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The demonstration that angiogenic growth factors can stimulate new blood vessel growth and restore perfusion in animal models of myocardial ischemia has led to the development of strategies designed for the local production of angiogenic growth factors in patients who are not candidates for conventional revascularization. The results of recent clinical trials of proangiogenesis gene therapy have been disappointing; however, significant limitations in experimental design, in particular in gene transfer strategies, preclude drawing definitive conclusions. In the REVASC study cardiac gene transfer was optimized by direct intramyocardial delivery of a replication-deficient adenovirus-containing vascular endothelial growth factor (AdVEGF121, 4 x 10(10) particle units (p.u.)). Sixty-seven patients with severe angina due to coronary artery disease and no conventional options for revascularization were randomized to AdVEGF121 gene transfer via mini-thoracotomy or continuation of maximal medical treatment. Exercise time to 1 mm ST-segment depression, the predefined primary end-point analysis, was significantly increased in the AdVEGF121 group compared to control at 26 weeks (P=0.026), but not at 12 weeks. As well, total exercise duration and time to moderate angina at weeks 12 and 26, and in angina symptoms as measured by the Canadian Cardiovascular Society Angina Class and Seattle Angina Questionnaire were all improved by VEGF gene transfer (all P-values at 12 and 26 weeks < or =0.001). However, if anything the results of nuclear perfusion imaging favored the control group, although the AdVEGF121 group achieved higher workloads. Overall there was no significant difference in adverse events between the two groups, despite the fact that procedure-related events were seen only in the thoracotomy group. Therefore, administration of AdVEGF121 by direct intramyocardial injections resulted in objective improvement in exercise-induced ischemia in patients with refractory ischemic heart disease.

Salvia divinorum is a widespread hallucinogenic herb traditionally employed for divination, as well as a medicament for several disorders including disturbances of gastrointestinal motility. In the present study we evaluated the effect of a standardized extract from the leaves of S. divinorum (SDE) on enteric cholinergic transmission in the guinea-pig ileum. SDE reduced electrically evoked contractions without modifying the contractions elicited by exogenous acetylcholine, thus suggesting a prejunctional site of action. The inhibitory effect of SDE on twitch response was abolished by the opioid receptor antagonist naloxone and by the kappa-opioid antagonist nor-binaltorphimine, but not by naltrindole (a delta-opioid receptor antagonist), CTOP (a mu-opioid receptor antagonist), thioperamide (a H(3) receptor antagonist), yohimbine (an alpha(2)-receptor antagonist), methysergide (a 5-hydroxytryptamine receptor antagonist), N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase) or apamin (a blocker of Ca(2+)-activated K(+) channels). Salvinorin A, the main active ingredient of S. divinorum, inhibited in a nor-binaltorphimine- and naloxone-sensitive manner electrically induced contractions. It is concluded that SDE depressed enteric cholinergic transmission likely through activation of kappa-opioid receptors and this may provide the pharmacological basis underlying its traditional antidiarrhoeal use. Salvinorin A might be the chemical ingredient responsible for this activity.

Background and Purpose —Endothelin 1 (ET-1) is a potent vasoconstrictor that may play a role in cerebral vasospasm following subarachnoid hemorrhage (SAH). However, data regarding its pathogenic role in the development of vasospasm are controversial. We planned a prospective, observational clinical study to investigate the temporal relationship between increased ET-1 production and cerebral vasospasm or other neurological sequelae after SAH. Methods —ET-1 levels in cerebrospinal fluid (CSF) were measured in 20 SAH patients from admission (within 24 hours from the bleeding) until day 7. Patients received a daily transcranial Doppler study and a neurological evaluation. On day 7, angiography was performed to verify the degree and extent of vasospasm. Patients were then classified as having (1) clinical vasospasm, (2) angiographic vasospasm, (3) no vasospasm, or (4) poor neurological condition without significant vasospasm (low Glasgow Coma Scale score [GCS]). Results —On admission, ET-1 levels were increased in the low-GCS group compared with the other groups ( P =0.04). On day 4 ET-1 levels were not significantly different among groups, whereas on day 7 ET-1 levels were significantly increased in both the clinical vasospasm and low-GCS groups compared with the angiographic vasospasm and no vasospasm groups ( P R 2 =0.73). Conclusions —CSF ET-1 levels were markedly elevated in patients with clinical manifestations of vasospasm (day 7) and with a poor neurological condition not related to vasospasm. However, ET-1 levels were low in clinical vasospasm patients before clinical symptoms were evident (day 4) and remained low in angiographic vasospasm patients throughout the study period. Thus, our data suggest that CSF ET-1 levels are increased in conditions of severe neuronal damage regardless whether this was due to vasospasm or to the primary hemorrhagic event. In addition, CSF ET-1 levels paralleled the neurological deterioration but were not predictive of vasospasm.

To determine: 1) whether obesity predisposes the myocardium to oxidative stress as evidenced by higher tissue levels of myocardial lipid peroxidation, and 2) what cellular mechanisms are responsible for this predisposition.Comparative, descriptive study of the myocardial tissue of lean and obese Fatty Zucker animals.12 month old lean (-/fa; n = 6; mean body weight = 590 g) and obese (fa/fa; na = 7; mean body weight= 882 g) male Fatty Zucker rats.Basal lipid peroxidation (assessed using thiobarbituric reactive acid substances (TBARS) and cumene hydroperoxide equivalents), oxidative and antioxidant enzyme activities (citrate synthase (CS), superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT), thiol content, heat shock protein expression (HSP72/73) and TBARS concentrations following an iron-mediated challenge in vitro.Compared to lean, lipid peroxidation was greater (P0.05) in the left ventricle (LV) from obese rats as indicated by higher levels of lipid hydroperoxides (mean = 11.48 vs 13.7 cumene hydroperoxide equivalents (CHPE)/mg lipid) and TBARS (mean = 11.1 vs 13.9 nMol/mg lipid.). The activity of the manganese isoform of superoxide dismutase in the LV was higher (P0.05) in obese animals, compared to controls (mean = 135 vs 117 U/mg protein). In contrast, LV catalase and glutathione peroxidase activities did not differ (P0.05) between groups. Also, LV levels of HSP 72 (inducible) and 73 (constitutive) did not differ (P0.05)( between lean and obese animals. Following an iron-stimulated oxidative challenge in vitro, TBARS concentration was significantly greater (P0.05) in LV of obese rats compared to the lean (mean = 12.7 vs 16.7 nMol/mg lipid).These results support the notion that obesity predisposes the myocardium to oxidative stress. However, the postulate that obesity is associated with elevated myocardial antioxidant enzyme activities and HSPs was only partially supported by these findings.

