Phase I clinical and pharmacokinetic study of oral penclomedine (NSC 338720) in adults with advanced solid malignancy.
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Penclomedine is a synthetic alpha-picoline derivative that has shown antitumor activity both in preclinical development and in Phase I work using an i.v. preparation. The main toxicities seen in those studies were dose dependent and mainly neurocerebellar, with hematological toxicity being far less severe. This Phase I trial of p.o. penclomedine was conducted to potentially alter the toxicity profile and to avoid the neurological side effects seen with i.v. penclomedine. Eligibility criteria included microscopic confirmation of a solid malignancy or lymphoma with a lack of effective anticancer therapy. Twenty patients were enrolled. The median age was 60.5 years, and the median performance status was one. All but one patient had received prior systemic therapy. The starting dose of penclomedine was 200 mg/m(2) p.o. for 5 days, and was escalated according to a traditional Fibonacci sequence until the maximum tolerated dose (MTD) was observed. No treatment-related deaths were observed during the study. The MTD was determined to be 800 mg/m(2) p.o. for 5 days. Dose-limiting toxicities included mainly neurocerebellar symptoms such as ataxia and dysmetria, but neurocortical symptoms, such as confusion, were seen as well. Myelosuppression was less common and resulted in the discontinuation of therapy in only two patients. Pharmacokinetics show that the observed MTD is consistent with the i.v. preparations, and that the bioavailability of p.o. penclomedine is 49 +/- 18%. This regimen can be considered for additional studies in patients with intracranial neoplasms, because good central nervous system penetration is evident. Further development of penclomedine metabolites, such as 4-O-demethylpenclomedine, should be considered to minimize dose-limiting neurotoxicity. (+info)
Magnetic resonance brain imaging in people with dizziness: a comparison with non-dizzy people.
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BACKGROUND: Dizziness is a common symptom affecting about 30% of people over the age of 65. OBJECTIVE: To investigate the hypothesis that structural abnormalities of the brain and cervical cord are more common in dizzy than in non-dizzy subjects. METHODS: A case-control study of subjects over the age of 65 with and without dizziness: 125 dizzy subjects and 86 non-dizzy subjects were recruited from the community through articles in the local press. Magnetic resonance imaging (MRI) of the brain and neck was performed, and was read by a consultant neuroradiologist blind to the clinical details. RESULTS: All dizzy subjects and all controls had at least one structural abnormality. Cerebral atrophy was found in 86% of dizzy subjects and 85% controls (p = 1.0) At least one white matter lesion was found in 69% of dizzy subjects and 78% controls (p = 0.21). White matter lesions in the midbrain were more common in dizzy than in non-dizzy subjects (22% v 4%, p < 0.001). There were no significant differences in the prevalence of cord compression, cervical subluxation, facet joint degeneration, vertebral artery compression, or vertebral artery occlusion between dizzy and non-dizzy subjects. CONCLUSIONS: Structural abnormalities of the brain and neck are common in both dizzy and non-dizzy subjects. "Routine" MRI is unlikely to reveal a specific cause for dizziness. The observation of more frequent white matter lesions in the midbrain in dizzy subjects requires further study to determine whether small vessel changes could cause dizziness in older people. (+info)
Blood pressure changes on upright tilting predict falls in older people.
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BACKGROUND: orthostatic hypotension may be an important risk factor for falls, though this has not yet been demonstrated in prospective studies. This may be because conventional methods of measuring blood pressure changes are too imprecise and not optimally timed. OBJECTIVES: to determine whether changes in blood pressure induced by upright tilt are associated with falls in older people, and whether medication use and symptoms of dizziness are associated with blood pressure changes and falls. METHODS: seventy men and women aged 62-92 years participated. We measured blood pressure with a plethysmograph monitor continuously before and after upright tilt. We recorded medication use and symptoms of dizziness in response to the tilt. Subjects were then followed up for 12 months to determine the incidence of falls. RESULTS: subjects who fell in the follow-up period had significantly greater decreases in systolic blood pressure when tilted than those who did not fall. Furthermore, those who had unstable systolic blood pressure during the 3 minutes after tilting, in addition to large blood pressure drops, had a two-fold increased risk of falling compared with those with neither of these conditions. Symptoms of dizziness on tilting were uncommon and not associated with blood pressure or heart rate changes, medication use, or falls incidence. Antidepressant and antihypertensive medication use were associated with decreases in diastolic rather than systolic blood pressure, but were not associated with falls. CONCLUSIONS: these findings indicate that both the decrease in blood pressure and the unstable nature of the blood pressure response following upright tilt are useful predictors of falls in older people. (+info)
Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300).
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BACKGROUND AND PURPOSE: Based on the hypothesis of glutamate-induced neurotoxicity (excitotoxicity) in cerebral ischemia, this study examined the efficacy and tolerability of memantine, an uncompetitive N-methyl-D-aspartate antagonist, in the treatment of mild to moderate vascular dementia. METHODS: In this multicenter, 28-week trial carried out in France, 321 patients received 10 mg/d memantine or placebo twice a day; 288 patients were valid for intent-to-treat analysis. Patients had to meet the criteria for probable vascular dementia and have a Mini-Mental State (MMSE) score between 12 and 20 at inclusion. The 2 primary end points were the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog) and the global Clinician's Interview Based Impression of Change (CIBIC-plus). RESULTS: After 28 weeks, the mean ADAS-cog scores were significantly improved relative to placebo. In the intention-to-treat population, the memantine group mean score had gained an average of 0.4 points, whereas the placebo group mean score had declined by 1.6 points, ie, a difference of 2.0 points (95% confidence interval, 0.49 to 3.60). The response rate for CIBIC-plus, defined as improved or stable, was 60% with memantine compared with 52% with placebo (P=0.227, intention to treat). Among the secondary efficacy parameters, which were analyzed in the per-protocol subset, MMSE was significantly improved with memantine compared with deterioration with placebo (P=0.003). The Gottfries-Brane-Steen Scale intellectual function subscore and the Nurses' Observation Scale for Geriatric Patients disturbing behavior dimension also showed differences in favor of memantine (P=0.04 and P=0.07, respectively). Memantine was well tolerated with a frequency of adverse events comparable to placebo. CONCLUSIONS: In patients with mild to moderate vascular dementia, memantine 20 mg/d improved cognition consistently across different cognitive scales, with at least no deterioration in global functioning and behavior. It was devoid of concerning side effects. (+info)
Methemoglobinemia following unintentional ingestion of sodium nitrite--New York, 2002.
