Assessment of the genotoxic and carcinogenic risks of p-nitrophenol when it is present as an impurity in a drug product.

According to the 2008 US FDA (draft) and 2006 EMEA guidance documents for genotoxic impurities, an impurity that is positive in an in vitro genotoxicity study, in the absence of in vivo genotoxicity or carcinogenicity data, should be treated as genotoxic and typically controlled to 1.5 microg/day for chronic use. For p-nitrophenol (PNP), existing study results (i.e., positive in vitro clastogenicity in mammalian cells, no information on its in vivo genotoxicity, and negative with respect to carcinogenicity in a dermal mouse study with no confirmation of systemic exposure) indicated that it should be considered genotoxic and exposure as a drug impurity limited. Therefore, to more completely characterize the genotoxic potential of PNP (consistent with the guidance documents), in vivo mouse micronucleus and dermal pharmacokinetic bridging studies were conducted. In the micronucleus study, PNP was negative, demonstrating that the reported in vitro clastogenicity is not present in vivo. In the pharmacokinetic study, PNP was well absorbed dermally, validating the negative dermal carcinogenicity assessment. These results indicate that PNP should be considered a non-genotoxic impurity and, as a drug impurity, a threshold limit of 4 mg/day would be set (per ICH Q3C). This threshold limit is higher than the EPA reference dose (listed in the 2006 Edition of the Drinking Water Standards and Health Advisories), so if present at such levels, the specification limits for PNP should be determined on a case-by-case basis, based on risk-benefit.

Effects of meals and meal composition on the bioavailability of fenretinide.

The effects of meals and meal composition on the bioavailability of fenretinide, N-(4-hydroxyphenyl) retinamide, a synthetic retinoid undergoing clinical trials, were examined in two separate studies using an open, randomized, crossover design. In the first study, 13 healthy male volunteers received 300-mg doses of fenretinide (1) while fasting and (2) after a high-fat breakfast. In a subsequent study, 15 subjects received 300 mg fenretinide after each of three different test meals (high-fat, high-protein, and high-carbohydrate) separated by a 1-week washout period. Plasma specimens obtained over a 72-hour period after each treatment were assayed by high-pressure liquid chromatography to characterize the effects of a meal and meal composition on the bioavailability of fenretinide. Results from the initial study demonstrated a significant increase in the bioavailability of fenretinide after a high-fat meal. In the follow-up study, the bioavailability of fenretinide, as assessed by total area under the plasma concentration curve, was three times greater after the high-fat meal than after the high-carbohydrate meal. This supported the findings of the first study. Although to a lesser extent, the high-protein meal also produced a greater area under the curve than the high-carbohydrate meal. These combined findings demonstrate that the bioavailability of fenretinide is markedly influenced not only by administration with meals but also by the specific composition of such meals.

Lasers in neurosurgery: a historical overview.

This contribution to the history of laser applications to neurosurgical patients gives the background against which the subsequent developments took place. It covers the important facts regarding the theoretical formulations that led to the invention of the world's first laser in 1960. This was a pulsed ruby laser, which proved lacking in desirable surgical procedures, and at high powers was shown to be damaging to vital organs, such as the brain. It could be lethal to small animals. These very early tests of laser tissue and organ interaction included studies on protein in solution, cultured cells, brain, spinal cord and their surrounding tissues, and transplantable melanomas, as well as ependymoblastomas in mice. Fortunately, the continuous wave CO 2 laser came along in 1967 to replace both the pulsed ruby and neodymium-in-glass lasers. The CO 2 laser was quickly seen to possess surgical properties, namely, vaporization, cutting, hemostasis, and sterilization, without additional damage at a distance or remotely in time. Research studies on normal and pathologic tissues in and around the brain and spinal cord quickly and dramatically showed the potential for benefit to animal and human patients with experimental and naturally occurring neoplasms, burns, and decubitus ulcers. Lasers in neurosurgery are used largely for benign and malignant brain and spinal neoplasms. For benign tumors, debulking of tumor mass, and ablation of unwanted neoplasm without damaging adjacent, vital, functioning neural tissue, the laser adds another therapeutic adjunct and will, at times, aid in complete tumor removal. For malignant vascular growths, the laser will aid greatly in the safest possible excision with maximum hemostasis. Studies around the world, ongoing or planned, will surely extend the uses of lasers for neurosurgery into vascular, infectious, and reconstructive fields, particularly with the proliferation of laser instruments that exploit additional wavelengths into the larger infrared levels and even the shorter ultraviolet region. Experimental and, to some extent, clinical applications are testing the value of Nd:YAG, holmium:YAG, and erbium:YAG lasers in various surgical fields.

Preoperative diagnosis of an extradural cyst arising from a spinal facet joint: case report.

A case of a lumbar spinal extradural cyst is reported. An accurate preoperative diagnosis was made using magnetic resonance imaging. Characteristic findings on magnetic resonance imaging obviate the need for any additional radiological studies. The clinical features, radiological findings, and pathogenesis of these lesions are discussed.

Correlates of memory in Parkinson's disease.

There is much controversy concerning the incidence and nature of dementia, particularly memory impairment, in the parkinsonian patient. Specifically, a question arises with respect to the relationship of numerous personal, neurological, medication, and disability variables to this memory impairment. We administered a recently developed standardized test of recent memory functions to 53 idiopathic parkinsonian patients undergoing Sinemet treatment. Memory scores were correlated with age, sex, education, marital status, length of illness, age at onset of illness, dosage and time on medication, functional status, and the major symptoms of parkinsonism. Of all factors assessed, only increased bradykinesia correlated consistently and pervasively with impaired memory. Some possible explanations are offered.