Palliation of malignant dysphagia can be achieved using self-expanding metal stents (SEMS). This study was conceived to confirm that the insertion of SEMS improved patient symptoms without serious complications and to allow comparison with recent national data. Retrospective case note review of all patients receiving SEMS over a 10-year period between March 1999 and February 2009 was used in this study. There were 138 consecutive patients (50 female), median age of 75 (range 46-90) years, 122 (88.5%) had primary malignant disease of the esophagus or gastroesophageal junction. In total, 250 endoscopic examinations were carried out, with 200 interventional procedures, including the insertion of 156 SEMS. Before stenting, 74.2% of patients had a dysphagia score of 2-3. Following stent insertion, dysphagia scores improved to 0-1 in 90.3% of patients (P0.0001, Wilcoxon signed ranks). No complications were encountered in 61 (44%) patients. Chest pain was the most frequent difficulty, encountered in 50 (36%) patients. Tumor overgrowth occurred in 17 (12.3%) patients and food bolus obstruction was seen in 7% of patients. There were no esophageal perforations attributable to SEMS insertion. Overall 30-day mortality for those with esophago-gastric malignancy was 11.6% (16 patients), although the SEMS-related mortality was 2.2% (3 patients). Median survival from SEMS insertion was 3 (IQR 1.5-7) months. Patients requiring re-intervention for tumor overgrowth had a significantly longer median survival of 9.2 months (P= 0.001, log rank). SEMS were well tolerated with overall mortality and complication rates comparable to national data. For the longer survivors, re-intervention for recurrent dysphagia was not unusual.

Two longitudinal experiments involving Merino sheep challenged with either bovine or ovine strains of Mycobacterium avium subsp. paratuberculosis (Map) have been conducted over a period of 54 and 35 months, respectively. Blood samples for the interferon-gamma test, the absorbed ELISA and faecal samples for bacteriological culture were taken pre-challenge and monthly post-challenge. Infections were induced with either a bovine or ovine strain of Map in separate experiments with infections being more easily established, in terms of faecal bacterial shedding and clinical disease when the challenge inoculum was prepared from gut mucosal tissue than cultured bacteria. The patterns of response for shedding and clinical disease were similar. Cell-mediated immune responses were proportionally elevated by at least an order of magnitude in all sheep dosed with either a bovine or ovine strain of Map. Conversely, antibody responses were only elevated in a relatively small proportion of infected sheep. Neither of the clinically affected tissue challenged sheep developed an antibody response despite the presence of persistent shedding and the development and decline in cell-mediated immunity. The results indicated that for sheep the interferon-gamma test may be useful for determining if a flock has been exposed to ovine Johne's disease.

Nitric oxide synthases (NOSs) generate nitric oxide (NO) and the by-product l-citrulline, via the catalytic combination of l-arginine and molecular oxygen. In mammals, there are three NOS genes: nNOS (NOS1), iNOS (NOS2) and eNOS (NOS3). The molecular structure, enzymology and pharmacology of these enzymes have been well defined, and reveal critical roles for the NOS system in a variety of important processes. The studies of NOS enzymes using knockout and transgenic mouse models have provided an invaluable contribution, highlighting critical roles in neuronal, renal, pulmonary, gastro-intestinal, skeletal muscle, reproductive and cardiovascular biology. This review will outline the data gleaned from complementary knockout and transgenic over-expression models in mice, and focus on the interactions between NOS enzymes and pathophysiology of the vascular system. These studies are a paradigm for the near future, which will involve the translation of an enormous amount of genomic data into physiological insights that penetrate the realms of both health care and biology.

Ischaemic heart disease (IHD) is a common condition with an annual hospital admission rate in England and Wales of around 6.3 per 1000.1 Guidelines produced by the joint audit committee of the British Cardiac Society and Royal College of Physicians recommend exercise electrocardiography in most new cases of angina. In accordance with current guidelines,2 many of these tests are now supervised by senior cardiac technicians without direct medical supervision. In our centre, around 2000 exercise tests are performed annually, 80–90% of which are technician supervised. All tests are reported by medical staff, which necessitates a significant increase in resources and an increase in reporting time. The purpose of this study was to evaluate the ability of experienced technical staff to provide accurate reports for technician supervised exercise tests. A total of 246 consecutive technician supervised exercise tests were collected prospectively. Tests were excluded if the requesting physician had indicated that medical supervision was required (n = 23), if bundle branch block was present at rest (n = 15), or where the purpose of the test was not primarily for the assessment of IHD (n = 8), leaving 200 tests for assessment. All tests were performed to Bruce or modified Bruce protocols. Each …

The role of nitric oxide (NO) in blood-brain barrier (BBB) breakdown and edema formation was investigated in the rat cortical cold injury model over a period of 10 min to 6 days post cold-injury by immunolocalization of fibronectin as a marker of BBB permeability alterations and endothelial (e) and inducible (i) nitric oxide synthases (NOS), which are markers of NO biosynthetic activity. BBB breakdown to fibronectin in lesion vessels was observed at 10 minutes post-injury, was maximal between 60 minutes and 3 hours and declined gradually thereafter, while perilesional vessels remained permeable up to 5 days. Increased eNOS immunoreactivity was observed in endothelium of perilesional permeable vessels starting at 12 hrs and was maximal between 4-6 days, after which immunoreactivity decreased reaching basal levels by 5-6 days. Immunoreactivity for iNOS was absent in normal brain and was first observed in polymorphonuclear leukocytes and endothelium of lesion vessels at 3 hrs. Maximal iNOS immunoreactivity was observed in endothelial cells and macrophages during the period of angiogenesis. Smooth muscle cells of overlying hyperplastic pial vessels showed iNOS immunoreactivity up to 6 days. The demonstration of increased NO synthases at the lesion site during BBB breakdown and edema formation and angiogenesis suggests that NO plays a role in these processes.

The Heart Outcomes Prevention Evaluation (HOPE) study was important because it showed the benefits of ramipril - an angiotensin-converting enzyme (ACE) inhibitor - in patients at high risk for cardiovascular events. Treatment with ramipril significantly reduced the rates of death, myocardial infarction, stroke, coronary revascularization, cardiac arrest and heart failure, as well as the risk of diabetes-related complications and of diabetes itself. The effects of therapy with vitamin E were also evaluated, but no statistical benefits were shown. The benefits of ACE inhibitor therapy that were observed were likely due to a variety of mechanisms, not just a reduction in blood pressure.

