Effect of sublingual application of cannabinoids on intraocular pressure:A pilot study

PURPOSE: The purpose of this study was to assess the effect on intraocular pressure (IOP) and the safety and tolerability of oromucosal administration of a low dose of delta-9-tetrahydrocannabinol (?-9-THC) and cannabidiol (CBD). PATIENTS AND METHODS: A randomized, double-masked, placebo-controlled, 4 way crossover study was conducted at a single center, using cannabis-based medicinal extract of ?-9-THC and CBD. Six patients with ocular hypertension or early primary open angle glaucoma received a single sublingual dose at 8 AM of 5 mg ?-9-THC, 20 mg CBD, 40 mg CBD, or placebo. Main outcome measure was IOP. Secondary outcomes included visual acuity, vital signs, and psychotropic effects. RESULTS: Two hours after sublingual administration of 5 mg ?-9-THC, the IOP was significantly lower than after placebo (23.5 mm Hg vs. 27.3 mm Hg, P=0.026). The IOP returned to baseline level after the 4-hour IOP measurement. CBD administration did not reduce the IOP at any time. However, the higher dose of CBD (40 mg) produced a transient elevation of IOP at 4 hours after administration, from 23.2 to 25.9 mm Hg (P=0.028). Vital signs and visual acuity were not significantly changed. One patient experienced a transient and mild paniclike reaction after ?-9-THC administration. CONCLUSIONS: A single 5 mg sublingual dose of ?-9-THC reduced the IOP temporarily and was well tolerated by most patients. Sublingual administration of 20 mg CBD did not reduce IOP, whereas 40 mg CBD produced a transient increase IOP rise. Copyright © 2006 by Lippincott Williams & Wilkins.

Allo-limbal transplantation in patients with limbal stem cell deficiency

Aim - To report the outcome of a series of patients with stem cell deficiency who underwent allo-limbal transplantation and to describe a technique for this procedure. Methods - Six consecutive patients underwent allo-limbal stem cell transplantation. The primary diagnosis included alkali burn (n = 2), trachoma (n = 1), chronic rosacea blepharitis and keratoconjunctivitis (n = 1), aniridia (n = 1), and Stevens-Johnson syndrome (n = 1). The limbal rim consisted of peripheral cornea and perilimbal sclera, FK-506 was used postoperatively for immunosuppression. Results - The length of follow up ranged from 3 to 24 months (mean follow up 11.8 (SD 9.3) months). The outcome was considered satisfactory in five of six cases. The corneal surface was completely epithelialised within 2 weeks, and there was a substantial improvement in vision and symptoms. One patient had recurrent epithelial defects related to eyelid abnormalities. No side effects associated with systemic immunosuppression were noted. Conclusion - Allo-limbal transplantation, with systemic immunosuppression with FK-506 is useful in reconstruction of the ocular surface with improvement in vision in patients with severe stem cell deficiency.

Incidence of glaucoma in patients with uveitis

Purpose: To evaluate the incidence of glaucoma and elevation of intraocular pressure (IOP) in patients with inflammatory eye disease. Methods: Retrospective review of medical records of 391 consecutive patients with uveitis attending a uveitis clinic of an academic Department of Ophthalmology from January 1999 to August 2002. Demographic, ocular and systemic variables were recorded. The diagnosis and treatment of uveitis were recorded. Uveitis was classified according to standard anatomic, etiological and clinical criteria. "Glaucoma" was defined as elevated IOP (>21 mm Hg) or glaucomatous optic nerve damage requiring medical and/or surgical anti-glaucoma treatment. Kaplan-Maier analysis and log-rank tests were used to evaluate and compare the incidence of glaucoma. Results: The incidence of glaucoma as defined above at 3 and 12 months after acute uveitis was 7.6%. In patients with chronic uveitis (n = 337), the incidence of glaucoma at 1 and 5 years was 6.5% and 11.1%, respectively. There was no statistically significant difference in the incidence of glaucoma between different types of uveitis, idiopathic versus non-idiopathic, and among anterior, intermediate, posterior and panuveitis. Visual loss occurred more frequently in patients with glaucoma than in patients without glaucoma. Conclusion: In patients with chronic inflammatory eye disease, the presence of glaucoma was associated with an increasing risk of visual loss. The incidence of glaucoma increased with time and was similar among the different types of uveitis.

