Efficacy of treatments for Demodex blepharitis: A systematic review and meta-analysis.

PURPOSE: We conducted a systematic review and meta-analysis to evaluate the efficacy of different treatment for Demodex blepharitis. Parameters studied were mites count, improvement of symptoms and mites' eradication, stratified on type of treatments and mode of delivery of treatments (local or systemic). METHOD: The PubMed, Cochrane Library, Embase, ClinicalTrials.gov, Google scholar and Science Direct databases were searched for studies reporting an efficacy of treatments for Demodex blepharitis. RESULTS: We included 19 studies (14 observational and 5 randomized clinical trials), for a total of 934 patients, 1741 eyes, and 13 different treatments. For mites count, eradication rate, and symptoms improvement, meta-analysis included fifteen, fourteen and thirteen studies, respectively. The overall effect sizes for efficiency of all treatments, globally, were 1.68 (95CI 1.25 to 2.12), 0.45 (0.26-0.64), and 0.76 (0.59-0.90), respectively. Except usual lid hygiene for mites count, Children's Hospital of Eastern Ontario ointment (CHEO) for both eradication rate and symptoms, and CHEO, 2% metronidazole ointment, and systemic metronidazole for eradication rate, all treatments were efficient. Stratified meta-analysis did not show significant differences between local and systemic treatments (1.22, 0.83 to 1.60 vs 2.24, 1.30 to 3.18 for mites count; 0.37, 0.21 to 0.54 vs 0.56, 0.06 to 0.99 for eradication rate; and 0.77, 0.58 to 0.92 vs 0.67, 0.25 to 0.98 for symptoms improvement). CONCLUSION: We reported the efficiency of the different treatments of Demodex blepharitis. Because of less systemic side effects, local treatments seem promising molecules in the treatment of Demodex blepharitis.

Long-term reproducibility of Edinger-Westphal stimulated accommodation in rhesus monkeys.

If longitudinal studies of accommodation or accommodation restoration procedures are undertaken in rhesus monkeys, the methods used to induce and measure accommodation must remain reproducible over the study period. Stimulation of the Edinger-Westphal (EW) nucleus in anesthetized rhesus monkeys is a valuable method to understand various aspects of accommodation. A prior study showed reproducibility of EW-stimulated accommodation over 14 months after chronic electrode implantation. However, reproducibility over a period longer than this has not been investigated and therefore remains unknown. To address this, accommodation stimulation experiments in four eyes of two rhesus monkeys (13.7 and 13.8 years old) were evaluated over a period of 68 months. Carbachol iontophoresis stimulated accommodation was first measured with a Hartinger coincidence refractometer (HCR) two weeks before electrode implantation to determine maximum accommodative amplitudes. EW stimulus-response curves were initially measured with the HCR one month after electrode implantation and then repeated at least six times for each eye in the following 60 months. At 64 months, carbachol iontophoresis induced accommodation was measured again. At 68 months, EW stimulus-response curves were measured with an HCR and photorefraction every week over four consecutive weeks to evaluate the short-term reproducibility over one month. In the four eyes studied, long-term EW-stimulated accommodation decreased by 7.00 D, 3.33 D, 4.63 D, and 2.03 D, whereas carbachol stimulated accommodation increased by 0.18 D-0.49 D over the same time period. The short-term reproducibility of maximum EW-stimulated accommodation (standard deviations) over a period of four weeks at 68 months after electrode implantation was 0.48 D, 0.79 D, 0.55 D and 0.39 D in the four eyes. Since the long-term decrease in EW-stimulated accommodation is not matched by similar decreases in carbachol iontophoresis stimulated accommodation, the decline in accommodation cannot be due to the progression of presbyopia but is likely to result from variability in EW electrode position. Therefore, EW-stimulated accommodation in anesthetized monkeys is not appropriate for long-term longitudinal studies of age-related loss of accommodation or accommodation restoration procedures.

Enhancement of vitamin D metabolites in the eye following vitamin D3 supplementation and UV-B irradiation.

