Ocular adverse effects of Topiramate: Two case reports

Topiramate, an antiepileptic drug is reported to cause various ocular adverse effects like acute onset myopia, glaucoma. Visual field defect is an uncommon, serious treatment emergent adverse effect. We are reporting two cases of suspected topiramate induced visual field defects.Both the cases were on topiramate for more than 6 months as add-on therapy at daily doses ranging from 100-150mg. The presenting complaints were insidious onset visual disturbances. Diagnosis was based of temporal association with drug intake, clinical examination and investigations. Automated perimetry revealed bilateral superior quadrantic and arcuate field defects in the two cases respectively. Marked improvement with drug dechallenge was noted which was also corroborated by perimetry. Using Naranjo's ADR Probability Scale, both cases revealed a "probable" association with topiramate. This report intends to improve awareness amongst clinicians to facilitate early diagnosis and intervention.     

Ocular adverse drug reactions

Drug-induced ocular side effects are described according to recent reports from the literature, the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization (WHO) and the FDA. Adverse events are categorised as certain, probable/likely, possible, unlikely, conditional/unclassified and unassessable/unclassifiable where indicated. Ocular side effects of clinical importance are highlighted with guidelines for recognition, reporting and treatment of adverse drug reactions (ADRs). The current and future status of pharmacovigilance in ocular toxicology is addressed.     

Ocular adverse effects associated with systemic medications : recognition and management

This article reviews several retrospective case series and reported adverse events regarding common ocular adverse effects related to systemic therapy. It is not intended as a comprehensive summary of these well described adverse drug reactions, nor is it intended to cover the complete spectrum of all ocular adverse effects of systemic therapy. Many systemic drugs may produce ocular toxicity, including bisphosphonates, topiramate, vigabatrin, isotretinoin and other retinoids, amiodarone, ethambutol, chloroquine and hydroxychloroquine, tamoxifen, quetiapine, cyclo-oxygenase (COX)-2 inhibitors, erectile dysfunction agents and some herbal medications. For this review, the certainty of the adverse effect profile of each medication was evaluated according to the WHO Causality Assessment Guide.A certain relationship has been established for pamidronate and alendronate as causes of scleritis, uveitis, conjunctivitis and blurred vision. Topiramate has been established as adversely causing symptoms consistent with acute angle-closure glaucoma, typically bilateral. Vigabatrin has been shown to cause bilateral irreversible visual field defects attributed to underlying medication-induced retinal pathology. Isotretinoin should be considered in the differential diagnosis of any patient with pseudotumour cerebri. Patients taking amiodarone and hydroxychloroquine should be monitored and screened regularly for development of optic neuropathy and maculopathy, respectively. Sildenafil has been reported to cause several changes in visual perception and is a possible, not yet certain, cause of anterior ischaemic optic neuropathy. Patients taking tamoxifen should also be monitored for development of dose-dependent maculopathy and decreased colour vision. COX-2 inhibitors should be included in the differential diagnosis of reversible conjunctivitis. Several herbal medications including canthaxanthine, chamomile, datura, Echinacea purpurea, Ginkgo biloba and liquorice have also been associated with several ocular adverse effects.It is the role of all healthcare professionals to detect, treat and educate the public about adverse reactions to medications as they are an important health problem.     

Molecular mechanisms of cardiostimulatory effects of sildenafil

To better understand the molecular mechanisms of the previously described cardiostimulatory action of the phosphodiesterase type-5 (PDE5) inhibitor sildenafil, we first evaluated its effects on cyclic AMP level in the canine ventricular membrane preparation. Sildenafil (10 micromol/L) significantly increased the net cyclic AMP production rate, the potency of which was similar to that of 3-isobutyl-1-methylxanthine (IBMX). Next, we assessed the inhibitory effect of sildenafil on PDE of bovine heart. Sildenafil (> or = 1 micromol/L) as well as IBMX significantly decreased the cyclic AMP hydrolyzing speed of PDE. These results suggest that a supra-therapeutic concentration of sildenafil may directly inhibit cyclic AMP hydrolyzing PDEs in the heart, although indirect inhibition of PDE3 via the "cross-talk" pathway cannot be totally excluded.     

