Microbiological efficacy of 3-day treatment with azithromycin 1.5% eye-drops for purulent bacterial conjunctivitis.

PURPOSE: Antibacterial efficacy of topically applied azithromycin 1.5% was compared with tobramycin 0.3% in a multicenter, randomized, investigator-masked study for the treatment of purulent bacterial conjunctivitis. METHODS: A total of 1043 adults and children received either azithromycin twice daily for 3 days (n=524) or tobramycin every 2 hours while awake for 2 days, then four times daily for 5 days (n=519). Conjunctival swabbing was taken at days 0, 3, and 9, using alginate swabs resuspended in a dissolution-transport medium, providing rapid and reproducible results. Cagle's criteria were used to define the pathogenicity level for each isolated bacterium. RESULTS: In the per-protocol set, the rate of bacteriologic resolution was 85.2% for azithromycin versus 83.8% for tobramycin on day 3, and 92.8% for azithromycin versus 94.6% for tobramycin on day 9. Azithromycin was demonstrated to be noninferior to tobramycin according to the 10% noninferiority margin. Although some bacteria were categorized as resistant to tested antibiotics, eradication was observed (for azithromycin: Acinetobacter, Enterobacteriaceae, Pseudomonas), highlighting the specific pharmacokinetics/pharmacodynamics of the ocular route. CONCLUSIONS: In total, topical therapy with azithromycin 1.5% administered only twice daily for 3 days effectively eradicates most pathogenic bacteria associated with bacterial conjunctivitis. These microbiologic results are in accordance with the observed clinical outcome. This new anti-infective product has the advantage of a short treatment course which could lead to an improvement in patient compliance.

Tear concentrations of azithromycin following topical administration of a single dose of azithromycin 0.5%, 1.0%, and 1.5% eyedrops (T1225) in healthy volunteers.

PURPOSE: To evaluate azithromycin tear concentrations after one drop of T1225 0.5%, 1.0%, and 1.5% eyedrops. METHODS: In this randomized, double-masked study, 91 healthy volunteers received one drop into each eye of T1225 0.5% (n=23), T1225 1.0% (n=38), or T1225 1.5% (n=38). Azithromycin tear concentrations were measured by HPLC-MS at seven time points for 24 hours. Tolerability was evaluated. RESULTS: T1225 1.0% and 1.5% had similar pharmacokinetic profiles. After a post-instillation peak (167 to 178 mg/L after 10 minutes), mean concentrations remained above 7 mg/L for 24 hours (except for T1225 1% at H24). A delayed increase of the azithromycin mean tear concentration might be explained by the known late azithromycin release from tissues after storage in cells. Areas under inhibitory curve (AUICs) of T1225 1.0% and 1.5% were higher than AUICs of T1225 0.5% and ranged between 47 and 90. The three T1225 concentrations were safe for the ocular surface. CONCLUSIONS: Once daily instillation of T1225 1.0% and 1.5% was shown to reach an AUIC markedly above the required threshold for an antibacterial activity against Gram-positive bacteria (25-35). These results suggest that a BID instillation is more likely to ensure antimicrobial activity against Gram-negative bacteria (threshold >100).

Safety and immunogenicity of subcutaneous or intramuscular administration of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae in healthy volunteers.

The safety and immunogenicity of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae was evaluated in 84 volunteers according to the route of administration, i.e., subcutaneous (SC) or intramuscular (IM), in a double-blind randomised trial. The volunteers were randomised into four groups: SC vaccine; IM vaccine; SC placebo; and IM placebo. Primary vaccination comprised two injections on day 0 and day 14, with a booster after 6 months. A second booster was given 30 months after primary vaccination. Local reactions within 1 h of injections were rare, with no difference between vaccine groups. Local reactions within 3 h were more frequent after the second, third and fourth SC injections than after IM injections. Systemic reactions never occurred within 1 h of vaccination and were rare within 3 days; the rates were comparable for the different vaccine groups. Evolution of the antibody responses, as assessed by microscopic agglutination tests and specific IgG and IgM ELISAs, were similar for both injection routes. IgG seroconversion rates after the first booster were 97% (95% CI 80-100%) for the SC vaccine group, and 96% (95% CI 80-100%) for the IM vaccine group, and both reached 100% for IgG after the second booster. The safety and immunogenicity of the anti-leptospiral vaccine were both good. Monitoring of antibody levels established that a booster dose triggered a strong antibody response in fully vaccinated subjects at 30 months after primary vaccination.

