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1.
Philos Trans R Soc Lond B Biol Sci ; 369(1639): 20120288, 2014 Apr 05.
Article in English | MEDLINE | ID: mdl-24535394

ABSTRACT

Achieving food security in a 'perfect storm' scenario is a grand challenge for society. Climate change and an expanding global population act in concert to make global food security even more complex and demanding. As achieving food security and the millennium development goal (MDG) to eradicate hunger influences the attainment of other MDGs, it is imperative that we offer solutions which are complementary and do not oppose one another. Sustainable intensification of agriculture has been proposed as a way to address hunger while also minimizing further environmental impact. However, the desire to raise productivity and yields has historically led to a degraded environment, reduced biodiversity and a reduction in ecosystem services (ES), with the greatest impacts affecting the poor. This paper proposes that the ES framework coupled with a policy response framework, for example Driver-Pressure-State-Impact-Response (DPSIR), can allow food security to be delivered alongside healthy ecosystems, which provide many other valuable services to humankind. Too often, agro-ecosystems have been considered as separate from other natural ecosystems and insufficient attention has been paid to the way in which services can flow to and from the agro-ecosystem to surrounding ecosystems. Highlighting recent research in a large multi-disciplinary project (ASSETS), we illustrate the ES approach to food security using a case study from the Zomba district of Malawi.


Subject(s)
Agriculture/methods , Climate Change , Conservation of Natural Resources/methods , Ecosystem , Food Supply/methods , Population Growth , Agriculture/trends , Conservation of Natural Resources/trends , Malawi
2.
Psychol Med ; 34(4): 693-703, 2004 May.
Article in English | MEDLINE | ID: mdl-15099423

ABSTRACT

BACKGROUND: Behavioural syndromes (thought disturbance, social withdrawal, depressed behaviour and antisocial behaviour) offer a different perspective from that of symptomatic syndromes on the disability that may be associated with schizophrenia. Few studies have assessed their relationship with neuropsychological deficits. We hypothesized that these syndromes may represent behavioural manifestations of frontal-subcortical impairments, previously described in schizophrenia. METHOD: Long-stay inpatients (n=54) and community patients (n=43) with enduring schizophrenia were assessed, using measures of symptoms and behaviour and tests of executive functioning. The relationship between syndromes and neuropsychological function was assessed using multiple regression and logistic regression analyses. RESULTS: Significant associations were found between performance on the spatial working memory task and the psychomotor poverty symptomatic syndrome, and between attentional set-shifting ability and both disorganization symptoms and the thought disturbance behavioural syndrome. These results were not explained by the effect of premorbid IQ, geographical location, length of illness or antipsychotic medication. Length of illness was an independent predictor of attentional set-shifting ability but not of working memory performance. CONCLUSION: The specific relationship between negative symptoms and spatial working memory is consistent with involvement of the dorsolateral prefrontal cortex. The associations between difficulty with set-shifting ability and both disorganization symptoms and behaviours may reflect inability to generalize a rule that had been learned and impaired ability to respond flexibly. The specific relationship of illness duration to set-shifting ability may suggest progressive impairment on some executive tasks. The nature of these relationships and their neurobiological and rehabilitation implications are considered.


Subject(s)
Attention , Behavioral Symptoms/diagnosis , Memory Disorders/diagnosis , Schizophrenia/diagnosis , Space Perception , Adult , Female , Humans , Male , Middle Aged , Neuropsychological Tests , Schizophrenic Psychology
3.
Nucleic Acids Res ; 29(9): 1951-9, 2001 May 01.
Article in English | MEDLINE | ID: mdl-11328879

ABSTRACT

The aim of the present study is to determine the chemical structure and conformation of DNA adducts formed by incubation of the bioactive form of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), N-acetoxy-PhIP, with a single-stranded 11mer oligodeoxyribonucleotide. Using conditions optimized to give the C8-dG-PhIP adduct as the major product, sufficient material was synthesized for NMR solution structure determination. The NMR data indicate that in duplex DNA this adduct exists in equilibrium between two different conformational states. In the main conformer, the covalently bound PhIP molecule intercalates in the helix, whilst in the minor conformation the PhIP ligand is probably solvent exposed. In addition to the C8-dG-PhIP adduct, at least eight polar adducts are found after reaction of N-acetoxy-PhIP with the oligonucleotide. Three of these were purified for further characterization and shown to exhibit lowest energy UV absorption bands in the range 342-347 nm, confirming the presence of PhIP or PhIP derivative. Accurate mass determination of two of the polar adducts by negative ion MALDI-TOF MS revealed ions consistent with a spirobisguanidino-PhIP derivative and a ring-opened adduct. The third adduct, which has the same mass as the C8-dG-PhIP oligonucleotide adduct, may contain PhIP bound to the N2 position of guanine.


