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A lcoholic liver disease (ALD) is a major cause of cirrhosis and a leading cause of death of end-stage liver disease in the United States and most of the Western world. The only means of restoring health in patients with end-stage liver disease at present is orthotopic liver transplantation. In the United States, between 3,000 and 4,000 liver transplants are performed each year, and a similar number are done yearly in Western Europe. Of the total, 20% to 25% are performed for ALD. The increasing demand for liver transplantation and lack of a similar increase in the supply of donor livers make it important to reassess the use of this precious resource on a regular basis. What criteria should be used in selecting patients with ALD for liver transplantation? How can survival and quality of life after liver transplantation for ALD be made optimal? These issues were addressed in a focused 2-day workshop, ‘‘Liver Transplantation for Alcoholic Liver Disease,’’ held under the auspices of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Institute for Alcohol Abuse and Alcoholism (NIAAA) in Bethesda, Maryland, December 6-7, 1996. This executive statement summarizes the issues raised at this conference and provides overall recommendations regarding treatment of patients with ALD who require liver transplantation. Most importantly, this summary focuses on important needs and directions for clinical research in liver transplantation for ALD. Alcohol is used by a majority of adults in the Western world. Population-based surveys indicate that 68% of adult Americans drink at least one alcoholic beverage per month, and 10% drink two or more per day, the usual definition used for ‘‘heavy drinking.’’ Heavy drinking is more common among men (18%) than women (3%) and among whites than blacks or Hispanics. Alcohol use is a major cause of morbidity and mortality; in the United States, 5% of deaths, approximately 100,000 per year, are either directly or indirectly attributable to alcohol abuse. Why some individuals are able to drink alcohol without dependence while others cannot is unknown. Among the factors associated with the development of alcoholism, both social and genetic factors are important. A family history of alcoholism is perhaps the major risk factor for developing alcohol dependence or abuse. The recent identification of genetic linkages to alcohol-seeking activity in laboratory animals promises to provide critical information on the genetic basis of alcoholism. Research into the nature of addiction is of central importance for the future of prevention and treatment of alcoholism. Encouragement of temperance and moderation should be the cornerstone to societal attempts to decrease alcoholism. ALD is perhaps the most widely recognized complication of chronic alcohol abuse. Nevertheless, only 15% to 20% of alcoholic subjects develop cirrhosis. The disease is more common in men than in women, and the average age of onset is in the mid-40s, typically after 10 to 20 years of heavy alcohol use. The average intake of alcohol in patients with ALD is more than 100 g of alcohol (approximately 8 drinks) per day, but the lower

1Asthma is a potentially dangerous disease. Asthma deaths occur at varying degrees throughout the world and there is evidence for epidemics occurring in different populations at different times. Such epidemics have been noted as early as last century. Much investigation has been made into the role of inhaled β-adrenoceptor agonists in these epidemics and indeed there is some evidence fenoterol is implicated. However, evidence for other β-adrenoceptor agonists is not substantiated. 2It is also noted that asthma deaths are not all the same, there being at least two types: deaths occurring in chronic severe asthmatics related to disease severity and sudden deaths of an anaphylactic nature that can occur in asthmatics of any disease severity. 3The important next step in the study of asthma deaths is to concentrate on other important factors rather than the role of therapy which cannot explain all the epidemics and the background instance of asthma death.

We have studied the effects of topical intranasal β-2-adrenoceptor agonists on nasal airflow resistance (Rnaw) and secretions. Pretreatment with salmeterol (SM) and salbutamol (SB) was given in two double-blind, placebo-controlled studies. In Protocol 1, 15 patients with allergic rhinitis were challenged with a threshold dose of allergen. Rnawand lavage fluid total protein, albumin, mucin, lysozyme, tryptase, histamine, and eosinophil cationic protein (ECP) were measured. In Protocol 2, 20 normal subjects were challenged with ascending doses of histamine and Rnawand lavage fluid total protein and albumin were measured. After allergen challenge, there was a significant, increase in Rnawtotal protein, albumin, and tryptase. SM significantly attenuated the rise in total protein (post-allergen challenge mean 218 mcg/mL, 95% c.i. 16–447; SB 344, 45–641; placebo 365, 105–725: P = 0.036). SM significantly reduced albumin concentration at 30 minutes post-drug (post-histamine challenge geometric mean 17.1 mcg/mL, interquartile range 8.2–29.4; SB 25.1, 15.2–43.0; placebo 24.2, 16.6–37.8: P = 0.027). SM has acute effects on the nasal response to allergen in allergic rhinitis and to histamine in normal subjects. These results imply an effect on glands and blood vessels in vivo that may represent part of the drug's clinical activity.

Autonomic receptors play a part in the physiology and pathology of the nasal mucosa. The effect of an alpha-agonist and an anti-muscarinic agent on histamine-challenge was examined on patients with perennial allergic rhinitis. Nine patients received saline, oxitropium bromide 0.075%, or xylometazoline hydrochloride 0.1% in a double-blind fashion. Sequential challenge with increasing doses of histamine were given and resistance changes, sneezes and volume and content of secretion measured. Histamine challenge produced dose-related increases in nasal resistance (P < 0.0001), lavage fluid volume (P < 0.01) and total protein (P < 0.01). Following xylometazoline, histamine produced little increase in resistance compared with saline and oxitropium bromide (P < 0.0001). The latter reduced the dose-related increase in resistance (P < 0.01) and nasal lavage fluid volume (P = 0.0007) and total protein (P = 0.023) seen with saline. These results confirm the importance of alpha-adrenergic and muscarinic receptors in the human nasal mucosa and suggest mechanisms of action for these drugs in perennial allergic rhinitis.