PURPOSE: To study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m2, day 1), or regimen B, cisplatin (100 mg/m2, day 1) plus vinorelbine (25 mg/m2, days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 × 1012 particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction. RESULTS: There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate. CONCLUSION: Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.

The purpose of this project was to assess the plasma pharmacokinetics of [(3)H]cholesterol following coadministration of a novel vegetable stanol mixture composed of sitostanol and campestanol (FCP-3P4) to fasting rats. Following an overnight fast (12-16 h) and 48 h post-surgery, adult male Sprague Dawley rats were divided into six treatment groups and received a single-dose oral gavage at 0700 h of either: [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (5 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (12.5 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (25 mg/kg) + [(3)H]cholesterol (25 microCi/mL), FCP-3P4 (50 mg/kg) + [(3)H]cholesterol (25 microCi/mL), or FCP-3P4 (100 mg/kg) + [(3)H]cholesterol (25 microCi/mL). Intralipid (10%) was the vehicle used to solubilize and coadminister [(3)H]cholesterol and FCP-3P4. Liquid chromatography-mass spectrometry analysis confirmed minimal cholesterol and vegetable stanol content within 10% Intralipid. Analysis of plasma pharmacokinetics was initiated by sampling 0.5 mL of blood prior to and 0.25, 0.5 1.0, 2.0, 4.0, 6.0, 8.0, 10, 24, 28, 32, and 48 h post-oral gavage. Plasma samples were obtained by centrifugation of the blood samples and analyzed for [(3)H]cholesterol radioactivity. Pharmacokinetics analysis was performed by standard noncompartmental methods using statistical moment theory. Thin-layer chromatography was used to confirm that the majority of radioactivity measured in plasma was cholesterol (in the form of esterified or unesterified cholesterol). Greater than 90% of the radioactivity measured in all plasma samples was cholesterol-associated (in the form of either esterified or unesterified cholesterol). The coadministration of FCP-3P4 significantly decreased the area under the curve of [(3)H]cholesterol concentration versus time from 0 to 48 h (AUC(0-48h)) and maximum concentration (C(max)) in a dose-dependent manner. However, coadministration of FCP-3P4 at 25, 50, and 100 mg/kg resulted in a significant increase in apparent total body clearance (CL/F, where F is the bioavailability constant), apparent volume of distribution (V(d)/F), and oral absorption rate constant (k(a)) of [(3)H]cholesterol compared with controls. These findings suggest that the novel vegetable stanol mixture, FCP-3P4, modifies the plasma pharmacokinetics of [(3)H]cholesterol in fasting rats on oral coadministration.

Our purpose in this study was to determine the efficacy and toxicity of losoxantrone (DuP-941), an anthrapyrazole, in patients with metastatic hormone-refractory prostate cancer. Patients with metastatic prostate cancer progressing on androgen ablation therapy without demonstrable antiandrogen withdrawal response were treated with losoxantrone 50 mg/m2 i.v. bolus every 21 days. All of the patients had elevated serum prostate-specific antigen (PSA) before study entry and had no prior chemotherapy. Forty-three assessable patients were entered. The median age was 70.6 years (range, 53.9-85.9), median Karnofsky performance scale (KPS), 70% (50-90%), and the median serum PSA, 173 microg/liter (12.5-11,140). The median number of courses was 4 (1-9). Five patients (25%) had a partial response as defined by50% decline in the serum PSA. Two of nine patients with measurable disease had partial responses and three had minor responses. Thirty percent of patients had improvement in KPS and 37% had an improvement in symptoms with decrease in pain and/or decrease in analgesic requirement. Nonhematological grade 3 and 4 toxicities were one each of grade 3 headache, grade 4 hypocalcemia, grade 3 hyperbilirubinemia, and grade 3 dyspnea. Twenty-six patients (60%) had grade 3 or 4 absolute neutropenia. In conclusion, losoxantrone demonstrated a partial biochemical response rate of 25%, response in measurable disease sites in 22%, and improvement in clinical symptoms in one-third of patients. In this study, PSA increase was not necessarily associated with lack of palliative response.

These experiments tested the hypothesis that short-term endurance exercise training would rapidly improve (within 5 days) the diaphragm oxidative/antioxidant capacity and protect the diaphragm against contraction-induced oxidative stress. To test this postulate, male Sprague-Dawley rats (6 weeks old) ran on a motorized treadmill for 5 consecutive days (40–60 min · day−1) at approximately 65% maximal oxygen uptake. Costal diaphragm strips were excised from both sedentary control (CON, n=14) and trained (TR, n=13) animals 24 h after the last exercise session, for measurement of in vitro contraction properties and selected biochemical parameters of oxidative/antioxidant capacity. Training did not alter diaphragm force-frequency characteristics over a full range of submaximal and maximal stimulation frequencies (P > 0.05). In contrast, training improved diaphragm resistance to fatigue as contraction forces were better-maintained by the diaphragms of the TR animals during a submaximal 60-min fatigue protocol (P < 0.05). Following the fatigue protocol, diaphragm strips from the TR animals contained 30% lower concentrations of lipid hydroperoxides compared to CON (P < 0.05). Biochemical analysis revealed that exercise training increased diaphragm oxidative and antioxidant capacity (citrate synthase activity +18%, catalase activity +24%, total superoxide dismutase activity +20%, glutathione concentration +10%) (P < 0.05). These data indicate that short-term exercise training can rapidly elevate oxidative capacity as well as enzymatic and non-enzymatic antioxidant defenses in the diaphragm. Furthermore, this up-regulation in antioxidant defenses would be accompanied by a reduction in contraction-induced lipid peroxidation and an increased fatigue resistance.

N-(phosphonacetyl)-L-aspartate (PALA) modulates the activity of 5-fluorouracil (5-FU) by inhibiting pyrimidine biosynthesis. A cross-over study was conducted to determine whether PALA affects the pharmacokinetic parameters of 5-FU in patients given 5-FU/folinic acid (FA). Six patients (3 males, 3 females) aged 63 4.3 (mean SD) years (body surface area of 1.84 18 m2) with metastatic colorectal carcinoma were given two courses of treatment. The treatment consisted of 250 mg/m2 of PALA on day 1 followed by 20 mg/m2 FA and 400 mg/m2 5-FU (5 min i.v. bolus injection) on days 2-5 in one cycle of treatment (PALA+). In another treatment cycle, these doses of 5-FU and FA were given for all 5 days without PALA (PALA-). The two courses were given four weeks apart. It was determined by random selection whether the course with PALA was given before or after the course without PALA. Blood samples were collected over a period of three hours, starting from the beginning of 5-FU infusion on days 2 and 5 of both courses. Plasma concentrations of 5-FU were determined by an HPLC technique. Pharmacokinetic parameters were calculated using a non-compartmental model. While there were no significant differences between pharmacokinetic parameters in the PALA+ vs PALA- courses, there was a trend towards a decreasing area under the curve (AUC) and increasing clearance (Cl) in PALA+ courses of treatment.