Correlation between corneal and scleral thickness in glaucoma

PURPOSE: To assess the correlation between central corneal thickness (CCT) and anterior scleral thickness (ST) in patients of primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), and ocular hypertension (OHT). PATIENTS AND METHODS: Consecutive patients with OHT, POAG, NTG, and normal individuals were recruited. CCT was measured by ultrasonic pachymetry, whereas ST was measured using ultrasonic biomicroscopy at the temporal quadrant, 2'mm posterior to the scleral spur. Investigators were masked to the diagnosis and CCT/ ultrasonic biomicroscopy data. Correlation between mean CCT and ST was analyzed. RESULTS: One hundred and twenty-four subjects (31 with OHT, 31 with POAG, 31 with NTG, and 31 normal individuals) were enrolled. The CCT (OHT 548.06±30.45'µm; POAG 519.39±42.95'µm; NTG 505.81±27.23'µm; controls 529.90±43.40'µm) was found to be thicker in patients with OHT than POAG (P=0.004) or NTG (P

Effect of cataract extraction on the Glaucoma Progression Index (GPI) in glaucoma patients

PURPOSE: To determine the effect of cataract extraction on the glaucoma progression index (GPI) in glaucoma patients with coexisting cataract.

PATIENTS AND METHODS: This is a retrospective noncomparative study. Consecutive eligible patients with glaucoma who underwent phacoemulsification alone or in combination with augmented trabeculectomy were included. All patients had Swedish Interactive Threshold Algorithm-standard 24-2 visual fields within 10 months of surgery. Exclusion criteria included other ocular morbidity, intraoperative complications, and perimetric reliability indices greater than 33%. Comparison was made between the immediate visual fields before and after surgery. The main outcome measure was the change in GPI. Changes in the pattern standard deviation (PSD) and mean deviation (MD) were also assessed. Comparison of means was performed with the paired t test.

RESULTS: Thirty-three eyes of 33 patients (all Whites) were analyzed. The mean age at surgery was 77.0+/-8.7 years. Visual field tests were performed 3.3+/-3.0 months SD before surgery and 5.4+/-2.6 months after surgery. There was a statistically significant increase in the GPI after cataract surgery (from 71.5+/-18.5% to 74.6+/-17.1%; P=0.02). The improvement in MD was also statistically significant (from -11.8+/-5.3 to -10.2+/-5.3 dB; P <0.01), but the change in PSD did not reach statistical significance.

CONCLUSIONS: Uncomplicated cataract extraction resulted in a statistically significant improvement in the 24-2 Swedish Interactive Threshold Algorithm-standard GPI and MD, but not in PSD. Both the MD and the GPI may be influenced by lens opacities, which could make detection of glaucoma visual field progression more difficult for clinicians in glaucoma patients with concurrent cataract.

Systematic review of the agreement of tonometers with Goldmann applanation tonometry

OBJECTIVE: To assess the agreement of tonometers available for clinical practice with the Goldmann applanation tonometer (GAT), the most commonly accepted reference device.

DESIGN: A systematic review and meta-analysis of directly comparative studies assessing the agreement of 1 or more tonometers with the reference tonometer (GAT).

PARTICIPANTS: A total of 11 582 participants (15 525 eyes) were included.

METHODS: Summary 95% limits of agreement (LoA) were produced for each comparison.

MAIN OUTCOME MEASURES: Agreement, recordability, and reliability.

RESULTS: A total of 102 studies, including 130 paired comparisons, were included, representing 8 tonometers: dynamic contour tonometer, noncontact tonometer (NCT), ocular response analyzer, Ocuton S, handheld applanation tonometer (HAT), rebound tonometer, transpalpebral tonometer, and Tono-Pen. The agreement (95% limits) seemed to vary across tonometers: 0.2 mmHg (-3.8 to 4.3 mmHg) for the NCT to 2.7 mmHg (-4.1 to 9.6 mmHg) for the Ocuton S. The estimated proportion within 2 mmHg of the GAT ranged from 33% (Ocuton S) to 66% and 59% (NCT and HAT, respectively). Substantial inter- and intraobserver variability were observed for all tonometers.

CONCLUSIONS: The NCT and HAT seem to achieve a measurement closest to the GAT. However, there was substantial variability in measurements both within and between studies.

Comparison of two fast strategies, SITA fast and TOP, for the assessment of visual fields in glaucoma patients

Purpose: To compare two fast threshold strategies of visual field assessment; SITA Fast (HSF) and Tendency Orientated Perimetry (TOP), in detecting visual field loss in patients with glaucoma. Methods: Seventy-six glaucoma, ocular hypertensive and normal patients had HSF and TOP performed in random order. Quantitative comparisons for the global visual field indices - mean deviation and defect (MD) for HSF and TOP, and pattern standard deviation (PSD) for HSF and loss variance (LV) for TOP - were made using correlation coefficients. Humphrey global parameters were converted to Octopus equivalents, and method comparison analysis was used to determine agreement between the two strategies. Test duration times were compared using t-test. Sensitivity and specificity for these two algorithms were determined according to predetermined criteria. Results: High correlation coefficient values were obtained for MD measurements between HSF and TOP (r=-0.89, P