162 asthmatic children aged 4 to 14 years were recruited in this study. All were regular and experienced users of the metered-dose inhaler (MDI), but had no history of powder inhaler use. The majority (90%) had suffered from asthma for more than 1 year, and most (78%) had used an MDI for more than 1 year. Children were interviewed either directly or via their parents (depending on their age) to determine their asthma history, attitudes towards their current inhaler, views on the ideal inhalation device and their attitude towards 2 different powder inhalers, the Diskus® (or Accuhaler®) inhaler and the Turbuhaler® inhaler. 82% found their currently used MDI easy or very easy to handle, with effectiveness in delivering the drug (54%) and ease of operation (43%) being regarded as the features of the device they were most satisfied with on spontaneous response. A dose counter and ease of use during an attack were the 2 features of an ideal inhaler that were rated most highly (62 and 69% of respondents, respectively). Other important features of an ideal inhaler included sensation of taking a dose, a pleasant tasting dose, and a hygienic device that was small in size. When their attitudes towards 2 different powder inhalers, the Diskus® inhaler and the Turbuhaler® inhaler, were assessed using an objective and independently administered questionnaire, 88% indicated that they would be quite happy or very happy to have a Diskus® inhaler prescribed for them, compared with 71% who would be quite happy or very happy to have a Turbuhaler® inhaler prescribed. When specific features were assessed for each device, the Diskus® inhaler scored significantly better (p < 0.0001) than the Turbuhaler® inhaler for the presence of an attached cover, assessing the number of doses left, attractiveness, shape, perceived ease of use, ease of holding, comfortable mouthpiece, hygiene, instruction leaflet and weight. The Turbuhaler® inhaler scored significantly better on size (p = 0.02), but only amongst the parents of the 4- to 9-year-old children. Overall, the Diskus® inhaler was preferred to the Turbuhaler® inhaler (p < 0.0001), with perceived ease of use and attractiveness being cited as the main reasons for preference. This study has shown that the Diskus® inhaler is perceived to be an easy to use device that is well liked by paediatric patients and their parents and compares favourably with a well established powder inhaler, the Turbuhaler®.

Idiopathic persistent nonproductive cough (PNPC) is characterized by enhanced cough sensitivity to inhaled capsaicin, suggesting that capsaicin-sensitive afferent airway nerves are either present in increased numbers or functionally upregulated. In 16 patients with idiopathic PNPC and eight healthy control subjects, we measured cough sensitivity to inhaled capsaicin and the anatomic density in bronchial epithelium of nerves immunoreactive for the general nerve-marker protein gene product (PGP)-9.5 and the sensory neuropeptides calcitonin-gene-related-peptide (CGRP) and substance-P (SP). The log concentrations of capsaicin required to elicit at least two (C2) and five (C5) coughs were significantly lower in patients (P) than in control subjects (C) (median [range] log C2, P = 0.3 [-0.3 to 1.2] microM; C = 1.5 [0.9 to 2.1], p0.0005; log C5, P = 0.8 [-0.3 to 2.1]; C = 2.6 [1.8 to 3.0], p0.0005). In bronchial epithelium taken from the carina of the right upper lobe (RUL) and a subsegmental carina of the right lower lobe (RLL), total nerve density (PGP-9.5 immunoreactivity) was greater in P than C, although this was not significant. CGRP-immunoreactive nerve density was significantly higher in P than in C in the RUL (median [range] P = 1.05% [0.13 to 5.08]; C = 0.02% [0 to 0.24], p = 0.001) and RLL (P = 0.59% [0.04 to 3.14]; C = 0% [0 to 0.50], p0.02). SP-immunoreactive nerves were not significantly different in the two groups. Abnormal intraepithelial airway nerves containing increased quantities of CGRP are present in patients with idiopathic PNPC.(ABSTRACT TRUNCATED AT 250 WORDS)

The bacterial polyester, poly(β-hydroxybutyrate-co-β-hydroxyvalerate) (PHB/V), was cross-linked with 1, 5, 7, 10, 20, and 30 wt% benzoyl peroxide by thermal decomposition reactions. Solvent extractions were carried out to determine the cross-linked fractions of the films. The sol/gel data were used to estimate cross-link densities. Films of PHB/V cross-linked with 10% benzoyl peroxide were placed in contact with purified depolymerase A secreted byP. lemoignei. These samples exhibited weight loss rates which were half that of un-cross-linked PHB/V, but the network was degraded completely by the enzyme. The results of this study suggest that anendo-type enzymatic degradation may occur, in addition to theexo-type activity, which is normally presumed to occur with theP. lemoignei depolymerase system.

To assess the role of enhanced cough sensitivity in the pathogenesis of cough, we measured cough severity on a visual analogue scale (VAS) and capsaicin cough sensitivity (the concentration required to elicit two [C2] and five [C5] coughs) in 87 consecutive patients referred with chronic cough. Measurements were repeated after complete investigation and treatment, when patients were entered into one of four study groups: (1) treatment success (primary cause of cough successfully treated with elimination of the cough, n = 48); (2) primary treatment failure (treatment of potential primary cause of cough unsuccessful, n = 12); (3) cough treatment failure subgroup A (potential primary cause of cough identified and successfully treated but no improvement in cough, n = 8); and (4) cough treatment failure subgroup B (no potential primary cause of cough identified, n = 19). All patients in groups 3 and 4 were nonsmokers, had normal chest radiography and negative histamine challenge test, and failed to respond to intensive empirical treatment for rhinitis and gastroesophageal reflux. The VAS cough severity was lower and log C2 and C5 higher after treatment compared with initial values in the treatment success group but not in the other three groups. Enhanced sensitivity of airway nerves that mediate cough is important in the pathogenesis of nonproductive cough, and successful treatment is associated with a reduction in cough sensitivity. While enhanced sensitivity of airway nerves is usually present in patients with identifiable causes of chronic nonproductive cough, it is also found in other patients in whom the cause of cough is unknown.

There has been controversy about possible beneficial effects of beta agonists on airway function in asthma, in addition to their effects on airway smooth muscle. We compared the protective effects of terbutaline on bronchoconstrictor responses to methacholine, which constricts smooth muscle directly, adenosine 5'-monophosphate (AMP), which acts indirectly by mast cell activation, and sodium metabisulfite (MBS), which stimulates sensory nerves, in 15 mild asthmatic subjects in a randomized double-blind study carried out in two phases. In the first phase 12 subjects inhaled two doses of 0.5 and 2.5 mg terbutaline or placebo administered as a dry power (Tubohaler) 20 min before challenge with methacholine and AMP. Each subject received increasing doubling doses of methacholine and AMP nebulized from a dosimeter. Challenges were terminated when FEV1 fell by 20% from baseline (PC20). In the second phase 10 subjects (seven of whom had participated in Phase 1) inhaled 0.5 mg terbutaline or placebo before similar challenge with methacholine and MBS. In Phase 1 terbutaline inhibited the bronchoconstrictor response to methacholine by 2.1 and 3.3 doubling doses but caused a significantly greater inhibition of the response to AMP of 3.4 and 4.8 doubling doses after 0.5 and 2.5 mg, respectively. In the second phase 0.5 mg terbutaline had equivalent effects on responses to both methacholine and MBS of 2.6 and 2.2 doubling dilutions, respectively. This effect on methacholine and MBS implies functional antagonism of airway smooth muscle. The enhanced effect on AMP implies an additional non-smooth muscle action that may involve suppression of airway mast cell function.

