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Objective: We reviewed evidence regarding a possible relationship between mood disorders and obesity to better inform mental health professionals about their overlap., Method: We performed a MEDLINE search of the English-language literature for the years 1966-2003 using the following terms: obesity, overweight, abdominal, central, metabolic syndrome, depression, mania, bipolar disorder, binge eating, morbidity, mortality, cardiovascular, diabetes, cortisol, hypertriglyceridemia, sympathetic, family history, stimulant, sibutramine, antiobesity, antidepressant, topiramate, and zonisamide. We evaluated studies of obesity (and related conditions) in persons with mood disorders and of mood disorders in persons with obesity. We also compared studies of obesity and mood disorders regarding phenomenology, comorbidity, family history, biology, and pharmacologic treatment response., Results: The most rigorous clinical studies suggest that (1). children and adolescents with major depressive disorder may be at increased risk for developing overweight; (2). patients with bipolar disorder may have elevated rates of overweight, obesity, and abdominal obesity; and (3). obese persons seeking weight-loss treatment may have elevated rates of depressive and bipolar disorders. The most rigorous community studies suggest that (1). depression with atypical symptoms in females is significantly more likely to be associated with overweight than depression with typical symptoms; (2). obesity is associated with major depressive disorder in females; and (3). abdominal obesity may be associated with depressive symptoms in females and males; but (4). most overweight and obese persons in the community do not have mood disorders. Studies of phenomenology, comorbidity, family history, biology, and pharmacologic treatment response of mood disorders and obesity show that both conditions share many similarities along all of these indices., Conclusion: Although the overlap between mood disorders and obesity may be coincidental, it suggests the two conditions may be related. Clinical and theoretical implications of this overlap are discussed, and further research is called for.

Background: To increase understanding of the relationships among sexual violence, paraphilias, and mental illness, the authors assessed the legal and psychiatric features of 113 men convicted of sexual offenses., Method: 113 consecutive male sex offenders referred from prison, jail, or probation to a residential treatment facility received structured clinical interviews for DSM-IV Axis I and II disorders, including sexual disorders. Participants' legal, sexual and physical abuse, and family psychiatric histories were also evaluated. We compared offenders with and without paraphilias., Results: Participants displayed high rates of lifetime Axis I and Axis II disorders: 96 (85%) had a substance use disorder; 84 (74%), a paraphilia; 66 (58%), a mood disorder (40 [35%], a bipolar disorder and 27 [24%], a depressive disorder); 43 (38%), an impulse control disorder; 26 (23%), an anxiety disorder; 10 (9%), an eating disorder; and 63 (56%), antisocial personality disorder. Presence of a paraphilia correlated positively with the presence of any mood disorder (p <.001), major depression (p =.007), bipolar I disorder (p =.034), any anxiety disorder (p=.034), any impulse control disorder (p =.006), and avoidant personality disorder (p =.013). Although offenders without paraphilias spent more time in prison than those with paraphilias (p =.019), paraphilic offenders reported more victims (p =.014), started offending at a younger age (p =.015), and were more likely to perpetrate incest (p =.005). Paraphilic offenders were also more likely to be convicted of (p =.001) or admit to (p <.001) gross sexual imposition of a minor. Nonparaphilic offenders were more likely to have adult victims exclusively (p =.002), a prior conviction for theft (p <.001), and a history of juvenile offenses (p =.058)., Conclusions: Sex offenders in the study population displayed high rates of mental illness, substance abuse, paraphilias, personality disorders, and comorbidity among these conditions. Sex offenders with paraphilias had significantly higher rates of certain types of mental illness and avoidant personality disorder. Moreover, paraphilic offenders spent less time in prison but started offending at a younger age and reported more victims and more non-rape sexual offenses against minors than offenders without paraphilias. On the basis of our findings, we assert that sex offenders should be carefully evaluated for the presence of mental illness and that sex offender management programs should have a capacity for psychiatric treatment.

The spermosphere represents a short-lived, rapidly changing, and microbiologically dynamic zone of soil surrounding a germinating seed. It is analogous to the rhizosphere, being established largely by the carbon compounds released into the soil once the seed begins to hydrate. These seed exudations drive the microbial activities that take place in the spermosphere, many of which can have long-lasting impacts on plant growth and development as well as on plant health. In this review, I discuss the nature of the spermosphere habitat and the factors that give rise to its character, with emphasis on the types of microbial activities in the spermosphere that have important implications for disease development and biological disease control. This review, which represents the first comprehensive synthesis of the literature on spermosphere biology, is meant to illustrate the unique nature of the spermosphere and how studies of interactions in this habitat may serve as useful experimental models for testing hypotheses about plant-microbe associations and microbial ecology.

Background: Binge-eating disorder is characterized by recurrent episodes of uncontrollable overeating without compensatory weight-loss behaviors. It commonly co-occurs with obesity. Zonisamide is a novel antiepileptic drug associated with weight loss. The purpose of this study was to preliminarily assess zonisamide in the treatment of binge-eating disorder., Method: Fifteen outpatients with DSM-IV-TR binge-eating disorder were enrolled from Jan. 25, 2002, through Sept. 10, 2002, in an open-label, prospective, 12-week, flexible dose (100-600 mg/day) study of zonisamide. The primary outcome measure was binge-eating episode frequency. Secondary measures included binge day frequency, body mass index (BMI), weight, Clinical Global Impressions-Severity of Illness scale (CGI-S) scores, Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating (YBOCS-BE) scores, Three Factor Eating Questionnaire (TFEQ) scores, and Hamilton Rating Scale for Depression scores. Safety measures included adverse events, routine blood chemical and hematology laboratory values, urinalyses, plasma zonisamide levels, physical examination findings, and electrocardiograms. Outcome measures were analyzed by a repeated-measures random regression analysis using all data and an endpoint analysis using last observation carried forward., Results: Eight subjects completed the 12 weeks of treatment. The mean (SD) zonisamide daily dose at endpoint evaluation was 513 (103) mg/day. Both the random regression and endpoint analyses found a highly significant decrease in binge-eating episode frequency, binge day frequency, BMI, weight, CGI-S scores, YBOCS-BE total scores, and TFEQ hunger and disinhibition scores (p <.0001 for all measures in both analyses except p =.001 for endpoint analysis of binge eating frequency, p =.0001 for endpoint analysis of TFEQ disinhibition, and p =.0008 for endpoint analysis of TFEQ hunger). The 7 subjects who discontinued zonisamide prematurely did so due to lack of response (N = 1), protocol non-adherence (N = 2), and adverse events (N = 4)., Conclusion: Zonisamide was effective in reducing binge-eating frequency, severity of illness, and weight and was generally well tolerated in an open trial of binge-eating disorder. Controlled trials appear warranted.