We studied the toxicity and efficacy of adding in sequence 4 resistance modulators to combination chemotherapy and radiotherapy in the treatment of glioblastoma multiforme and poor prognosis anaplastic astrocytomas. Patients received cisplatin plus mitomycin-C concurrently with and following 60 Gy of radiotherapy administered over 6 weeks. Resistance modulators were added in sequence to chemotherapy in each cohort of 6 patients as follows: metronidazole + pentoxifylline (cohort 1); + dipyridamole (cohort 2), + beta carotene (cohort 3). Central nervous system toxicity (which ranged from drowsiness to seizures and loss of consciousness) was frequent. The incidence of gastrointestinal symptoms was substantial, but was usually mild to moderate in severity. Three of 11 patients evaluable for response achieved a partial remission with treatment. The median survival duration for all patients was 26 weeks from initial diagnosis. The study was terminated prematurely because of significant toxicity (in this study as well as in parallel concurrent studies of similar design in other tumor types) and apparent lack of benefit.

The purpose of this study was to investigate the efficacy and safety of oral ondansetron, given alone or in combination with dexamethasone in the control of cisplatin-induced delayed emesis.This was an international, multicentre, double-blind, randomised, placebo-controlled, parallel group study. A total of 640 chemotherapy-naïve patients received ondansetron 8 mg i.v. and dexamethasone 20 mg i.v. for the control of acute emesis prior to cisplatin (or = 70 mg/m2) on day 1. Patients who were not rescued or withdrawn on day 1 were to be randomised 24 hours after the start of cisplatin administration to one of four groups; group I placebo oral (p.o.), twice daily (bd) on days 2-6 (n = 125); group II ondansetron (8 mg p.o. bd) on days 2/3 followed by placebo (p.o. bd) on days 4-6 (n = 199); group III ondansetron (8 mg p.o. bd) on days 2-6 (n = 214); group IV ondansetron (8 mg p.o. bd) plus dexamethasone (4 mg p.o. bd) on days 2-6 (n = 66).On day 1, 81% of patients had complete control of acute emesis, with 68% having no emesis and no nausea. Over days 2/3 and over days 2-6, significantly more patients receiving ondansetron plus dexamethasone (group IV) reported no emesis and no nausea (49% and 45%, respectively) compared to ondansetron alone (32% and 27%, respectively) or placebo (group I; 33% and 27%, respectively; P0.05 for all pairwise comparisons). There were no significant differences in the control of emesis over days 2/3, where 61% of patients had complete emetic control (0 emetic episodes) with ondansetron plus dexamethasone (group IV), 54% with ondansetron (groups II + III) and 49% with placebo (group I). In the distribution of nausea grades, ondansetron plus dexamethasone (group IV) was significantly superior to ondansetron (groups II + III); P = 0.037) and placebo (group I; P = 0.013) over days 2/3. Over days 2-6 there were no significant differences in the control of emesis, however a comparison of the distribution of nausea grades over days 2-6 showed ondansetron plus dexamethasone (group IV) to be significantly superior to ondansetron (group III; P = 0.043) and placebo (group I; P = 0.024). All treatments were well tolerated and no unexpected drug-related adverse events were reported. There were no differences in the overall incidence of adverse events between the active treatment groups or placebo. Constipation and headache, recognised side effects of 5-HT3 receptor antagonists, were the most commonly reported adverse events with the incidence of constipation with ondansetron alone (group III) being significantly greater than with over days 2-6 (14% vs. 6%; P = 0.030).In contrast to some previous investigations, in this study, ondansetron alone appears to have a minor role in the control of cisplatin-induced delayed emesis and nausea. In conclusion, the combination of oral ondansetron plus dexamethasone is superior to ondansetron and to placebo.

Two cases of Lambert-Eaton myasthenic syndrome (LEMS) who presented with primary respiratory failure are reported. In each case, although not initially suspected clinically, the electrophysiological findings, which included reduced compound muscle action potential amplitudes, decrement to 3-Hz stimulation, and potentiation after 40-Hz stimulation, led to the diagnosis in the critical care unit. Electrophysiological studies of the respiratory system, including repetitive nerve stimulation of the phrenic nerve, were extremely valuable in management. As shown by these cases, the severe respiratory failure in LEMS is reversible with treatment. Thus, LEMS should be considered in cases of unexplained respiratory failure, other clinical features of the disorder sought, and the electrophysiological hallmarks looked for including studies of the respiratory system.

Elderly patients with small cell lung cancer (SCLC) and/or those with comorbid conditions are frequently not considered candidates for standard combination chemotherapy. An active, but less toxic regimen is needed for this group of patients.Forty-seven elderly (65 years) or medically unfit patients with SCLC were treated with oral etoposide 100 mg/m2 x 7 days and carboplatin 150 mg/m2 day 1. Treatment was given every 3-4 weeks for six cycles in responding patients. Patients responding to the chemotherapy regimen were also treated with prophylactic cranial irradiation, and limited-stage patients received thoracic radiotherapy. The study population included 36 extensive-stage patients and 11 limited-disease patients with renal or cardiac disease that precluded standard chemotherapy. The median age of the study population was 69 years (range: 47-84).Nine of 47 patients were inevaluable for response, including four patients who succumbed to sepsis. Of the 38 patients evaluable for response, 71% responded (95% CI: 56-86%) (88% LD; 67% ED) with a complete response in 29% of patients (50% LD; 23% ED). Based on an analysis of intent to treat, the overall response rate was 60% and the median survival time of the whole group was 46 weeks (LD, 59 weeks; ED, 45 weeks). Treatment was generally well tolerated. Neutropenia was the dose-limiting toxicity; the median nadir granulocyte count was 1.04 x 10(9)/L (range: 0-8.2).We conclude that this regimen can provide palliation to SCLC patients who might not otherwise be considered for systemic chemotherapy.