Ocular symptoms and signs with preserved and preservative-free glaucoma medications.

PURPOSE: To compare the prevalence of side effects between eyedrops with or without preservatives, in terms of subjective symptoms and objective signs in patients with open-angle glaucoma. METHODS: In a multicenter cross-sectional epidemiologic survey in four European countries, ophthalmologists in private practice enrolled 9658 nonconsecutive patients using preservative (P) or preservative-free (PF) beta-blocking eyedrops between June 1997 and December 2003. Subjective symptoms, conjunctival and palpebral signs, and superficial punctate keratitis were explored before and after a change in therapy. For statistical analysis, a Chi-square test was used to calculate the differences in the prevalence of symptoms and signs with or without preservatives. RESULTS: A total of 74% of the patients used P, 12% PF, 10% a P-PF combination, and in 4% the type of medication was unknown. Each recorded symptom and all the palpebral, conjunctival, and corneal signs were significantly more frequent (p<0.0001) in the P-group than in the PF-group, such as pain or discomfort during instillation (48 vs 19%), foreign body sensation (42 vs 15%), stinging or burning (48 vs 20%), and dry eye sensation (35 vs 16%). A total of 68% of the patients had a sec-ond visit performed, of whom 63% (6083) had been evaluated on treatment difference. A significant decrease (p<0.0001) of all ocular symptoms and signs was observed in patients in whom the preserved eyedrops were diminished in number or altered into preservative free drops. CONCLUSIONS: Compared to preserved eyedrops, preservative free eyedrops are significantly less associated with ocular symptoms and signs of irritation.

Comparison of a non-preserved 0.1% T-Gel eye gel (single dose unit) with a preserved 0.1% T-Gel eye gel (multidose) in ocular hypertension and glaucomatous patients.

AIM: This comparative, open design, phase III study was to assess the non-inferiority of the non-preserved T-Gel 0.1% single dose unit (SDU) versus its preserved multidose (MD) reference. METHODS: 175 patients with bilateral POAG or OHT were randomised: 87 patients were to receive one drop daily of T-Gel 0.1% MD and 88 patients were to receive one drop daily of T-Gel 0.1% SDU, for a treatment period of 12 weeks. The primary efficacy variable was the change in intraocular pressure (IOP) in the worse eye between the baseline and the last assessment. Subjective and objective ocular signs as well as adverse events were recorded for safety. Global tolerance was assessed by the investigator and by the patient. RESULTS: The mean percentage reduction from baseline IOP was 24% for both treatments groups, which was consistent with previous studies. The safety results were comparable in both treatment groups. Because of gel formulation, mild short lasting episodes of blurred vision occurred for about 20% of patients. The global tolerance assessment reported that both treatments were well tolerated. CONCLUSION: The overall study results demonstrated that T-Gel 0.1% SDU is not inferior to T-Gel 0.1% MD.

Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication.

AIM: To determine the incidence of ocular toxicity of preservatives with glaucoma medications. METHODS: A prospective epidemiological survey was carried out in 1999 by 249 ophthalmologists on 4107 patients. Ocular symptoms, conjunctiva, cornea, and eyelids were assessed. A chi(2) test was used for differences between preserved eye drops (P) and preservative free eye drops (PF). RESULTS: 84% patients used P, 13% received PF, and 3% a combination of P and PF eye drops. All symptoms were more prevalent with P than with PF drops (p<0.001): discomfort upon instillation (43% versus 17%), and symptoms between instillations such as burning-stinging (40% versus 22%), foreign body sensation (31% versus 14%), dry eye sensation (23% versus 14%), tearing (21% versus 14%), and eyelid itching (18% versus 10%). An increased incidence (>2 times) of ocular signs was seen with P eye drops. The prevalence of signs and symptoms was dose dependent, increasing with the number of P drops. A reduction in the symptoms and signs was observed when patients changed from P to PF eye drops (p<0.001). CONCLUSIONS: Symptoms and signs are less prevalent when PF drops are used. Moreover, most of the adverse reactions induced by P glaucoma medication are reversible after removing preservatives.

Current-mode subthreshold MOS circuits for analog VLSI neural systems.