PURPOSE: This study was designed to measure vitamin D metabolites in the aqueous and vitreous humor and in tear fluid, and to determine if dietary vitamin D3 supplementation affects these levels. We also determined if the corneal epithelium can synthesize vitamin D following UV-B exposure. METHODS: Rabbits were fed a control or vitamin D3 supplemented diet. Pilocarpine-stimulated tear fluid was collected and aqueous and vitreous humor were drawn from enucleated eyes. Plasma vitamin D was also measured. To test for epithelial vitamin D synthesis, a human corneal limbal epithelial cell line was irradiated with two doses of UV-B (10 and 20 mJ/cm(2)/day for 3 days) and vitamin D was measured in control or 7-dehydrocholesterol treated culture medium. Measurements were made using mass spectroscopy. RESULTS: 25(OH)-vitamin D3 and 24,25(OH)(2)-vitamin D3 increased significantly following D3 supplementation in all samples except vitreous humor. Tear fluid and aqueous humor had small but detectable 1,25(OH)(2)-vitamin D3 levels. Vitamin D2 metabolites were observed in all samples. Vitamin D3 levels were below the detection limit for all samples. Minimal vitamin D3 metabolites were observed in control and UV-B-irradiated epithelial culture medium except following 7-dehydrocholesterol treatment, which resulted in a UV-B-dose dependent increase in vitamin D3, 25(OH)-vitamin D3 and 24,25(OH)(2)-vitamin D3. CONCLUSIONS: There are measurable concentrations of vitamin D metabolites in tear fluid and aqueous and vitreous humor, and oral vitamin D supplementation affects vitamin D metabolite concentrations in the anterior segment of the eye. In addition, the UV exposure results lead us to conclude that corneal epithelial cells are likely capable of synthesizing vitamin D3 metabolites in the presence of 7-dehydrocholesterol following UV-B exposure.

Pupillary changes among Nigerian adults following the instillation of Garcinia kola nut extracts: multicentric studies.

BACKGROUND: A multi-centre, open, within-patient controlled study was performed on 106 adult volunteers to investigate the effects of Garcinia kolanut extracts on the pupillary sizes. STUDY DESIGN: 106 participants in three Nigerian Ophthalmic Centres with no pupillary defects and associated ocular or systemic co-morbidities had their pupillary diameters measured at 0, 15, 30 and 45 minutes respectively with a pupillometer (Neuroptics model # 586009). Using the left eyes as control, Garcinia kolanut extract was instilled into the right eyes at 15 minutes intervals. RESULTS: There were 63 females and 43 males ranging in age from 18 to 58 years with the mean age of 34.9 years. Average pupillary diameter measured among participants was 4.1 - 8.4 mm with the mean value of 6.0 mm prior to garcinia kola nut extract instillation. There was a gradual reduction in the baseline pupillary size with age in years at 0.2mm per decade without garcinia extract instillation. There was a significant higher baseline pupillary diameter in males than females with males and females mean values of 6.29mm (6.00 - 6.56mm) and 5.85mm (5.60 - 6.11mm) in the right eye (p=0.026) and mean pupillary diameters 6.16mm (5.90 - 6.42mm) and 5.80mm (5.56 - 6.04mm) in the left eyes (p=0.05) respectively. There were consistent significant miosis in the right eyes with instilled Garcinia kola nut extract compared to the left eyes at 15, 30 and 45 minutes (p=0.0000). CONCLUSION: 4% Garcinia kola nut extract drop has a transient miotic effect on human pupils not sustainable for more than 45 minutes.

Exogenous and endogenous ghrelin in gastroprotection against stress-induced gastric damage.

Ghrelin, identified in the gastric mucosa has been involved in control of food intake and growth hormone (GH) release but little is known about its influence on gastric secretion and mucosal integrity. The effects of ghrelin on gastric secretion, plasma gastrin and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) were determined. Exogenous ghrelin (5, 10, 20, 40 and 80 microg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS and this was accompanied by the significant rise in plasma ghrelin level, gastric mucosal blood flow (GBF) and luminal NO concentrations. Ghrelin-induced protection was abolished by vagotomy and attenuated by suppression of COX, deactivation of afferent nerves with neurotoxic dose of capsaicin or CGRP(8-37) and by inhibition of NOS with L-NNA but not influenced by medullectomy and administration of 6-hydroxydopamine. We conclude that ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol and WRS, and these effects depend upon vagal activity, sensory nerves and hyperemia mediated by NOS-NO and COX-PG systems.