Background: Binge-eating disorder is a newly recognized eating disorder characterized by recurrent episodes of binge eating without compensatory weight loss behaviors. It commonly co-occurs with depressive disorders and obesity. Citalopram is a highly selective serotonin reuptake inhibitor antidepressant. The purpose of this study was to assess the efficacy and safety of citalopram in the treatment of binge-eating disorder., Method: Thirty-eight outpatients with a DSM-IV diagnosis of binge-eating disorder were enrolled in the study between August 2000 and July 2001 and were randomly assigned to receive either citalopram (N = 19) or placebo (N = 19) in a 6-week, double-blind, flexible-dose (20-60 mg/day) study. The primary measure of efficacy was frequency of binge-eating episodes. Secondary measures included frequency of binge days, body mass index (BMI), weight, Clinical Global Impressions-Severity of Illness scale scores, Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating (YBOCS-BE) scores, Hamilton Rating Scale for Depression (HAM-D) scores, and response categories. The outcome measures were analyzed using 2 random regression methods, with a time trend analysis (primary analysis) and an endpoint analysis. In addition, response categories were analyzed using an exact trend test., Results: Compared with placebo-treated subjects, subjects receiving citalopram (mean dose of 57.9 mg/day) had a significantly greater rate of reduction in frequency of binge eating (p =.003), frequency of binge days (p <.001), BMI (p <.001), weight (p <.001), severity of illness (p =.028), and YBOCS-BE score (p =.007) and a marginally significant rate of reduction in HAM-D score (p =.053). Differences between groups in response categories were marginally significant (p =.068 for intent-to-treat analysis)., Conclusion: In a 6-week, placebo-controlled, flexible-dose trial, citalopram was efficacious in reducing binge-eating frequency, weight, and severity of illness and was generally well tolerated in subjects with binge-eating disorder.

The pharmacologic treatment of bipolar depression has not been well studied in randomized, controlled trials. Thus important clinical questions regarding the efficacy in bipolar depression of mood stabilizers, antidepressants, and new antiepileptic and atypical antipsychotic agents have been relatively unaddressed. Until recently there were few data regarding the degree to which mood stabilizers reduce the risk of switching associated with antidepressant treatment. Likewise, although treatment guidelines have often recommended limiting antidepressant exposure in the maintenance treatment of bipolar depression, the potential risks of depressive relapse after antidepressant discontinuation were largely unknown. We review here data from new randomized, controlled trials published or presented during the past 5 years regarding the efficacy of antidepressants, mood stabilizers, lamotrigine, and olanzapine in the acute and maintenance treatment of bipolar depression. We also review new studies clarifying the protective effect of coadministration of mood stabilizers from antidepressant-associated switching and the risk of depressive relapse when antidepressants are discontinued during maintenance treatment., (Copyright 2003 Society of Biological Psychiatry)

This study was initiated to understand whether differential biological control efficacy of Enterobacter cloacae on various plant species is due to differences in the ability of E. cloacae to inactivate the stimulatory activity of seed exudates to Pythium ultimum sporangium germination. In biological control assays, E. cloacae was effective in controlling Pythium damping-off when placed on the seeds of carrot, cotton, cucumber, lettuce, radish, tomato, and wheat but failed to protect corn and pea from damping-off. Seeds from plants such as corn and pea had high rates of exudation, whereas cotton and cucumber seeds had much lower rates of exudation. Patterns of seed exudation and the release of P. ultimum sporangium germination stimulants varied among the plants tested. Seed exudates of plants such as carrot, corn, lettuce, pea, radish, and wheat were generally more stimulatory to P. ultimum than were the exudates of cotton, cucumber, sunflower, and tomato. However, this was not directly related to the ability of E. cloacae to inactivate the stimulatory activity of the exudate and reduce P. ultimum sporangium germination. In the spermosphere, E. cloacae readily reduced the stimulatory activity of seed exudates from all plant species except corn and pea. Our data have shown that the inability of E. cloacae to protect corn and pea seeds from Pythium damping-off is directly related to its ability to inactivate the stimulatory activity of seed exudates. On all other plants tested, E. cloacae was effective in suppressing damping-off and inactivating the stimulatory activity of seed exudates.

Leaf composts were studied for their suppressive effects on Pythium ultimum sporangium germination, cottonseed colonization, and the severity of Pythium damping-off of cotton. A focus of the work was to assess the role of fatty-acid-metabolizing microbial communities in disease suppression. Suppressiveness was expressed within the first few hours of seed germination as revealed by reduced P. ultimum sporangium germination, reduced seed colonization, and reduced damping-off in transplant experiments. These reductions were not observed when cottonseeds were sown in a conducive leaf compost. Microbial consortia recovered from the surface of cottonseeds during the first few hours of germination in suppressive compost (suppressive consortia) induced significant levels of damping-off suppression, whereas no suppression was induced by microbial consortia recovered from cottonseeds germinated in conducive compost (conducive consortia). Suppressive consortia rapidly metabolized linoleic acid, whereas conducive consortia did not. Furthermore, populations of fatty-acid-metabolizing bacteria and actinobacteria were higher in suppressive consortia than in conducive consortia. Individual bacterial isolates varied in their ability to metabolize linoleic acid and protect seedlings from damping-off. Results indicate that communities of compost-inhabiting microorganisms colonizing cottonseeds within the first few hours after sowing in a Pythium-suppressive compost play a major role in the suppression of P. ultimum sporangium germination, seed colonization, and damping-off. Results further indicate that fatty acid metabolism by these seed-colonizing bacterial consortia can explain the Pythium suppression observed.

Compared to major depression without psychosis, psychotic depression often responds poorly to treatment with tricyclic antidepressants alone. Atypical antipsychotics, which appear to possess thymoleptic properties, may represent a new treatment alternative for patients with psychotic mood disorders. This open-label, pilot study evaluated the efficacy of olanzapine monotherapy in patients with psychotic depression. Seven inpatients who met DSM-IV criteria for a major depressive episode (unipolar) with psychotic features participated in a 10-week open-label trial of olanzapine 10-20 mg/day. The Hamilton Rating Scale for Depression (HRSD), the Scale for the Assessment of Positive Symptoms (SAPS), and the Clinical Global Impression Scale (CGI) were performed at each visit to evaluate clinical response. Four out of the 5 study completers responded during the trial. Overall, there was a statistically significant change between baseline and final visit on the SAPS, HRSD, and the CGI Scale (p < .001). The results of this pilot study suggest that olanzapine may be an effective treatment for some patients with unipolar psychotic depression. However, these observations require replication in randomized, controlled trials.