Since doxorubicin causes cardiotoxicity, we wished to assess relative concentrations of doxorubicin and its metabolites in cardiac tissues of patients who had been treated antemortem. We also wished to determine factors that correlate with human cardiac doxorubicin and doxorubicinol concentrations.Autopsy tissues were collected from 35 patients who had received doxorubicin at any time antemortem, and were assayed by high pressure liquid chromatography.The major species found in human autopsy cardiac tissues were doxorubicinol (median concentration 92 ng/g, range 0 to 484 ng/g), and doxorubicin (median 58 ng/g, range 0-1665 ng/g). Other doxorubicin metabolites were detected in cardiac tissues inhalf the patients. Of ten organs studied, heart ranked fifth with respect to median doxorubicin concentration and ranked fourth with respect to median doxorubicinol concentration. By multiple stepwise regression analysis, factors most closely associated with cardiac doxorubicin concentrations were time from last treatment divided by dose intensity, serum total protein, albumin, and hemoglobin (negative correlations). Factors most closely associated with cardiac doxorubicinol concentrations were cumulative doxorubicin dose, total protein, hemoglobin, and uric acid (positive associations), and respiratory rate (negative association). The physiologic significance of these associations (if any) is uncertain. By paired t-tests, cardiac doxorubicin and doxorubicinol concentrations were significantly (p0.05) higher than concentrations in skeletal muscle and smooth muscle organs.Overall, the results suggest that the much greater tendency to develop doxorubicin toxicity in heart than in other types of muscle may be due to a propensity of cardiac muscle to accumulate doxorubicin. The results also suggest that doxorubicinol may play a role in doxorubicin cardiac toxicity, and that doxorubicin may be gradually converted to doxorubicinol in human tissues.

To determine whether cholinergic stimulation of human coronary endothelial cells induces the release of endothelium-derived relaxing factor (EDRF), denuded human coronary artery rings or denuded rabbit aorta rings were either directly perfused or superfused by the effluent of intact or denuded human coronary artery segments in a perfusion bioassay system.Coronary vessels were dissected from hearts of organ donors and prepared for use as donor segments and detector rings in the perfusion bioassay system. Segments were continuously perfused by an oxygenated Krebs-Ringer solution. Rings were suspended between two stirrups, one of which was connected to an isometric force transducer. They were either directly perfused (no tissue had been previously perfused by the same Krebs-Ringer) or superfused by the effluent of an endothelium-intact or -denuded coronary segment. Human rings were contracted with prostaglandin F2 alpha (2 x 10(-6) M) and rabbit rings were contracted with phenylephrine (10(-6) M).Tension in detector tissue did not change during superfusion with effluent from endothelium-denuded or -intact human coronary artery segments, showing that there was no basal release of EDRF/nitric oxide (NO) in this preparation. Acetylcholine (ACh) (10(-6) or 10(-5) M) added to the perfusate increased the tension of the precontracted endothelium-denuded human rings directly perfused (50 +/- 32%) but not of the precontracted rabbit rings, showing that ACh is a potent agonist of human coronary vascular smooth muscle. ACh added to the coronary segment in the endothelium-intact superfusion mode had no effect in 33% or induced a small relaxation (8.8 +/- 1.6%) in 66% of the preparations. Hemoglobin (10(-5) M), a scavenger of EDRF/NO, caused a further increase in tension (32 +/- 15%). Adding calcium ionophore (A 23187;10(-5) M), which stimulates EDRF/NO release through a nonreceptor-mediated mechanism, to the coronary artery segment induced a relaxation in the endothelium-perfused detector rings which did not relax to ACh (30 +/- 2%); this relaxation was reversed by methylene blue (10(-5) M), a blocker of soluble guanylate cyclase. NO endothelin, a potent vasoconstrictor released by the endothelial cells, was detected in the effluent of intact coronary vessels.The results suggest that in two-thirds of the six preparations studied, cholinergic stimulation can release EDRF from human donor coronary artery endothelial cells.

Twenty-eight patients were treated with oral menogaril daily x 14 every 4 weeks. Granulocytopenia was dose-limiting at 50-60 mg/m2 per day. Neutropenic fever occurred in one patient. Thrombocytopenia occurred in 3 of 6 patients treated with menogaril 60 mg/m2/day. Nausea and vomiting and other toxic effects were generally mild. No cardiac toxicity was seen. One partial remission and three minor responses were noted among 11 previously treated patients with carcinoma of the bladder. One minor response was noted among 3 patients with colorectal cancer. The dose recommended for phase II studies is 50 mg/m2 per day for 14 days. Phase II studies are recommended in carcinoma of the bladder. Gastrointestinal toxicity is substantially less on this schedule than with oral menogaril administered on a weekly or q4wk schedule, but thrombocytopenia may be more common.

Slices of rat submandibular gland were preloaded with 86Rb, an isotope that can substitute for K+ in the K+ release process. The efflux of 86Rb was monitored in a superfusion apparatus that efficiently removed the 86Rb as it exited from the tissue slices. Carbachol and the calcium ionophore A23187 activated a calcium-dependent increase in 86Rb efflux. Dibutyryl cGMP had no detectable effect on 86Rb efflux in contrast to its activation of ouabain-sensitive uptake of 86Rb observed in an earlier study. The stimulated release of 86Rb was not dependent on the presence of either sodium or chloride ions. When 86Rb efflux was stimulated by carbachol, the efflux rate returned toward the basal rate after a few minutes of exposure to carbachol in the medium. If ouabain was then introduced into the superfusate, a large increase in efflux was stimulated. In the absence of carbachol, only a small increase in 86Rb efflux was stimulated by ouabain. The effect of ouabain indicates that there was a substantial recycling of 86Rb between the release and uptake processes in the extracellular space of the tissue slice. The significance of this observation is discussed.

Na+,K+-ATPase activity was monitored by measuring ouabain-sensitive K+-dependent p-nitrophenylphosphatase (p-NPPase) activity in rat submandibular gland slices. Carbachol (carbamylcholine chloride) stimulated the p-NPPase activity in the presence of calcium but not in its absence. Carbachol activation of the enzyme was totally ouabain sensitive and could be blocked by atropine. A minimal requirement of sodium ion extracellularly was required for this carbachol stimulation. cGMP and its dibutyryl analogue was also effective in stimulating the enzyme activity, whereas, cAMP was ineffective. Calcium, however, was not required for cGMP activation of the p-NPPase activity. The result indicates that calcium is the second messenger and cGMP is the tertiary connection between cholinergic stimulation and Na+,K+-ATPase activation in these glands. Activation of Na+,K+-ATPase is postulated to be responsible for primary fluid formation.