Subject(s)
DNA Adducts/chemistry , DNA Adducts/chemical synthesis , Deoxyguanosine/analogs & derivatives , Deoxyguanosine/chemistry , Deoxyguanosine/chemical synthesis , Imidazoles/chemistry , Imidazoles/chemical synthesis , Base Sequence , Chromatography, High Pressure Liquid , Nuclear Magnetic Resonance, Biomolecular , Nucleic Acid Conformation , Oligodeoxyribonucleotides/chemical synthesis , Oligodeoxyribonucleotides/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
4.
Aust N Z J Psychiatry ; 35(1): 91-8, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11270464

ABSTRACT

OBJECTIVE: Australia's National Mental Health Strategy aims to achieve improved consumer outcomes. The development and refinement of consumer outcome measures is targeted within the Second National Mental Health Plan. The National Standards for Mental Health Services identify measures of functioning, quality of life and satisfaction with services as relevant to assessing and monitoring consumer outcome. Consumers have described gauging their own recovery through the achievement of functional goals in everyday life. This paper reviews how functioning is viewed within the mental health field, and implications for developing better functional outcome measures. METHOD: Literature describing the development of measures of functioning, principles of outcome measurement, and functional outcomes for people with severe mental illness was identified, using PsycLIT. A review yielded themes reflecting a number of assumptions about the concept of functioning. RESULTS: Functioning is inadequately defined, raising issues about what is focused on, and from whose viewpoint, each of which has implications for using measures of functioning to monitor consumer outcome. Conflation of dissimilar functional domains, and flawed assumptions about the importance of symptomatology in influencing functional outcome limit the sensitivity to meaningful change of functional measures. Consumer perspectives are relatively neglected in functional tool development. CONCLUSIONS: A conceptual framework that recognizes lived experience and the interaction between persons and their environment is much needed to guide the development of functional outcome measures. Qualitative and quantitative research methodologies should be used to advance understanding of functioning and to address limitations of current approaches to functional outcome measurement.


Subject(s)
Consumer Behavior , Mental Disorders/therapy , Mental Health Services/standards , Treatment Outcome , Australia , Humans , Quality of Life , Social Behavior
5.
Schizophr Res ; 37(2): 165-76, 1999 May 25.
Article in English | MEDLINE | ID: mdl-10374651

ABSTRACT

In a previous large epidemiological survey of patients with strictly defined schizophrenia in the London borough of Camden, we extracted four behavioural syndromes (Social withdrawal, Thought disturbance, Anti-social behaviour and Depressed behaviour) by factor analysis of MRC Social Behaviour Schedule (SBS) data. These syndromes had significant differential relationships to symptoms assessed using the Manchester Scale (MS), symptom-derived syndromes, and social functioning variables. A second inner-London epidemiological survey of schizophrenia in South Westminster using identical methodology found the same four behavioural syndromes with identical core component items. The same four behavioural syndromes were extracted, whether applying strict Feighner diagnostic criteria (n=112) or broader DSM-III-R criteria (n=198). The four syndromes extracted from the Feighner positive sample showed relationships to symptoms and social functioning variables similar to those found in the original Camden study. However, the symptom-derived factors were not the same and did not conform to the three recognised symptom-based syndromes of schizophrenia. This successful replication suggests that assessment of the four behavioural syndromes of schizophrenia offers a different perspective on disability and a potentially relevant measure in clinical practice, clinical trials and studies of the neuropsychology and pathophysiology of schizophrenia.