Objective: To evaluate the efficacy and safety of ibuprofen, 200 mg and 400 mg, compared with placebo and each other for the treatment of pain of migraine headache., Background: Migraine headache is a common illness with significant social and economic impact., Design: Randomized, placebo-controlled, double-blind trial of 6 hours' treatment duration., Methods: Fifteen investigators at 17 private practice and referral centers in the United States participated in this study of 660 outpatient adults aged 18 to 84 years with migraine headache of moderate to severe intensity. Each patient was randomly assigned to a single dose of study medication: ibuprofen 200 mg (n = 216) or 400 mg (n = 223), or placebo (n = 221). The percentage of patients with a reduction in baseline headache intensity from severe or moderate to mild or none 2 hours after treatment and the headache pain intensity difference from baseline at 2 hours were the primary efficacy measures. Secondary outcomes included other measures of pain relief, severity differences from baseline for migraine-associated symptoms of nausea, photophobia, phonophobia, and functional disability, and percentage of patients with migraine-associated symptoms reduced to none., Results: Significantly (P < or = .006) more patients treated with ibuprofen, 200 mg or 400 mg, reported mild to no pain after 2 hours (41.7% and 40.8%, respectively), compared with those treated with placebo (28.1%). The mean pain intensity difference from baseline measured at 2 hours was significantly (P < or = .001) greater for patients treated with ibuprofen 200 mg or 400 mg (0.68 and 0.65, respectively), compared with those treated with placebo (0.39). Statistically significant differences in favor of both doses of ibuprofen over placebo were observed for mean pain intensity difference at 1 hour after treatment. In patients with severe baseline pain intensity, ibuprofen, 400 mg, was significantly (P < or = .048) superior to placebo for the primary efficacy end points, while ibuprofen, 200 mg, was not. Ibuprofen, 200 mg and 400 mg, were statistically significantly more effective than placebo for all clinically important secondary pain relief outcomes. Mean severity changes of migraine-associated symptoms of nausea, photophobia, phonophobia, and functional disability at 2 and 6 hours were significantly (P < or = .03) in favor of both doses of ibuprofen over placebo, and results for the percentage of patients with symptoms reduced to none consistently, although less often statistically significant, favored ibuprofen. No statistically significant differences in adverse events were found among treatment groups., Conclusions: Ibuprofen at doses of 200 mg and 400 mg is an efficacious, cost-effective, well-tolerated, single-ingredient nonprescription treatment for pain of migraine headache. In addition, while not always statistically significant, ibuprofen provided a beneficial effect on associated symptoms of migraine including nausea, photophobia, phonophobia, and functional disability.

Background: Sexual side effects are commonly associated with serotonin reuptake inhibitor (SRI) therapy. The mechanism underlying SRI-induced sexual dysfunction has been hypothesized to be mediated by direct serotonergic effects. Evidence from open-label reports suggests that cyproheptadine, nefazodone, mirtazapine, and mianserin, which block one or more serotonin receptors, may reverse sexual side effects. The current study was a prospective, randomized, crossover trial comparing granisetron, a serotonin-3 antagonist, with placebo in outpatients who developed sexual dysfunction during SRI treatment., Method: Thirty-one outpatients who were currently experiencing sexual dysfunction associated with SRIs were randomly assigned to double-blind treatment with granisetron (1-1.5 mg) or placebo for use 1 to 2 hours prior to sexual activity. Patients rated sexual symptoms after each trial using the Sexual Side Effect Scale (SSES). After 4 trials of the medication, patients crossed over to the other treatment for 4 more trials., Results: Twenty patients received at least 1 dose of placebo and granisetron. Analysis by repeated-measures analysis of variance showed no significant effects of granisetron relative to placebo. Significant improvement between baseline and treatment-phase SSES scores was observed for both granisetron (p = .0004) and placebo (p = .0081). The study medication was generally well tolerated., Conclusion: The results of this study do not support the efficacy of granisetron (1-2 mg) in the treatment of SRI-associated sexual side effects. A significant placebo response may be associated with the treatment of SRI-induced sexual dysfunction.

Interactions between plant-associated microorganisms play important roles in suppressing plant diseases and enhancing plant growth and development. While competition between plant-associated bacteria and plant pathogens has long been thought to be an important means of suppressing plant diseases microbiologically, unequivocal evidence supporting such a mechanism has been lacking. We present evidence here that competition for plant-derived unsaturated long-chain fatty acids between the biological control bacterium Enterobacter cloacae and the seed-rotting oomycete, Pythium ultimum, results in disease suppression. Since fatty acids from seeds and roots are required to elicit germination responses of P. ultimum, we generated mutants of E. cloacae to evaluate the role of E. cloacae fatty acid metabolism on the suppression of Pythium sporangium germination and subsequent plant infection. Two mutants of E. cloacae EcCT-501R3, Ec31 (fadB) and EcL1 (fadL), were reduced in beta-oxidation and fatty acid uptake, respectively. Both strains failed to metabolize linoleic acid, to inactivate the germination-stimulating activity of cottonseed exudate and linoleic acid, and to suppress Pythium seed rot in cotton seedling bioassays. Subclones containing fadBA or fadL complemented each of these phenotypes in Ec31 and EcL1, respectively. These data provide strong evidence for a competitive exclusion mechanism for the biological control of P. ultimum-incited seed infections by E. cloacae where E. cloacae prevents the germination of P. ultimum sporangia by the efficient metabolism of fatty acid components of seed exudate and thus prevents seed infections.

Objective: The authors' goal was to assess the efficacy of sertraline in the treatment of binge eating disorder., Method: Thirty-four outpatients with DSM-IV binge eating disorder were randomly assigned to receive either sertraline (N=18) or placebo (N=16) in a 6-week, double-blind, flexible-dose (50-200 mg) study. Except for response level, outcome measures were analyzed by random regression methods, with treatment-by-time interaction as the effect measure., Results: Compared with placebo, sertraline was associated with a significantly greater rate of reduction in the frequency of binges, clinical global severity, and body mass index as well as a significantly greater rate of increase in clinical global improvement. Patients receiving sertraline who completed the study demonstrated a higher level of response, although the effect was not significant., Conclusions: In a 6-week trial, sertraline was effective and well tolerated in the treatment of binge eating disorder.

This randomized, double-blind, placebo-controlled trial of 48 hours' duration conducted in 13 primary care ambulatory practices in the United States and Mexico was used to compare the efficacy and safety of loperamide with placebo for the treatment of acute diarrhea in children aged 2 through 11 years. Two hundred fifty-eight children with acute nonspecific diarrhea were enrolled. Children were randomly assigned to treatment with loperamide HCl 0.5 mg/5 mL (n = 130) or placebo (n = 128). The first dose of loperamide consisted of either 1.0 mg (children 2 through 5 years of age) or 2.0 mg (children 6 through 11 years of age) of study medication under the observation of study personnel. This was followed by 1 mg after each unformed stool, with a total daily dose of up to 3.0 mg in the children 2-5 years of age, 4.0 mg in the children 6-8 years of age, and 6.0 mg in the children 9-11 years of age. The primary outcome measures were time to last unformed stool, time to first unformed stool, number of unformed stools during six consecutive 8-hour periods, and overall rating of efficacy/acceptability. Secondary outcomes included abdominal pain/cramping, vomiting, and fever. Children who received loperamide had significantly shorter time to last unformed stool (p = 0.0017) and fewer numbers of unformed stools (p = 0.0237) than children who received placebo. The end-of-study overall efficacy/acceptability rating of loperamide was significantly better than for placebo (p = 0.0107). All other clinically important outcome measures related to diarrhea relief favored loperamide. There was no significant difference in the incidence of drug-related adverse events between treatment groups, although total adverse events were reported more frequently (p = 0.048) by the loperamide group (15%) compared with the placebo group (7%). In conclusion, this controlled study provides data demonstrating that at recommend doses, loperamide is well tolerated and significantly shortens the duration and severity of symptoms of acute nonspecific diarrhea in children 2 through 11 years of age.