Two patients with hairy cell leukemia treated with the anthracycline antibiotic rubidazone are presented. One achieved a complete remission and the other a good partial hematologic and bone marrow remission. Neither has relapsed (at 20 and 13 mo, respectively), and neither has been retreated. Intensive supportive measures were required during the prolonged myelosuppression that followed treatment. The relative youth of the patients (ages 24 and 39 yr) may have contributed to their ability to survive until normal marrow recovered. Chemotherapy should not be employed in the initial management of hairy cell leukemia. However, if life-threatening granulocytopenia and thrombocytopenia occur secondary to bone marrow replacement by leukemic cells, and improvement does not occur using alternative methods of therapy, consideration could be given to chemotherapy with rubidazone. Facilities for intensive supportive care should be available.

Oxygen free radicals contribute significantly to ischemia-reperfusion myocardial damage in vivo. We studied the effect of reactive products of O2 generated by electrolysis of the saline perfusate on coronary vasomotor tone and endothelium-mediated vasodilator responsiveness in 41 isolated rabbit hearts. Under constant flow conditions, electrolysis induced a progressive increase in perfusion pressure associated with a modest reduction in myocardial contractile function. The responses to the endothelium-independent vasodilators papaverine and adenosine tended to be increased by 1.5- to 2-fold, indicating that the increase in perfusion pressure was due, at least in part, to increased resistance vessel tone. However, resistance vessel dilations to the endothelium-dependent agents acetylcholine and serotonin were markedly reduced. Various degrees of protection against increases in perfusion pressure and inhibition of endothelium-dependent dilation during electrolysis were obtained with catalase, a scavenger of hydrogen peroxide; superoxide dismutase, a scavenger of superoxide; and desferrioxamine, which chelates iron and thereby inhibits hydroxyl radical production. Furthermore the action of nitroprusside, a direct-acting stimulator of soluble guanylate cyclase, was not diminished during the electrolytic treatment. We conclude that inhibition of endothelium-dependent dilation is a prominent action of reactive products of O2 in the coronary resistance bed. In combination with a free radical-induced increase in resistance vessel tone this might limit recovery of myocardial perfusion post ischemia.

A low molecular weight substance is present in the soluble fraction of the rat submandibular gland which activates Na+,K+-ATPase. Varying amounts of cytosolic protein from rat submandibular gland were added to a heavy microsomal preparation of the same tissue. A dose-dependent activation of the Na+,K+-ATPase was observed, with a peak activation of approximately 82% occurring when 9.0 μg/mL of cytosolic protein was included in the assay. The activating factor is heat stable and soluble following heat treatment. The factor elutes at a molecular mass of 600 daltons as determined by molecular sieve column chromatography. Ultraviolet–visible scanning of the eluted material results in an absorbance at 210 nm, which is characteristic of a low molecular weight peptide.

Oxygen consumption of slices of rat submandibular gland was monitored with an oxygen electrode method. Carbachol stimulated an immediate increase in tissue respiration that was inhibitable by ouabain. The stimulation required the presence of calcium in the incubation medium and was blocked by atropine. The calcium ionophore A23187 also stimulated ouabain-sensitive oxygen consumption in the tissue slices. The results show that the mechanism using the extra energy during cholinergic stimulation is the sodium pump. Amiloride at a 1, 10, or 100 microM concentration had no effect on stimulation of ouabain-sensitive respiration by carbachol. Since amiloride, which is known to block the sodium reabsorption process in the ductal segment, has no effect on the stimulation, the increased sodium pump activity is probably located in the acinar region and is associated with the primary fluid secretion process.

The frequency of prior occupational, accidental, or therapeutic radiation exposure was significantly higher for hairy cell leukemia patients than for a control group of solid tumor patients (8/23 vs. 4/56, P0.01). Hairy cell leukemia patients were also more frequently involved in occupations at high risk of radiation exposure such as chemist, engineer, physicist, and health care facility worker (7/23 vs. 4/56, P0.01). The observation that the incidence of thyroid disorders among hairy cell leukemia patients was also unusually high (5/23 vs. 2/56, P0.05) was interpreted as further indirect evidence of excessive radiation exposure. It appears that radiation exposure may be an important contribution factor in the development of some case of hairy cell leukemia.

A similar defect host defense mechanisms in hairy cell leukemia was defined in two patients. Surface-adherent monocytes were not detected in the peripheral blood nor were monocytes that mediate antibody-dependent cell-mediated cytotoxicity (ADCC) to isoantibody-coated human erythrocytes. In addition, lymphocytes of both patients failed to show blastogenic responses to concanavalin A (Con-A) and pokeweed mitogen (PWM) but showed a vigorous response to phytohemagglutinin (PHA). Other immunologic abnormalities were present but were either moderate in degree or were not present in both patients. In vitro lymphocyte blastogenic responses were fully restored by incubation of patients' leukocytes with a normal donor's adherent monocytes. One patient received daily allogeneic leukocyte transfusion for 4 days. This resulted in complete normalization of monocyte adherence and ADCC that persisted for several months after transfusion and was associated with hemotalogic improvement. Therapy in case 1 resulted in correction of the blastogenic responses to Con-A and PWM. Thus, a host defense defect in hairy cell leukemia has been defined in 2 patients and a preliminary result suggests that therapy with leukocyte transfusions may be useful in the postsplenectomy patient with an infectious complication and should be explored further.

Na-K-ATPase will hydrolyze an alternate substrate, p-nitrophenylphosphate (pNPP). The hydrolysis is ouabain sensitive and occurs at an external site on the cell membrane, thereby allowing measurement of Na-K-ATPase activity in the intact cell. pNPP hydrolysis was monitored in salt gland slices incubated in a bicarbonate-buffered Ringer solution. Methacholine-stimulated pNPP hydrolysis was inhibited by either atropine or ouabain. The hydrolysis was also dependent on the presence of calcium and sodium in the Ringer solution. cGMP stimulated ouabain-sensitive pNPP hydrolysis at concentrations from 10(-8) M to 10(-4) M with an optimum at 10(-5) M. cAMP did not produce a significant activation of pNPP hydrolysis. The effect of cGMP ws not dependent on either sodium or calcium in the Ringer solution and was not inhibited by atropine. Hydrolysis of pNPP promoted by either methacholine or cGMP occurred under conditions where no net influx of Na+ into the cells could occur. Sodium-pump activation during cholinergic stimulation, therefore, does not depend on an elevation of cell sodium but must occur by another mechanism. cGMP appears to play a direct role in that mechanism.