Subject(s)
Schizophrenia/epidemiology , Schizophrenic Psychology , Adult , Female , Humans , London/epidemiology , Male , Middle Aged , Psychiatric Status Rating Scales , Syndrome
6.
Aust N Z J Psychiatry ; 31(4): 488-95, 1997 Aug.
Article in English | MEDLINE | ID: mdl-9272258

ABSTRACT

OBJECTIVE: There has been an accumulation of so-called 'new long-stay' (NLS) patients in psychiatric hospitals. To date, no Australian studies have characterised this patient group. We aimed to study the demography, and clinical and social functioning of the NLS population at Royal Park Hospital (RPH) together with patients' attitudes to treatment and views on future placement. METHOD: All 30 NLS patients at RPH were identified. Twenty-seven consenting patients were assessed using the following standardised instruments: Manchester Scale for psychopathology, Life Skills Profile (LSP), Physical Health Index and Patient Attitude Questionnaire. Information on past psychiatric history, past treatment and current treatment was collected. Insight and compliance were assessed. RESULTS: The majority of patients were single men with a diagnosis of schizophrenia. Forty-one percent were detained in hospital involuntarily and 56% were considered dangerous to themselves or others. The patients were characterised by high levels of positive and negative symptoms. They were most impaired with respect to 'social contact' relative to the other subscales of the LSP. While 10 (48%) patients expressed a desire to leave hospital, only one patient considered that anyone would cohabit with them. Over two-thirds considered they had been unwell and that medication had helped. Staff rated one-third as having major problems with compliance. About two-thirds of patients had disability secondary to comorbid physical illnesses. CONCLUSION: Like other NLS patients studied in the United Kingdom and Ireland, this group had significant handicaps secondary to psychiatric illness, concomitant physical illness and disability and behaviour unacceptable in community settings. They were also characterised by significant social isolation. These factors may be important determinants of rehabilitation failure and need to be addressed in the process of de-institutionalisation as well as in longitudinal studies examining these and other factors predicting NLS status.


Subject(s)
Long-Term Care , Schizophrenia/therapy , Schizophrenic Psychology , Urban Population , Activities of Daily Living/psychology , Adolescent , Adult , Australia , Comorbidity , Deinstitutionalization , Female , Hospitals, Psychiatric , Humans , Male , Middle Aged , Prognosis , Psychiatric Status Rating Scales , Schizophrenia/diagnosis , Social Adjustment
7.
Br J Psychiatry ; 170: 301-6, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9246245

ABSTRACT

BACKGROUND: A point prevalence study of schizophrenia was carried out in 1986 in the former Hampstead Health District using a key informant method to identify cases. The point prevalence of broadly defined schizophrenia was 4.7 per 1000. METHOD: A repeat census of people with schizophrenia, using the same method, was carried out in 1991 and the point prevalence calculated. The accuracy of the census method was estimated. Contact with services, social and occupational activity, and medication usage in the 1986 and 1991 samples were compared. RESULTS: The point prevalence rate of broadly defined schizophrenia in 1991 was 5.1 per 1000. The results of both censuses showed we underestimated the number of individuals with DSM-III-R positive schizophrenia by about 14%. The level of contact with specialist services was greater in 1991 than 1986. Patients in 1991 were discharged on higher doses of medication, and their most recent admission was more likely to be due to non-compliance, than the 1986 group. CONCLUSION: The point prevalence confirmed the high rate reported in 1986. The accuracy of the census was within acceptable limits for service planning. Contact with specialist services increased between 1986 and 1991.


Subject(s)
Mental Health Services/statistics & numerical data , Schizophrenia/epidemiology , Adolescent , Adult , Aged , Employment , Health Care Surveys , Humans , London/epidemiology , Mental Health Services/trends , Middle Aged , Prevalence , Schizophrenia/drug therapy , Schizophrenia/rehabilitation , Social Support , Urban Health Services/statistics & numerical data , Urban Health Services/trends
8.
Br J Psychiatry ; 170: 307-11, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9246246

ABSTRACT

BACKGROUND: The previous paper reports a high prevalence of schizophrenia (broad definition) in an inner London area. In this paper we test hypotheses for this finding and examine the characteristics of people with schizophrenia who move frequently. METHOD: People with schizophrenia in the Hampstead area were identified by key informant methodology, at two censuses five years apart. This allowed identification of incident cases during these five years and identification of people who had moved into and out of the area. RESULTS: The incidence of DSM-III-R schizophrenia in Hampstead between 1986 and 1991 was at least 0.21 per 1000 of the population aged 15 to 54. There was a significant movement of people with schizophrenia to this inner London area from outer London between 1986 and 1991. People with schizophrenia who were relatively mobile were significantly more likely to be male, to suffer with prominent hallucinations, and to have no contact with a GP. CONCLUSIONS: The high prevalence of broad schizophrenia in this inner London area is, in part, due to geographical drift. A significant excess of the people with schizophrenia who move frequently are men with positive symptoms.


