A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus.

A new, competitive, nonpeptide cholecystokinin (CCK) antagonist, asperlicin, was isolated from the fungus Aspergillus alliaceus. The compound has 300 to 400 times the affinity for pancreatic, ileal, and gallbladder CCK receptors than proglumide, a standard agent of this class. Moreover, asperlicin is highly selective for peripheral CCK receptors relative to brain CCK and gastrin receptors. Since asperlicin also exhibits long-lasting CCK antagonist activity in vivo, it should provide a valuable tool for investigating the physiological and pharmacological actions of CCK.

A structurally unique, potent, and selective oxytocin antagonist derived from Streptomyces silvensis.

The in vitro and in vivo oxytocin/arginine vasopressin (OT/AVP) antagonist properties of two cyclic hexapeptides derived from a newly discovered natural product (L-156,373) of Streptomyces silvensis are described. In radioligand binding assays, L-156,373 [cyclo(L-Pro-D-Phe-N-OH-L-Ile-D-piperazyl-L-piperazyl-N-Me-D -Phe)] exhibited moderate affinity for rat uterine OT receptors (Ki, 150 nM), with some selectivity (approximately 20-fold) vs. liver AVP-V1 and kidney AVP-V2 receptors. Dehydroxylation of N-hydroxyisoleucine and oxidation of the piperazic acid residues of L-156-373 produced an interesting derivative, L-365,209. These structural modifications increased OT receptor affinity and selectivity by 20- and 2.5-5-fold, respectively. In the isolated rat uterus, L-365,209 was a potent (apparent dissociation constant, 1.7 nM) and competitive OT antagonist. L-365,209 also blocked the effects of AVP at both AVP-V1 (phosphatidylinositol turnover in rat hepatocytes) and AVP-V2 (adenylate cyclase in rat kidney medulla) receptors, but only at low micromolar concentrations. L-365,209, given iv to anesthetized rats, antagonized the action of exogenous OT on the uterus (ID50, 460 micrograms/kg) with a relatively long duration of action. L-365,209 represents a unique class of compounds that provides an entirely new approach for the design of antagonists for these neurohypophyseal hormones.

Structure, histone deacetylase, and antiprotozoal activities of apicidins B and C, congeners of apicidin with proline and valine substitutions.

[structure: see text]. Isolation and structure elucidation of two novel cyclic tetrapeptides that show a variety of potent antiprotozoal activities by reversibly inhibiting HDAC have been reported. These are the new members of a unique family of cyclic tetrapeptides that do not require the electrophilic alpha-epoxyketone moiety of HC-toxin, trapoxin A, or chlamydocin for their potent activities against HDAC and the malarial parasite.

Candelalides A-C: novel diterpenoid pyrones from fermentations of Sesquicillium candelabrum as blockers of the voltage-gated potassium channel Kv1.3.

[figure: see text] Blockers of the voltage-gated potassium channel Kv1.3 are potential immunosuppressants. Candelalides A-C are three novel diterpenoid pyrones that block this channel. The structure, stereochemistry, and activity against Kv1.3 are described.

Alcohol use and pregnancy: improving identification.

OBJECTIVE: To test the effectiveness of a four-item prenatal-alcohol-use, self-administered screening questionnaire that asks about tolerance to alcohol, being annoyed by other's comments about drinking, attempts to cut down, and having a drink first thing in the morning ("eye-opener") (T-ACE) in an ethnically and socioeconomically diverse sample. METHODS: Two hundred fifty T-ACE-positive and 100 T-ACE-negative women completed a comprehensive assessment of their alcohol use after initiating prenatal care at the Brigham and Women's Hospital in Boston, Massachusetts. This comprehensive assessment, which included the Alcohol Use Disorders Identification Test and the Short Michigan Alcoholism Screening Test as comparisons to the T-ACE, generated three criterion standards: Diagnostic and Statistical Manual of Mental Disorders, Third Ed., Revised (DSM-III-R), lifetime alcohol diagnoses, risk drinking (regularly having more than one fluid ounce of alcohol per drinking day before pregnancy), and current drinking. RESULTS: T-ACE-positive pregnant women were more likely than T-ACE-negative women to satisfy DSM-III-R criteria for lifetime alcohol diagnoses (40% versus 14%, P < .001) and risk drinking (39% versus 8%, P < .001) and to have current alcohol consumption (43% versus 13%, P < .001). In contrast, obstetric staff members documented only 33 (9%) women as using alcohol at any time, even though nearly all subjects (96%) were asked about drinking upon initiation of prenatal care. CONCLUSION: The T-ACE was the most sensitive screen for lifetime alcohol diagnoses, risk drinking, and current alcohol consumption. It outperformed obstetric staff assessment of any alcohol use by pregnant women enrolled in the study.

