally important that we realize that we can often learn more about a pharmaceutical substance, a device or a therapy after it earns FDA approval, when it is put to more widespread use than was allowed by the restrictions of an FDA clinical trial. Some examples include the accepted use of conductive keratoplasty for correcting near vision, and the use of brimonidine for papillary constriction and enhancement of night vision following LASIK. We must keep in mind that years may pass before the true difference between one pharmaceutical and another is fully appreciated. A classic example of this is the Moran Eye Center Study that unintentionally showed a statistically significant difference in endophthalmitis rates between patients receiving ofloxacin verses ciprofloxacin following cataract surgery. Likely, differences between current fourth-generation fluoroquinolones and antibiotic medications will arise in time. My own personal research has shown that gatifloxacin has faster killing times compared to those of moxifloxacin--but confirmatory studies are needed before clinicians can or should draw any conclusions. Let us take care that we do not leap from one product to another or decide that one device is better than another based on a recent Internet discussion we participated in, or because a "throw away" we just read claimed it was so. We cannot allow ourselves to go from evidence-based medicine to anecdotally based medicine. Let us remain those critical reviewers of scientific literature that we were as residents. Stephen E. Pascucci, MD Medical Editor [email protected]

Associations Between Serum Lipoproteins and Severity of Diabetic Retinopathy This study, a part of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), aimed to determine associations between retinopathy status and detailed serum lipoprotein subclass profiles in people with Type 1 diabetes from the DCCT/EDIC cohort. Researchers from the University of Oklahoma, the Medical University of South Carolina and the University of Alabama studied 440 women and 548 men from the DCCT/EDIC cohort. They characterized retinopathy by Early Treatment Diabetic Retinopathy Study (ETDRS) scores, hard exudate scores and ETDRS scores minus the hard exudate component. They characterized lipoproteins by conventional lipid profile, nuclear magnetic resonance lipoprotein subclass profile (NMR-LSP), apoA1, apoB, lipoprotein(a) and susceptibility of low-density lipoprotein (LDL) to oxidation. Investigators then analyzed data with and without the following covariates: age, gender, duration of diabetes, HbA1c, albumin excretion rate, creatinine clearance, hypertension, body mass index, waist-hip ratio, DCCT treatment group and smoking status. The severity of retinopathy was positively associated with triglycerides (combined cohort) and negatively associated with high-density lipoprotein (HDL) cholesterol (men, combined cohort). NMR-LSP identified retinopathy as being positively associated with small and medium very low-density lipoprotein (VLDL) and negatively with VLDL size. In men only, retinopathy was positively associated with small LDL, LDL particle concentration, apoB concentration and small HDL; it was negatively associated with large LDL, LDL size, large HDL and HDL size. No associations were found with apoA1, Lp(a), or susceptibility of LDL to oxidation. All three measures of retinopathy revealed the same associations. Results of the study suggest that NMR-LSP reveals new associations between serum lipoproteins and severity of retinopathy in Type 1 diabetes. The data are consistent with a role for dyslipoproteinemia involving lipoprotein subclasses in the pathogenesis of diabetic retinopathy.

SOURCE: Lyons, TJ, Jenkins AJ, Zheng D, et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci 2004;45:910-8.