Subject(s)
Schizophrenia/epidemiology , Transients and Migrants/statistics & numerical data , Urban Health/statistics & numerical data , Adolescent , Adult , Humans , Incidence , London/epidemiology , Male , Middle Aged , Schizophrenic Psychology , Sex Factors , Transients and Migrants/psychology
10.
Br J Psychiatry ; 168(4): 410-7, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8730936

ABSTRACT

BACKGROUND: The development of appropriate community care requires knowledge of the characteristics of the severely mentally ill. METHOD: All patients with a broad diagnosis of schizophrenia (n = 528) were identified via key informants within an inner London health district; Feighner and DSM-III-R criteria for schizophrenia were applied. Clinical and social status, psychopathology (Manchester Scale) and problem behaviours (Social Behaviour Schedule) were assessed in a 4:5 representative sample. RESULTS: Fifty-seven per cent had experienced at least one compulsory admission. Forty-five per cent (excluding long-stay in-patients) had marked positive psychotic symptoms; social isolation and lack of daytime activity was more common than among comparable populations elsewhere. One hundred and eleven (25%) of the non-hospitalised patients were not in contact with specialist services. CONCLUSIONS: Difficulties in establishing and maintaining a therapeutic alliance between patients and professionals present a challenge to services in inner London. Many social and occupational needs were not being met by existing community provision.


Subject(s)
Schizophrenia/epidemiology , Schizophrenic Psychology , Social Behavior , Urban Population/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Community Mental Health Services/statistics & numerical data , Female , Forecasting , Health Services Needs and Demand/trends , Humans , London/epidemiology , Male , Middle Aged , Patient Admission/statistics & numerical data , Patient Care Team/statistics & numerical data , Psychiatric Status Rating Scales , Rehabilitation, Vocational , Schizophrenia/classification , Schizophrenia/diagnosis , Schizophrenia/rehabilitation
11.
Br J Psychiatry ; 168(4): 418-26, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8730937

ABSTRACT

BACKGROUND: Investigation of the geographical distribution of schizophrenia and its relationship to socio-demographic factors is useful for planning services. METHOD: Individuals with schizophrenia (n = 980) were identified by key informants within an inner London borough and point prevalence calculated for broad, Feighner and DSM-III-R schizophrenia. The distribution of cases was tested for significant variation using the Poisson process model. Regression models using the Jarman-8 score and its component variables were tested for their ability to predict the prevalence of schizophrenia. RESULTS: A high point prevalence of schizophrenia (5.3 per 1000 resident population) was demonstrated. Case distribution showed a marked and significant variation associated with socio-demographic factors. The prediction of prevalence was more accurate for broad than for narrower definitions of schizophrenia; unemployment rate performed best. CONCLUSIONS: Unemployment rates and Jarman-8 scores may provide crude estimates for resource allocation in planning mental health services, highlighting the need for additional services in deprived inner city areas.


Subject(s)
Schizophrenia/epidemiology , Schizophrenic Psychology , Social Behavior , Urban Population/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Community Mental Health Services/statistics & numerical data , Cross-Sectional Studies , Female , Forecasting , Health Services Needs and Demand/trends , Humans , Incidence , London/epidemiology , Male , Middle Aged , Poisson Distribution , Psychiatric Status Rating Scales , Regression Analysis , Rehabilitation, Vocational/statistics & numerical data , Schizophrenia/classification , Schizophrenia/diagnosis , Schizophrenia/rehabilitation
12.
Life Support Biosph Sci ; 2(3-4): 181-2, 1996.
Article in English | MEDLINE | ID: mdl-11538566

ABSTRACT

Increasing complexity of hyperbaric treatments and emergency treatment profiles make it highly desirable to add a real-time computerized recording and analysis system to hyperbaric chambers. These systems keep track of each person who enters the chamber as a patient or support person and compute their individual decompression obligation and pulmonary oxygen toxicity doses. The technology exists and the cost and training are worth the price.