Background: To increase understanding of the relationship between sexual violence and mental illness, the authors assessed the legal histories and psychiatric features of 36 males convicted of sexual offenses., Method: Thirty-six consecutive male sex offenders admitted from prison, jail, or probation to a residential treatment facility received structured clinical interviews for DSM-IV Axis I and II disorders. The participants' legal histories, histories of sexual and physical abuse, and family histories of psychiatric disorders were also assessed., Results: The participants' mean +/- SD age was 33+/-8 years. They had been convicted a mean of 1.8+/-1.4 times (range, 1-9 times) for sexual offenses and incarcerated a mean of 8+/-6 years (range, 0-22 years). Participants displayed high rates of lifetime DSM-IV Axis I disorders: 30 (83%) had a substance use disorder; 21 (58%), a paraphilia; 22 (61%), a mood disorder (13 [36%] with a bipolar disorder); 14 (39%), an impulse control disorder; 13 (36%), an anxiety disorder; and 6 (17%), an eating disorder. Participants also displayed high rates of Axis II disorders, with 26 (72%) meeting DSM-IV criteria for antisocial personality disorder. In addition, subjects reported experiencing high rates of sexual (but not physical) abuse and high rates of Axis I disorders, especially substance use and mood disorders, in their first-degree relatives. Compared with subjects without paraphilias, subjects with paraphilias displayed statistically significantly higher rates of mood, anxiety, and eating disorders, as well as significantly higher rates of childhood sexual abuse., Conclusion: Recognition and treatment of major psychiatric disorders among sex offenders may increase chances for successful rehabilitation, reduce recidivism and public victimization, and produce significant public health and economic benefits. More studies in this area appear warranted to search for more effective interventions for this severe public health problem.

Context: Acute diarrhea with gas-related abdominal discomfort is a common, usually self-limited disorder with substantial social and economic impact., Objective: To compare the efficacy and safety of a loperamide hydrochloride-simethicone combination product with those of loperamide alone, simethicone alone, and placebo in treating acute diarrhea with gas-related abdominal discomfort., Design: Randomized, placebo-controlled, double-blind trial of 48 hours' duration., Setting: A primary care, ambulatory practice in Acapulco, Mexico., Patients: A total of 493 outpatient adults aged 18 to 63 years, with acute nonspecific diarrhea with at least moderately severe abdominal discomfort., Interventions: Each patient was randomly assigned to receive 2 chewable tablets containing loperamide hydrochloride, 2 mg, and simethicone, 125 mg (n = 124); loperamide hydrochloride, 2 mg (n = 123); simethicone, 125 mg (n = 123); or placebo (n = 123). This was followed by 1 tablet after each unformed stool, up to 4 tablets in any 24-hour period., Main Outcome Measures: Time to last unformed stool and time to complete relief of gas-related abdominal discomfort were the protocol-specified primary outcomes. Secondary outcomes included time to complete relief of diarrhea, number of unformed stools, and patient-assessed variables at the end of the study (overall illness relief, diarrhea relief, and abdominal discomfort relief)., Results: Patients who received loperamide-simethicone had significantly (P < .001) shorter time to last unformed stool and faster relief of gas-related abdominal discomfort than patients who received loperamide, simethicone, or placebo alone. Loperamide-simethicone was significantly (P < or = .01) more effective than the other 3 treatments for all end-of-study patient-assessed outcomes and all clinically important secondary outcomes. No significant differences in adverse events were found among treatment groups., Conclusions: The loperamide-simethicone combination chewable product provides faster and more complete relief of acute nonspecific diarrhea and associated gas-related abdominal discomfort (gas pain, cramps, gas pressure, and bloating) than either of its components or placebo. The combination is well tolerated.

The suppressiveness of compost amendments to pre-emergence damping-off of cucumber incited by isolates of Pythium aphanidermatum, P. myriotylum, and P. irregulare was studied. Growth chamber experiments were designed to examine the effects of temperature (20, 24, 28, and 32°C), compost type (municipal biosolids [MC] and leaves [LC]), and compost dose (40, 80, 160, and 320 mg/cm 3 ) on suppression of damping-off (i.e., increase in seedling stands) caused by different Pythium isolates obtained from different hosts. In dose-response experiments, LC was suppressive at dosage rates ≥80 mg compost/cm 3 of sand, whereas MC was suppressive at rates ≥40 mg/cm 3 . Damping-off severity induced by each of the three Pythium spp. was temperature-dependent. For example, P. aphanidermatum and P. myriotylum caused damping-off at each of the four temperatures tested, whereas P. irregulare caused disease only at 20 and 24°C. MC was suppressive to P. aphanidermatum at 20 and 24°C, whereas LC was suppressive at 28 and 32°C. Both composts significantly suppressed damping-off caused by P. irregulare at 20°C (85% suppression in MC and 60% suppression in LC) and at 24°C (approximately 60% suppression in both composts), and by P. myriotylum at all temperatures tested. In experiments with a variable temperature cycle (32°C for 14 h, day and 22°C for 10 h, night), only P. aphanidermatum and P. myriotylum caused damping-off of cucumber seedlings. Under these conditions, LC significantly suppressed damping-off caused by P. aphanidermatum (20% suppression) or P. myriotylum (37% suppression) but MC was not suppressive. In experiments where the two composts were mixed, a significant negative interaction between the two composts was observed for the suppression of P. myriotylum and P. irregulare at 20°C and of P. irregulare at 24°C, but not for P. aphanidermatum at any of the tested temperatures. There was no difference in aggressiveness among isolates within each of the three Pythium spp., regardless of their host origin. However, a significant variation in suppressiveness of LC was observed among isolates of P. aphanidermatum (11 isolates) derived from the same host, but not for P. irregulare (9 isolates) or P. myriotylum (7 isolates).

Objective: The objective of this study was to endoscopically assess in healthy subjects the gastrointestinal effects of over-the-counter (OTC) doses of ketoprofen. Ketoprofen is a potent nonsteroidal antiinflammatory agent (NSAID) recently approved for OTC use as an analgesic/antipyretic at doses of 75 mg versus the usual dose of < or = 300 mg daily. In epidemiological studies, ketoprofen at prescription doses has consistently been in the higher relative risk group of NSAIDs in the occurrence of gastrointestinal complications of therapy. The gastrointestinal effects of the OTC (US) dose of ketoprofen have not been reported., Methods: In a randomized, double blind, three way crossover study, 24 healthy subjects received 7 days of therapy with ketoprofen 75 mg/day, acetaminophen 4000 mg/day, and placebo. Gastroduodenal endoscopy was performed before and at the end of each treatment period. The condition of the mucosa was graded compositely for the gastric antrum, fundus, body, and duodenum., Results: Significantly more frequent and severe gastric mucosal injury was observed after dosing with ketoprofen compared with acetaminophen (p = 0.0001). The acetaminophen group showed no difference from placebo (p = 0.8783). Two subjects developed frank gastric ulcers with ketoprofen therapy. Marginally more frequent (p = 0.0703) and significantly more severe (p = 0.0117) duodenal mucosal injury was seen. No significant differences were observed between treatment groups with respect to subjective symptoms of gastric discomfort or adverse events., Conclusion: These results indicate that even at lower (OTC) doses (75 mg/day) ketoprofen is associated with significant gastrointestinal irritation.

