ICH S1 prospective evaluation study and weight of evidence assessments: commentary from industry representatives.

Industry representatives on the ICH S1B(R1) Expert Working Group (EWG) worked closely with colleagues from the Drug Regulatory Authorities to develop an addendum to the ICH S1B guideline on carcinogenicity studies that allows for a weight-of-evidence (WoE) carcinogenicity assessment in some cases, rather than conducting a 2-year rat carcinogenicity study. A subgroup of the EWG composed of regulators have published in this issue a detailed analysis of the Prospective Evaluation Study (PES) conducted under the auspices of the ICH S1B(R1) EWG. Based on the experience gained through the Prospective Evaluation Study (PES) process, industry members of the EWG have prepared the following commentary to aid sponsors in assessing the standard WoE factors, considering how novel investigative approaches may be used to support a WoE assessment, and preparing appropriate documentation of the WoE assessment for presentation to regulatory authorities.

Developing a pragmatic consensus procedure supporting the ICH S1B(R1) weight of evidence carcinogenicity assessment.

The ICH S1B carcinogenicity global testing guideline has been recently revised with a novel addendum that describes a comprehensive integrated Weight of Evidence (WoE) approach to determine the need for a 2-year rat carcinogenicity study. In the present work, experts from different organizations have joined efforts to standardize as much as possible a procedural framework for the integration of evidence associated with the different ICH S1B(R1) WoE criteria. The framework uses a pragmatic consensus procedure for carcinogenicity hazard assessment to facilitate transparent, consistent, and documented decision-making and it discusses best-practices both for the organization of studies and presentation of data in a format suitable for regulatory review.

The Accumulative Effect of Intravenous Prostaglandin E1 over Nineteen Years to Treat the Ocular Ischemia in High Myopia Keywords: Ocular ischemia, high myopia, prostaglandin E1 (PGE1), extreme choroidal thinning Prostaglandin E1 in High Myopia.

Purpose: The purpose of this paper is to present the clinical history of the use of intrarvenous (IV) prostaglandin E1(PGE1), a potent vasodilator of the peripheral vascular system, to treat the ischemia in high myopia. This was originally reported in 2009.

Methods: Three patients with high myopia and progressive visual loss were seen.

Visual improvement in a patient with paracentral acute middle maculopathy treated with prostaglandin E1.

The authors present the use of prostaglandin E1 (PGE1) for the treatment of an acute paracentral acute middle maculopathy (PAMM). A 78-year-old white female was seen with a sudden loss of vision in her left eye (OS) to 20/200 noted upon awakening. The right eye (OD) saw 20/20.

Abnormal stereopsis and reduced retinal sensitivity in patients with retinitis pigmentosa.

Purpose: The aim of the study was to evaluate retinal sensitivity and stereoacuity (SA) in retinitis pigmentosa (RP) patients.

Methods: Twenty-six patients with RP were examined, mean age 36.4 ± 7.

Cyclodextrin Reduces Intravenous Toxicity of a Model Compound.

Solubilization of new chemical entities for toxicity assessment must use excipients that do not negatively impact drug pharmacokinetics and toxicology. In this study, we investigated the tolerability of a model freebase compound, GDC-0152, solubilized by pH adjustment with succinic acid and complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) to enable intravenous use. Solubility, critical micelle concentration, and association constant with HP-β-CD were determined.

Visual field improvement in non-arteritic posterior ischemic optic neuropathy in a patient treated with intravenous prostaglandin E1 and steroids.

Non-arteritic posterior ischemic optic neuropathy (NA-PION) is a disorder of reduced blood flow to the retrobulbar optic nerve. There is usually an acute loss of visual acuity and field. Previous studies have noted an improvement in visual acuity and in ocular and retrobulbar blood flow with the use of a potent vasodilator of the microcirculation, prostaglandin E1 (PGE1), and steroids.

An ultra-low-molecular-weight heparin, fondaparinux, to treat retinal vein occlusion.

Retinal vein occlusions may decrease visual acuity. There is no known therapy to treat ocular thrombosis. The authors used fondaparinux, an ultra-low-molecular-weight heparin, to treat 13 consecutive cases of recent-onset retinal vein occlusions.