Groups of sheep were immunised twice with one or other of six vaccines consisting of purified pili from Bacteroides nodosus at three dose levels (10, 38 and 154 micrograms) and emulsified with either complete (CFA) or incomplete Freund's adjuvant (IFA). Beginning one month after vaccination the sheep were homologously challenged on irrigated pasture, with naturally transmitted foot rot for a period of 26 weeks. Statistical analyses of the number of feet per sheep with severe foot rot demonstrated that there was a significant effect of vaccinal dose but neither an adjuvant effect nor an interaction between dose and adjuvant. Similar conclusions were reached when the titres of antipilus agglutinins in the serum were analysed. By both criteria the responses to doses of 154 and 38 micrograms of pili were significantly better than to 10 micrograms, but not significantly different from each other. The IFA vaccines caused less reaction at the sites of injection than the CFA vaccines and within the former the vaccines containing 10 and 38 micrograms pilus produced less reaction than those containing 154 micrograms. Hence a vaccine containing 38 micrograms of purified pili in IFA is nearly optimal for homologous protection against severe foot rot and is acceptable in terms of the reaction at the injection site.

Sheep were vaccinated against foot-rot with various antigenic extracts of Bacteroides nodosus and challenged to assess their resistance. The protective immunogen was shown to be a heat-labile, high molecular weight surface antigen which was removed by ultrafiltration and was either identical to or closely associated with the fimbriae of the organism. Resistance appeared to be associated with the presence of a single high molecular precipitinogen distinct from the 0 antigen. Agglutinating antibodies to the surface antigen in immunised sheep were predominantly IgG1 whereas the 0 antigen induced predominantly IgM indirect haemagglutinating antibodies. Reactions at vaccination sites were less marked to the surface antigen than to the 0 antigen.

A rapid high-pressure liquid chromatographic assay for the detection and quantitation of 3-deazauridine-5'-triphosphate (deazaUTP), the active metabolite of the anticancer drug 3-deazauridine (deazaUrd), in cell extracts is described. This procedure permits the simultaneous detection and quantitation of CTP, the cellular concentration of which is affected by treatment with deazaUrd. Human lymphoblastoid cells (line CCRF-CEM) treated with 100 nmols of deazaUrd/ml in culture accumulate deazaUTP to greater than 25 nmols/10(7) cells after 4 hours. The concentration of CTP in these cells decreased exponentially with a half-life of 1.1 hours. After these cells had been incubated with 100 nmols of deazaUrd/ml and were resuspended in drug-free medium, the intracellular deazaUTP concentration decreased exponentially with a half-life of 3.4 hours. This assay has been applied to clinical studies of deazaUrd; high cellular deazaUTP concentrations have been detected in brain tumor tissue after deazaUrd infusion.

Of 22 patients with hairy cell leukemia, 18 developed life-threatening infections. Susceptibility to infection appeared to be increased nonspecifically, in that a wide range of infecting organisms were noted. Pseudomonas aeruginosa was the organism isolated most frequently. Four patients had disseminated Mycobacterium kansasii, and one had bacillus Calmette-Guerin lymphadenitis. Two patients developed serious fungal infections (Candida albicans in one and Allescheria boydii in the other). One patient had disseminated cytomegalovirus infection and two had toxoplasmosis. Splenectomy did not appear to decrease the infection rate. The infection rate initially increased following chemotherapy (P less than 0.001), then returned to pretreatment levels by two months following treatment. Infections were most frequent during granulocytopenia (P less than 0.01), but granulocytopenia was not a prerequisite for either life-threatening or fatal infections. Monocytopenia may be a more important factor than granulocytopenia in risk of infection in hairy cell leukemia patients.

Venodilation is thought to contribute to the hemodynamic actions of atrial peptides. Therefore, we measured the effective vascular compliance (EVC) as a parameter of overall venous tone in 7 pentobarbital anesthetized dogs under autonomic blockade during i.v. infusions of rat atriopeptin II (AP II, up to 100 pmol/kg/min), rat α-atrial natriuretic factor, and nitroglycerin (GIN). AP II lowered mean arterial pressure by reducing peripheral vascular resistance with a threshold between 3 and 10 pmol/kg/min (but was ineffective in anesthetized or conscious dogs without autonomic blockade). Neither atrial peptide altered EVC, while GIN augmented EVC and caused a 4.6-fold larger reduction of central venous pressure than AP II at equihypotensive dosage. These findings, with infusion rates probably close to endogeneous release, reveal a vasodilator potency of atrial peptides, which is restricted to systemic arterioles without affecting venous tone.

Two children recovered vision after penetrating injury of the orbit by wood had produced sudden blindness. Absent light perception demands urgent action as early visual loss does not necessarily indicate a poor prognosis. The depth and direction of penetration and size of wooden fragments is difficult to assess clinically and radiologically. Immediate and delayed neurological complications should always be anticipated. Removal of all fragments of wood is of paramount importance in restoring visual acuity. Prolonged visual loss with symptoms and signs of retained foreign body demands vigorous management.

Thirty-five patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation +/- chemotherapy received cisplatin, 60 to 120 mg/m2, into the internal carotid artery by a transfemoral approach. Courses of therapy were repeated every 4 weeks. Therapeutic evaluation was performed monthly using the CT scan of the brain and clinical neurologic examination. Thirty patients were evaluable for response. Of 20 evaluable patients with primary malignant brain tumors, 6 responded to therapy and 5 had stable disease. The median time to tumor progression for responding patients was 33 weeks, for stable patients 16 weeks, and 13 weeks for all patients. Five of 10 evaluable patients with brain metastases responded to intracarotid cisplatin, and 2 patients had stable disease. The estimated median time to progression for responding patients was 30+ weeks and 12+ weeks for patients with stable disease. Side effects included seizures in 5 courses, mental agitation and motor restlessness in 1, and transient hemiparesis in 7. One patient may have had a drug-related death, and one patient appeared to develop encephalopathy after treatment. Five patients had clinical deterioration in vision; in two patients it was bilateral. Intracarotid cisplatin has definite activity in patients with malignant primary brain tumors and in patients with brain metastases. The recommended starting dose for intracarotid cisplatin is 60 to 75 mg/m2. At this dose level side effects are uncommon, but includes the risk of neurologic and retinal toxicity.