An overview of the current-mode approach for designing analog VLSI neural systems in subthreshold CMOS technology is presented. Emphasis is given to design techniques at the device level using the current-controlled current conveyor and the translinear principle. Circuits for associative memory and silicon retina systems are used as examples. The design methodology and how it relates to actual biological microcircuits are discussed.

[Allergy and preservatives. Apropos of 3 cases of allergy to benzalkonium chloride]. / Allergie et conservateurs. A propos de trois cas d'allergie au chlorure de benzalkonium.

BACKGROUND: Ophthalmologists are not always aware of the hypersensitising potential of benzalkonium chloride (preservative widely used in ophthalmology). OBSERVATIONS: Hypersensitivity to benzalkonium chloride was asserted by allergologic exploration in the three cases reported. Contact allergy, a frequent phenomenon, was diagnosed in two cases. The third case represents one of the few cases described in ophthalmology of immediate hypersensitivity associated to vital risk: chemosis and angioneurotic edema is reported in a woman who had been already presented an anaphylactic shock to a quaternary ammonium family anaesthetic. DISCUSSION: The ocular allergologic evaluation is specified. Risk to benzalkonium chloride sensitisation factors (ophthalmology, presence of benzalkonium chloride in numerous daily used products) are reviewed. The risk of severe immediate allergy is increased due to the relationship of benzalkonium chloride to other quaternary ammonium compounds. CONCLUSION: Best risk prevention remains allergen eviction.

[Efficacy and safety of substituting a twice-daily regimen of timolol with a single daily instillation of nonpreserved beta-blocker in patients with chronic glaucoma or ocular hypertension]. / Intérêt de la substitution d'un traitement journalier de 2 instillations de timolol par 1 instillation quotidienne de bêtabloquant non conservé chez des patients présentant un glaucome chronique ou une hypertonie oculaire.

AIM: To evaluate the efficacy and safety of a single daily instillation of nonpreserved timolol in patients with chronic glaucoma or ocular hypertension previously treated with a twice-daily regimen of timolol 0.25% or 0.50%. PATIENTS AND METHODS: A prospective open clinical trial was undertaken by 220 ophthalmologists in 435 patients with chronic glaucoma or ocular hypertension controlled with twice-daily instillations of timolol 0.25% or 0.50%. In this population, the previous regimen was substituted with a single daily instillation of preservative-free timolol 0.25% or 0.50% for 3 months. The changes in intraocular pressure (IOP) were recorded as well as local and systemic tolerance and patient compliance. RESULTS: It was found that 398 patients (93.6%) maintained stable IOP: in 92%, IOP increased no more than 2 mmHg. The mean IOP was 17.0 +/- 2.2 mmHg at D0, 16.5 +/- 2.4 mmHg at D28/42 and 16.6 +/- 2.4 mmHg at D84. The proportion of patients with at least one ocular symptom upon instillation or at another time decreased (p<0.0001 and p=0.03, respectively). The proportion of conjunctival hyperemia reduced from 24.4% to 14.6% (p=0.0002). The rate of folliculopapillar reactions and superficial punctate keratitis was halved (p=0.005 and p=0.02, respectively). CONCLUSION: During this study in daily practice, the switch from a twice-daily regimen of timolol to a once-daily application maintained stable intraocular pressure with a notable improvement in tolerance.

[Exfoliative syndrome and cataract surgery]. / Syndrome exfoliatif et chirurgie de la cataracte.

In the present prospective study, we compared the results of cataract surgery in two groups with or without exfoliation syndrome; 210 eyes were studied. The preoperative pupillary dilatation was smaller in the group with exfoliation syndrome (SE). We noticed a higher incidence of complications during planned extracapsular cataract extraction in patients with SE. A pupillary diameter smaller than 6 mm increases the incidence of capsulozonular rupture (22.5%) in these patients. After surgery, an inflammatory reaction and a transient increase in intraocular pressure were more frequent and the visual results were less favourable in the group with SE. The exfoliation syndrome is a major risk factor for cataract surgery. We recommend extracapsular extraction associated with a sector iridectomy when the pupillary diameter measures less than 6 mm.

[Efficacy and safety of a fluid carbomer gel versus a conventional carbomer gel in dry eye treatment]. / Efficacité et tolérance d'un gel de carbomère fluide versus un gel de carbomère classique lors du traitement du syndrome sec.

