Selective estrogen receptor modulators (SERMs).

Naturally occurring estrogens, such as 17 beta-estradiol and estrone, have traditionally been thought to play a central role in the development and maintenance of the female reproductive system and secondary sexual characteristics. In recent years, their beneficial effects on the skeleton, the cardiovascular system, and the central nervous system, as well as the cancer risks associated with long term exposure have also been recognized. The widespread use of "antiestrogens" such as tamoxifen for the prevention and treatment of breast cancer has revealed that such compounds, while functioning as estrogen antagonists in mammary tissue, actually mimic the effects of estrogen in other tissues. The search for more selective agents has led to the development of raloxifene, a Selective Estrogen Receptor Modulator, which functions as an estrogen antagonist in the breast and uterus and as an estrogen agonist in the skeleton and cardiovascular system. Recent progress in the development of SERMs is the subject of this review, with an emphasis on structure activity relationships and on their effects in non-traditional target tissues.

Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs.

Wortmannin, a fungal metabolite, was identified as a potent inhibitor (IC50 = 4.2 nM) of phosphatidylinositol 3-kinase (PI 3-kinase). Due to the importance of PI 3-kinase in several intracellular signaling pathways, structure-activities studies on wortmannin analogs were performed in an effort to understand the structural requirements necessary for PI 3-kinase inhibition. Since wortmannin is an irreversible inhibitor of PI 3-kinase, it was postulated that covalent attachment at the electrophilic C-21 site was a possible mode of action for PI 3-kinase inhibition. We have prepared various wortmannin analogs which address the possibility of this mechanism. Of particular interest are compounds which affect the C-21 position of wortaminnin either sterically or electronically. Our results support the conclusion that nucleophilic addition by the kinase onto the C-21 position of wortmannin is required for inhibition of PI 3-kinase by wortmannin analogs. Additionally, we have prepared several D-ring analogs of wortmannin, and their activities are reported herein. We conclude that the wortmannin D ring is an important recognition site since modifications have such a dramatic effect on inhibitor potency. Finally, the identification of 17beta-hydroxywortmannin represents the first reported subnanomolar inhibitor of PI 3-kinase. These studies, along with in vivo antitumor experiments, suggest that the mechanism of PI 3-kinase inhibition correlates to the associated toxicity observed with wortmannin-based inhibitors of PI 3-kinase.

Comparison of three regimens in the management of acute gastroenteritis in infants.

Sixty infants were randomly assigned to one of three groups on admission to hospital with a diagnosis of gastroenteritis. After rehydration, Group A received a low-lactose, low-fat feed (HN25) in full strength; Group B were regarded on to a conventional formula (SMA); Group C received a hydrolysed soya and collagen feed (Prejomin) in full strength. All feeds were continued for 5 days. The median duration of loose stools from starting the feed was 24 hours in Group A, compared to 119 hours and 95 hours in Groups B and C, respectively. Group A showed a mean percentage increase in weight of 2.34%, Group B showed a mean loss of 1.45%, and Group C a mean increase of 0.15%. These differences were statistically significant. Recovery from gastroenteritis is hastened by the use of a low-lactose, low-fat feed in the initial post-rehydration phase of the disease.

Comparison between a standard pancreatic supplement and a high enzyme preparation in cystic fibrosis.

This study compared the relative effectiveness of a standard pancreatic enzyme supplement ('Creon', Duphar) and a new preparation ('Pancrease HL', Cilag) containing about 3 times the lipase and more than 5 times the protease activity. Capsule dosage was adjusted to a ratio of approximately 3:1. Fat balances showed that absorption of fat did not change significantly on conversion to the new high-lipase product, and the coefficient of absorption of total energy was similarly maintained. The coefficient of protein absorption was significantly enhanced with the high enzyme preparation (P less than 0.01), which may explain the reported subjective improvement in stool odour. No adverse effects were recorded. Patient acceptability of the new compound was high; the great reduction in the number of capsules required at each meal was cited by all patients as the reason for their preference.

Environmental estrogens: effects on cholesterol lowering and bone in the ovariectomized rat.