Relationship between socioeconomic deprivation or urban/rural residence and visual acuity before cataract surgery in Northern Scotland

Purpose: To evaluate the influence of socioeconomic factors on visual acuity before cataract surgery. ?Methods: The medical case notes of 240 consecutive patients listed for cataract surgery from January 1, 2010, at Grampian University Hospital, Aberdeen, were reviewed retrospectively. Patients with ocular comorbidity were excluded. Demographics, postal codes, and visual acuity were recorded. Scottish Index of Multiple Deprivation was used to determine the deprivation rank. Home location was classified as urban or rural. The effect of these parameters on preoperative visual acuity was investigated using chi-square tests or Fisher exact test as appropriate. ?Results: A total of 184 patients (mean 75 years) were included. A total of 127 (69%) patients had visual acuity of 6/12 or better. An association was found between affluence and preoperative visual acuity of 6/12 or better (?2trend = 4.97, p = 0.03), with a significant rising trend across quintile of deprivation. There was no evidence to suggest association between geographical region and preoperative visual acuity (p = 0.63). ?Conclusion: Affluence was associated with good visual acuity (6/12 or better) before cataract surgery. There was no difference in preoperative visual acuity between rural and urban populations.

Therapeutic effects of PPARα agonists on diabetic retinopathy in type 1 diabetes models

Retinal vascular leakage, inflammation, and neovascularization (NV) are features of diabetic retinopathy (DR). Fenofibrate, a peroxisome proliferator-activated receptor a (PPARa) agonist, has shown robust protective effects against DR in type 2 diabetic patients, but its effects on DR in type 1 diabetes have not been reported. This study evaluated the efficacy of fenofibrate on DR in type 1 diabetes models and determined if the effect is PPARa dependent. Oral administration of fenofibrate significantly ameliorated retinal vascular leakage and leukostasis in streptozotocin-induced diabetic rats and in Akita mice. Favorable effects on DR were also achieved by intravitreal injection of fenofibrate or another specific PPARa agonist. Fenofibrate also ameliorated retinal NV in the oxygen-induced retinopathy (OIR) model and inhibited tube formation and migration in cultured endothelial cells. Fenofibrate also attenuated overexpression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and vascular endothelial growth factor (VEGF) and blocked activation of hypoxia-inducible factor-1 and nuclear factor-?B in the retinas of OIR and diabetic models. Fenofibrate's beneficial effects were blocked by a specific PPARa antagonist. Furthermore, Ppara knockout abolished the fenofibrate-induced downregulation of VEGF and reduction of retinal vascular leakage in DR models. These results demonstrate therapeutic effects of fenofibrate on DR in type 1 diabetes and support the existence of the drug target in ocular tissues and via a PPARa-dependent mechanism.

Lipoproteins and diabetic microvascular complications

Risk factors for the microvascular complications (nephropathy and retinopathy) of Type 1 and Type 2 diabetes mellitus and the associated accelerated atherosclerosis include: age, diabetes duration, genetic factors, hyperglycaemia, hypertension, smoking, inflammation, glycation and oxidative stress and dyslipoproteinaemia. Hypertriglyceridaemia, low HDL and small dense LDL are common features of Type 2 diabetes and Type 1 diabetes with poor glycaemic control or renal complications. With the expansion of knowledge and of clinical and research laboratory tools, a broader definition of 'lipid' abnormalities in diabetes is appropriate. Dyslipoproteinaemia encompasses alterations in lipid levels, lipoprotein subclass distribution, composition (including modifications such as non-enzymatic glycation and oxidative damage), lipoprotein-related enzymes, and receptor interactions and subsequent cell signaling. Alterations occur in all lipoprotein classes; chylomicrons, VLDL, LDL, HDL, and Lp(a). There is also emerging evidence implicating lipoprotein related genotypes in the development of diabetic nephropathy and retinopathy. Lipoprotein related mechanisms associated with damage to the cardiovascular system may also be relevant to damage to the renal and ocular microvasculature. Adverse tissue effects are mediated by both alterations in lipoprotein function and adverse cellular responses. Recognition and treatment of lipoprotein-related risk factors, supported by an increasing array of assays and therapeutic agents, may facilitate early recognition and treatment of high complication risk diabetic patients. Further clinical and basic research, including intervention trials, is warranted to guide clinical practice. Optimal lipoprotein management, as part of a multi-faceted approach to diabetes care, may reduce the excessive personal and economic burden of microvascular complications and the related accelerated atherosclerosis.