Three episodes of non-arteritic posterior ischemic optic neuropathy in the same patient treated with intravenous prostaglandin E1.

Non-arteritic posterior ischemic optic neuropathy (NA-PION) is a disorder involving reduced blood flow to the retrobulbar portion of the optic nerve. This disorder usually develops acutely, and research has suggested that high-dose steroid therapy soon after the onset of visual loss can result in significant visual improvement. This treatment, however, is not universally successful.

Pycnogenol® and Centella asiatica in the management of asymptomatic atherosclerosis progression.

Aim: The aim of the study was to evaluate the effect of the nutritional supplements Pycnogenol® and total triterpenic fraction of Centella asiatica (TTFCA) on atherosclerosis progression in low-risk asymptomatic subjects with carotid or femoral stenosing plaques.

Methods: This was an observational pilot, substudy of the San Valentino epidemiological cardiovascular study. The study included 824 subjects aged 45-60 without any conventional risk factors who had a stenosing atherosclerotic plaque (>50-60%) in at least one carotid or common femoral bifurcation, allocated into 6 groups: Group 1 (Controls): management was based on education, exercise, diet and lifestyle changes.

An ischemic diabetic eye treated with intravenous prostaglandin E1.

Purpose: To present the use of intravenous prostaglandin E1 (PGE1), a powerful vasodilator of the microcirculation, in the treatment of an ischemic diabetic eye.

Methods: A 27-year-old diabetic man with ischemic diabetic retinopathy and glaucoma had a decreased visual acuity of no light perception in his right eye and hand motions in his left eye. He was started on intravenous PGE1 and has been treated for over 4.

Multifocal and pattern-reversal visual evoked potentials vs. automated perimetry frequency-doubling technology matrix in optic neuritis.

Background: To compare the usefulness of the traditional pattern-reversal Visual Evoked Potentials (VEP) with multifocal VEP (mfVEP) and Frequency-Doubling Technology (FDT) perimetry in the evaluation of the ocular abnormalities induced by acute or subacute optic neuritis (ON).

Materials And Methods: The test results of 24 ON patients were compared with those obtained in 40 normal control subjects. MfVEP recordings were obtained by using an Optoelectronic Stimulator that extracts topographic VEP using a pseudorandom m-sequence stimulus.

Idiopathic juxtafoveal retinal telangiectasis and retinal macroaneurysm treated with indocyanine green dye-enhanced photocoagulation.

This case report presents the use of indocyanine green dye-enhanced photocoagulation (ICG-DEP) for the treatment of idiopathic juxtafoveal retinal telangiectasis and a retinal macroaneurysm. A 35-year-old male with 20/20 vision had been followed for 5 years for a retinal macroaneurysm with retinal telangiectasis outside the macular area. He then presented with a recently decreased vision in his right.

Forskolin and rutin prevent intraocular pressure spikes after Nd:YAG laser iridotomy.

Aim: the purpose of this research was to evaluate whether an oral treatment with an association of forskolin and rutin can blunt the intraocular pressure (IOP) spikes and avoid the damage that may occur after laser iridotomy.

Methods: Ten patients underwent bilateral Neodymium:YAG (Nd:YAG) laser iridotomy (Visulas YAG III Laser, Zeiss), for the prevention of primary closed-angle glaucoma. IOP was measured in subjects before and after 7 days of pretreatment with placebo or forskolin and rutin by Goldman applanation tonometry.

Meriva®, a lecithinized curcumin delivery system, in diabetic microangiopathy and retinopathy.

Background: In the present study, the improvement of diabetic microangiopathy and retinopathy was evaluated in 38 diabetic patients treated with a novel curcumin phospholipids delivery form (Meriva®).

Methods: Diabetes was diagnosed at least 5 years before inclusion and all patients had signs of retinal oedema and of peripheral microangiopathy. Meriva® was administered at the dosage of 2 tablets/day (each tablet containing 500 mg Meriva® corresponding to 100 mg curcumin) for a period of at least 4 weeks in addition to the standard management plan, while a comparable group of subjects (n = 39) followed the standard management plan alone.