ABSTRACT A beta-glucuronidase (GUS) reporter gene and a hygromycin B (hygB) phosphotransferase gene were integrated separately into the Trichoderma harzianum strain 1295-22 genome, using biolistic transformation. The mycelial growth and biocontrol ability of the transformed strains did not differ from that of the original strain. The transformed Gus(+)-kanamycin-resistant (Gus(+)Kan(R)) strains were used to monitor growth and interactions with Rhizoctonia solani on creeping bentgrass plants. The hygB-resistant (hygB(R)) strains were used to selectively recover strain 1295-22 from the rhizosphere soil and phylloplane of creeping bentgrass after spray applications. The population levels of two hygB(R) strains and the original strain were very similar for all treatments. All three strains persisted for the duration of the experiment (28 days) in both the rhizosphere soil and on leaves, although population levels declined somewhat over the course of the experiment in unautoclaved soils. In this study, the results demonstrated that hygB(R) strains remained dominant over time when assayed on Trichoderma-selective medium containing hygB. The hygB(R) strains were not displaced by strains that colonized untreated plants. Microscopic observation showed that the Gus(+)Kan(R) strains colonized the rhizoplane, seed coat, and phylloplane of creeping bentgrass. These results supported our earlier observation that strain 1295-22 was rhizosphere and phyllo-plane competent. Interactions between T. harzianum and R. solani were readily observed in situ and changed over time. Two types of reactions were found in these experiments. In the first type, sections of hyphae of R. solani near the hyphae of T. harzianum appeared damaged, and the pathogen appeared necrotic when viewed with a microscope. The second type, observed less frequently than the first type, was typical of myco-parasitism. The findings in this study provide new insight into the interactions between R. solani and T. harzianum, providing a basis for future research.

Objective: The authors examined Continuous Performance Test scores of patients with major depression with or without psychosis and schizophrenia., Method: Patients with major depression with psychosis (N = 13), major depression without psychosis (N = 14), and schizophrenia (N = 15) and normal volunteers (N = 14) completed the degraded-stimulus version of the Continuous Performance Test. Patients were rated with the Hamilton Depression Rating Scale and measures of positive formal thought disorder., Results: Continuous Performance Test scores of patients with major depression with psychosis and schizophrenia were significantly worse than those of patients with major depression without psychosis and of normal volunteers. Positive formal thought disorder was correlated with performance on this test in patients with schizophrenia., Conclusions: These findings suggest that attentional impairment on the Continuous Performance Test is associated with psychosis in general and may be specifically associated with positive formal thought disorder in patients with schizophrenia.

Trichoderma harzianum strain 1295-22 is an effective biocontrol agent for several fungal diseases. The efficacy of granule and spray applications of strain 1295-22 for control of Pythium root rot, brown patch, and dollar spot of creeping bentgrass was investigated. Spray applications of conidial suspensions (SA) of strain 1295-22 significantly reduced all three diseases of creeping bentgrass turf in both greenhouse and field experiments. Control was greatest when Triton X-100 at 0.1% was added to aqueous spray suspensions. When SA were applied weekly, the biocontrol treatments were equivalent to standard fungicides. Broadcast granule applications (GA) also significantly reduced foliar symptoms of Pythium root rot, dollar spot, and brown patch; turf quality also was enhanced. The populations of Trichoderma spp. in the root zone of a bentgrass putting green treated with SA or GA of strain 1295-22 increased 10- to 100-fold after treatment compared with untreated plots. However, strain 1295-22 was present at high levels on bentgrass leaves only following SA. Collectively, the results suggest that strain 1295-22 possesses both rhizosphere and phylloplane competence. The combination of broadcast applications of granules followed by spray applications of conidia reduced damage from both root and foliar diseases.

Composts prepared from a variety of feedstocks were tested for their ability to suppress seedling and root diseases of creeping bentgrass caused by Pythium graminicola. Among the most suppressive materials in laboratory experiments were different batches of a brewery sludge compost and a biosolids compost from Endicott, N.Y. Batches of these composts that were initially not suppressive to Pythium damping-off became more suppressive with increasing compost age. Leaf, yard waste, food, and spent mushroom composts as well as certain biosolids, cow manure, chicken-cow manure, and leaf-chicken manure composts were not suppressive to Pythium damping-off. In some cases, turkey litter, chicken manure, chicken-leaf, and food waste composts were inhibitory to creeping bentgrass seed germination in laboratory experiments. Microbial populations varied among all of the composts tested. Bacterial populations were high in all composts except the turkey litter compost, in which populations were 1,000- to 10,000-fold lower than in the other composts tested. Among the highest populations of heterotrophic fungi and antibiotic-producing actinomycetes were those found in all batches of the brewery sludge compost, whereas the lowest populations were found in turkey litter, chicken manure, and food waste composts. Heat treatment of suppressive composts reduced populations of bacteria, fungi, and actinomycetes in all composts tested. Disease suppressiveness was also reduced or eliminated in heated composts. Amending heated composts with small amounts of nonheated compost restored suppressive properties and partially restored microbial populations to wild-type levels. A strong negative relationship between compost microbial activity (as measured by the hydrolysis of fluorescein diacetate) and Pythium damping-off severity was observed. When composts were applied to creeping bentgrass in field experiments, a significant level of suppressiveness was evident with some composts when disease pressure was high (i.e., disease ratings high in uninoculated plots). A 1991 batch of turkey litter compost and the 1990 batch of Endicott biosolids were consistently suppressive to foliar symptoms of Pythium root rot on creeping bentgrass. This study indicates that suppression of Pythium diseases of creeping bentgrass in batches of brewery sludge and Endicott biosolids composts, and possibly in other suppressive composts examined in less detail in this study, is related directly to the microbial activities in the composts. On the other hand, the mechanisms of Pythium suppression in turkey litter and perhaps other poultry-based composts is not related directly to the compost microbial activity. Although turkey litter showed a lack of suppressiveness in laboratory bioassays and low microbial populations and activity, it resulted in a significant and consistent level of suppressiveness in field experiments. Therefore, the microbiological properties of Pythium-suppressive composts may differ substantially, and measurements of microbial populations and activity may not be predictive of the level of disease suppression in all composts.