Subject(s)
Atmosphere Exposure Chambers , Decompression/instrumentation , Hyperbaric Oxygenation/instrumentation , Computers , Data Interpretation, Statistical , Software
13.
Int Clin Psychopharmacol ; 9(3): 207-9, 1994 Sep.
Article in English | MEDLINE | ID: mdl-7814831

ABSTRACT

Urinary incontinence may occur in patients with severe mental illness. Psychosis and neuroleptic medication have both been implicated, but there has been a lack of systematic evaluation of the precise relationship between these phenomena. Incontinence has been recognized as a complication of clozapine treatment and we examined this in 16 consecutively treated patients. Thirteen were established on therapeutic doses, one of whom was excluded from further study due to pre-existing incontinence. Retrospective assessment revealed that nocturnal incontinence was experienced by five of the remaining 12 patients, occurring in the first 3 months of treatment and resolving spontaneously in all cases. Incontinence was documented in the case notes in only one of the five cases and there was a tendency for affected patients to be embarrassed and reluctant to report it to staff. Specific enquiry may be necessary to elicit this phenomenon and incontinence should be considered as a possible factor in poor compliance with clozapine.


Subject(s)
Clozapine/adverse effects , Enuresis/chemically induced , Psychotic Disorders/drug therapy , Urinary Incontinence/chemically induced , Adult , Clozapine/therapeutic use , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Patient Compliance/psychology , Psychotic Disorders/psychology , Retrospective Studies
14.
Pharmacol Biochem Behav ; 38(1): 147-54, 1991 Jan.
Article in English | MEDLINE | ID: mdl-1673248

ABSTRACT

These studies characterise the pharmacology of ropinirole, a selective D-2 agonist. High-affinity human caudate binding revealed a Ki for D2 receptors of 2.9 x 10(-8) M with no affinity for D1 at 10(-4) M in the rat. Ropinirole was weakly active at alpha 2-adrenoceptors and 5-HT2 receptors but inactive at 5-HT1, benzodiazepine and gamma-aminobutyric acid receptors or alpha 1 and beta-adrenoceptors. In rodents, ropinirole, like apomorphine, caused biphasic spontaneous locomotor activity and contralateral circling in 6-OHDA-lesioned mice with no tolerance to the latter after 14 days treatment. Amphetamine caused ipsilateral responses in the lesioned mice. Ropinirole did not cause marked stereotypies. In marmosets ropinirole (0.05-1.0 mg/kg SC or 0.1 mg/kg PO) reversed all motor and behavioural deficits induced by MPTP. This response started 10-20 minutes after dosing, and exceeded 2 hours. No tolerance was seen following chronic b.i.d. treatment. Similar results were obtained with 1-dopa plus benserazide; however, 1-dopa always caused emesis, whereas beneficial effects were shown with ropinirole in the absence of this side effect. These results support the continued clinical assessment of ropinirole for the treatment of Parkinson's disease.


Subject(s)
Dopamine Agents/pharmacology , Indoles/pharmacology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Adenylyl Cyclases/metabolism , Animals , Antiparkinson Agents , Blood Platelets/metabolism , Callitrichinae , Cattle , Caudate Nucleus/drug effects , Caudate Nucleus/enzymology , Cell Membrane/drug effects , Cell Membrane/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Female , Humans , In Vitro Techniques , Male , Motor Activity/drug effects , Parkinson Disease, Secondary/chemically induced , Parkinson Disease, Secondary/physiopathology , Rats , Rats, Inbred Strains , Receptors, Adrenergic, alpha/drug effects , Receptors, Adrenergic, alpha/metabolism , Receptors, Adrenergic, beta/metabolism , Receptors, Dopamine/metabolism , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Receptors, Serotonin/metabolism , gamma-Aminobutyric Acid/metabolism
15.
16.
Consultant ; 29(8): 86-8, 91, 1989 Aug.
Article in English | MEDLINE | ID: mdl-10294289

ABSTRACT

Aging of the "baby-boom" generation and increased life expectancy will mean a projected population increase of persons 65 and older from 39 to 65 million between 2010 and 2030. Surveys conducted among members of the American Association of Retired Persons (AARP) reflect their wish to establish a more equal part in the physician-patient relationship and to participate in local and federal health care monitoring and reform. Accordingly, many are asking for health information and are prepared to change heretofore ineffectual communication with the health care system--whether in their personal physician's office or at the federal level. Only a fraction of practicing physicians report geriatrics as a primary or secondary specialty. Family practitioners and internists are likely to continue to provide the major share of medical care to the elderly in the future.