Evaluation of a hospital-based youth violence intervention.

To decrease adolescent morbidity and mortality and improve the quality of life, a violence-prevention consultation is offered to hospitalized victims of nondomestic violence. The context is a violence-prevention team approach to patient assessment, treatment, and follow-up. Psychoeducational counseling emphasizes the individual through a cognitive behavioral approach and also recognizes the individual in the proximal social setting through referrals to community resources. The in-hospital component draws on the health beliefs model, self-efficacy, the theory of reasoned action and their synergy with cognitive mediation theory as expressed in developmental psychology. The target group for the intervention is adolescents (12-17 years of age) who have been victims of violent assaults severe enough to warrant treatment at a Level One trauma center. The six steps in the intervention are to (1) review and assess the incident, (2) review the patient's conflict-resolution strategies and introduce nonviolent alternatives, (3) provide information on the prevalence of violence/homicide and determine the patient's risk status, (4) explore the patient's coping skills and support system, (5) develop a plan to stay safe, and (6) refer patient to services for follow-up activities. Approximately 15 study participants are identified each month, half of whom are randomly assigned to receive the intervention. Over the 12-month recruitment interval, approximately 180 adolescent patients will be identified. Baseline data are collected through hospital intake procedures and chart reviews. A battery of standardized measures supplemented by a brief structured, closed-ended interview is collected four months after the youths leave the hospital. Preliminary baseline data for 39 youths are reported. The "typical" youth is a 16-year-old African-American male. Even though nearly one third of victims had been shot, the typical patient was injured in a fight during which he was kicked, bitten, or beaten with or without a blunt instrument. The majority of incidents involved only one attacker who was known to the victim. Nearly half the injuries were precipitated by an argument or fight. No statistically significant differences between intervention subjects and nonintervention controls in terms of baseline variables have been observed. For inner-city adolescent victims of violent assaults, a hospital-based intervention offers a unique opportunity for reduction of the incidence of reinjury. We describe the elements of the intervention, including the theoretical basis and implementation; detail the overall evaluation design including modifications; and present preliminary analyses of baseline data.

Brief intervention for alcohol use in pregnancy: a randomized trial.

AIMS: To assess the impact of a brief intervention on antepartum alcohol consumption. DESIGN: A randomized clinical trial. SETTING: The obstetrics practices of the Brigham and Women's Hospital in Boston, MA, USA. PARTICIPANTS: Two hundred and fifty eligible women initiating prenatal care. INTERVENTION: A comprehensive assessment of alcohol use (assessment only, AO) or the same comprehensive assessment with a brief intervention (BI). MEASUREMENT: Demographic background and obstetric history of subjects, current and lifetime use of alcohol and substances, composite Addiction Severity Index scores, and antepartum alcohol use. FINDINGS: Of the 250, 247 (99%) subjects provided information on their antepartum drinking. Both the AO and BI groups had reductions in antepartum alcohol consumption, but differences in reductions by group were not statistically significant (p > 0.05). Risk of antepartum drinking after either the AO or BI was increased nearly threefold if the subject had any prenatal alcohol consumption before assessment (p = 0.0001). For the 143 subjects who were abstinent pre-assessment, however, those who received the BI maintained higher rates of abstinence (86% versus 72%, p = 0.04). CONCLUSIONS: After a comprehensive assessment of alcohol use, subjects in both the AO and BI groups reduced their antepartum alcohol consumption. The importance of screening for prenatal alcohol use is underscored by the findings that any prenatal alcohol consumption increases the risk of continued antepartum drinking.