Versatile effects of sildenafil: recent pharmacological applications

Sildenafil is a phosphodiesterase-5 (PDE5) inhibitor and is predominantly used in the treatment of erectile dysfunction. While maintaining an excellent safety and tolerability profile in the management of erectile dysfunction, sildenafil also provides a prolonged benefit in various other diseases. Sildenafil has been shown to have a potential therapeutic efficacy for disorders related to the central nervous system and pulmonary system. In the central nervous system, it exerts its neuroprotective effects in multiple sclerosis and has a significant memory enhancing action. Sildenafil also significantly enhances neurogenesis. Several lines of evidence indicate that targeting PDE5 with sildenafil offers novel strategies in the treatment of age-related memory impairment. Guanylate cyclase/cGMP/protein kinase G pathway or glutamate/nitric oxide/cGMP pathway appears to mediate memory enhancing effects. Some of the positive cognitive features of sildenafil therapy are likely attributable to the mechanisms reviewed here. Sildenafil has been shown to reduce pulmonary hypertension and alleviate pain in animals and humans. The present review primarily focuses on the various pharmacological effects of sildenafil with regard to its influence on the nervous and pulmonary system.     

Ocular hypotensive effects of medifoxamine.

Medifoxamine is a novel monoamine re-uptake inhibiting antidepressive drug which preferentially inhibits dopamine reuptake. In human volunteer studies it has been found to reduce significantly intraocular pressure after single oral doses of 300-1000 mg, and to produce a small but statistically significant miosis. Its maximal ocular hypotensive action was less than that of oral timolol 20 mg.     

Cardiovascular adverse effects of coxibs

(1) All nonsteroidal antiinflammatory drugs (NSAIDs), including coxibs, can worsen arterial hypertension and heart failure. (2) Combining a standard NSAID with a vitamin K antagonist increases the risk of bleeding. The same applies to coxibs. (3) Available data point to a higher risk of severe cardiovascular events with rofecoxib than with naproxen. (4) There is no reason to postpone aspirin therapy at antiplatelet doses in patients who are also receiving another NSAID. Rofecoxib should not be used in patients with coronary disease     

Immunoallergic adverse effects of fluindione

Bleeding is the main adverse effect of all vitamin K antagonists. Fluindione, an indanedione derivative, can also have serious immunoallergic adverse effects. Several hypersensitivity reactions affecting various organ systems have been reported in detail in patients taking fluindione, mainly cutaneous, hepatic or renal disorders, often associated with fever. Cases of isolated kidney and liver damage have also been reported. Fluindione has been linked to cases of acute generalised exanthematic pustulosis. An immunoallergic mechanism is suspected, based on several factors, including the involvement of several organs, the types of damage, the chronological sequence of events, outcome after fluindione withdrawal, and cases of positive rechallenge. About a hundred reports of non-haemorrhagic adverse effects attributed to fluindione were recorded in the French pharmacovigilance database during the course of a single year (July 2008 to June 2009). In practice, when anticoagulant therapy with a vitamin K antagonist is needed, it is better to use warfarin, the best-assessed oral anticoagulant. If fluindione is nonetheless prescribed, the patient must not only be taught how to manage vitamin K antagonist therapy but also how to recognise signs of hypersensitivity.     

Ocular side effects associated with bisphosphonates

Bisphosphonates are used to inhibit bone resorption in postmenopausal women and in the management of hypercalcemia of malignancy. Recently, some drugs within this class of medicines have been proven to cause scleritis. Prior to this, bisphosphonates had been reported to cause a variety of ocular side effects, most of which are inflammatory. This review discusses the many different medicines called bisphosphonates and highlights the ocular side effect profile of each. In cases where information on dechallenge is provided, all the ocular side effects resolved after discontinuation of the medication. Recognition of adverse ocular events in association with bisphosphonate therapy should alert clinicians to the need for ophthalmic evaluation and the consideration of discontinuation of therapy in all cases of scleritis.     