Representative non-steroidal estrogens, from common environmental sources such as plants, pesticides, surfactants, plastics, and animal health products, demonstrated an ability to lower serum cholesterol and prevent bone loss. Specifically, select environmental estrogens (coumestrol, genistein, methoxychlor, bisphenol A, and zeranol) effectively lowered total serum cholesterol in an estrogen-dependent animal model, the ovariectomized rat. Of these entities, coumestrol, methoxychlor, and zeranol prevented ovariectomy-induced bone loss. In an in vitro environment, these compounds competed with 17beta-estradiol for estrogen receptor binding and stimulated cell proliferation in a human breast cancer cell line (MCF-7). In addition to their well-documented effects on reproductive tissue, various environmental estrogens can dramatically affect non-reproductive parameters such as cholesterol lowering and bone metabolism.

Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity.

Raloxifene (LY139481 HCl) is a selective estrogen receptor modulator (SERM) which blocks the effects of estrogen on some tissues, such as the breast and uterus, while mimicking estrogen in other tissues, such as bone. To study the origins of this unique pharmacology, we have prepared the major metabolites of raloxifene as chemical probes for examining the estrogen receptor function in vitro and in vivo. In human breast cancer cell (MCF-7) related assays, these glucuronide conjugates show little affinity for the estrogen receptor and are more than two orders of magnitude less potent at inhibiting cell proliferation than raloxifene. In non-traditional estrogen target tissue, such as bone, these metabolites are less effective than the parent at inhibiting cytokine-stimulated bone resorbing activity in rat osteoclasts or producing transforming growth factor beta-3 (TGF-beta3). In animal models, tissue distribution studies with radiolabelled metabolite indicate that conversion to raloxifene occurs readily in a variety of tissues including the liver, lung, spleen, kidney, bone and uterus. Differential conversion of metabolite in target organs, such as bone and the uterus, is not observed indicating that the origin of raloxifene's pharmacology does not result from tissue-selective deconjugation of metabolite to parent.

Neonatal screening for cystic fibrosis in Wales and the West Midlands: 1. Evaluation of immunoreactive trypsin test.

A study programme was set up in Wales and the West Midlands to evaluate serum immunoreactive trypsin screening for cystic fibrosis in neonates using blood spots collected for metabolic screening. By screening half the blood spots from each area, it was hoped to generate two comparable groups of fibrocystic children; those detected by screening and those not screened who would be diagnosed clinically. Over almost three years, more than 120,000 specimens were screened and 37 infants detected with cystic fibrosis. Four additional fibrocystic patients were missed on screening: two had negative immunoreactive trypsin values, of which one had meconium ileus, and two, although giving initial positive tests, were negative on follow up. Excluding infants known to be at risk, comparison of the numbers of children detected in the screened and unscreened groups showed more than a two-fold difference in favour of the screened group. There may be a large number of undiagnosed fibrocystic patients in the general population.

The influence of nutrition on neonatal respiratory muscle function.

Advances in neonatal intensive care have resulted in increasing survival of very small babies, who often require prolonged periods of mechanical ventilation. These babies have limited nutritional reserves, and are difficult to feed by either parenteral or enteral routes. This review article discusses the interaction between undernutrition and respiratory muscle function in the critically ill preterm baby.

Cystic fibrosis serum stimulates mucin secretion but not calcium efflux from rat submandibular acini.

Cystic fibrosis serum stimulated release of mucins from rat submandibular acini to a significantly greater degree than did control serum. This action was not due to non-specific cell lysis, as monitored by lactate dehydrogenase release and was not accompanied by increases in 45Ca2+-efflux. The actions of cystic fibrosis serum and control serum in stimulating amylase release from rat exocrine pancreatic acini could not be distinguished. Thus, a specific action of cystic fibrosis serum in increasing mucin secretion, but not calcium permeability, in rat exocrine acini has been demonstrated.

Adrenergic secretory responses of submandibular tissues from control subjects and cystic fibrosis patients.