Pilocarpina oral en el tratamiento de la xerostomía y xeroftalmía en pacientes con síndrome de Sjögren primario / Usefulness of oral pilocarpin therapy in the treatment of xerostomia and xerophtalmia in patients with primary Sjögren's syndrome

FUNDAMENTO Y OBJETIVO: Evaluar la eficacia de la pilocarpina en el tratamiento de la xerostomía y xeroftalmía en pacientes afectados de síndrome de Sjögren primario. PACIENTES Y MÉTODO: Se incluyó a 40 enfermos (38 mujeres y 2 varones), con una edad media de 49,2 años (intervalo, 35-68), con xerostomía y xeroftalmía intensas. Se practicaron pruebas objetivas (gammagrafía salival, prueba de Schirmer, tiempo de rotura lagrimal, tinción corneal con rosa de Bengala) y subjetivas (cuestionario de síntomas) para valorar la función glandular antes de inicio del tratamiento y a los 6 meses. RESULTADOS: Todos los pacientes recibieron inicialmente 15 mg/día de pilocarpina distribuidos en 3 tomas; 12 (30 por ciento) recibieron 20 mg/día. El 57,5 por ciento refirió mejoría subjetiva de la xerostomía y el 35 por ciento, de la xeroftalmía. La xerostomía mejoró objetivamente en el 35 por ciento de los pacientes y la xeroftalmía, en el 30 por ciento. CONCLUSIONES: El tratamiento con pilocarpina es beneficioso en pacientes con síndrome de Sjögren primario con moderada o escasa función glandular. No siempre existe una adecuada correlación entre la mejoría objetiva y la subjetiva (AU)

Vasodilatation in hyperalgesic rat skin evoked by stimulation of afferent A beta-fibers: further evidence for a role of dorsal root reflexes in allodynia.

In areas of secondary hyperalgesia, innocuous mechanical stimuli evoke pain (allodynia). We have proposed that this is produced by a central pre-synaptic interaction whereby A beta-fibers evoke spike activity (dorsal root reflexes) in nociceptive afferents (Pain, 68 (1996) 13). This activity should conduct centrally, evoking allodynia, and peripherally, evoking neurogenic vasodilatation. Here we tested this hypothesis by examining the effects of electrical stimulation of A beta-fibers on cutaneous blood flow before and after producing secondary hyperalgesia in anesthetized rats. Cutaneous blood flow was recorded in the hind paw skin innervated by the sural nerve using a laser Doppler flowmeter. The sural nerve was prepared for electrical stimulation, and the evoked activity was recorded from the sciatic nerve in continuity. Electrical stimulation (1 Hz, 4 x 0.2 ms pulses, 20 s) was applied to the sural nerve at 2T (A beta-fibers only) and 4T and 6T (A beta + A delta-fibers). Flux was recorded at baseline and after capsaicin or mustard oil application outside the sural nerve territory. The effects of intravenous administration of the calcitonin gene-related peptide (CGRP) receptor antagonist, alpha-CGRP(8-37), or of section of the sciatic nerve or of the L4-L6 dorsal roots were examined. Selective activation of the sural nerve A beta-fibers reliably evoked increases in cutaneous blood flow close to areas of chemical irritation or skin damage. A beta-fiber-evoked vasodilatation was abolished by sciatic nerve or dorsal root section and had a spatial arrangement and optimal stimulation pattern suggesting a central synaptic interaction similar to that responsible for dorsal root reflexes. The flux increases were dose-dependently and reversibly inhibited by alpha-CGRP(8-37), indicating that the A beta-fiber-evoked vasodilatation resulted from the antidromic activation of nociceptive cutaneous afferent fibers. These results support our hypothesis by showing activation of nociceptive primary afferents by A beta-fibers in areas of allodynia in a manner consistent with a pre-synaptic interaction evoking dorsal root reflexes.

Acupuncture for pilocarpine-resistant xerostomia following radiotherapy for head and neck malignancies.

OBJECTIVE: Xerostomia is a frequent and potentially debilitating toxicity of radiotherapy (XRT) for cancers of the head and neck. This report describes the use of acupuncture as palliation for such patients. METHODS AND MATERIALS: Eighteen patients with xerostomia refractory to pilocarpine therapy after XRT for head and neck malignancy were offered acupuncture as palliation. All patients are without evidence of cancer recurrence at the primary site. Acupuncture was provided to three auricular points and one digital point bilaterally, with electrostimulation used variably. The Xerostomia Inventory (XI) was administered retrospectively to provide an objective measure of efficacy. RESULTS: Acupuncture contributed to relief from xerostomia to varying degrees. Palliative effect as measured by the XI varied from nil to robust (pre- minus post- therapy values of over 20 points). Nine patients had benefit of over 10 points on the XI. CONCLUSIONS: Acupuncture reduces xerostomia in some patients who are otherwise refractory to best current management.