Differential vasoactive effects of sildenafil and tadalafil on cerebral arteries

Phosphodiesterase 5 (PDE5) is associated with migraine pathophysiology, stroke recovery and vasospasm treatment. The potential vascular interplay of PDE5 inhibitors sildenafil, tadalafil and UK-114,542 was studied by intra- versus extra-luminal administration in rat middle cerebral arteries in vitro and on middle meningeal arteries in vivo. By Western blot PDE5 was detected in both cerebral and meningeal arteries, though with minor variations in band intensity between vascular beds. Rat middle cerebral artery diameter was investigated using pressurised arteriography, applying UK-114,542, sildenafil, and tadalafil intra- or extra-luminally. Effects on the dural middle meningeal artery were studied in the in vivo closed cranial window model. At high concentrations, abluminal sildenafil and UK-114,542, but not tadalafil, induced dilatation of the middle cerebral artery. Luminal application elicited a contraction of 4% (sildenafil, P=0.03) and 10% (tadalafil, P=0.02). In vivo, sildenafil, but not tadalafil, dose-dependently dilated middle meningeal artery concomitant to blood pressure reduction (1-3mg/kg);1mg/kg sildenafil inducing 60 ± 14% (P=0.04) and vehicle (DMSO) 13 ± 6% dilatation. In conclusion, PDE5 inhibitors applied luminally had minor contractile effect, whereas abluminal sildenafil induced middle cerebral artery dilatation above therapeutic levels. In vivo, sildenafil dilated middle meningeal artery concomitant with a reduction in blood pressure. Tadalafil had no dilatory effects. PDE5 inhibitors show differential vascular activity in cerebral arteries from healthy animals; arterial dilatation is seen primarily above therapeutic levels. Such findings support clinical studies showing no vasodilator effects of sildenafil on cerebral arteries in healthy subjects.     

Ocular side effects associated with isotretinoin

Isotretinoin is used for severe recalcitrant nodular acne and has a variety of associated ocular side effects. This review classifies these ocular side effects according to World Health Organization (WHO) criteria and reviews the existing literature as well as 2449 spontaneous case reports collected from around the world. Ocular sicca, decreased dark adaptation and intracranial hypertension are identified as "certain" side effects from isotretinoin and clinicians are provided guidelines for care and follow-up.     

A placebo-controlled study of sildenafil effects on cognition in schizophrenia

Background

Phosphodiesterase 5 (PDE5) inhibitors increase cyclic guanosine monophosphate (cGMP) concentrations in the intracellular pathway activated by N-methyl-d-aspartic acid receptors which is believed to mediate long-term potentiation and memory consolidation. The PDE5 inhibitor sildenafil has been shown to enhance memory in animal models. In addition, neuronal nitric oxide synthase, another component of the NMDA/nitric oxide/cGMP intracellular pathway, has been reported to be dysregulated in schizophrenia patients.

Materials and methods

Seventeen adult schizophrenia outpatients treated with a stable dose of antipsychotic received a single oral dose of placebo, sildenafil 50 mg, and sildenafil 100 mg in random order with a 48-h interval between administrations. Psychiatric symptom ratings and a cognitive battery were performed at baseline and 1 hour following each administration of the study drug. In addition, memory consolidation was examined by testing recall 48 h later, prior to the next administration of the study drug.

Results

Fifteen subjects completed all three treatment conditions. One subject developed irritability and required hospitalization 2 days after receiving sildenafil 100 mg. Neither dose of sildenafil significantly affected cognitive performance or symptom ratings compared to the placebo.