AIM: To compare the risk/benefit for C974P (a 0.25% fluid carbomer gel in a vial allowing dropwise instillation) versus a conventional carbomer gel. MATERIAL AND METHODS: During this multicenter, randomized, investigator-masked trial, patients with dry eye syndrome were treated with C974P or C940. Control visits were planned on day 7, day 28 (efficacy evaluation) and day 56 (tolerance evaluation). The main criterion was dry eye symptoms globally assessed by a visual analog scale (VAS). The non-inferiority limit for the between-group difference of VAS changes was 10 mm. RESULTS: In the population of 169 patients (87 patients for C974P, 82 for C940), C974P was at least as effective as C940 on symptoms (non-inferiority hypothesis confirmed). The mean VAS value fell by one third in the two groups. The objective signs improved identically in the two groups: corneal staining by fluorescein (p=0.96), rose Bengal score (p=0.73), and lacrimal break-up time (p=0.73). The dosage adaptation was slightly lower than three instillations per day (p=0.16). The adverse events were mild or moderate. CONCLUSION: C974P galenic changes are able to reach the same level of efficacy on dry eye symptoms and ocular surface damages as the conventional tube carbomer gels.

[Ocular tolerance of a new formulation of nonpreserved diclofenac]. / Intérêt d'une nouvelle formulation de diclofénac sans conservateur pour la surface oculaire.

AIM: To compare the ocular tolerance of nonpreserved diclofenac versus thiomersal-preserved diclofenac in healthy volunteers. MATERIALS AND METHODS: Forty healthy volunteers instilled Dicloabak in the randomised eye and thiomersal-preserved diclofenac in the other eye, according to a strictly identical dosing regimen, for 28 days. Each volunteer thus served as his or her own control. The dose regimen was five drops/day for 7 days followed by three drops/day for 20 days. Ocular tolerance was assessed by the discomfort upon instillation (measured on a visual analogue scale [VAS]), subjective ocular symptoms following instillation (irritation/burning/stinging, eye dryness and foreign body sensation) and finally by an objective examination of the ocular surface. These criteria were evaluated on days 0, 14, 21 and 28. RESULTS: The subjective ocular symptoms following instillation were significantly lower in the nonpreserved group at Day 7 and nearly significantly lower until the end of the study. The biomicroscopy exam confirmed that there was better tolerance without thiomersal. There was less follicular-papillary conjunctivitis and a significantly better lissamine green score in the Dicloabak group. CONCLUSION: The results of this study demonstrate that the nonpreserved formulation of diclofenac is better tolerated by the ocular surface and thus constitutes a therapeutic benefit.

[Comparison of once-daily nonpreserved timolol and timolol maleate gel-forming solution associated with latanoprost]. / Comparaison du timolol sans conservateur et du timolol à délivrance prolongée donnés une fois par jour en association à du latanoprost.

AIM: To compare the efficacy and safety of a single daily instillation of nonpreserved timolol to a timolol maleate gel-forming solution in patients with chronic glaucoma or ocular hypertension already treated with latanoprost. PATIENTS AND METHODS: A randomized, prospective, multicenter, open, parallel-group clinical trial was undertaken with 73 patients with chronic glaucoma treated with latanoprost and a timolol maleate gel-forming solution. In 36 patients, the previous regimen was substituted by nonpreserved timolol given instead of timolol maleate gel for 3 months. The changes in intraocular pressure (IOP) were recorded as well as local and systemic tolerance and patient compliance. RESULTS: At 3 months, both regimens were found equivalent in maintaining IOP control between D0 and D84. The difference with baseline was -0.08 +/- 2.22 mmHg and -0.38 +/- 2.41 mmHg in the nonpreserved timolol group and in the timolol maleate gel-forming solution group, respectively (CI 95% [-0.79; 1.38]). After 84 days of treatment, blurred vision (5.9%) and eyelid deposits (5.9%) were reduced in the preservative-free timolol group compared to the other group (respectively, 33.3% and 24.2%). These differences were statistically significant for both signs (blurred vision: p < 0.0001 and for eyelid deposits: p = 0.03). CONCLUSION: This short-term study has demonstrated the equivalence of nonpreserved timolol to timolol maleate gel-forming solution in terms of IOP control. Moreover, the local tolerance of nonpreserved timolol was better.

Prevalence of vernal keratoconjunctivitis: a rare disease?