The effects of topical beclomethasone dipropionate on changes in nasal resistance and secretion induced by topical histamine were studied in eight patients with perennial rhinitis. Patients were studied at enrollment, after 3 weeks of beclomethasone (100 micrograms spray to each nasal cavity twice daily), and after 3 weeks of placebo (saline) treatment administered in a double-blind cross-over trial. Nasal airflow resistance (Rnaw) and total protein, albumin, lysozyme and glycoconjugate secretion in nasal lavage fluids were measured after topical application of histamine to the nasal mucosa. Resistance measurements and secretory parameters were similar for the initial study and after placebo treatment. In those studies, histamine (1 and 10 mg) increased both nasal resistance and secretion of total protein, albumin and glycoconjugates. After beclomethasone treatment the rise in respiratory resistance in response to histamine was significantly attenuated (delta Rnaw, +11.57 cm H2O/l/s with placebo, +5.80 with beclomethasone, P < 0.05). Beclomethasone had no effect on histamine-induced secretion. Because nasal resistance is determined mainly by vascular processes, beclomethasone treatment appears to have a prominent action on the vascular bed to reduce mediator-induced vasodilatation in perennial rhinitis.

The mechanism of action of the antiasthmatic drug sodium cromoglycate (SCG) is unclear. One possibility is that SCG antagonizes the effects of the tachykinin substance P (SP), an agent known to cause airway edema. However, when SP is inhaled by humans, it has no demonstrable effect on airway function; therefore, the possibility that SCG prevents SP-induced changes in microvascular permeability was examined in human skin in vivo where potent edema-producing effects are seen. SCG (5–500 nmol) caused significant (P < 0.05) dose-dependent inhibition of SP-induced edema (wheal) formation when coadministered by intradermal injection. There was no effect on the nonreceptor-mediated flare response. SCG also significantly (P < 0.05) inhibited the wheal response to the related tachykinin neurokinin B but had no inhibitory effect on the cutaneous responses to histamine and prostaglandin E2. In addition, SCG (0.1–10 mM) caused dose-dependent inhibition of binding of SP labeled with 125I-labeled Bolton-Hunter to a number of tissues known to contain SP binding sites, as assessed by autoradiography. These concentrations were equivalent to the final concentrations of SCG found to inhibit the wheal response in the skin. The possibility that SCG interacted with SP was investigated both by gel filtration and high-performance liquid chromatography. No strong interaction was demonstrated with an 8,000 M excess of SCG under both hydrophobic and hydrophilic conditions. These results raise the possibility that SCG may have tachykinin antagonist properties.

OBJECTIVE--To compare safety of salmeterol and salbutamol in treating asthma. DESIGN--Double blind, randomised clinical trial in parallel groups over 16 weeks. SETTING--General practices throughout the United Kingdom. SUBJECTS--25,180 patients with asthma considered to require regular treatment with bronchodilators who were recruited by their general practitioner (n = 3516). INTERVENTIONS--Salmeterol (Serevent) (50 micrograms twice daily) or salbutamol (200 micrograms four times a day) randomised in the ratio of two patients taking salmeterol to one taking salbutamol. All other drugs including prophylaxis against asthma were continued throughout the study. MAIN OUTCOME MEASURES--All serious events and reasons for withdrawals (medical and non-medical) whether or not they were considered to be related to the drugs. RESULTS--Fewer medical withdrawals due to asthma occurred in patients taking salmeterol than in those taking salbutamol (2.91% v 3.79%; chi 2 = 13.6, p = 0.0002). Mortality and admissions to hospital were as expected. There was a small but non-significant excess mortality in the group taking salmeterol and a significant excess of asthma events including deaths in patients with severe asthma on entry. Use of more than two canisters of bronchodilator a month was particularly associated with the occurrence of an adverse asthma event. CONCLUSIONS--Treatment over 16 weeks with either salmeterol or salbutamol was not associated with an incidence of deaths related to asthma in excess of that predicted. Overall control of asthma was better in patients allocated to salmeterol. Serious adverse events occurred in patients most at risk on entry and were probably due to the disease rather than treatment.

1. In animal studies monoamine oxidase (MAO) inhibition has been shown to reduce the cough response through elevation of 5-HT in the central nervous system. In this study the effect of selective inhibition of the two subtypes of MAO (MAO-A and MAO-B) was studied on human airway reflexes. 2. Capsaicin-induced cough and reflex increase in respiratory resistance were measured in nine normal volunteers before and after MDL 72394 (MAO-A inhibitor) 16 mg or MDL 72974A (MAO-B inhibitor) 12 mg. 3. Neither inhibitor altered capsaicin-induced cough. Following treatment with MDL 72394, however, the capsaicin-induced reflex increase in resistance was enhanced, by 5.97 +/- 2.1 fold of the placebo value at 1 h. 4. Thus, neurotransmitters in the central nervous system which are substrate for MAO-A (i.e. noradrenaline, 5-HT) may be involved in the control of capsaicin-induced reflex bronchoconstriction.

BACKGROUND: Potassium (K+) channel activators, such as cromakalim, open ATP sensitive K+ channels and relax airway smooth muscle in vitro and inhibit induced bronchoconstriction in vivo in animals. The prolonged half life of cromakalim gives it potential as an oral bronchodilator. The effect of orally administered BRL 38227 (the active enantiomer of cromakalim), at doses of 0.125, 0.25, and 0.5 mg, on airway function and airway responsiveness to histamine and methacholine has been investigated in asthmatic patients. METHODS: Seventeen patients with asthma were studied in three separate randomised double blind, placebo controlled studies. In the first study eight patients with moderately severe asthma were given 0.125, 0.25, and 0.5 mg of BRL 38227 or placebo, and responses to histamine were assessed before and five hours after treatment. In the second study responses to methacholine were measured before and five hours after 0.125 and 0.5 mg of BRL 38227 or placebo were given to nine patients with mild asthma. In the third study the effect of 0.5 mg of BRL 38227 or placebo was assessed in eight patients with mild asthma. Responses to histamine were measured before treatment and two and five hours after treatment. To provide a positive control study eight subjects who had taken part in studies 1 and 3 were also given oral salbutamol (8 mg) in a placebo controlled, double blind study. Responses to histamine were assessed before and two hours after treatment. RESULTS: BRL 38227 did not cause significant bronchodilatation or changes in airway responsiveness in any of the studies. Headache was reported in 19 of 25 of patients receiving (in some cases twice) 0.5 mg of BRL 38227. By contrast, oral salbutamol gave significant protection against histamine challenge (geometric mean 2.23 doubling dilutions). CONCLUSIONS: After a single oral dose of BRL 38227 no beneficial effect on airway function was detected, despite a high incidence of side effects, which indicates that the orally administered K+ channel activator BRL 38227 may not be useful in the management of asthma.