Vitreous, Aqueous and Plasma Concentration of Orally Administered Voriconazole A study conducted at Houston’s Cullen Eye Institute suggests that orally administered voriconazole, a new-generation triazole antifungal agent, achieves therapeutic aqueous and vitreous levels in the noninflamed human eye. It also suggests that the activity spectrum appears to appropriately encompass the most frequently encountered mycotic species involved in the various causes of fungal endophthalmitis. The prospective, nonrandomized clinical study included 14 patients scheduled for elective pars plana vitrectomy surgery between December 1, 2002, and February 28, 2003, at the Cullen Eye Institute. Researchers obtained and analyzed aqueous, vitreous and plasma samples from all patients after oral administration of two 400-mg doses of voriconazole taken 12 hours apart before surgery. They performed assays by means of high-performance liquid chromatography. Mean +/- SD voriconazole concentrations in plasma (14 patients), vitreous (14 patients) and aqueous (11 patients) were 2.13 +/- 0.93 µg/mL, 0.81 +/- 0.31 µg/mL and 1.13 +/- 0.57 µg/mL, respectively. Mean +/- SD sampling times after oral administration of the second voriconazole dose for plasma, vitreous and aqueous were 2.4 +/- 0.6 hours, 3.0 +/- 0.5 hours and 2.9 +/- 0.5 hours, respectively. The percentages of plasma voriconazole concentration achieved in the vitreous and aqueous were 38.1 percent and 53.0 percent, respectively. Mean vitreous and aqueous minimum inhibitory concentrations for 90 percent of isolates (MIC90) were achieved against a wide spectrum of yeasts and molds, including Aspergillus species and Candida species, as well as many other organisms. Authors of the study conclude that because of its broad spectrum of coverage, low MIC90 levels for the organisms of concern, good tolerability and excellent bioavailability with oral administration, voriconazole may represent a major advance in the prophylaxis or management of exogenous or endogenous fungal endophthalmitis.

SOURCE: Hariprasad SM, Mieler WF, Holz ER, et al. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans. Arch Ophthalmol 2004;122:42-47.

Protease IV Activity in P. aeruginosa Strains The protease IV gene and its product are common to P. aeruginosa, but not to other Pseudomonas species, according to a study by the Louisiana State University Eye Center and the LSU Health Sciences Center. Investigators aimed to determine the distribution of the protease IV gene, the production of this and other proteases by multiple strains of Pseudomonas and the virulence of a mutant that is specifically deficient in protease IV. They cloned the protease IV gene, analyzed its sequence and determined its chromosomal location using pulse-field gel electrophoresis. They conducted three polymerase chain reactions (PCRs) to detect the protease IV gene in 30 Pseudomonas isolates; they then determined protease production by Western blot analysis, colorimetric assay and zymography. They analyzed an allelic replacement mutant deficient in the protease IV gene for enzyme production, corneal growth and corneal virulence. The protease IV gene was identified in all P. aeruginosa, but none of the non-aeruginosa strains tested. The protease IV genes of strains PA103-29 and PAO1 were in a common chromosomal site and had 98.5 percent sequence identity, with variations occurring mainly in the promoter region. The protease IV activity of the 23 wild-type P. aeruginosa strains tested varied from 2.3 to 221.5 x 10-3 U/mg protein in the culture supernatant. Protease IV was produced by all P. aeruginosa wild-type strains. A protease IV-deficient mutant, derived from strain PA103-29, reduced virulence compared with its parent strain and unexpectedly produced alkaline protease.

SOURCE: Caballero A, Thibodeaux B, Marquart M, et al. Pseudomonas keratitis: protease IV gene conservation, distribution, and production relative to virulence and other Pseudomonas proteases. Invest Ophthalmol Vis Sci 2004;45:522-30.

Orbital Radiotherapy for Mild Graves’ Ophthalmopathy Radiotherapy is often used in Graves’ ophthalmopathy, but its efficacy has been doubted. In this study, Dutch researchers compared the efficacy of radiotherapy with sham irradiation in mild ophthalmopathy. In a double-blind randomized trial, 44 patients received orbital irradiation and 44 were sham-irradiated. The primary outcome was assessed using major and minor criteria. As secondary outcome, investigators used a disease-specific quality of life questionnaire (the GO-QoL) and compared cost-effectiveness and need for follow-up treatment. The primary outcome was successful in 23 of 44 (52 percent) irradiated patients vs. 12 of 44 (27 percent) sham-irradiated patients at 12 months after treatment. Radiotherapy was effective in improving eye muscle motility and decreasing the severity of diplopia. However, quality of life improved similarly in both groups. Those in the radiotherapy group had less need for follow-up treatment: 66 percent of this group required further treatment vs. 84 percent of the sham-irradiated patients. Retrobulbar irradiation did not prevent worsening of ophthalmopathy, which occurred in 14 percent of the irradiated and 16 percent of the sham-irradiated patients. The authors concluded that while radiotherapy is an effective treatment in mild ophthalmopathy, the improvement upon irradiation may not be associated with an increase in quality of life or a reduction in treatment costs.