Subject(s)
Community Participation/trends , Geriatrics , Health Services for the Aged/trends , Physician-Patient Relations , Aged , Attitude of Health Personnel , Consumer Organizations , Data Collection , Geriatrics/education , Humans , Life Expectancy , Population Growth , Prejudice , Workforce
17.
Clin Exp Hypertens A ; 9(5-6): 889-912, 1987.
Article in English | MEDLINE | ID: mdl-2887313

ABSTRACT

The availability of highly selective dopamine receptor agonists has allowed the characterization of the role of DA1 and DA2 receptors in the cardiovascular system. Fenoldopam (SK&F 82526) is a potent agonist at DA1 receptors, with much less agonist activity at the DA2 subtype or at alpha and beta adrenoceptors. In contrast, SK&F 89124 activates only the DA2 subtype. SK&F 85174, the N-allyl derivative of fenoldopam, retains potent DA1 agonist activity but also has moderately potent agonist activity at the DA2 receptor. All three compounds will reduce blood pressure in hypertensive rats. In the anesthetized dog, each agonist will reduce blood pressure and total peripheral resistance. The overall hemodynamic profile is remarkably similar, despite the marked difference in dopamine receptor subtype selectivity. The principal pharmacologic difference is enhanced bradycardia with the compounds having DA2 agonist activity, resulting from activation of neuroinhibitory DA2 receptors on cardiac sympathetic nerve terminals. In the dog, each compound will increase renal blood flow. Studies in the anesthetized rat with fenoldopam and SK&F 89124, using radiolabelled microspheres to measure blood flow to various vascular beds, also show a significant increase in renal flow, with a tendency toward increased blood flow in the splenic and intestinal beds. Hence, dopamine receptor agonists offer a useful approach to cardiovascular therapy via DA1 mediated vascular dilation, DA2 mediated modulation of sympathetic tone or a combination of both activities.


Subject(s)
Hemodynamics/drug effects , Receptors, Dopamine/drug effects , Anesthesia , Animals , Antihypertensive Agents/pharmacology , Benzazepines/pharmacology , Dogs , Female , Fenoldopam , Hypertension/physiopathology , Indoles/pharmacology , Male , Rats , Rats, Inbred Strains , Regional Blood Flow/drug effects , Species Specificity , Synaptic Transmission/drug effects , Time Factors , Vasodilator Agents/pharmacology
18.
N Engl Reg Allergy Proc ; 7(2): 126-33, 1986.
Article in English | MEDLINE | ID: mdl-2886901

ABSTRACT

SK&F 93319 (icotidine), 2-[4-(3-methoxypyrid-2-yl)butylamino]-5-[(6-methylpyrid-3-yl )-methyl]- pyrimidin-4-one trihydrochloride, has been identified as a novel agent which combines into one molecule the ability to antagonize the actions of histamine at H1 and H2 receptors across a similar concentration or dose range. The degree of antagonism of vascular responses to histamine exceeds that possible with either an H1- or H2-receptor histamine antagonist alone. SK&F 93319 may have therapeutic utility in conditions requiring simultaneous antagonism of histamine at H1 and H2 receptors.