Digital, video-enhanced fluorescence microscopy and spectrofluorometry were used to follow the internalization into the yeast Saccharomyces cerevisiae of phosphatidylcholine molecules labeled on one acyl chain with the fluorescent probe 7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD). Two pathways were found: (1) transport by endocytosis to the vacuole and (2) transport by a non-endocytic pathway to the nuclear envelope and mitochondria. The endocytic pathway was inhibited at low temperature (< 2 degrees C) and by ATP depletion. Mutations in secretory (SEC) genes that are necessary for membrane traffic through the secretory pathway (including SEC1, SEC2, SEC4, SEC6, SEC7, SEC12, SEC14, SEC17, SEC18, and SEC21) almost completely blocked endocytic uptake. In contrast, mutations in the SEC63, SEC65, or SEC11 genes, required for translocation of nascent secretory polypeptides into the ER or signal peptide processing in the ER, only slightly reduced endocytic uptake. Phospholipid endocytosis was also independent of the gene encoding the clathrin heavy chain, CHC1. The correlation of biochemical analysis with fluorescence microscopy indicated that the fluorescent phosphatidylcholine was degraded in the vacuole and that degradation was, at least in part, dependent on the vacuolar proteolytic cascade. The non-endocytic route functioned with a lower cellular energy charge (ATP levels 80% reduced) and was largely independent of the SEC genes. Non-endocytic transport of NBD-phosphatidylcholine to the nuclear envelope and mitochondria was inhibited by pretreatment of cells with the sulfhydryl reagents N-ethylmaleimide and p-chloromercuribenzenesulfonic acid, suggesting the existence of protein-mediated transmembrane transfer (flip-flop) of phosphatidylcholine across the yeast plasma membrane. These data establish a link between lipid movement during secretion and endocytosis in yeast and suggest that phospholipids may also gain access to intracellular organelles through non-endocytic, protein-mediated events.

To investigate the hypothesis that problems characteristic of eating disorders may often be associated with distance running, 20 women who had lost weight through distance running were compared with a control group who did not exercise and had not lost weight and a comparison group of bulimia nervosa patients. Dependent variables were measures of depression, bulimia nervosa symptomatology, and body image disturbance. No differences were found between the runner group and the normal controls. Bulimics differed from runners and controls on most measures. Thus, the results did not support the proposition that weight loss through running leads to problems related to eating and body image. The failure to find disturbances in body image in runners suggests that body image disturbances are not a direct result of weight loss, as suggested by some theorists.

Prostaglandins have been shown to influence the sensitivity of the cough reflex. To investigate putative mechanisms of this, we examined the effects of inhaled prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha) on human cough responses elicited by two challenges, low chloride solution and capsaicin, which may activate different neural pathways. Baseline cough challenges were followed after 2 h by five breaths of PGE2, PGF2 alpha, or citric acid as a control. Cough challenges were repeated after 1 min. Potentiation of capsaicin responses occurred after PGE2 (median increase 2 coughs/min, range 0–7, P less than 0.01) and PGF2 alpha (median increase 8 coughs/min, range -3 to 27, P less than 0.01) compared with control. The effect of PGF2 alpha was greater (P less than 0.05) than that of PGE2. Potentiation of low chloride responses also occurred after PGF2 alpha (median increase 7 coughs/2 min, range -1 to 19, P less than 0.01), but effects of PGE2 were insignificant against this challenge (median change -1 coughs/2 min, range -4 to 13). These data suggest that PGE2 and PGF2 alpha have different effects on the sensitivity of the human cough reflex, which may be relevant during airway disease.

Activation of mu opioid receptors on sensory nerves in the lung represents an attractive mechanism for reducing cough and reflex bronchoconstriction. We have examined the effect of the peptide 443C81, a peripherally acting mu opioid agonist, on the cough and reflex increase in respiratory resistance (Rrs) produced by capsaicin in nine healthy male volunteers. Using a randomised, double-blind crossover design, each subject inhaled either saline, 1 mg ml-1 443C81 or 4 mg ml-1 443C81 for 10 min from an ultrasonic nebuliser. The cough response to a range of doses of inhaled capsaicin and the increase in Rrs caused by inhalation of a single subtussive dose of capsaicin were measured before and after each treatment. There was no evidence of an effect of either 1 or 4 mg ml-1 443C81 on cough or increase in Rrs produced by capsaicin when compared with the saline placebo. It is concluded that inhalation of this mu opioid receptor agonist had no effect on capsaicin-induced cough or reflex bronchoconstriction in healthy volunteers.

The effects of a highly selective leukotriene D4 receptor antagonist, ICI 204.219, on allergen-induced bronchoconstriction and changes in airway reactivity were evaluated in a double-blind, placebo-controlled, crossover trial. Ten atopic subjects were selected for the study on the basis of an immediate fall in forced expiratory volume in 1 s (FEV1) of at least 15% and a least a doubling dose fall in their PC20-histamine (the concentration of histamine needed to reduce FEV1 by 20%) after antigen challenge. Baseline PC20-histamine was determined before the ingestion of a single oral 40 mg dose of ICI 204.219 or matched placebo. 2 h later subjects were challenged with aerosolised allergen; FEV1 was measured for the next 6 h then PC20-histamine was remeasured. Two subjects did not complete the study for reasons not related to the trial medication. ICI 204.219 significantly attenuated the early and late phase bronchoconstriction to inhaled allergen (mean treatment difference in area under the FEV1-time curves 2529 [95% Cl 1085-3972] delta %FEV1.min; p less than 0.005: and 3537 [528-6545] delta %FEV1.min; p less than 0.03) and suppressed the allergen-induced increase in non-specific bronchial reactivity (mean treatment difference 1.03 [0.34-1.71] doubling dilutions of histamine; p less than 0.01). These findings suggest that ICI 204.219 may be a disease-modifying agent in asthma. Further studies are under way to evaluate its clinical efficacy.