The effect of latanoprost and influence of changes in body position on patients with glaucoma and ocular hypertension.

Background And Objectives: Some patients have an elevation of intraocular pressure (IOP) in the supine position (IOPSP). It has been suggested that topical latanoprost 0.005% (LP) has an attenuating effect on these IOP elevations.

Retrospective study of glaucoma and closed-eyelid test: long-term outcomes in an Italian native population.

AIM: To establish a threshold value of intraocular pressure (IOP) increase after the closed-eyelid test (CET) that correlates with the highest probability of developing overt primary open-angle glaucoma (OAG) in an Italian native population from 1980 to 2010. METHODS: Retrospective analysis of data obtained from 161 patients with ocular hypertension who performed the CET in 1980, and were subsequently followed to see whether they developed OAG. CET was performed always in the morning Eyelids were closed by bandaging for 1 h in a quiet environment, with the patient seated and not sleeping.

Dogs are more sensitive to antagonists of inhibitor of apoptosis proteins than rats and humans: a translational toxicokinetic/toxicodynamic analysis.

Inhibitor of apoptosis (IAP) proteins suppress apoptosis and are overexpressed in a variety of cancers. GDC-0152 is a potent and selective IAP antagonist being developed as an anticancer agent. In preclinical safety studies, dogs were particularly sensitive to GDC-0152 showing adverse signs of a tumor necrosis factor alpha (TNF-α) driven systemic inflammatory response, related to cellular IAP degradation and activation of NFκB signaling, at lower exposures compared with rat.

Ocular and optic nerve ischemia: recognition and treatment with intravenous prostaglandin E1.

Ischemia of the optic nerve, the retina and the choroid are common problems in ophthalmology. This paper presents the different types of ischemia and their treatment with prostaglandin E1 (PGE1), a powerful vasodilator of the microcirculation. This is a review article of various previously published case reports and studies presenting patients with different types of ocular and optic nerve ischemia.

Branch retinal arterial occlusion treated with intravenous prostaglandin e1 and steroids.

Purpose: To present the use of 6-methylprednisolone IV and prostaglandin E1 IV, a powerful vasodilator of the microcirculation, in the treatment of a branch retinal arterial occlusion.

Methods: A 63-year-old man presented with a 3-hour history of a sudden loss of vision in the right eye. On ophthalmic examination, the diagnosis of a superior temporal branch retinal arterial occlusion was made.

Non-arteritic Posterior Ischaemic Optic Neuropathy Treated with Intravenous Prostaglandin E1 and Oral Corticosteroids.

Intravenous prostaglandin E1 and oral corticosteroids were used to treat the ischaemic phase of a non-arteritic posterior ischaemic optic neuropathy with immediate visual improvement. Non-arteritic posterior ischaemic optic neuropathy is a disorder of reduced blood flow to the retrobulbar optic nerve, usually of acute onset. It has been suggested that high-dose steroid therapy given soon after the onset of visual loss can result in significant visual improvement.

Arteritic anterior ischemic optic neuropathy treated with intravenous prostaglandin E(1) and steroids.

Arteritic anterior ischemic optic neuropathy (AAION) is an acute ischemia of the posterior ciliary arteries and/or ophthalmic artery due to inflammation. Therapy is immediate intervention with systemic steroids, especially to protect against vision loss in the other eye. The addition of a potent vasodilator to the steroids could help restore ocular blood flow and improve visual acuity.

Retina in rheumatic diseases: standard full field and multifocal electroretinography in hydroxychloroquine retinal dysfunction.

Background: The purpose of this study was to evaluate and compare full-field electroretinography (ERG) and multifocal electroretinography (mfERG) results in detecting retinal dysfunction in a large number of asymptomatic patients treated with hydroxychloroquine (Hy).

Methods: Fifty eyes in 50 patients with rheumatic diseases who had been using Hy for a period of time ranging from 30 months to 15 years, and 25 eyes in 25 healthy controls, were evaluated. Receiver operator characteristic (ROC) curves were calculated to determine the sensitivity and specificity of abnormal values in patients compared to the normal controls.