The efficacy and safety of various doses of losartan potassium, a specific and selective angiotensin II receptor antagonist, were compared with those of placebo and enalapril maleate 20 mg in patients with mild to moderate essential hypertension in a randomized, double-blind, parallel study. We randomly allocated 576 patients at the end of a 4-week placebo baseline period to 8 weeks of once-daily double-blind treatment with losartan potassium 10, 25, 50, 100, or 150 mg, enalapril maleate 20 mg, or placebo. After 8 weeks of treatment, mean reductions from baseline in supine systolic/diastolic pressure 24 hours after dosing (trough) for losartan potassium 10, 25, 50, 100, and 150 mg, enalapril maleate 20 mg, and placebo were 7.6/7.9, 7.8/6.8, 13.0/10.1, 8.9/9.9, 10.5/9.7, 14.7/11.2, and 3.8/5.6 mm Hg, respectively. Compared with mean changes in supine diastolic pressure in the placebo group, losartan potassium 50 to 150 mg and enalapril maleate 20 mg produced clinically important and statistically significant reductions (P < or = .01) in blood pressure. At 24 hours after dosing, the blood pressure changes obtained with losartan potassium 50 mg were essentially identical to those obtained with enalapril maleate 20 mg. While there was a dose-related effect with losartan potassium from 10 to 50 mg at peak (6 hours after dosing), doses of 10 and 25 mg were not consistently different from placebo 24 hours after dosing. To assess the once-daily effect of losartan potassium, trough-to-peak ratios of the mean changes in supine diastolic pressure after 8 weeks of treatment were calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Losartan potassium, the first nonpeptide selective blocker of angiotensin II at the AT1 receptor, has been shown to exhibit clinical antihypertensive effects. The aim of the present study was to characterize the efficacy and duration of action of losartan by ambulatory blood pressure monitoring., Methods: The study was performed in nonblack hypertensive patients whose baseline untreated clinical diastolic blood pressures were 95 mm Hg or higher and whose average 24-hour ambulatory diastolic blood pressures were 85 mm Hg or higher. Patients were randomized, double-blind, into four treatment groups: placebo (n = 32) or losartan, 50 mg once daily (n = 29), 100 mg once daily (n = 30), or 50 mg twice daily (n = 31). Clinical and 24-hour ambulatory blood pressures were measured at baseline (off treatment for at least 4 weeks) and after 4 weeks of treatment., Results: By clinical sphygmomanometer measurements at the end of the 24-hour or 12-hour dosing intervals (trough), all three losartan dosages were significantly more effective than placebo at decreasing systolic and diastolic blood pressures. By average 24-hour ambulatory systolic/diastolic blood pressure measurements, the decreases produced were 0.0/0.2 mm Hg for placebo and 9.2/6.9, 9.9/6.4, and 13.2/8.5 mm Hg, respectively, for losartan, 50 mg once daily, 100 mg once daily, and 50 mg twice daily. All drug effects were different from placebo (P < .01). The effects of losartan, 50 mg twice daily, were not significantly different from those of losartan, 100 mg once daily, but, as expected, the effects were greater than those of losartan, 50 mg once daily (P < .05). Addition of hydrochlorothiazide, 12.5 mg/d, during an additional 2-week treatment period in patients whose clinical diastolic blood pressure remained at 85 mm Hg or higher while receiving monotherapy produced additional and clinically meaningful blood pressure decrements that were similar in all four treatment groups. There was no clinically important difference in the incidence of adverse events among the losartan-treated and placebo groups [corrected]., Conclusion: Ambulatory blood pressure monitoring, which virtually eliminated antihypertensive placebo responses, demonstrated clear 24-hour efficacy for losartan, 50 mg once daily, as well as for higher doses of 100 mg once daily and 50 mg twice daily. This AT1 receptor blocker had antihypertensive effects that appeared additive when combined with low-dose diuretic therapy. Losartan was generally well tolerated.

Objective: To compare the incidence of cough in patients with a history of angiotensin converting enzyme (ACE) inhibitor-related cough who received losartan [a type 1 angiotensin II (Ang II) receptor antagonist], lisinopril (an ACE inhibitor) or hydrochlorothiazide (a diuretic)., Design: An international, multicentre, randomized double-blind, parallel-group controlled trial., Setting: Outpatient clinics at 20 tertiary care medical centres in 11 countries., Patients: One hundred and thirty-five patients with uncomplicated primary hypertension with a history of ACE inhibitor-related cough were randomly assigned to the double-blind treatment phase and completed the study., Intervention: After confirming that the cough was ACE inhibitor-related by a single-blind rechallenge, followed by a placebo washout period, patients were randomly assigned to receive 50mg losartan, 20mg lisinopril or 25mg hydrochlorothiazide once a day for 8 weeks., Main Outcome Measures: Cough incidence, severity and frequency were assessed by a self-administered questionnaire and a visual analogue scale., Results: The percentage of patients who complained of cough was significantly higher with lisinopril than with losartan or hydrochlorothiazide. The mean visual analogue scale scores for patients treated with lisinopril demonstrated that these patients coughed more frequently than those who received losartan or hydrochlorothiazide., Conclusion: The incidence of cough related to the type 1 Ang II receptor antagonist losartan is significantly lower than that observed with lisinopril, and similar to that observed with hydrochlorothiazide in patients with a rechallenged ACE inhibitor cough. Type 1 Ang II receptor antagonists represent a potential new treatment for hypertensive patients in whom ACE inhibitors are indicated, but who develop a cough with these agents.

Background: A common adverse experience in hypertensive patients treated with angiotensin converting enzyme (ACE) inhibitors is a tickling dry cough., Objectives: The aim of the present study was to review clinical observations and mechanisms of cough associated with ACE inhibitors. In addition, since the AT1-type angiotensin II antagonists (represented by losartan, MK954, DuP753) are not expected to influence other systems (kinins, prostaglandins) affected by ACE inhibitors, we explored the hypothesis that antihypertensive therapy with these agents will not be associated with cough at a similar frequency or quality to that seen with ACE inhibitors., Design and Methods: Patients with a history of an ACE inhibitor-associated dry cough confirmed by a second challenge with lisinopril were enrolled into an international, multicenter, randomly allocated, double-blind, parallel-group, controlled trial, to be treated with losartan, lisinopril or hydrochlorothiazide. The presence and severity of cough were assessed by a self-administered questionnaire and a visual analog scale, respectively., Conclusions: It is expected that the new class of antihypertensive agents, angiotensin II antagonists, will not be associated with the high incidence of dry cough associated with the use of ACE inhibitors. It appears that this cough is not related to alterations in the renin-angiotensin system but to kininase II effects.

Two hundred eighty-six patients with mild to moderate hypertension who had untreated diastolic blood pressure while seated of 95 to 115 mm Hg were randomized to receive placebo or once-daily doses of 2.5, 5, or 10 mg of the dihydropyridine calcium channel blocker felodipine extended release (ER). Blood pressure was measured 24 hours after dosing (at trough). Mean reductions in diastolic blood pressure after 8 weeks of double-blind treatment were significantly greater in each of the ER felodipine treatment groups (2.5, 5, and 10 mg ER felodipine: -7.8, -9.5, and -11.3 mm Hg, respectively) than in the placebo group (-5.3 mm Hg). The effect was dose dependent for both diastolic and systolic blood pressure. Moreover, much of the peak antihypertensive effect was still present at trough, confirming the 24-hour efficacy of the drug. Felodipine was well tolerated.

Aim: To compare the biological activity of losartan as seen in several animal studies with results from similar clinical studies in hypertensive patients or normal volunteers., Results: With regard to oral bioavailability and estimates of oral angiotensin II blocking activity, the animal models were reasonably good predictors of the human response. Although formation of the major losartan metabolite E 3174 differs according to species, both animal and human studies suggest an association between plasma drug levels and angiotensin II blockade. The finding that losartan demonstrated increased sensitivity during salt depletion in animals was confirmed in humans. Possible beneficial effects on renal function await further detailed clinical trials., Conclusions: Losartan has been shown to lower blood pressure in patients with essential hypertension. However, cross-species comparisons are difficult because, unlike humans, animal models of hypertension follow clearly defined hypertensive mechanisms. Differing profiles of E 3174 metabolite formation also make cross-species comparisons difficult.