Focal irradiation of perforating eye injuries

Plaques constructed with 125I were used to irradiate the sites of perforating ocular injuries in rabbits. An approximate dose of 16Gy given over a period of 6 days was shown to significantly reduce intraocular cellular proliferation when irradiation was commenced within 24 hours after injury. If irradiation was delayed until day 5, this reduction in cellular proliferation and intraocular membrane formation did not occur. Smaller radiation doses of approximately 6Gy given within 24 hours post-injury and administered over 6 days also reduced the extent of cellular proliferation but was not as effective as the 16Gy dose.

α-adrenoceptors do not mediate reflex mydriasis in rabbits

The aim of this study was to identify receptors that mediate reflex mydriasis in pentobarbital-anesthetized rabbits, in which the cervical sympathetic nerve was sectioned unilaterally. Voltage-response curves of pupillary dilation were generated bilaterally by stimulation of the sciatic nerve. Evoked mydriatic responses were mediated mainly by efferent parasympathetic innervation, and, to a lesser extent, by sympathetic innervation. The a-adrenergic antagonist, phenoxybenzamine (0.3 mg/kg, intravenously (i.v.)), antagonized mydriasis of the neurally intact eye, but not that on the sympathectomized side. The a- adrenergic antagonist, RS 79948 (0.3 mg/kg, i.v.), potentiated mydriasis of the normal eye, but was without either a potentiating or inhibitory effect on the mydriasis of the sympathectomized eye. In addition, the dopamine-receptor antagonist, haloperidol (1 mg/kg, i.v.), inhibited evoked mydriasis of the sympathectomized eye. These results suggest that, unlike some other species (cats and rats), a-adrenoceptors do not mediate reflex mydriasis elicited by sciatic-nerve stimulation in the rabbit, and support the previous finding in humans that dopamine receptors may mediate this response.

Studies of alpha-adrenoceptor antagonists on sympathetic mydriasis in rabbits

This study was undertaken to identify the alpha-adrenergic receptor type responsible for sympathetically evoked mydriasis in pentobarbital-anesthetized rabbits. Frequency-response curves of pupillary dilation were generated by stimulation of the preganglionic cervical sympathetic nerve (1-64 Hz). Evoked mydriatic responses were inhibited by systemic administration of nonselective alpha-adrenergic antagonists, phentolamine (0.3-10 mg/kg) and phenoxybenzamine (0.03-0.3 mg/kg), as well as the selective alpha(1)-adrenergic antagonist, prazosin (0.1-1 mg/kg). The alpha(2)-adrenergic antagonist, RS 79948 (0.3 mg/kg, i.v.) was without inhibitory effect, but potentiated the mydriatic response. In addition, the selective alpha(1A)-adrenoceptor antagonist, 5-methylurapidil (0.1-1 mg/kg, i.v.), antagonized the elicited mydriasis in a dose-dependent fashion. Unlike previous observations that prazosin does not block the adrenoceptor in rabbit iris dilator muscle, our results suggest that prazosin is effective in inhibiting neuronally elicited mydriasis in this species, and that alpha(1A)-adrenoceptors appear to mediate the response.

Clinical and experimental links between diabetes and glaucoma

Glaucoma is a leading cause of blindness. It is a multifactorial condition, the risk factors for which are increasingly well defined from large-scale epidemiological studies. One risk factor that remains controversial is the presence of diabetes. It has been proposed that diabetic eyes are at greater risk of injury from external stressors, such as elevated intraocular pressure. Alternatively, diabetes may cause ganglion cell loss, which becomes additive to a glaucomatous ganglion cell injury. Several clinical trials have considered whether a link exists between diabetes and glaucoma. In this review, we outline these studies and consider the causes for their lack of concordant findings. We also review the biochemical and cellular similarities between the two conditions. Moreover, we review the available literature that attempts to answer the question of whether the presence of diabetes increases the risk of developing glaucoma. At present, laboratory studies provide robust evidence for an association between diabetes and glaucoma.

Glial and neuronal dysfunction in streptozotocin-induced diabetic rats

Neuronal dysfunction has been noted very soon after the induction of diabetes by streptozotocin injection in rats. It is not clear from anatomical evidence whether glial cell dysfunction accompanies the well-documented neuronal deficit. Here, we isolate the Müller cell driven slow-P3 component of the full-field electroretinogram and show that it is attenuated at 4 weeks following the onset of streptozotocin-hyperglycaemia. We also found a concurrent reduction in the sensitivity of the phototransduction cascade, as well as in the components of the electroretinogram known to indicate retinal ganglion cell and amacrine cell integrity. Our data support the idea that neuronal and Müller cell dysfunction occurs at the same time in streptozotocin-induced hyperglycaemia.