The olfactory and cognitive deficits of Parkinson's disease: evidence for independence.

In the present study we sought to determine whether the olfactory deficits of parkinsonism are related to the cognitive and perceptual-motor manifestations of the disease. Pearson correlation coefficients were computed among a number of olfactory, neurological, and neuropsychological measures obtained from 58 Parkinson's disease patients, including the University of Pennsylvania Smell Identification Test, a modified Randt memory test, a reaction time test, a finger-tapping test, ratings of motor and neurological function, and selected verbal and performance subtests of the Wechsler Adult Intelligence Scale--Revised. Data from 38 patients with Parkinson's disease who received odor detection threshold testing were also evaluated. The intercorrelation matrix was subjected to a principal components factor analysis which yielded six clear-cut factors: cognitive/memory, gross motor, oral motor, fine motor, olfactory, and tremor. The olfactory factor received strong and nearly exclusive loadings from the olfactory measures (which did not evidence meaningful loadings on any of the other factors). A ten-trial jackknife procedure revealed the factor structure to be stable. Further support of the independence of the olfactory variables from the other measures was provided by multiple regression and canonical correlation analyses. Overall, these findings lend support to the hypothesis that the olfactory disorder of parkinsonism is independent of the cognitive, perceptual-motor, and memory manifestations of the disease.

Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration.

To explore the nature of the olfactory dysfunction associated with Parkinson's disease (PD), 81 PD patients who scored well on a cognitive screening test were administered the 40-odorant University of Pennsylvania Smell Identification Test; 38 were additionally given a forced-choice phenylethyl alcohol odor detection threshold test. Clinical ratings of 11 neurologic symptoms (three bilateral) were obtained at the time of testing, and odor identification was retested in 24 patients at intervals ranging from 5 to 39 months. Relative to matched controls, the PD patients exhibited consistent and marked decrements on both types of olfactory tests (ps less than 0.0001). The odor identification deficit was not restricted to any subset of odorants and did not evidence longitudinal change. A factor analysis of the intercorrelations among the variables yielded six easily interpretable factors: general motor, oral motor, olfactory function, cognitive function, tremor, and gender. Olfactory test scores were independent of all other measures, including disease stage and duration. Seventy-two percent of the PD patients were unaware of a smell disorder before testing; those who were aware had significantly lower test scores. A statistical comparison of PD patients' olfactory test scores to those obtained from Alzheimer's disease patients found the olfactory disorders of these diseases to be indistinguishable. The data support the hypothesis that the olfactory deficit of PD is a general and stable one which likely occurs early in the disease process.

Migraine prevention with timolol. A double-blind crossover study.

One hundred seven patients (77 women and 30 men) with migraine headache were given prophylactic treatment with timolol maleate, 20 to 30 mg/day, or matching placebo during a 20-week, double-blind crossover study. Among the 94 patients who completed the study, timolol was significantly better than placebo in terms of decrease in frequency of headaches from baseline, numbers of patients who had a 50% reduction in headache frequency, global response, and patient preference. Overall global response rates were 65% with timolol compared with 40% with placebo. The severity and duration of headaches that occurred were unchanged. Few side effects were reported with either timolol or placebo. The study demonstrates that the beta-blocker timolol is a safe and effective treatment in patients with frequent migraine headaches.

Present status of laser neurosurgery.

A three-fold approach to the status of laser neurosurgery was taken: 1) Questionnaire to Program Directors for neurosurgery training in the United States and Canada; 2) an analysis of titles in the preliminary neurosurgery program of the Fifth International Congress of Neurosurgery; 3) A literature survey covering the last 3 years of publication. The results showed increasing interest in the use of lasers in neurosurgery, especially for neoplasms in brain and spinal canal. The CO2 laser still dominates the field but Neodymium YAG is also finding wide use. The author comments on directions that laser neurosurgery may take in the future. Special emphasis is made on new applications combining advanced technologies, including CAT scanning, ultrasonography, stereotaxic techniques, and computer control.

The carbon dioxide surgical laser in neurological surgery, decubitus ulcers, and burns.

Laser surgery has become an established part of general and specialty surgical techniques. Of all the lasers available today, the carbon dioxide laser possesses the physical and biological-surgical properties of most value to the surgeon. The CO2 laser puts out a spatially and temporally coherent beam of high intensity, infrared radiation at 10.6 micrometers, a wavelength nearly 100% absorbed by tissue. Its action is dependent on heat, and it has the ability to vaporize, cut, and excise all tissue hemostatically, sterilizing as it proceeds. Experimental work in animal patients and man has laid the groundwork for clinical application. The CO2 laser's value as a surgical tool has been clearly shown in the treatment of cancers and other neoplasms in brain, thoracic, and abdominal viscera; larynx; pharynx; nasal and sinus cavities; rectum; vulva, vagina; and uterus, for palliation and, at times, cure. It has been found of undoubted value in the debridement of decubitus ulcers and burns and has great potential for orthopedic surgery and breast surgery. The surgical laser is safe for patient and operating personnel, relatively simple to use, rapid in its action and without untoward impact on tissue locally or at a distance.