The effects of propylbutyldopamine ( PBDA ), an analog of dopamine lacking significant vasoconstrictor effects, were examined in seven patients with essential hypertension. Cardiovascular hemodynamics, renal plasma flow, urinary sodium excretion, and the renin-angiotensin-aldosterone system were examined during PBDA infusion both before and after administration of low (8 micrograms/kg) and high (40 micrograms/kg) doses of the dopamine receptor antagonist metoclopramide. Infusion of PBDA at a rate of 20 micrograms/kg/min lowered mean arterial pressure from an average control value of 112 +/- 4 to 94 +/- 3 mm Hg during the last 5 minutes of infusion (p less than 0.01), and increased effective renal plasma flow from 330 +/- 22 ml/min to 591 +/- 46 ml/min (p less than 0.01). Changes in heart rate (+ 16% +/- 5% increase from control values of 77 +/- 3 bpm), urinary sodium excretion (+ 13% +/- 5% increase from control value of 121 +/- 11 muEq/min), plasma renin activity (+ 23% +/- 15% increase over control value of 1.3 +/- 0.3 ng angiotensin I/ml/hr), and plasma aldosterone (+ 26% +/- 12% increase over control value of 17 +/- 6 ng/dl) accompanied PBDA infusion. Pretreatment with metoclopramide at a dose of 8 micrograms/kg prior to PBDA infusion partially blunted the blood pressure reduction produced by PBDA alone (-10% +/- 8% vs -20% +/- 4% compared to control values, p less than 0.1) but had no effect on PBDA -induced increases in renal plasma flow (+ 179% +/- 15% vs + 179% +/- 9% compared to control).(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized, parallel, controlled study was conducted to evaluate the safety and efficacy of isradipine, 2.5 to 10 mg orally twice a day, compared with propranolol hydrochloride, 60 to 240 mg orally twice a day, in 78 hypertensives whose supine diastolic blood pressure was greater than 95 mm Hg while receiving 50 mg/d or more of hydrochlorothiazide. Isradipine or propranolol was titrated during a 10-week double-blind phase to achieve a supine diastolic blood pressure below 90 mm Hg while a fixed dose of hydrochlorothiazide was maintained. Supine diastolic blood pressure was reduced by 10 mm Hg in 88% of the isradipine/hydrochlorothiazide-treated and 83% of the propranolol/hydrochlorothiazide-treated groups and to less than 90 mm Hg in 55% of the isradipine/hydrochlorothiazide-treated and 69% of the propranolol/hydrochlorothiazide-treated patients. There was no significant difference in supine blood pressure reduction between either group, but there was a 3-to 4-beats per minute increase in supine heart rate in isradipine-treated patients and an expected 15- to 20-beats per minute decrease in heart rate in propranolol-treated patients. Five of 7 patients in the isradipine-treated group and 8 of 9 patients in the propranolol-treated group discontinued the therapy because of adverse reactions or treatment failure. Using Fisher's Exact Test, we found no significant difference in the relative frequency of individual adverse reactions between groups, although the absolute adverse reaction frequency was significantly higher with isradipine. This study demonstrates the effectiveness and safety of supplemental isradipine in the treatment of hypertension not controlled by hydrochlorothiazide alone.

One hundred and six patients with uncomplicated mild to moderate essential hypertension received nitrendipine 10 mg twice a day or 20 mg once a day in a double-blind, randomized design. At the end of the dosing interval, supine and standing blood pressures were lowered 6/4 and 6/3 mm Hg respectively with the former regimen, and 2/3 mm Hg with the latter. In 10 patients, blood pressure variability through the dosing interval was not increased by nitrendipine 10 mg twice daily, but in another 10, 20 mg daily increased the variability by 28% compared to placebo. Significantly more patients had adverse effects with 20 mg daily than 10 mg twice daily; and both regimens caused more side effects than placebo. In 20 patients, serum glucose levels did not change significantly during treatment with nitrendipine, but in 10 of those with noninsulin-dependent diabetes, the range of maximum plasma insulin in response to a high-carbohydrate meal was 7 times as great during treatment with nitrendipine as it was during treatment with placebo. Nitrendipine lowers blood pressure when given once or twice daily, but twice-daily administration appears to be better tolerated.

Microsomes were prepared from human adrenals obtained at the time of cadaveric renal transplantation. Microsomes were assayed for cytochrome P-450 concentrations (mean =0.63 nmol/mg protein) and NADPH-cytochrome c reductase activity (mean 65 nmol times min-1 times mg-1 protein). Rates of steroid hydroxylation were measured. In man, the rate of 21-hydroxylation of 17-hydroxyprogesterone was approximately three times the rate of 21-hydroxylation of progesterone. The rate of 17-hydroxylation of progesterone was approximately three times the rate of 21-hydroxylation of progesterone. Substrate binding to microsomes showed a type I spectrum with progesterone and 17-hydroxy-progesterone. Both substrates bound all spectrally identifiable sites. Antibody prepared against procine NADPH-cytochrome c reductase inhibited concomitantly human reductase, 21-hydroxylation of progesterone and 17-hydroxyprogesterone, and 17-hydroxylation of progesterone. These results were compared to previous studies with beef adrenal microsomes. No specific evidence was obtained to suggest multiple forms of 21-hydroxylase in human adrenal microsomes. It appears as though the human adrenal microsomal cytochrome P-450 electron transport chain is immunologically similar to those studied previously--beef adrenal, and rat and human liver.

Lisinopril (LIS) is a lysine analog of enalaprilat, the active metabolite of enalapril, an angiotensin-converting enzyme inhibitor (ACEI). Unlike enalapril, the precursor of enalaprilat, LIS is not a prodrug but has equal ACEI efficacy and potency and a slightly longer duration of action after oral administration. Short-term (12 weeks) and long-term (24 weeks) blood pressure control has been studied with LIS, hydrochlorothiazide (HCTZ), and LIS + HCTZ when given once a day. Drug treatment had three phases: (i) 2-4 weeks of single-blind placebo washout; (ii) 12 weeks of double-blind comparison therapy with LIS 20, 40, and 80 mg vs. HCTZ 12.5, 25, and 50 mg, vs. LIS + HCTZ 20 + 12.5, 40 + 25, and 80 + 50 mg; (iii) 13-24 weeks single-blind LIS vs. LIS + HCTZ. Starting double-blind therapy at the lowest dose, all three groups doubled the dose at weeks 4 and 8 if BP was not controlled with sitting diastolic BP (SDBP) less than 90 mm Hg. At the end of 12 weeks of double-blind therapy, uncontrolled HCTZ-only and LIS-only treatment groups were advanced to combination LIS + HCTZ therapy but uncontrolled LIS + HCTZ patients were dropped. Mean BP reductions (systolic/diastolic, mm Hg) for all three groups after 12 weeks of double-blind comparison therapy were: (i) LIS (n = 162), -16.6/-12.5; (ii) HCTZ (n = 155), -10.4/-6.8; (iii) LIS + HCTZ (n = 74), -23.9/-18.2 with p less than 0.01 for all groups compared to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Isradipine (Sandoz PN 200-110), a new dihydropyridine calcium channel antagonist, was evaluated in a randomized, double-blind, placebo-controlled trial for antihypertensive efficacy in 24 patients with essential hypertension. Two groups were studied: one received placebo throughout the entire study (n = 12) and the other received isradipine (n = 12), 2.5 mg b.i.d., for the first week, 5 mg b.i.d. the second week, and 10 mg b.i.d. the third week after an initial 3-week baseline placebo period. Blood pressure was measured approximately 3 hours after dosing. Isradipine, at a total daily dose of 10 mg, lowered average supine diastolic blood pressure 11.8 mm Hg, with only a 3.5 mm Hg decrease in systolic blood pressure compared with baseline. At a total daily dose of 20 mg, average supine diastolic blood pressure decreased 14.8 mm Hg and supine systolic blood pressure declined 13.9 mm Hg; both were significantly decreased compared with placebo or baseline. Heart rate was increased only minimally by isradipine. Renin level activity was increased slightly by isradipine. No serious adverse clinical or laboratory experiences were noted. Isradipine appears to be effective in lowering blood pressure without reflex tachycardia.