Adrenergic secretory responses of submandibular glands from control subjects and cystic fibrosis patients have been studied in vitro. In control tissues, isoproterenol (10 mumol/l) and noradrenaline (10 mumol/l) increased release of mucins and amylase to a similar extent (approximately 3-fold) and their actions were mediated by stimulation of beta-adrenergic receptors. In cystic fibrosis tissues, isoproterenol did not significantly increase release of mucins or amylase above the basal rate during 40 min incubation, whereas secretion in response to noradrenaline was not significantly different from that in control tissues. In the presence of a phosphodiesterase inhibitor, secretion of mucins and amylase in response to isoproterenol (10 mumol/l) in cystic fibrosis tissues was increased to the same level as that of noradrenaline (10 mumol/l); giving the same pattern of adrenergic responses in cystic fibrosis tissues as in control. The results suggest that overactivity of phosphodiesterase in cystic fibrosis cells might be the cause of the observed decreased secretion in response to a beta-adrenergic agonist.

Development of analytical and preparative chromatographic separations of novel growth hormone secretagogue compounds.

Chromatographic separations of new growth hormone secretagogue compounds were developed to support structure-activity relationship (SAR) studies in conjunction with lead optimization. These new compounds differed from Merck's MK-677 by having two chiral centers and thus diastereomeric mixtures were generated. Separation of initial compounds in the SAR was achieved on a Kromasil C18 column using an ammonium acetate buffer and acetonitrile. However, additional candidates were not separable on C18 columns and a chiral Kromasil CHI-DMB column was used to resolve the diastereomeric compounds. The Kromasil CHI-DMB packing was also used in a preparative chromatographic system to resolve multigram quantities of secretagogue candidates for testing. Chiral separations of different intermediates were also developed in support of evolution of an asymmetric synthetic route. This report summarizes development of the preparative chromatographic system used to purify diastereomeric mixtures and chiral separations of intermediates in the synthesis.

Nutritional aspects in cystic fibrosis.

The achievement and maintenance of energy balance in cystic fibrosis (CF) is one of the central aims of management. Growth retardation in affected children and wasting in CF adults remain major clinical problems. We consider the basis for the energy deficit, examine the spectrum of nutrient imbalance and review the current guidelines for dietary management.

Life events and family history in children with recurrent abdominal pain.

Children suffering from recurrent abdominal pain (RAP) were compared with matched controls on measures of illness behaviour, parents' illness behaviour, early parent-child relationships and stressful life events. Relatively, the RAP children stayed away from school more, needed more attention when ill, tended to show more anxiety in various ways, had parents who reported more symptoms, and had suffered a greater number of stressful experiences in the few months before pain onset.

Randomised controlled trial of an aggressive nutritional regimen in sick very low birthweight infants.

AIMS: To improve energy intake in sick very low birthweight (VLBW) infants; to decrease growth problems, lessen pulmonary morbidity, shorten hospital stay, and avoid possible feeding related morbidity. Morbidity in VLBW infants thought to be associated with parenteral and enteral feeding includes bronchopulmonary dysplasia, necrotising enterocolitis, septicaemia, cholestasis and osteopenia of prematurity. METHODS: A prospective randomised controlled trial (RCT) comparing two types of nutritional intervention was performed involving 125 sick VLBW infants in the setting of a regional neonatal intensive care unit. Babies were randomly allocated to either an aggressive nutritional regimen (group A) or a control group (group B). Babies in group B received a conservative nutritional regimen while group A received a package of more aggressive parenteral and enteral nutrition. Statistical analysis was done using Student's t test, the Mann-Whitney U test, the chi 2 test and logistic regression. RESULTS: There was an excess of sicker babies in group A, as measured by initial disease severity (P < 0.01), but mean total energy intakes were significantly higher (P < 0.001) in group A at days 3 to 42 while receiving total or partial parenteral nutrition. Survival and the incidences of bronchopulmonary dysplasia, septicaemia, cholestasis, osteopenia and necrotising enterocolitis were similar in both groups. Growth in early life and at discharge from hospital was significantly better in babies in group A. There were no decreases in pulmonary morbidity or hospital stay. CONCLUSION: Nutritional intake in sick VLBW infants can be improved without increasing the risk of adverse clinical or metabolic sequelae. Improved nutritional intake resulted in better growth, both in discharge, but did not decrease pulmonary morbidity or shorten hospital stay.

Impact of self-management education on the functional health status of older adults with heart disease.

