Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist

Although the selectivity and potency of adenosine amine congener (ADAC) at adenosine A1 receptors are similar to other highly selective agonists at this receptor type, the chemical structure of the N6 substituent is completely different. We now demonstrate that the characteristics of the therapeutic profile of ADAC are distinct from those observed during our previous studies of adenosine A1 receptor agonist-mediated neuroprotection. Most significantly, chronic treatment with low microgram doses of ADAC (25-100 microg/kg) protects against both mortality and neuronal damage induced by 10 min bilateral carotid occlusion in gerbils. At higher chronic doses, the statistical significance of the protective effect is lost. Acute preischemic administration of the drug at 75-200 microg/kg also results in a statistically significant reduction of postischemic mortality and morbidity. These data indicate that, contrary to other adenosine A1 receptor agonists whose chronic administration enhances postocclusive brain damage, ADAC may be a promising agent in treatment of both acute (e.g., cerebral ischemia) and chronic (seizures) disorders of the central nervous system in which adenosine A receptors appear to be involved.     

A phase I and pharmacokinetic trial of terephthalamidine (NSC 57155) as a 120-hour continuous infusion

In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m²/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m². Both plasma concentrations achieved during infusion (r² = 0.9) and area under the curve (AUC) (r² = 0.8) were proportional to increase in dose (p < 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m². Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented.     

Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkin's lymphoma

Summary Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m² of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 g/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m² with a relatively large apparent volume of distribution at steady-state of 1012 l/m² indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.     

Pulse oximetry during helicopter transport

The study objective was to determine if pulse oximetry readings obtained during helicopter transport were indicative of subsequent arterial blood-gas measured saturations. A prospective study design was chosen. Data were gathered on a convenience sample of patients 18 years and older not under cardiopulmonary resuscitation; 101 patients were used for the study. Pulse oximeter readings of oxygen saturation and heart rate were recorded along with simultaneous vital signs. Arterial saturation in blood gases drawn in the emergency department were added to the patient record. Improper functioning of the pulse oximeter was recorded on 10 (9.9%) of the patients. No correlation was found between the probe type and the documented problems (PHI = 0.009). The pulse oximeter saturation readings were not significantly different from arterial saturation in blood gases when compared by paired samples t-test (t = 0.880, p = 0.383). There was also no significant difference between the patient's heart rate sensed by the pulse oximeter and the simultaneous palpated pulse rate. Percent saturation readings by repeated measures were statistically different (p < 0.05) showing a minimal improvement in saturation over time. Based on this study's findings, the authors feel the pulse oximeter can be a valuable adjunct to patient care during helicopter transport.     

Perioperative nutritional support: a randomised clinical trial

Ever since methods of artificial nutritional support became available, attempts have been made using this form of treatment to reduce mortality and morbidity in surgical patients. Many trials have addressed this question, but very few have given a meaningful answer because of conceptual and methodological flaws. We therefore undertook a prospective randomised trial investigating the effects of at least 10 days pre-operative total parenteral nutrition (TPN) (n = 51) or total enteral nutrition (TEN) (n = 50) providing 150% basal energy expenditure (BEE) non-protein energy, to reduce major postoperative complications and mortality in a homogeneous patient group with signs of depletion. 50 patients served as a depleted control group (D) and 49 patients served as a non-depleted reference group (ND) and were operated upon without delay. Depleted control patients suffered significantly more septic complications than did patients in the non-depleted reference group (p < 0.05). There was no significant difference, however, in septic complications between either of the nutritional support groups and the non-depleted control group. In high risk patients, with weight loss >10% of body weight and over 500 ml blood loss during operation, a significant decrease in major complications was observed (p < 0.05) as a result of nutritional support. We conclude that pre-operative nutritional support, in patients with severe depletion, results in a reduction in major complications to a degree that justifies its routine use in this selected group of patients.     

Community activation and health promotion: identification of key organizations

PURPOSE. The purpose of this study is to identify the kinds of community organizations community leaders consider important for community health promotion efforts. DESIGN. Key informants were identified by reputational sampling of organizations relevant to community health promotion. Key informants were asked to list organizations they considered important for community health promotion. Differences in identified organizations were compared across informants from seven urban, five suburban, seven rural, and three Native American communities, with significance evaluated by chi-square tests. SETTING. This survey was conducted in 22 Western U.S. communities comprising the intervention and control communities of the Community Health Promotion Grants Program of the Henry J. Kaiser Family Foundation. SUBJECTS. Key informants (N = 184) from community organizations, identified using a reputational sampling technique beginning with the health department, were interviewed by telephone. MEASURES. Key informants listed organizations considered important for community health promotion in five areas: adolescent pregnancy, substance abuse, tobacco use, cancer, and cardiovascular disease. RESULTS. Informants frequently identified the health department (mentioned by 78% of informants overall), schools (72%), governmental agencies (55%), hospitals (47%), health clinics (42%), churches (33%), and newspapers (32%) as important. Organizations more prominent in urban and suburban areas than in rural and Native American areas included television stations, health-related private nonprofit organizations, substance abuse treatment centers, and colleges. Private physicians were frequently identified in rural areas (44% of informants).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cell Type-specific Effects of the Neural Adhesion Molecules L1 and N-CAM on Diverse Second Messenger Systems