The design for a 0.60 caliber, augmented, laminated, solid-armature railgun is presented. Included is the discussion of the magnetic pressure distribution and heating on the molybdenum and copper conductors, and gun stiffness as predicted by finite-element analysis. The inductance gradient is calculated and correlated to experimental results. The materials selection, fabrication details, and insulation methods are also discussed. Finally, gun performance is presented through experimental data collected from testing solid-armature projectiles. >

After review of 461 consecutive amniocentesis examinations, 428 fetuses with normal karyotype and 13 with chromosomal abnormalities were analyzed. Six of the abnormal fetuses had trisomy 21, and seven had other chromosomal abnormalities. The ratio of measured-to-expected femur length (MFL/EFL) was determined for each fetus. The MFL/EFL values were 1.0 +/- 0.7 (mean +/- standard deviation) for the control group, 0.94 +/- 0.06 for trisomy 21 fetuses, 0.94 +/- 0.10 for non-trisomy 21 fetuses, and 0.94 +/- 0.08 for the entire group of fetuses with chromosomal abnormalities. The mean MFL/EFL value for the abnormal fetuses differed significantly from that for the control group (P less than .003). An MFL/EFL of 0.90 or less resulted in a sensitivity of 46.2% and a specificity of 94.1% for detection of all chromosomal abnormalities. For detecting trisomy 21, the sensitivity and specificity were 50% and 93.5%, respectively. Assuming a pretest probability for trisomy 21 of one in 250, an MFL/EFL of 0.90 or less resulted in a positive predictive value of 3%. It is concluded that an MFL/EFL of less than 0.90 modifies the relative risk for chromosomal abnormalities and may significantly influence the decision for amniocentesis.

Polyhydroxyalkanoate (PHA) cellular inclusions consist of polyesters, phospholipids, and proteins. Both the polymerase and the depolymerase enzymes are active components of the structure. Recently, proteins associated with these inclusions have been described in a number of bacterial species. In order to further clarify the structure and function of these proteins in relation to polymer inclusions, ultrastructural studies of isolated polymer inclusions were initiated. The surface boundary characteristics of polymer inclusions, produced by several genera of bacteria, two different Pseudomonas putida deletion mutants and by Escherichia coli recombinants, were examined. The recombinant E. coli carried either the PHB biosynthesis operon (phaCAB) from Ralstonia eutropha alone, or both this operon and a gene encoding an inclusion surface protein of R. eutropha (phaP). The results support two suggestions: (i) specific genes in the PHA gene cluster code for the proteins forming the surface boundary arrays which characterize the polymer inclusion; and (ii) transfer of such a gene would result in subcellular compartmentalization of accumulating polymer. Although the proteins appear to serve a similar function among different genera, nevertheless, the different surface proteins are encoded by a variety of non-homologous genetic sequences.

1. Fluticasone propionate (FP) is a potent glucocorticoid used in the treatment of asthma. Prior to reporting the pharmacokinetics following the inhaled and oral routes, the pharmacokinetics need to be established following intravenous dosing. The present study determines the intravenous pharmacokinetics of FP, using non-compartmental analysis, in healthy male subjects over the 250 to 1000 micrograms dose range. 2. The pharmacokinetics of FP can be regarded as being linear over this dosing range. FP was extensively distributed within the body (Vss 3181), rapidly cleared (CL 1.1 l min-1) with a terminal elimination half-life of 7.8 h and a mean residence time of 4.9 h. 3. In order that future pharmacokinetic/pharmacodynamic and other modelling can be carried out, the plasma concentration-time profiles were parameterized using a model based on sums of exponentials, the appropriateness of this model was justified as the secondary kinetic parameters from the model were similar to those obtained using non-compartmental analysis.

The mechanism of cough associated with upper respiratory infection (URI) is poorly understood. This paper reports a study of the role of altered sensitivity of capsaicin-sensitive airway nerves. In a prospective study, baseline (B) capsaicin-induced cough and methacholine-induced airway responsiveness were measured in 103 healthy volunteers. During the following year, 31 subjects reattended for challenge testing during URI (I) and after recovery (R). The log concentration of capsaicin required to elicit two coughs (C2) was significantly lower during infection than recovery but not baseline [median (interquartile range) B = 0.59 (0.28-1.20), I = 0.27 (0-0.89), R = 0.89 (0.28-1.49)]. Log C5 (concentration causing five coughs) was lower during infection than baseline and recovery [B = 1.79 (1.20-2.70), I = 1.49 (0.89-2.08), R = 1.79 (1.20-2.40)]. FEV1 and PC15 methacholine values were unchanged during infection compared to baseline. Subjects with dry cough (n = 14) had lower C5 values during infection than both baseline and recovery, and lower C2 values during infection than recovery; in these subjects, increase in capsaicin sensitivity correlated with cough severity score. Subjects with productive cough or no cough showed no consistent changes during infection. Twenty-six control subjects who reattended without URI showed no change in capsaicin sensitivity. Upper respiratory infection may cause cough as a result of increased sensitivity of capsaicin-sensitive afferent airway nerves without affecting airway calibre or responsiveness.

PURPOSE: To evaluate involvement of the lower uterine segment (LUS) in adenocarcinoma of the endometrium and to identify patterns of treatment failure. MATERIALS AND METHODS: Two hundred four patients, aged 29-92 years, with endometrial carcinoma underwent surgery. Postoperative radiation therapy was administered for adverse histologic criteria, including deep myometrial invasion, high grade, or LUS involvement. RESULTS: The incidence of tumor involvement of the LUS was 19%; of the cervix, 14%; and of the corpus, 67%. Distant metastasis occurred in 3% of patients with LUS involvement and in 17% of patients with cervical involvement. The local recurrence rate was 50% among patients with LUS involvement with no other risk factors and no postoperative radiation therapy and was 3% among those who underwent radiation therapy (P = .023). CONCLUSION: Early local-regional spread may be the primary mechanism of treatment failure in tumor invasion of the LUS. Aggressive local management, including postoperative rad...

The mechanism of action of topical intranasal steroids is obscure. To investigate this, we have studied the effects of a topical intranasal corticosteroid, fluticasone propionate on nasal airflow resistance (Rnaw), secretions, cytological smears and symptoms. Fluticasone propionate aqueous nasal spray was given to 11 patients with perennial allergic rhinitis in a double-blind, placebo-controlled study. On each day, patients were challenged with ascending doses of histamine. Rnaw, secretion volume, total protein, mucin, lysozyme and albumin were measured. Nasal smears were taken and sneezes counted. Diary card data were collected for both treatment periods. There was a significant, dose-related increase in Rnaw and sneezing on histamine challenge. A single dose of fluticasone had no effect on any parameter. After 4 weeks of treatment, resistance measurements were reduced (post-challenge g.m.2.8 cmH2O/l/s, Q1-Q3 1.6-4.8; placebo 4.2, 2.9-5.3: P < 0.0001) as were baseline secretion volumes (mean 2.4 ml/5 min, c.i.1.9-3.0; placebo 3.3, 2.8-3.8: P < 0.05). Eosinophil counts were suppressed (fluticasone 5.8%, c.i. 4.0-15.7; placebo 23.3%, 12.4-34.1: P < 0.05) and the composite symptom score reduced (P < 0.05). Fluticasone has long-term effects on the nasal response to histamine in perennial allergic rhinitis and part of this effect is likely to be vascular.