Conclusion

Despite evidence for cognitive-enhancing effects of sildenafil in animal models, the strategy for treating putative NMDA receptor-mediated memory deficits in schizophrenia with sildenafil 50 and 100 mg was not successful. It is possible that the doses used in this study were not optimal or that repeated dosing may be necessary to achieve therapeutic effects. Agents under development that inhibit other subtypes of PDE remain promising for schizophrenia and dementia.     

Acute cardiac and hemodynamic effects of sildenafil on resistant hypertension

Purpose

Failure to control blood pressure (BP) despite the use of three or more drugs characterizes resistant hypertension (RHTN). Impaired endothelial function is associated with this condition and phosphodiesterase-5 inhibitors (PDE5i)—inhibiting cGMP breakdown—reduce BP in RHTN patients. We hypothesized that acute administration of PDE5i could ameliorate hemodynamic, endothelial parameters and left ventricular diastolic function (LVDF) in RHTN patients. Also, an exploratory analysis was performed to assess the influence of the T-786C endothelial NO synthase polymorphism on those responses.

Methods

Subjects (n?=?26) underwent a 6-month clinical screening for RHTN diagnosis. Increasing doses of oral sildenafil were given at 30 min intervals (37.5, 50 and 100 mg) while continuous non-invasive hemodynamic measures were assessed. LVDF, flow mediated dilation (FMD), nitrite and cGMP levels were also determined.

Results

Mean arterial pressure and total peripheral resistance decreased in all patients (84.17?±?21.04 to 75?±?17.21 mmHg; 1149?±?459.7 to 1037?±?340 dyn.s/cm^?5, respectively). Likewise, sildenafil improved diastolic dysfunction parameters (Left atrial volume: 25?±?5.8 to 20?±?4.4; IVRT: 104?±?19.33 to 88?±?15.22; E/e’ septal: 9.7?±?3.8 to 7.9?±?2.9; E/e’ lateral: 7.7?±?3.4 to 6.4?±?3.2). No statistical changes were found in FMD, nitrite and cGMP with PDE5i.

Conclusion

Our data suggest PDE5i acutely improves diastolic function and hemodynamic profile in RHTN subjects, despite unchanging endothelial dysfunction.     

Fluoroquinolones: psychiatric adverse effects

(1) In France, between 1985 and 2002, there were 590 reports of psychiatric adverse effects in patients receiving fluoroquinolones. These mainly included cases of confusion, hallucinations, agitation, delirium, insomnia and drowsiness. Elderly patients appear to be at greatest risk. (2) The reports implicated all available fluoroquinolones and, in most cases, oral intake. (3) Fluoroquinolone dose regimens should be reduced in cases of renal failure. The Cockcroft formula is used to derive creatinine clearance from plasma creatinine levels.     

Cutaneous adverse effects of inhaled steroids

(1) Oral steroids can damage the skin. Cutaneous thinning and bruising have also been reported with inhaled steroids. (2) A randomised double-blind placebo-controlled trial of inhaled triamcinolone in chronic obstructive pulmonary disease provides useful data on the frequency of such effects. (3) The frequency of bruising was 11.2% with the steroid and 3.7% with placebo, while delayed wound healing occurred in respectively 2.4% and 0.5% of patients. These cutaneous adverse effects were dose-dependent and increased with age. (4) The inhaled route does not prevent steroid adverse effects occurring at a distance from the airways. This is one more reason for using the minimal effective dose of inhaled steroids, especially in older patients.     

别嘌醇不良反应临床案例分析

目的通过对我院临床案例的分析,获得近年别嘌醇不良反应发生及治疗的总体趋势、特点及相关因素,为临床安全合理用药提供依据。方法根据我院临床110例案例,总结归纳别嘌醇引起的不良反应。结果临床案例共110例,其中死亡4例（3.64%）。最常见的不良反应均为皮肤-黏膜反应,占100%,其主要表现为药疹。其次是发热,血液系统损害、肝、肾功能损害等不良反应。结论临床上使用该药时应加强药品不良反应监测。