Novel cholecystokinin antagonists from Aspergillus alliaceus. II. Structure determination of asperlicins B, C, D, and E.

Asperlicins B (1, C31H29N5O5), C (2, C25H18N4O2), D (3, C25H18N4O2), and E (4, C25H18N4O3) are novel cholecystokinin antagonists produced by Aspergillus alliaceus. The structures of these compounds have been determined by 1H NMR and MS analysis.

On the biosynthesis of asperlicin and the directed biosynthesis of analogs in Aspergillus alliaceus.

Feeding of 14C-labeled amino acids to resting cells of Aspergillus alliaceus strongly supported the intuitive hypothesis that asperlicin is biosynthesized from tryptophan, anthranilate and leucine. The resting cell system was used also to prepare 25 asperlicin analogs via directed biosynthesis in presence of analogs of tryptophan and leucine.

Cochlioquinone A, a nematocidal agent which competes for specific [3H]ivermectin binding sites.

Cochlioquinone A, isolated from the fungus Helminthosporium sativum, was found to have nematocidal activity. Cochlioquinone A is a competitive inhibitor of specific [3H]ivermectin binding suggesting that cochlioquinone A and ivermectin interact with the same membrane receptor.

Novel cholecystokinin antagonists from Aspergillus alliaceus. I. Fermentation, isolation, and biological properties.

The discovery and biological properties of four novel cholecystokinin antagonists produced by Aspergillus alliaceus is described. One of these was seven times more potent than the previously reported asperlicin.

L-155,175: a new antiparasitic macrolide. Fermentation, isolation and structure.

A new antiparasitic macrolide, L-155,175, produced by a strain of Streptomyces hygroscopicus, has been isolated; its structure was determined by physico-chemical means. It is active against the tapeworm Hymenolepis diminuta in rats.

Asperlicin, a novel non-peptidal cholecystokinin antagonist from Aspergillus alliaceus. Fermentation, isolation and biological properties.

The fermentation and isolation of a new, non-peptide cholecystokinin antagonist, asperlicin, produced by Aspergillus alliaceus is described. The potent and specific interaction of asperlicin with cholecystokinin receptors was shown using in vitro biochemical assays.

Discovery of an angiotensin II binding inhibitor from a Cytospora sp. using semi-automated screening procedures.

Cytosporin A, B and C, three antagonists of [125I]-angiotensin II binding to rat adrenal glands were discovered in fermentations of an endophytic Cytospora sp. during routine screening using semi-automated procedures. The most potent of these displayed an IC50 of 1.5-3 microM and was specific for angiotensin II AT2.

Resorcylic acid lactones: naturally occurring potent and selective inhibitors of MEK.

A resorcylic acid lactone, L-783,277, isolated from a Phoma sp. (ATCC 74403) which came from the fruitbody of Helvella acetabulum, is a potent and specific inhibitor of MEK (Map kinase kinase). L-783,277 inhibits MEK with an IC50 value of 4 nM. It weakly inhibits Lck and is inactive against Raf, PKA and PKC. L-783,277 is an irreversible inhibitor of MEK and is competitive with respect to ATP. L-783,290, the trans-isomer of L-783,277, was isolated from the same culture and evaluated together with several semi-synthetic resorcylic acid lactone analogs. A preliminary structure-activity relationship is presented. Several independent cell-based assays have been carried out to study the biological activities of these resorcylic acid lactone compounds and a brief result summary from these studies is presented.

A brief intervention for prenatal alcohol use: an in-depth look.

About 20% of pregnant women will drink alcohol, even though no universally safe level of prenatal alcohol consumption has been established. This study of 123 alcohol screen-positive pregnant women receiving a brief intervention in the 16th week of gestation examines the relationship of drinking goals, reasons for the goals, recognition of situations increasing risk of drinking, and subsequent antepartum consumption. While women who named abstinence as their antepartum drinking goal were more likely not to be consuming alcohol at the time of study enrollment (chi(2) = 16.80, df = 1, p =.001), current drinkers who named abstinence as their goal did reduce subsequent prenatal alcohol use (chi(2) = 10.04, df = 1, p =.002). All current drinkers who indicated fetal alcohol syndrome as a reason not to drink reduced their subsequent alcohol consumption (chi(2) = 11.04, df = 1, p =.001). Future efforts may include the partners and support systems of pregnant women in education or intervention programs to reduce prenatal alcohol consumption to enhance their effectiveness.

