An evaluation of chemical photoreactivity and the relationship to phototoxicity

The existing regulatory guidance for photosafety testing of new drug products states that studies are warranted for those chemicals that both absorb light in the range of 290–700 nm, and that are either applied locally/topically, or “reach” (EMEA)/“significantly partition” (FDA) to the skin or eyes. The initial in vitro study recommended for the assessment of phototoxic potential is the 3T3 Neutral Red Uptake (NRU) Assay. The current study was undertaken to establish superior triggers for the initiation of biological photosafety testing. In this study, photophysical and photochemical parameters for 40 drug or drug-like molecules were studied. Principal Component Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA), and a fivefold cross-validation PLS algorithm were used to evaluate the relationship between subsets of photophysical and photochemical parameters with the 3T3 NRU PIF/MPE (Photo Irritation Factor/Mean Photo Effect) results. The parameters most indicative of a 3T3 NRU positive PIF or MPE score were the extent of degradation in solution, the quantum yield of formation of singlet oxygen and the relative formation of superoxide anion. The results demonstrate that while absorption of light is critical to the induction of a light-induced process, it is the resultant events that may be used to predict the 3T3 NRU assay result. It is therefore proposed that the trigger for photosafety testing be revised to include a molecular basis for photoreactivity. From this limited investigation, estimated thresholds leading to 3T3 NRU positive results due to photodegradation, formation of singlet oxygen quantum yield or a relative superoxide anion formation value are proposed.     

Some poststimulatory effects on the whole nerve action potential

Short-term poststimulatory effects on the N1 component of the auditory-nerve compound action potential (CAP) were investigated in Mongolian gerbils. Some effects of conditioner level, conditioner frequency and probe level were assessed. In most cases, poststimulatory decrements occurred. The decrements were independent of probe intensity when the conditioner was close in frequency and of equal or less intensity than the probe. At some other conditioner frequencies, decrements decreased as probe intensity increased. Departures from these relationships occurred when a more intense conditioner was applied. In some instances, increases in CAP amplitude were also observed. The roles of single unit responses including spread of cochlear excitation, and possible mechanisms for poststimulatory facilitation are discussed.     

Levocabastine. Evaluation in the histamine and compound 48/80 models of ocular allergy in humans

The efficacy of a new antihistamine, levocabastine, in alleviating the ocular allergic reactions induced by both histamine and 48/80 was evaluated in humans. Levocabastine (0.5%) was instilled in one eye of 30 volunteers, and vehicle in the contralateral eye. After 15 minutes, half of the subjects received histamine (25 mg/ml) and half, 48/80 (7.5 mg/ml). The signs and symptoms of allergy were graded clinically after 30 minutes. Compared with a buffer control, levocabastine significantly alleviated itching (P = 0.01), redness (P = 0.0156), and chemosis (P = 0.005) induced by histamine, and itching (P = 0.032) and redness (P = 0.029) induced by 48/80. The results from these pharmacologic models support the clinical use of levocabastine for the treatment of allergic conjunctivitis.     

The nasal junction scotoma in giant aneurysms

Thirteen giant aneurysms in ten patients were retrospectively reviewed. Careful visual field testing of both peripheral and central fields revealed an ipsilateral nasal scotoma in 7 of the 13 aneurysms (54%), or six of the ten patients. A review of 47 giant carotid aneurysms reported in the literature revealed 16 ipsilateral nasal scotomas (34%). The more common intraocular causes of ipsilateral nasal field defects were excluded by careful funduscopic examination. In the absence of intraocular pathologic characteristics, an ipsilateral nasal junction scotoma should alert the clinician to suspect the presence of an otherwise silent internal carotid artery aneurysm.     

Spontaneous resolution of herpes simplex blepharoconjunctivitis in children

We observed three children, aged 1 year 8 months to 9 years 7 months, in whom herpes simplex blepharoconjunctivitis resolved promptly without treatment. A fourth child, 8 years old, developed probable toxic manifestations from topical vidarabine. These manifestations, as well as the blepharoconjunctivitis, resolved when the medication was discontinued. Herpes simplex ocular infection without corneal involvement in children is usually benign and self-limited.     

Essential night blindness with cone monochromasy

A young patient with reduced vision complained of night blindness and color blindness. Clinical examination data and retinal densitometry were consistent with essential night blindness. Spectral sensitivity and color vision testing revealed cone monochromasy.This study was supported in part by USPHS NIH Research Grants EY 00901 and EY 01765, and by a grant from ZWO, the Dutch Organization for the Advancement of Pure Research     

An algorithmic approach to diagnosis of hypoglycemia

An algorithm has been devised to facilitate the diagnostic approach to the causes of hypoglycemia. This systematic approach enables the physician to reach the final diagnosis in a logical way without subjecting the child to unnecessary and possibly hazardous investigations. The algorithm is based on the following measurements as required by each patient: concentrations of blood glucose, lactate, ketone bodies, and glucose-regulating hormones. These measurements are performed with the patient in the fasting state and after loading tests (glycerol and galactose) as needed. If indicated, an enzymatic test is performed to establish the final diagnosis. Eighteen children aged 1 month to 7 years who had persistent or recurrent hypoglycemia have been examined according to this algorithm. The correct diagnosis was arrived at in 17 patients. The diagnosis was not reached in one neonate who had glucose-6-phosphatase deficiency and initially did not have lactic acidosis; once lactic acidosis developed, his illness fitted perfectly into the algorithm.     

Biopterin and neurotransmitter amine metabolism in children with acute lymphoblastic leukemia receiving methotrexate therapy

To test the hypothesis that some of the neurologic sequelae of treatment for acute lymphoblastic leukemia (ALL) might be related to abnormalities in biopterin metabolism associated with methotrexate (MTX) therapy, total biopterin levels in cerebrospinal fluid (CSF) and plasma, and homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) were measured in a cross-sectional study of 80 children with ALL. For comparison, biopterins were also measured in a group of children of similar age undergoing investigation for neurologic disease. In children with ALL studied before therapy, no significant difference was found between the means of plasma biopterin or CSF biopterin concentrations and the means in the control group. In children receiving MTX, plasma biopterin values were higher in the group given maintenance therapy than in children observed before treatment. CSF levels were significantly increased only in those patients who had completed 2 years of maintenance therapy. CSF concentrations of HVA and 5HIAA in patients with ALL who had received no treatment (median values 52 and 18 ng/ml, respectively) showed a wide scatter and were inversely related to age. In patients receiving MTX, concentrations of these metabolites were higher than in the untreated group, again reaching a peak in patients just completing 2 years of treatment (median HVA 110 ng/ml, 5HIAA 34 ng/ml). These results provide no support for the idea that neurotransmitter amine deficiency occurs in children with ALL receiving MTX, and indicate, rather, that amine and biopterin synthesis increases in such patients.