Effects of Dimethyl Sulfoxide (DMSO) on the Contraction of the Rat Iris Muscle

PURPOSE: To evaluate the effects of DMSO on the iris muscle contractility and to compare DMSO with other detergents(ethanol and triton-x 100). METHODS: After anesthesizing rats with an intraperitoneal injection of pentobarbital sodium, each animal was fixed under microscope. The pupil response to the drugs was examined by CCD camera and the video edge motion detector was used for measurement of alteration of the pupil size. The pupil response to the drugs was recorded by MacLab chart(version 3.6/s). RESULTS: Miosis induced by DMSO was initiated after 5 minutes, peaked at around 30 minutes and maintained until 3 hours after instillation. Miotic effect of DMSO was in a dose dependent manner ranging 0.01%-10% and was not reversed after washout. All detergents used in the present experiment induced miosis, however, DMSO elicited the strongest miotic response. After pretreatment with atropine, DMSO-induced miotic response was not affected, showing similar changes with control group. CONCLUSIONS: Taken together, it is concluded that DMSO induces miosis by inducing relaxation of iris dilator muscle.

Increased partitioning of pilocarpine to the oily phase of submicron emulsion does not result in improved ocular bioavailability.

Submicron emulsions containing pilocarpine as ion-pair with mono-dodecylphosphoric acid were prepared. Physical stability of these preparations was confirmed during 4 months of storage at 4 degrees C. Approximately 50% of the drug was found in the aqueous phase of emulsion separated using an ultrafiltration technique, while the rest was present in the oily phase and interphase. The miotic effect observed in rabbits after application of the ion-pair in aqueous solution or in submicron emulsion was the same; indicating that the drug distribution into the oily phase of the colloidal vehicle does not improve ocular bioavailability.

Studies on the effect of pilocarpine incorporation into a submicron emulsion on the stability of the drug and the vehicle.

In order to obtain a novel ocular formulation with a potential for prolonging pilocarpine activity, the drug (2.0%) was incorporated into a submicron emulsion containing soya-bean oil and lecithin as emulgator. The effect of drug incorporation into the emulsion on its physical stability and on the other hand, the potential of the vehicle to reduce drug degradation at pH higher than 5.0 was studied. The pH was adjusted to 6.5 or 5.0 and the physicochemical stability of the formulations was observed. The mean diameter of oily particles in the resulting emulsions measured by a laser diffractometer was 0.6-0.7 micron and this was larger than in a drug-free emulsion where a 0.33 micron value was measured. The formulations were physically stable for 6 months at 4 degrees C, but progressing chemical degradation of pilocarpine was noted at pH 6.5. At that pH nearly 8% of pilocarpine was degraded to isopilocarpine and pilocarpic acid, both in the emulsion and in the solution. Thus, it may be concluded that pilocarpine in submicron emulsion is not protected against degradation. The presence of pilocarpine changes the physical stability of the vehicle since the formulation was easily destabilized during autoclaving or at room temperature. In the presence of higher concentration of lecithin (2.4%) or co-emulgators (poloxamer 2.0% or Tween 80 0.5%) the mean droplet size in the emulsions was the same as in a drug-free system. However the emulsions containing poloxamer were not stable during storage. Viscosity of pilocarpine emulsions can be increased by addition of methylcellulose or sodium carmellose (1.0%), but an intensive creaming occurs in these systems. Pilocarpine base is less suitable for emulsion preparation than hydrochloride salt, and emulsions prepared at pH 5.0 show the most satisfying stability.

[The preparation and bioactivities of chiral analogs of baogongteng A].

Eight chiral analogs of baogongteng A were prepared from (+/-)-3 alpha-hydroxy-6 beta-acetoxytropane by chemical resolution. In myotic or mydriatic tests in rabbits, (-)-3 alpha-paramethyl benzenesulfonyloxy-6 beta-acetoxytropane showed cholinergic activities, while (+)-3 alpha-benzoyloxy-6 beta-acetoxytropane and (+)-3 alpha-parachloro benzoyloxy-6 beta-acetoxytropane showed anticholinergic activities.

Reversal of topical antiglaucoma medication effects on the conjunctiva.