The efficacy and safety of doxazosin (DOX) for the treatment of hypertension was investigated. A multicenter, double-blind, placebo-controlled, parallel design was employed. A 4-week placebo runin period was followed by a 9-week double-blind period during which patients were randomly assigned to placebo or 2, 4, or 8 mg doxazosin. Blood pressures (BP) and heart rates (HR) were measured 24 hours postdose. The mean changes in standing BP (mmHg) were -6.2/-6.9 (2-mg regimen), -5.7/-5.8 (4-mg regimen), -8.5/-7.7 (8-mg regimen) for DOX patients and 0.7/-2.9 for placebo patients. The mean changes in supine BP (mmHg) were -3.2/-4.7 (2-mg regimen), -4.0/-5.1 (4-mg regimen), -4.6/-5.6 (8-mg regimen) for DOX patients and -0.5/-3.3 for placebo patients. There was no evidence of a dose-response relationship for DOX; however, DOX serum levels were linearly related to the dose. Responder rate for the combined DOX patients was 38% (32/84) and for the placebo patients 27% (8/30). HR (24 hours postdose) was not modified by DOX. Patients in the 8-mg regimen had a significantly higher gain in mean body weight (+ 1.3 +/- 0.3 kg; P less than 0.05) compared to the 2-mg regimen, 4-mg regimen, and placebo groups. Plasma norepinephrine was not significantly modified by DOX. DOX had a favorable effect on plasma lipids. DOX lowered LDL cholesterol (P less than 0.05), total cholesterol, and apoprotein B and increased HDL/(LDL + VLDL) ratio (0.05 less than or equal to P less than 0.1) compared to placebo. Dropout rate and treatment-related side effects were equally distributed among the DOX and placebo groups. No patients had the dose of medication reduced because of side effects. Three DOX patients were withdrawn because of postural dizziness.

Purpose: Symptoms suggesting altered autonomic regulation of cardiovascular function have been noted in some patients with mitral valvular prolapse (MVP) but may also occur in patients with other disorders. We evaluated cardiovascular responses to autonomic stimuli in 118 patients with symptoms of dysautonomia, 78 of whom had MVP, and 40 of whom did not, to determine if unique patterns of these responses distinguished patients in one symptomatic subgroup from another., Subjects and Methods: The responses of patients to standing, quantitated Valsalva maneuver, facial immersion in ice water, and administration of isoproterenol, phenylephrine, and tyramine were compared with those in 12 asymptomatic patients with MVP and 23 normal volunteers., Results: Constitutional, cardiovascular, and neuropsychiatric symptoms occurred with similar frequency in the two symptomatic patient groups. The most common pattern of abnormal responses in symptomatic patients with or without MVP was (1) an increased heart rate and elevated plasma norepinephrine levels while supine and then while standing quietly for five minutes, (2) an exaggerated increase in heart rate during phase II of Valsalva, (3) a diminished bradycardic response during phase IV of Valsalva, and (4) an exaggerated heart rate response to administration of isoproterenol. The increased heart rate during Valsalva, but not the exaggerated sensitivity to isoproterenol, was correlated with the magnitude of the chronotropic response to standing only in symptomatic patients with MVP. Exaggerated hypertensive overshoot during phase IV of Valsalva was observed in only a few symptomatic patients. No consistent pattern of these abnormalities, however, was noted in any of the patient subgroups. Hemodynamic responses to autonomic stimuli in asymptomatic MVP patients were generally indistinguishable from those observed in normal subjects., Conclusion: These findings suggest that abnormal cardiovascular responses to autonomic stimuli may occur in any patient with symptoms of dysautonomia regardless of the presence or absence of MVP and that the pattern of these abnormal responses may be diverse. It is therefore important to characterize the pattern of altered autonomic regulation of cardiovascular function in each patient when considering mechanistic implications or making therapeutic decisions about these patients.

Magnetic resonance imaging (MRI) was utilized to localize ectopic pheochromocytomas in two patients. In both cases, MRI proved superior to computed tomography. Differentiation from surrounding tissue was excellent. MRI permits spatial localization and by assessment of signal contrast intensity provides a suggestion as to the characteristics of the tumor without the use of invasive procedures or intravenous injections. MRI should be considered as an alternative to computed tomography when evaluating patients with a suspected pheochromocytoma.

Two angiotensin converting enzyme inhibitors are currently available for clinical use. Captopril, a sulfhydryl-containing compound, is a direct acting enzyme inhibitor. Enalapril is a non-sulfhydryl pro-drug that requires enzymatic conversion to enalaprilic acid, a potent angiotensin converting enzyme inhibitor. Both drugs lower blood pressure, suppress blood pressure response to angiotensin I infusion, and elevate plasma renin activity. Enalapril bioavailability is unaffected by food, whereas captopril availability is suppressed by food. Dose adjustments are necessary for patients with congestive heart failure and renal failure.

Overdose with angiotensin-converting enzyme (ACE) inhibitors is still a relatively underreported phenomenon. We report here a case of an unintentional overdose of enalapril (100 mg) together with other medications. The patient experienced no adverse consequences. Pharmacokinetic evaluation revealed a t 1/2 for enalaprilat (prodrug) of seven hours and for enalapril at 36 hours. Based on this case report as well as others, guidelines for assessment and treatment of these patients are proposed. Management of hypotension is the primary therapeutic intervention.

CGS 16617, a direct-acting angiotensin-converting-enzyme inhibitor, was administered as a single dose of 20 mg in aqueous solution to 12 healthy male volunteers on two occasions in a randomized, cross-over design study. On one occasion, the dose was administered after an overnight fast; on the other occasion, it was administered after subjects ate a standard breakfast. Administration of CGS 16617 after food was associated with statistically significant decreases in peak plasma concentrations (58%) and areas under the plasma concentration-time curves (23%) compared with drug administration in the fasted state. Also, the time to peak plasma concentration was increased (57%) in a statistically significant manner when CGS 16617 was administered after food. Thus, the ingestion of food decreased both the rate and extent of absorption of this drug, but the mechanism of the interaction is unknown at present.