We have previously shown that the neural adhesion molecules L1 and N-CAM influence second messenger systems when triggered with specific antibodies at the surface of the phaeochromocytoma PC12 cell line (Schuch et al., Neuron, 3, 13 - 20, 1989). To determine whether the two molecules are linked to the same intracellular signalling cascades, independent of the cell type expressing them, or whether different neural cell types respond with different signal transduction mechanisms, we have investigated the effects of antibodies to L1 and N-CAM, and the isolated molecules themselves, on second messenger systems in different neural cell types. We have investigated cultures of cerebellar and dorsal root ganglion neurons and transformed Schwann cells and related these results to those obtained with the PC12 cell line. Here we show that addition of L1 and N-CAM antibodies and the isolated molecules themselves elicit cell type-specific responses that can be modulated by the substrate on which the cells are maintained. Depending on the cell type, cells respond to the triggering of L1 and N-CAM with antibodies, or addition of the purified molecules, by either up-regulation or down-regulation of inositol phosphate turnover, by a rise in intracellular Ca2+ levels dependent on or independent of the opening of voltage-gated Ca2+ channels, or by an increase or decrease in intracellular pH. Moreover, cerebellar neurons expressing N-CAM respond to addition N-CAM, but not to N-CAM antibodies, in contrast to the other neural cell types studied, which respond to both triggers. Furthermore, cerebellar neurons were the only cells to show a rise in cAMP levels in response to any of the ligands tested. This stimulation of cAMP production by L1 antibodies depended on the cross-linking of L1 molecules at the cell surface, whereas the other responses did not depend on clustering of L1. Simultaneous addition of L1 and N-CAM antibodies either elicited an additive or more than additive effect on the intracellular responses which, for cerebellar neurons, depends on the substrate on which the cells are maintained. These observations indicate that L1 and N-CAM or their antibodies activate cell type-specific intracellular signalling systems and that the two molecules can act interdependently or independently of each other.     

Combination chemotherapy with cisplatin, bleomycin, and methotrexate in patients with advanced head and neck cancer

Twenty-six patients with advanced head and neck cancer, 22 of whom had failed prior surgery and/or radiotherapy, were treated with a combination regimen of cis-diamminedichloroplatinum II, bleomycin, and methotrexate. There were no complete responses. Nine patients achieved a partial response (35%). Three of the four (75%) patients without prior therapy achieved a partial response while only 6 of the 22 patients (27%) with prior surgery and/or radiation therapy obtained a partial response. The median response duration was 3 months. Patients with a partial response did not live significantly longer than those who did not live significantly longer than those who did not respond. Toxic reactions were frequent: there were three episodes of sepsis secondary to leukopenia and two cases of bleomycin pulmonary toxicity. Mucositis was noted in 40% and nausea and vomiting in 60% of patients. We conclude that this triple-drug regimen has little value in the treatment of patients with advanced squamous cell carcinoma of the head and neck who have failed prior surgery and radiotherapy.     

Growth hormone secretagogue activation of the arcuate nucleus and brainstem occurs via a non-noradrenergic pathway

Noradrenergic systems are integrally involved in the release of growth hormone (GH) from the anterior pituitary gland and in regulating the activity of hypothalamic growth hormone-releasing hormone (GHRH) neurones. GH secretagogues act at both the pituitary and the hypothalamus to facilitate the release of GH. In male rats, using the induction of Fos protein as an indicator of neuronal activation, we examined whether neurones in the brainstem, the main noradrenergic input to the hypothalamus, were activated by systemic administration of peptide and non-peptide GH secretagogues. In addition, we examined the effects of chronic central noradrenaline depletion upon GH secretagogue-induced activation of the arcuate nucleus. Systemic injection of the GH secretagogues, GHRP-6 and MK-0677 induced Fos protein expression in a population of area postrema cells, but less than 10% of these cells were noradrenergic. Depletion of hypothalamic noradrenaline by the specific neurotoxin, 5-ADMP, did not alter GH secretagogue-induced activation of Fos protein in the arcuate nucleus compared to vehicle-treated controls. We conclude that the central actions of GH secretagogues involve the activation of non-noradrenergic cells in the area postrema and that GH secretagogue-induced activation of the arcuate nucleus occurs independently of noradrenergic tone.