Prenatal alcohol consumption. Self versus collateral report.

The reservations expressed about the accuracy of patient self-reports of drinking may be heightened when obtaining information about prenatal alcohol consumption, which may be subject to fears of social or medical disapproval. Thus, clinicians may seek collateral reports to confirm patients' reports during this critical time. The purpose of this study is to compare the self and collateral reports of antepartum alcohol consumption by 247 pregnant women, obtained shortly after the initiation of prenatal care, and again after delivery. Collateral reports of subjects were exceeded by the subjects' self-reports of alcohol consumption before pregnancy and in the antepartum.

The TWEAK: application in a prenatal setting.

OBJECTIVE: The TWEAK is a screening instrument used to identify women who are risk drinkers. Potential limitations of previous studies of the TWEAK in the prenatal setting include indirect administration of the instrument to minority, indigent pregnant women. The purpose of this study is to assess the efficacy of the TWEAK when it is given directly to a sample of pregnant women of different socioeconomic backgrounds. METHOD: The original TWEAK, with two different tolerance questions, was administered to a sample of 135 pregnant women enrolled in a study of alcohol use during pregnancy at the obstetrics practices of the Brigham and Women's Hospital in Boston, Massachusetts. RESULTS: The TWEAK, using the first tolerance question (number of drinks before feeling the first effects of alcohol) with the cut point set at more than two drinks, had the best predictive ability for lifetime alcohol diagnoses and risk drinking. The sensitivity of the TWEAK can be increased if the cut point for the first tolerance question is set at two drinks, with some loss of specificity and predictive ability. Medical record assessment was the least sensitive but most specific method of identifying alcohol use by pregnant women. CONCLUSIONS: The TWEAK has promise as a screening instrument for identifying risk drinking during pregnancy. Future work should include testing in other clinical populations.

Mountain cedar allergens found in nonpollen tree parts.

BACKGROUND: Mountain cedar (Juniperus ashei) pollen is the principal aeroallergen in south central Texas from late December through February. The major mountain cedar allergen is a 40-kD glycoprotein, gp40. OBJECTIVE: To identify allergens in mountain cedar wood, leaves, and berries and to detect mountain cedar allergen in smoke from burning male or female trees. METHODS: SDS-PAGE plus mountain cedar human sIgE and monoclonal antibody immunoblots identified mountain cedar allergens within pollen and nonpollen tree part extracts. RESULTS: IgE immunoblots identified a single wood allergen at 36 kD and three berry allergens at 36, 26-27, and 21 kD, in addition to known pollen allergens. Mountain cedar monoclonal antibody bound an allergen epitope present not only on 40, 33, and 28-kD pollen allergens, but also on 36 and 32-kD wood allergens, and the 26-27-kD berry allergen. Immunoblot studies detected no mountain cedar allergen in leaves and no allergen in smoke from burning male and female trees. Allergens constituted a much smaller percentage of extractable protein in wood and berries than in pollen. CONCLUSIONS: Mountain cedar berry allergen content is too small to give credence to the ingestion of berries as a folk medicine treatment of mountain cedar pollinosis. In addition, while smoke from burning mountain cedar trees may be irritating, it contains no allergens that could cause allergic rhinoconjunctivitis.

Women and alcohol abuse in primary care. Identification and intervention.

Female problem drinkers are less likely than men to be identified in the primary care setting. The authors studied 24 adult women attending a general, internal medicine clinic to assess the efficiency of self-reports of alcohol consumption when compared with physician identification and other measures and the impact of a brief intervention on alcohol consumption. Despite the high rate of lifetime (79%) and current (67%) alcohol diagnoses, no patient was in alcohol treatment. Physician identification of alcohol problems was least sensitive but most specific, when compared with other measures. Brief intervention, as offered in this study, did not appear to modify alcohol consumption.