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Methemoglobinemia is an unusual and potentially fatal condition in which hemoglobin is oxidized to methemoglobin and loses its ability to bind and transport oxygen. The most common cause of methemoglobinemia is the ingestion or inhalation of oxidizing agents such as nitrates or nitrites (e.g., sodium nitrite, which is used commonly as a preservative in curing meats and fish). This report summarizes the investigation of an incident of methemoglobinemia in five members of a household in New York who became ill after eating a meal seasoned with a white crystalline substance from a plastic bag labeled "Refined Iodized Table Salt" (Figure). The findings underscore the need for proper storage of hazardous materials to avoid unintentional ingestion and the importance of collaboration by multiple agencies to address a potential public health emergency. (+info)
A status report on chronic fatigue syndrome.
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Medical history has shown that clinical disease entities or syndromes are composed of many subgroups--each with its own cause and pathogenesis. Although we cannot be sure, we expect the same outcome for chronic fatigue syndrome (CFS), a medically unexplained condition characterized by disabling fatigue accompanied by infectious, rheumatological, and neuropsychiatric symptoms. Although the ailment clearly can occur after severe infection, no convincing data exist to support an infectious (or immunologic) process in disease maintenance. Instead, data point to several possible pathophysiological processes: a covert encephalopathy, impaired physiological capability to respond to physical and mental stressors, and psychological factors related to concerns about effort exacerbating symptoms. Each of these is under intense investigation. In addition, some data do exist to indicate that environmental agents also can elicit a state of chronic fatigue. We expect data to accumulate to support the belief that CFS has multiple causes. (+info)
Contrast-enhanced 2D cine phase MR angiography for measurement of basilar artery blood flow in posterior circulation ischemia.
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BACKGROUND AND PURPOSE: Dizziness is a symptom that develops with internal ear disturbances and with dysfunctions of the brain stem and cerebellum, in particular with blood flow disturbances of the brain stem and cerebellum (posterior circulation ischemia [PCI]). Patients with PCI often present with various neurologic signs and symptoms. To examine the usefulness of contrast-enhanced 2D cine phase MR angiography in the diagnosis of PCI, we examined quantitative blood flow of the basilar artery in patients with PCI who had primarily complained of dizziness. METHODS: We quantitatively measured the blood flow volume rate of the basilar artery by using a contrast-enhanced 2D cine phase MR angiographic technique in 21 patients diagnosed with PCI and in 16 age- and sex-matched control participants. RESULTS: Maximum and mean average flow velocities of the basilar artery in the PCI group were significantly lower than those of the control group (29.2 +/- 9.2 cm/s versus 38.5 +/- 8.2 cm/s [P <.005] and 18.0 +/- 5.6 cm/s versus 22.6 +/- 5.0 cm/s [P <.01], respectively). The flow volume rates of the basilar arteries were also significantly lower in the PCI group (103.3 +/- 37.3 mL/min versus 148.8 +/- 40.0 mL/min [P <.001]). CONCLUSION: The flow volume rate of the basilar artery in patients with PCI during intermittent ischemic attacks with dizziness was chronically reduced compared with that in the control participants. This suggests that flow volume rates may influence the development of the clinical signs and symptoms of PCI. We think that contrast-enhanced 2D cine phase MR angiography is a valuable method for the diagnosis of PCI. (+info)
A meta-analysis of GCS 15 head injured patients with loss of consciousness or post-traumatic amnesia.
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OBJECTIVES: The classification of patients with "minor head injury" has relied largely upon the Glasgow Coma Scale (GCS). The GCS however is an insensitive way of defining this heterogeneous subgroup of patients. The aim of the study was to develop an extended GCS 15 category by meta-analysis of previously published case-control studies that have identified symptom risk factors for an abnormal head tomogram. METHODS: Eligibility for the study was defined as: (1) Full papers and not abstracts. (2) Case-control or nested case-control studies on GCS 15 patients (adults or adults plus children). Outcome variable being head tomography: normal or abnormal. (3) Documentation of one or more symptom variables such that the odds ratio could be calculated. Five symptom variables were defined for the purpose of the study: headache, nausea, vomiting, blurred vision, and dizziness. RESULTS: Three articles fulfilled the criteria for the study. The Mantel-Haenszel test using a pooled estimate was used to calculate the common odds ratio for an abnormal head tomogram for each of the five symptom variables. The odds ratio for the symptom variables was: dizziness 0.594 (95%CI 0.296 to 1.193), blurred vision 0.836 (95%CI 0.369 to 1.893), headache 0.909 (95% CI: 0.601 to 1.375), severe headache 3.211 (95% CI: 2.212 to 4.584), nausea 2.125 (95% CI 1.467 to 3.057), vomiting 4.398 (95% CI 2.790 to 6.932). CONCLUSION: The results of this study provide a framework on which GCS category 15 patients can be stratified into four risk categories based upon their symptoms. (+info)