OBJECTIVE: To determine the prevalence of vernal keratoconjuntivitis (VKC) in Europe. METHODS: A cross-sectional survey was mailed to 3003 ophthalmologists from six countries (Finland, France, Italy, The Netherlands, Norway and Sweden) representing 151.9 million inhabitants. Results were analysed per country, and VKC prevalence for the 15 European member states in 2002 was extrapolated. Six hypotheses were used: disease duration (4 or 8 years) combined with three prevalence hypotheses for non-responding ophthalmologists. RESULTS: The response rate to the survey was 29.5%. The estimates of VKC prevalence in Western Europe (per 10,000 inhabitants) ranged from 1.16 to 10.55. The prevalence of VKC with corneal complications ranged from 0.30 to 2.26. The VKC prevalences per country were in the following ranges: Italy 2.4-27.8, Finland, 0.7-8.4, Sweden 1.2-8.7, The Netherlands 0.6-4.6, France 0.7-3.3 and Norway 0.3-1.9. VKC with corneal complications were: Italy 0.4-4.8, Sweden 0.3-2.4, Finland 0.2-2.8, The Netherlands 0.2-1.6, France 0.3-1.4 and Norway 0.1-1.0. CONCLUSIONS: Based on the most likely hypotheses concerning disease duration and non-responding ophthalmologists' VKC case rate, the best estimate of VKC prevalence in Western Europe is 3.2/10,000 inhabitants. The prevalence of VKC with corneal complications is 0.8/10,000 inhabitants.

Clinical and biological efficacy of preservative-free NAAGA eye-drops versus levocabastine eye-drops in vernal keratoconjunctivitis patients.

AIMS: This comparative and randomised pilot study assessed the clinical and biological efficacy of Naaxia Sine(R) eye-drops versus levocabastine eye-drops in the treatment of vernal keratoconjunctivitis (VKC). METHODS: Twenty-three VKC patients were randomised and treated bilaterally for 28 days with N-acetyl-aspartyl-glutamate (NAAGA) or levocabastine (LEVO) eye-drops. The primary efficacy variable, overall evolution of eosinophil cationic protein (ECP) tear concentrations, was assessed in a masked fashion on D0, D7 and D28. Clinical symptoms and signs were reported at the same time points. Biological parameters were analysed with a non-parametric rank-based approach. Global tolerance was assessed by the investigator and patient. RESULTS: At all time points, ECP tear levels were significantly reduced in the NAAGA compared with the LEVO group (p = 0.023). Reduction of eosinophil leucocytes and tear lymphocytes was higher not significant in the NAAGA group. The same trend was observed for the evolution of total ocular symptom score. There were no significant differences between treatment groups in the occurrence of adverse effects, except for burning which was more frequent in the LEVO group (p = 0.002). CONCLUSION: The anti-eosinophilic actions of NAAGA were shown by a significant reduction of ECP tear concentrations. A decreased lymphocyte count and an overall improvement of the symptomatology were also noted. Moreover, the tolerability of NAAGA appeared to be better.

[Improvement of dry eye symptoms with polyunsaturated fatty acids]. / Amélioration de la symptomatologie chez des patients atteints de sécheresse oculaire et traités oralement par des acides gras polyinsaturés.

INTRODUCTION: Polyunsaturated fatty acids (PUFAs) are involved in inflammatory pathways via prostaglandins. Conjunctival inflammation is a hallmark of all dry eye syndromes. We investigated the role of dietary n-6 and n-3 fatty acids in patients suffering from ocular dryness. PATIENTS AND METHODS: Seventy-one patients presenting with mild to moderate dry eye syndromes were randomly assigned to Nutrilarm or placebo capsules, twice a day for 6 months. The Schirmer test, BUT, fluorescein staining, and lissamin green stainings were performed at inclusion and after 1, 3, and 6 months. Furthermore, a questionnaire related to the dry eye symptoms and global discomfort was provided at every visit. RESULTS: The Schirmer test, BUT, fluorescein staining, and lissamin green stainings were improved with treatment when compared to placebo but the difference was not statistically significant. The efficacy evaluated by the patients and the investigator were nearly significant (p=0.052 and p=0.054, respectively). For some signs, such as reflex tearing and conjunctival hyperemia, the improvement reached the threshold of significance (p=0.047 and p=0.045, respectively). The same results were found with skin quality and emotional condition, which were improved (61% with treatment versus 36% with placebo). CONCLUSION: This double-masked pilot study shows that PUFAs seem to be an interesting tool to alleviate the symptoms related to dry eye syndrome. These results should be confirmed using a larger study population.