SOURCE: Prummel MF, Terwee CB, Gerding MN, et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves’ ophthalmopathy. J Clin Endocrinol Metabol 2004;89(1):15-20.

BRIEFLY FDA APPROVES CANCER THERAPY FOR INHIBITING ANGIOGENESIS. The FDA has approved Genentech’s Avastin (bevacizumab) for use in combination with intravenous 5-Fluorouracil-based chemotherapy as a treatment for patients with first-line or previously untreated metastatic cancer of the colon or rectum. Avastin is the first FDA-approved therapy designed to inhibit angiogenesis, the process by which new blood vessels develop, which is necessary to support tumor growth and metastasis. It is the predecessor to Genentech’s Lucentis, a drug with the same anti-Vascular Endothelial Growth Factor (VEGF) inhibitor. Lucentis is in Phase III trials to evaluate its safety and efficacy compared with verteporfin photodynamic therapy in treating patients with age-related macular degeneration. JAPANESE FIRM BEGINS LARGE-SCALE STUDY OF DIABETIC RETINOPATHY TREATMENT. Takeda Chemical Industries, a Japan-based firm focusing on pharmaceutical development, has completed patient enrollment for its three-part Diabetic Retinopathy Candesartan Trials (DIRECT). DIRECT is the first program designed to establish whether treatment with an angiotensin II type 1 (AT1) receptor blocker, candesartan cilexetil, targeting the renin angiotensin system, can provide effective treatment against the onset and progression of diabetic retinopathy. The large-scale, double-blind trials will include 5,238 patients in about 300 investigational sites in 30 EU countries; they will be jointly conducted and sponsored by Takeda and AstraZeneca. Patients will receive 32 mg of candesartan cilexetil or placebo; the three separate clinical studies will investigate the effect of candesartan cilexetil in Type 1 diabetic patients without retinopathy for primary prevention; Type 1 diabetic patients with retinopathy for secondary prevention; and Type 2 diabetic patients with retinopathy for secondary prevention. For more information, go to www.takeda.co.jp/index-e.html. FDA APPROVES SANTEN TREATMENT FOR BACTERIAL CORNEAL ULCER. The FDA has approved Santen Pharmaceutical Company’s new ocular anti-infective medication, IQUIX (levofloxacin ophthalmic solution 1.5%, indicated for the treatment of bacterial corneal ulcer (the full spectrum of susceptible organisms can be found in the product’s package insert). The treatment is a sterile topical ophthalmic solution containing 1.5% levofloxacin, a potent fluoroquinolone active against a broad spectrum of Gram-positive and Gram-negative ocular pathogens. Levofloxacin"s high solubility, at neutral pH, allows the solution to be formulated with a concentration of active drug three times higher than any other ophthalmic fluoroquinolone on the market. In two randomized, double-masked multicenter controlled clinical trials, IQUIX achieved a clinical cure rate of 73 to 87 percent. The most frequently reported adverse events in the overall study population were headache and a taste disturbance following instillation, occurring in approximately 8 to 10 percent of patients. Vistakon Pharmaceuticals will be the exclusive U.S. distributor for IQUIX. EDITOR"S NOTE: Although concentration is an important consideration with flouroquinolones, it is only one factor in treating ocular infections. Other drugs that were not specifically tested for the purpose of treating ulcers may be equally effective, especially in light of increasing drug resistance.

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