Tetraethylthiuram (disulfiram) is used for the treatment of alcoholism. Its use is intended to prevent relapse from abstinence by deterring impulsive drinking. This rationale is based on the fact that an intense adverse reaction, the disulfiram-ethanol reaction (DER), occurs when alcohol is ingested subsequent to the administration of disulfiram. Within 5–10min after ingesting an alcoholic beverage, peripheral cutaneous vasodilation manifested by flushing and tachycardia occurs, and an intense throbbing is often felt in the head and neck. Vertigo, nausea, vomiting, chest pain, and hypotension may also occur. Fatal DERs have been reported. Most of these occurred with the higher dosages that were used when disulfiram was initially introduced into clinical practice. Because of its action, disulfiram belongs to a category of drugs referred to as alcohol-deterrent, alcohol-sensitizing, or antialcohol drugs.

Topical sodium cromoglycate is used to treat allergic diseases of the upper and lower airways. To investigate its mechanisms of action, intranasal histamine challenge was used in nine subjects with perennial allergic rhinitis. After a preliminary day where subjects' reactivity thresholds (D100) for histamine were determined, intranasal sodium cromoglycate was administered in a double-blind, placebo-controlled fashion. Graded (D100/3, D100, D100X3), sequential challenges were performed on days 1 and 21 of each course, and responses measured by changes in nasal airway resistance, sneezes, secretion volume and secretion content: total protein, lysozyme and mucin. After a single dose of sodium cromoglycate, there was no change in resistance, but secretion volumes fell significantly (3.12 ml/5 min c.i. 2.83-3.4; placebo 3.61, c.i. 3.32-3.90: P = 0.026). After a 3-week-course, there was a significant fall in resistance (4.29 cm H2O/l/s, c.i. 3.85-4.72; placebo 5.45, c.i. 5.01-5.88: P < 0.0001). No change in other parameters was observed. Thus, in perennial allergic rhinitis, intranasal sodium cromoglycate has both short- and long-term effects on nasal reactivity to histamine challenge. Acutely, there is a reduction in nasal lavage fluid volume which may be the result of reduced irritant receptor activity. After a 3-week course, there is a reduction in nasal resistance responses, a possible anti-inflammatory effect.

Summary: Increased hypoxia has been found after β 2 adrenoceptor agonists (but not adrenaline) in asthmatics. Combined with hypokalaemia and sympathomimetic stimulation, this may predispose to cardiac arrhythmias. We have compared the effects of nebulized adrenaline and a selective β 2 agonist (salbutamol) on the arterial oxygen saturation (SaO 2 ), minute ventilation (VE), forced expiratory volume in 1 s (FEV 1 ), plasma potassium and the electrocardiogram (ECG) in patients with chronic stable asthma. Six patients were studied according to a randomized, placebo-controlled, double-blind cross-over protocol. Adrenaline (5 mg), salbutamol (5 mg) and placebo were administered during 4 min tidal breathing using a nebulizer driven by air. There was a fall in SaO 2 after both adrenaline (mean % fall (SEM) 3.3 (0.2)) and salbutamol (4.0 (0.7)) associated with an increase in FEV 1 , with no change in V E. Therefore, the fall in SaO 2 must have been caused by increased ventilation-perfusion imbalance. There was an increased heart rate after both adrenaline and salbutamol and ventricular ectopic beats and a short run of parasystole were recorded on the ECG in one patient after adrenaline and in two patients after sulbutamol. No change was found in plasma potassium levels. We conclude that both adrenaline and a selective β 2 agonist salbutamol can cause a fall in SaO 2 and ventricular ectopy in some asthmatic patients.

A series of investigations was performed in which histamine challenge was used to compare nasal responsiveness in 20 normal subjects and 20 with allergic rhinitis. There was found to be a lower threshold of reactivity (D100) to histamine in allergic subjects as measured by resistance changes (geometric mean, 0.53 mg/ml; normal subjects, 2.15: p = 0.022). This may represent increased number or sensitivity of histamine receptors on the nasal capacitance vessels. The loss of a laser Doppler response to a supramaximal histamine stimulus (normal subjects, 102% increase in flux at 3 minutes; p < 0.05) was observed in patients with allergic rhinitis and indicates either a down-regulation of the capillary system or an altered effect of histamine on superficial vessels, perhaps mediated by a shift in histamine receptor type. There was an observed increase in neutrophils at the mucosal surface under baseline conditions (rhinitis median, 49.6%; normal subjects, 32.72%: p < 0.05), which suggests an important primary role in the pathogenesis of this condition for this active cell. The observed increase in secretory volume response to histamine in allergic subjects, which persisted beyond 40 minutes after a single D100 challenge, may be related to an altered sensitivity of glandular tissue. There are important changes in nasal reactivity to histamine challenge in allergic rhinitis that may have implications for its pathogenesis.

BACKGROUND--While high doses of caffeine may affect pulmonary function and bronchial challenge tests in patients with mild asthma, the effects of lower doses (< or = 5 mg/kg) are less well documented. Specific recommendations exist for withholding theophylline, but not caffeine, before bronchoprovocation and pulmonary function testing. METHODS--To assess the effect of a single oral dose of caffeine (5 mg/kg) on FEV1 and bronchial responsiveness to histamine a double blind, placebo controlled study was performed in eight patients with mild stable asthma. RESULTS--While caffeine had no effect on FEV1, mean (95% confidence interval) log PC20 histamine was significantly higher 150 minutes [caffeine = 0.99 (0.2) mg/ml, placebo = 0.53 (0.29)] and 240 minutes [caffeine = 0.89 (0.24), placebo = 0.44 (0.26)] after administration of caffeine than after placebo. CONCLUSIONS--Caffeine should be excluded from the diet for a period of more than four hours before bronchial provocation testing. The exact length of time for which it must be excluded requires further study.