OBJECTIVE: To determine whether the adverse effects of antiglaucoma medications could be reversed before filtration surgery, potentially reducing the risk of subsequent failure. METHODS: One month before surgery, 30 patients who were receiving multiple antiglaucoma medications underwent an inferior bulbar conjunctival biopsy, ceased using sympathomimetic drops, and began treatment with topical corticosteroid, (1% fluorometholone four times daily). At the time of surgery two conjunctival biopsy specimens were obtained, one from the operation site (superior bulbar region), and one from the inferior bulbar region. The biopsy specimens were quantitatively analyzed by light microscopy. In addition, the outcome of first trabeculectomy for 16 of these patients was compared with that of 16 matched patients who had not undergone an altered preoperative regimen of topical therapy. RESULTS: During a 1-month period a notable decrease occurred in the number of fibroblasts and inflammatory cells throughout the conjunctiva. Inferior bulbar conjunctiva was found to be representative of superior bulbar conjunctiva with respect to these changes. Furthermore, evidence comparing the matched patients suggested that the altered preoperative regimen may have improved the success rate of trabeculectomy. CONCLUSIONS: The preoperative regimen used reversed the adverse conjunctival effect of topical medication. The regimen may be of clinical benefit in improving the success rate of trabeculectomy.

The morphology of conjunctiva after long-term topical anti-glaucoma treatment. A quantitative analysis.

On biopsy material, differences in the degree of conjunctival inflammation and fibrosis between topically treated glaucoma patients and age matched controls, were examined histologically. Eighteen patients with primary glaucoma underwent goniotrephinations, because maximal medical therapy had failed. The patients had received at least two types of topical anti-glaucoma drugs for at least 12 months (mean 46 months). The control group consisted of 18 age-matched control patients without glaucoma, who had received no topical therapy. These patients underwent cataract surgery or squint surgery. Biopsies were taken from the infero-temporal bulbar quadrant with a biopsy forceps. The specimens were fixed while stabilized on a rubber support to exclude any major shrinkage. Specimens were analyzed by light microscopy for the content of inflammatory cells (plasma cells, lymphocytes, polymorphs, macrophages and mast cells), goblet cells and fibroblasts. No significant difference in the histologic parameters between the two groups could be demonstrated. The study suggests that topical treatment for periods up to 4 years with anti-glaucoma drugs does not induce morphological signs of inflammation and fibrosis of the conjunctiva.

[The synthesis and bioactivities of cholinergic tropane alkaloids].

Ten analogs of baogongteng A, the natural cholinergic tropane alkaloid isolated from Erycibe obtusifolia Benth, were designed and synthesized. The tropane skeleton was kept unchanged, while the substituting groups on N and C3 were modified. In myotic experiments in rabbits 3-paramethyl benzoyloxy-6-acetoxy nortropane(4), 3-propionyloxy-6-acetoxy nortropane(5), and 3-isobutyryloxy-6-acetoxy nortropane(6) showed cholinergic activities.

Ophthalmology's botanical heritage.

Many of today's important ophthalmic pharmaceuticals have a rich ethnobotanical history. Solanaceous plants, the source of atropine, have contributed to medical therapy since the beginning of Western civilization. The botanical source of physostigmine played a pivotal role as an ordeal poison in the culture of Old Calabar, West Africa. Native peoples of Amazonia treasured plants containing pilocarpine as panaceas because of their impressive diaphoretic effect. Nineteenth century scientists examining these plants because of their folkloric reputations discovered their active compounds and documented their physiological effects. Ophthalmologists such as Argyll Robertson, Laqueur, and Weber built upon this research to bring these pharmaceuticals into therapeutic use. The ongoing loss of the world's tropical rain forests threatens to destroy a vast storehouse of untested biological compounds.

[Synthesis of baogongteng A analogs].

In order to search for antiglaucoma drugs, three analogs (5, 12 and 10) of Baogongteng A were synthesized. The analog 12 shows myotic and reducing intraocular pressure activities in rabbit.

Pigmentary dispersion syndrome and suspected low tension pigmentary glaucoma.

Recent evidence suggests that pigmentary dispersion syndrome is a result of the mechanical abrasion of the posterior iris surface and the anterior zonular fibers causing pigmentary release onto the ocular structures. Irreversible glaucomatous changes may be the result of the inability of the endothelial cells lining the trabecular beams to continue to phagocytize the release pigment. Glaucomatous field changes may occur despite low intraocular pressures and no clinically observable cupping. Visual field testing is indicated in any patient presenting with pigmentary dispersion syndrome since pressure spikes inducing nerve damage occur with stress, exercise, or prolonged mydriasis. Treatment may include miotics to prevent further abrasion rather than typical pressure-lowering medication.