This paper presents findings from the evaluation of a self-management education program based on self-regulation principles. Older men and women (N = 324) were randomly assigned to program and control groups. Outcomes were measured using the Sickness Impact Profile. Twelve months following baseline data collection, psychosocial functioning of program participants was significantly better than that of controls. Different program effects were noted when results were analyzed by participant gender.

Self-management of the health care regimen: a comparison of nurses' and cardiac patients' perceptions.

This study compared perceptions of 129 elderly cardiac patients regarding their health status and self-management skills with corresponding assessments by outpatient nursing staff members. Nurse-patient perceptions were most congruent on general questions regarding the heart condition. Differences were most apparent regarding how aware patients were of being asked to follow a regimen for managing their heart problems; what specific components comprised the regimens the patients were to follow; and how much confidence patients had in their ability to comply with specific components of the regimen. Congruence in perceptions of nurses and patients varied by the sex of the patient. Findings suggest that careful and continuous assessment of patients' perceptions about their condition and ongoing instruction regarding specifics of the therapeutic regimen are key elements in efforts to enhance elderly patients' self-management skills.

Exploring self-efficacy as a predictor of disease management.

Self-efficacy is posited in social cognitive theory as fundamental to behavior change. Few health behavior studies have examined self-efficacy prospectively, viewed it as part of a reciprocal behavioral process, or compared self-efficacy beliefs in the same population across different behaviors. This article first discusses self-efficacy in its theoretical context and reviews the available prospective studies. Second, it explores self-efficacy as a predictor of disease management behaviors in 570 older women with heart disease. Although the R2 statistics in each case were modest, the construct is shown to be a statistically significant (p<.05) predictor at both 4 and 12 months postbaseline of several disease management behaviors: using medicine as prescribed, getting adequate exercise, managing stress, and following a recommended diet. Building self-efficacy is likely a reasonable starting point for interventions aiming to enhance heart disease management behaviors of mature female patients.

Changes in functional health status of older women with heart disease: evaluation of a program based on self-regulation.

OBJECTIVES: This study involving 570 women aged 60 years or older with heart disease, assessed the effects of a disease management program on physical functioning, symptom experience, and psychosocial status. METHODS: Women were randomly assigned to control or program groups. Six to eight women met weekly with a health educator and peer leader over 4 weeks to learn self-regulation skills with physical activity as the focus. Evaluative data were collected through telephone interviews, physical assessments, and medical records at baseline and 4 and 12 months post baseline. RESULTS: At 12 months, compared with controls, program women were less symptomatic (p < .01), scored better on the physical dimension of the Sickness Impact Profile (SIP; p < 0.05), had improved ambulation as measured by the 6-minute walk (p < 0.01), and lost more body weight (p < .001). No differences related to psychosocial factors as measured by the SIP were noted. CONCLUSION: A self-regulation-based program that was provided to older women with heart disease and that focused on physical activity and disease management problems salient to them, improved their physical functioning and symptom experience. Psychosocial benefit was not evident and may be a result of measurement error or due to insufficient program time spent on psychosocial aspects of functioning.

Malnutrition and age-specific nutritional management in cystic fibrosis.

Malnutrition is recognised as a major prognostic factor adversely affecting survival in cystic fibrosis (CF) and is the result of an unfavourable energy balance in these patients. A high resting energy expenditure, dependent on the patient's genotype, in addition to pulmonary infection play an important role in producing anorexia and weight loss. Nutritional management with the aim to gain weight and catch up with growth is age-specific. It is important to repair nutritional status as early as possible after diagnosis. In infancy breast feeding is advised with, if necessary, supplemental feeding with predigested formulae such as Pregestimil. In childhood nutritional management must be aimed towards a normal weight gain and growth velocity. The latter is the best guide of nutritional adequacy. If weight gain falters the first principle is to treat any associated respiratory infection, the second is to ensure adequate enzyme therapy and control of steatorrhoea, and only then should dietary energy supplements be introduced. When oral hypernutrition fails, nocturnal naso-gastric tube feeding of a non-elemental formula may be considered. Parenteral nutrition is rarely indicated and should be reserved as a last solution for CF-patients.