In some species serotonin (5-HT) has been shown to act as a central modulator of the cough reflex. To investigate whether serotonergic mechanisms influence the control of the human cough reflex, we have induced cough responses before and during infusions of 5-HT; its precursor 5-hydroxytryptophan (5-HTP), which, in contrast to 5-HT, crosses the blood-brain barrier; and saline control. At the start of each study day, eight normal male volunteers were challenged with a single inhalation of a solution lacking chloride ions (0.15 M sodium bicarbonate) and a single breath of capsaicin during a sham infusion. After 3 h they received repeat cough challenges during experimental infusions of 5-HT, 5-HTP, or saline control, which were given randomly and single blind. Heart rate, respiratory rate, and blood pressure were measured before, during, and after each infusion. Both 5-HT and 5-HTP reduced cough responses to the chloride-deficient solution (P = 0.035 and P = 0.017, respectively) with respect to saline control, whereas neither infusion reduced responses to capsaicin. 5-HT caused a transient increase in heart rate that was not observed with a similar dose of 5-HTP or saline (P < 0.01). Respiratory rate and blood pressure were not affected by experimental infusions but rose during cough challenge. We conclude that 5-HT exerts an inhibitory influence over the human cough reflex at peripheral and possibly central sites.

Recent evidence suggests that the cysteinyl-leukotrienes (LTC4, LTD4, and LTE4) may be important in the pathogenesis of exercise-induced asthma. To evaluate the role of these mediators further, nine asthmatic subjects with exercise-induced bronchoconstriction were studied on two occasions. On visit 1, subjects performed 6 min of treadmill exercise; the mean maximal percent fall in FEV1 was 38.0 +/- 5.3%. On visit 2, maximal bronchoconstriction observed after exercise was matched with aerosolized methacholine. Urine was collected in two 90-min fractions (0–90 and 90–180 min) after challenges and analyzed by high-performance liquid chromatography-radioimmunoassay for LTE4. There were no significant differences in urinary LTE4 excretion between exercise and methacholine challenges for the periods 0-90 min (16.9 +/- 5.4 vs. 20.4 +/- 4.2 ng/mmol urinary creatinine), 90–180 min (24.9 +/- 8.2 vs. 20.1 +/- 5.5), or 0-180 min (21.5 +/- 6.5 vs. 18.8 +/- 4.1). Thus in contrast to allergen-induced bronchoconstriction, there is little evidence for enhanced cysteinyl-leukotriene generation in exercise-induced bronchoconstriction as assessed by urinary LTE4. If local release and subsequent participation of functionally active cysteinyl-leukotrienes in the pathways that ultimately lead to bronchoconstriction after exercise challenge do occur, these are of insufficient magnitude to perturb urinary LTE4 excretion.

Fluoxetine selectively inhibits serotonin uptake in vitro and in vivo and thus enhances serotonergic function, leading to a decrease in food intake beginning with the first dose and a decrease in body weight or in weight gain after multiple doses of fluoxetine. Fluoxetine and other drugs that increase serotonergic function decrease food intake with characteristics that make them attractive for use in weight reduction. In rats, for instance, fluoxetine and other serotonergic drugs suppress stress-induced eating, suppress carbohydrate consumption selectively, and suppress insulin-induced hyperphagia. Fluoxetine and other serotonergic drugs do not cause amphetamine-like behavioral stimulation in animals and have no known abuse or addiction liability. In obese yellow mice and in normal mice, as in rats, fluoxetine causes a sustained decrease in food intake and body weight. The pharmacologic effects of fluoxetine in animals suggest its potential use in weight-reduction programs in obese humans.

Platelet-activating factor (PAF) is a potent bronchoconstrictor in humans and has been implicated as an inflammatory mediator in asthma. This study was performed to evaluate whether PAF-induced bronchoconstriction in vivo could be mediated through the release of the bronchoconstrictor eicosanoids, thromboxane (Tx) A2 and the cysteinyl leukotrienes. Ten asthmatic subjects were studied on three occasions after bronchial challenges with aerosolized PAF, methacholine, or isotonic saline. PAF caused bronchoconstriction in all 10 subjects (mean maximal percent fall in specific airway conductance 48.2 +/- 4.6) and was matched by methacholine challenge. Saline caused no changes in specific airway conductance. Urinary leukotriene E4 was significantly elevated after inhaled PAF (366.0 +/- 66.9 ng/mmol creatinine, P less than 0.01) compared with methacholine (41.6 +/- 13.3) and saline (33.6 +/- 4.6). The major urinary TxA2 metabolite 2,3-dinor TxB2 was elevated after inhaled PAF (41.3 +/- 7.1 ng/mmol creatinine, P less than 0.01) compared with methacholine (14.0 +/- 2.7) and saline (17.1 +/- 3.9). Urinary 2,3-dinor 6-oxo-prostaglandin F1 alpha after PAF (22.2 +/- 1.4) was raised with respect to the methacholine challenge (13.9 +/- 1.8, P less than 0.02), although no significant increase was observed compared with the saline control (18.6 +/- 3.3). Inhaled PAF leads to the secondary generation of cysteinyl leukotrienes and TxA2, and it is possible that these mediate some of the acute effects of inhaled PAF in vivo.

Cough is a common respiratory symptom, the mechanism of which is poorly understood. In this study the role of 5-HT3 receptors was investigated. Capsaicin-induced cough and increase in airways resistance were measured in six male volunteers before and after infusion with granisetron 160 micrograms kg-1 or placebo. Neither cough nor the increase in respiratory resistance was altered by the active treatment. These results suggest that 5-HT3 receptors are not involved in these two respiratory responses to inhaled capsaicin in humans.

Serum corticosterone and adrenocorticotropin (ACTH) concentrations are increased in rats by numerous direct-acting and indirect-acting serotonin receptor agonists. Antagonism of these increases by serotonin receptor antagonists has been useful in verifying their serotonergic nature and in defining central vs. peripheral sites of action. In addition, the use of agonists and antagonists with selectivity toward particular subtypes of serotonin receptors helps elucidate the identity of receptors that mediate agonist-elicited increases in serum corticosterone concentration. At least two serotonin receptor subtypes, 5-HT1A and 5-HT2/ 1C receptors, appear capable of mediating increases in serum corticosterone concentrations. The use of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and quipazine as agonists at these receptors, respectively, provides a convenient means of assessing central serotonin receptor-blocking efficacy of newly developed serotonin receptor antagonists in rats. Data from studies in humans are beginning to appear, suggesting that neuroendocrine markers in humans will also be useful in characterizing serotonin receptor antagonists clinically.