Subject(s)
Histamine H1 Antagonists , Histamine H2 Antagonists , Pyridines/pharmacology , Animals , Bronchi/drug effects , Chemical Phenomena , Chemistry , Gastric Acid/metabolism , Heart/drug effects , Humans , Imidazoles/pharmacology , In Vitro Techniques , Pyridines/metabolism , Structure-Activity Relationship , Vascular Resistance/drug effects
19.
Br J Pharmacol ; 87(3): 569-78, 1986 Mar.
Article in English | MEDLINE | ID: mdl-2879585

ABSTRACT

SK&F 93944 (temelastine), a novel histamine H1-receptor antagonist, has been studied in a variety of in vitro and in vivo test systems. SK&F 93944 was a competitive antagonist of histamine-induced contractions of guinea-pig ileum with a pA2 of 9.55 and a weak, non-competitive, inhibitor of the effects of histamine on guinea-pig atrium. In anaesthetized guinea-pigs SK&F 93944 displaced histamine bronchoconstriction dose-response curves at doses which had negligible effects on histamine tachycardia. In anaesthetized cats SK&F 93944 antagonized depressor responses to the histamine H1-receptor agonists, 2-(2-aminoethyl)pyridine and betahistine, at doses which had no effects on responses to the histamine H2-receptor agonist, dimaprit. Oral pretreatment with SK&F 93944 in conscious rats and guinea-pigs afforded protection versus the response to intradermal histamine injection. Comparative studies in each of the test systems showed that SK&F 93944 was of comparable or significantly greater potency than the standard compound, mepyramine. SK&F 93944 was found to be a weak, non-competitive antagonist of carbachol on the guinea-pig ileum but was devoid of measurable anticholinergic activity in vivo. Studies on the penetration of [14C]-SK&F 93944, labelled either in the isocytosine ring or in the butyl chain, showed that brain concentrations were very low when compared with the steady-state blood concentrations. In contrast, brain concentrations of [3H]-mepyramine exceeded blood concentrations by a factor of approximately 3. SK&F 93944 may have an advantage over classical histamine H1-receptor antagonists in that it is likely to be devoid of untoward effects on the central nervous system.


Subject(s)
Central Nervous System/metabolism , Histamine H1 Antagonists/pharmacology , Pyrimidinones/pharmacology , Animals , Autonomic Nervous System/drug effects , Cerebrovascular Circulation/drug effects , Female , Guinea Pigs , Hemodynamics/drug effects , Histamine/pharmacology , Histamine H1 Antagonists/metabolism , Male , Parasympatholytics/pharmacology , Pyrilamine/metabolism , Skin Absorption/drug effects , Sympathetic Nervous System/drug effects
20.
Br J Pharmacol ; 83(2): 427-32, 1984 Oct.
Article in English | MEDLINE | ID: mdl-6148984

ABSTRACT

Cardiovascular studies have been made in anaesthetized cats with SK&F 93319, an antagonist of histamine at both H1- and H2-receptors. SK&F 93319, 8 X 10(-8) and 4 X 10(-7) mol kg-1 min-1 antagonized depressor responses to injections of histamine and the maximum displacement of histamine dose-response curves exceeded that which can be obtained with either an H1-receptor antagonist or an H2-receptor antagonist alone. SK&F 93319, 8 X 10(-8) and 4 X 10(-7) mol kg-1 min-1, also caused dose-dependent antagonism of histamine-induced falls in blood pressure and total peripheral resistance during intravenous infusions of histamine. SK&F 93319 inhibited depressor responses to intravenous injections of 2-(2-aminoethyl)pyridine, dimaprit and impromidine. The displacement of the 2-(2-aminoethyl)pyridine dose-response curve was similar to the displacement of histamine dose-response curves. SK&F 93319 caused greater displacement of dimaprit or impromidine dose-response curves than of histamine or 2-(2-aminoethyl)pyridine dose-response curves. SK&F 93319 was an effective antagonist of histamine, 2-(2-aminoethyl)pyridine or dimaprit-induced vasodilatation in femoral and gastric vasculature. SK&F 93319 has been shown to be an effective antagonist of vascular responses to histamine in anaesthetized cats. SK&F 93319 appeared to be more effective as an H2-receptor antagonist than as an H1-receptor antagonist in these vascular studies.


Subject(s)
Hemodynamics/drug effects , Histamine H1 Antagonists/pharmacology , Histamine H2 Antagonists/pharmacology , Pyridines/pharmacology , Animals , Blood Pressure/drug effects , Cats , Female , Femoral Artery/drug effects , Male , Regional Blood Flow/drug effects , Stomach/blood supply , Vascular Resistance/drug effects , Vasodilation/drug effects
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