The rates of ethanol oxidation in various species are linked to the rates of general metabolism, and more specifically that of O2 utilization by the liver. After chronic ethanol administration, increased oxidation of ethanol is accompanied by increased total hepatic O2 utilization, as studied in the whole animal, the perfused liver, and isolated liver slices. The correlation is particularly striking in the spontaneously hypertensive rat. This linkage makes the liver of the chronically ethanol-consuming rat abnormally vulnerable to hypoxic damage. Exposure to 5% oxygen atmosphere for 6 hours produced major elevations of SGOT and SOCT activities and marked centrilobular necrosis, in alcohol-treated animals but not in controls. The same differential susceptibility was found to acute anemia produced by bleeding. The possible relation of these findings to alcoholic liver damage in humans is discussed.

Twenty previously untreated patients with advanced colorectal carcinoma were treated with acivicin given in a 5-day iv schedule at a starting dose of 15 mg/m2, escalating to 26 mg/m2. Therapy was repeated every 3 weeks. Nineteen patients were evaluable for toxicity, which was mild and tolerable overall. Hematological toxicity was minimal, with only one patient developing severe myelosuppression at the starting dose. Nonhematological toxicity was also mild to moderate, occurring in 70% of the patients. Nausea, vomiting, and stomatitis were the most common side effects. CNS toxicity was moderate and occurred in 55% of the patients. Some patients found these symptoms distressing, although the treatment had to be discontinued in only one patient. There were no objective responses among 17 patients evaluable for response. This study indicates that acivicin given in a 5-day schedule is well-tolerated overall.

Sixteen patients with primary malignant brain tumors, recurrent or progressive after surgery and radiation therapy, were treated with mitoguazone. Starting dose was 500 mg/m2 iv on a weekly schedule. In 15 evaluable patients no tumor regressions were observed. Four patients had stabilization of disease.

Prognostic factors were examined in 31 patients with hairy cell leukemia seen at M. D. Anderson Hospital. Long survival from presentation was significantly associated with ease of aspiration of iliac crest bone marrow, absence of major infection, hemoglobin greater than 10 g/dl, and absence of a prior history of pneumonia. Long survival from splenectomy was associated most closely with absence of a prediagnosis history of pneumonia, suggesting that a long-standing host defense abnormality may exist that is not corrected by splenectomy. Generally, patients with sustained improvement in hematologic parameters postsplenectomy lived longest from splenectomy, although the results were not statistically significant.

The involvement of postsynaptic alpha 2-adrenergic receptors in the adrenergic constriction of the capacitance vessels was studied in anesthetized, spontaneously breathing dogs under ganglionic blockade (hexamethonium, 10 mg/kg + 10 mg/kg/hr; methylatropine, 0.5 mg/kg). Effective vascular compliance was measured as an indicator of venous tone (blood volume was varied by +/- 4 ml/kg in an 11-minute cycle of infusion, withdrawal, withdrawal, and reinfusion) and was calculated from the correlation between the observed changes in central venous pressure and the changes in blood volume. Sympathetic activity and central venous pressure were lower and effective vascular compliance was higher than values in untreated conscious dogs. The alpha 2-agonist UK 14,304 (5-bromo-6-[imidazolin-2-ylamino]-quinoxaline; 0.04 and 0.12 micrograms/kg/min; n = 6) dose-dependently lowered compliance and increased central venous pressure to levels found in conscious dogs, as did the alpha 1-agonist methoxamine (10 and 30 micrograms/kg; n = 6). Rauwolscine (alpha 2-antagonist), 0.3 mg/kg, significantly attenuated the effects of UK 14,304, but not those of methoxamine, while prazosin (alpha 1-antagonist), 0.12 mg/kg, attenuated the effects of methoxamine, but not those of UK 14,304 (n = 6 each). Under beta-blockade (nadolol, 2 mg/kg; n = 12) venous tone was increased to about physiological levels by norepinephrine, 0.15 micrograms/kg/min i.v., or by neuronal norepinephrine release induced by tyramine, 10 micrograms/kg/min i.v. These increases were significantly attenuated by prazosin as well as by rauwolscine and were abolished by a combination of both. These results indicate that postsynaptic alpha 2-adrenergic receptors (in addition to alpha 1-adrenergic receptors) are functional in the venous system in vivo and contribute substantially to adrenergic sympathetic and humoral regulation of venous tone.

We examined the effect of nitroglycerin (GTN) tolerance on an important determinant of nitrate-antianginal action, large coronary artery dilation, in 11 chronically instrumented conscious dogs. In addition, endothelium-mediated coronary artery dilation was studied because this shares a common dilator pathway with the nitrates, i.e., activation of soluble guanylate cyclase. With long-term GTN (1.5 micrograms/kg/min iv for 5 days) the diameters of the left circumflex and anterior descending coronary arteries showed an initial increase of 8.2 +/- 0.3% and 10.8 +/- 0.9%, respectively, returning to control levels by the second to third day of treatment. On days 4 and 5, the dose-response relations for GTN-induced epicardial artery dilation were shifted (p less than .01) to 17- to 20-fold higher doses. However, there was no attenuation of epicardial artery dilation induced by SIN-1 (n = 7), another activator of guanylate cyclase, or of endothelium-mediated dilation assessed both as flow-dependent dilation (n = 7) and as direct intra-arterial acetylcholine-induced dilation (n = 4). In addition, there was no clear tolerance to the peripheral vascular actions of GTN responsible for reflex tachycardia and increased coronary flow. We conclude that a moderate degree of nitrate tolerance to epicardial artery dilation does not affect the responsiveness to other exogenous or endogenous activators of guanylate cyclase. However, this tolerance to epicardial artery dilation, together with the maintenance of peripheral vascular actions that can induce reflex tachycardia, result in a potentially unfavorable balance of GTN effects.

A phase I trial of the uridine analog 3-deazauridine was undertaken in 44 adults with solid tumors. The drug was given as a 5-day continuous infusion repeated every 3-4 weeks. The dose-limiting toxic effect was granulocytopenia. Patients with prior nitrosourea therapy or extensive irradiation also had significant thrombocytopenia, and the lowest dose tested, 800 mg/m2/day, was excessive for this group. Mucositis was occasionally severe and was particularly marked in previously irradiated areas. Nausea was mild to moderate. There were isolated episodes of rash, headache, chest pain, and blurred vision. For patients without extensive prior therapy, the recommended dose is 1000 mg/m2/day. No complete or partial remissions were noted.