N tau-methylimidazole acetic acid (N tau-MIAA) is the principal urinary metabolite of histamine. The basal urinary excretion rate of N tau-MIAA was determined as 0.117 +/- 0.008 (SE) mg/h, with a renal clearance for N tau-MIAA of 273 +/- 27 ml/min implying active secretion. After subpharmacological infusion of histamine (50 ng.kg-1.min-1 over 2 h) in five volunteers that increased plasma histamine from 0.28 +/- 0.04 to 0.71 +/- 0.15 ng/ml, urinary excretion of N tau-MIAA over 8 h was increased by less than 17% compared with a control saline infusion. Urinary N tau-MIAA excretion in normal controls (273 +/- 14 micrograms/mmol creatinine) was similar to that observed in patients with severe acute asthma (253 +/- 22 micrograms/mmol), antigen-induced bronchoconstriction (269 +/- 21 micrograms/mmol), seasonal allergic rhinitis (304 +/- 31 micrograms/mmol), and clinically stable bronchiectasis (270 +/- 22 micrograms/mmol). In contrast, large increases in metabolite excretion (greater than 7,000 micrograms/mmol creatinine) were observed in a patient with systemic mastocytosis where very high plasma histamine levels were recorded (greater than 500 ng/ml) and marked systemic hemodynamic effects occurred. We conclude that urinary N tau-MIAA will only be increased in pathologies where sustained hyperhistaminemia occurs and that increased local histamine production in the lung or the upper airway does not cause a measurable change in the basal urinary excretion of this metabolite.

Inhaled s2 agonists are widely accepted as the most appropriate bronchodilator therapy for asthma. So why is there a question over their safety? The possibility that s2 agonists may increase asthma mortality stems from two increases in death rates from asthma that occurred at the same time as sales of high dose inhaled isoprenaline and fenoterol.1,2 The explanation that the increased death rate was due to s agonists ignores, firstly, epidemics before the discovery of inhaled s2 agonists3; secondly, the lack of epidemics in other countries where the drugs were used; and, thirdly, that the New Zealand asthma deaths were also associated with other drugs (theophylline and prednisolone).2 It is accepted that cause and effect cannot be established by the retrospective analysis of these epidemics and that the relation is weak.2 The hypothesis of a causal link between s2 agonists and death from asthma relies on showing that the use of inhaled s2 agonists can worsen asthma control. Some studies have reported decreased lung function, increased bronchial reactivity, and more attacks with s agonists, but most have had a small sample size and no placebo control.4 A placebo controlled study was done by Sears …

Nasal symptoms in the general population commonly arise from infection, allergy, or exposure to inhaled irritants. There are two mechanism by which the symptoms occur: first, vasodilatation leading to mucosal swelling and plasma exudation into the nose; second, glandular secretion [1, 2]. These effects can follow either direct stimulation of the blood vessel or glands by either inflammatory mediators [1] or irritants, or stimulation of nasal or extranasal sensory nerves leading to reflex activation of the glands and blood vessels [3]. Gustatory rhinorrhoea has been reported after eating spicy food and is a common and sometimes embarrassing symptom. It could occur through direct irritation by vapours arising from the food during swallowing, through local absorption of the spices, or through stimulation of neural reflexes within the nose or the oropharynx. We have investigated the hypothesis that the symptoms of gustatory rhinorrhoea are due to the stimulation of neural reflexes by giving the antimuscarinic agent ipratropium bromide intranasally to healthy volunteers who all ate the same spicy curry. We studied 43 volunteers aged 27 (SEM 1) y (26 m and 15 f). The volunteers marked visual analogue scales from 0-100 mm documenting their current perception of runny nose, sneezing, cough, blocked nose, itchy nose, sweating, flushing, and use of paper tissues. They then tool either ipratropium bromide 400 ~tg per nostril or a matched placebo from a metered dose inhaler in double-blind random order. After 30 rain they then ate the same quantity of mutton nahari (a strong curry) served with plain boiled rice over 10 min. Then 20 rain later they again marked the visual analogue scales and noted the number of tissues that they had used. The number of tissues and the change in distance from zero in mm on the visual analogue scales were analysed by non-parametric analysis of variance and the Mann-Whitney U test. A summary of the results is shown in Table 1. The volunteers who took placebo reported a significant (P < 0.003) increase in the symptoms of runny nose and flushing and in the use of tissues. Those treated with ipratropium bromide had a similar increase in flushing, but had significantly fewer symptoms of runny nose (P < 0.05). They also used fewer tissues, but this was not statistically significantly different from placebo. This study confirms the results of two earlier studies in small numbers of volunteers [5, 6], and shows that gustatory rhinorrhoea is due to stimulation of a neural reflex, probably arising outside the nose. Treatment with the antimuscarinic agent ipratropium bromide significantly reduced the symptoms of runny nose and reduced the use of tissues, although the latter did not reach statistical significance, probably due to the small number of tissues used in the placebo group. However, the symptom of facial flushing was not reduced, suggesting that ipratropium was exerting its effect locally in the nose. Gustatory rhinorrhoea is therefore probably due to a neural reflex rather than to the direct action of the spices on the glands and blood vessels of the nose itself. This study also confirms the effectiveness of anticholinergic agents in reducing rhinorrhoea, as has been reported in patients suffering from rhinorrhoea due to other causes, such as allergy [7] and vasomotor rhinitis [4]. This implies that maj or control of the volume of nasal secretion

In vitro affinity for vascular 5HT2 and alpha receptors was determined for several compounds (spiperone, ketanserin, mianserin, trazodone, mepiprazole, benzoctamine, m-trifluoro-methylphenylpiperazine, m-chlorophenylpiperazine, and 1-(1-naphthyl)piperazine) known to interact with serotonin receptors. All compounds competitively inhibited 5HT2 and alpha receptors with differing degrees of selectively. Based on these observations, ketanserin, benzoctamine, and 1(1-naphthyl)piperazine were evaluated as antihypertensive agents in spontaneously hypertensive rats (SHR). Of these compounds, 1-(1-naphthyl)piperazine was a highly selective 5HT2 receptor antagonist with a ratio of 5HT2 to alpha receptor affinity of greater than 2000. The ratio of 5HT2 to alpha receptor affinity for ketanserin and benzoctamine was 63 and 16, respectively. However, the order of affinity toward 5HT2 receptors was ketanserin greater than 1-(1-naphthyl)piperazine greater than benzoctamine whereas the order of affinity toward alpha receptors was ketanserin greater than benzoctamine greater than 1-(1-naphthyl)piperazine. A similar order of potency toward both 5HT2 and alpha receptors was found in pithed SHR based on antagonism of the pressor response to serotonin and methoxamine, respectively. In the SHR, maximum blood pressure reduction at a dose of 10 mg/kg i.p. was approximately 65 and 30 mm Hg for ketanserin and benzoctamine, respectively; 1-(1-naphthyl)piperazine did not affect blood pressure. Thus, blood pressure reduction more closely paralleled the in vitro and in vivo potency of these agents toward vascular alpha rather than 5HT2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)