ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

This paper reviews the theoretical concepts and methods utilised with isolated tissues to characterise drugs and drug receptors. Specifically the impact, on thein vitromeasurement of agonist affinity and relative efficacy, of the idea that receptors bind to transduction proteins in the lipid bilayer of the cell membrane is discussed. The effects of ternary complex formation of agonist-receptor equilibria raise theoretical objections to the measurement of agonist receptor equilibrium dissociation constants. Possible ‘promiscuity’ of receptors with respect to the G-proteins with which they can interact makes classification of receptors by agonists suspect. The use of Schild analysis for the measurement of antagonist affinity and subsequent classification of receptors is considered in the light of recent data showing that estimates calculated with this method are heterogeneous. Resultant analysis for the detection of allosteric effects is also discussed. Lastly, the impact of molecular biology on the drug and drug receptor classification process is considered, as well as the effects of pathological processes on drug action at the receptor level.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

At any age hypnotic drug use can give rise to 3 major problems: unwanted effects on daytime mood and behaviour associated with drug consumption; rebound effects associated with drug withdrawal; and dependency associated with long term drug use. For 2 reasons elderly hypnotic users are both more vulnerable and more exposed to each of these problems. Firstly, age-related changes in pharmacodynamic and pharmacokinetic processes amplify the behavioural impact of many hypnotics; and secondly, age-related changes in the structure and quality of sleep tend to increase the demand for, and the long term use of, sedative hypnotic compounds in old age. The existence of physical illness, cognitive impairment, or daytime behaviour already compromised by normal aging processes further increases the likelihood of hypnotic drugs detrimentally affecting well-being in later life.These important causes for concern emphasise the need for 2 separate clinical responses: the need for greater circumspection in the choice and use of hypnotic drugs among elderly patients, and the need for a more broadly based clinical approach to the management of sleep problems in old age.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Psoriasis is an inflammatory disease of the skin associated with increased epidermal proliferation. The aetiology of the disease is unknown, but there seems to be a genetic predisposition.The goal of therapy in the treatment of psoriasis is to decrease the rate of epidermal proliferation and the underlying inflammation. Topical application of steroids and coal tar are the therapies of choice; however, for those patients with severe recalcitrant psoriasis who have failed conventional topical therapy methotrexate is an established alternative.The use of methotrexate in psoriasis is limited by its toxicity, and proper patient selection and close monitoring are essential in achieving good clinical response. The dosage used should be the lowest that will maintain the patient in comfort, not necessarily that which produces total resolution. Caution should be exercised when other agents are used concurrently with methotrexate, and possible drug interactions should be identified as these may influence the effectiveness and toxicity of methotrexate therapy.The common side effects associated with the use of methotrexate in psoriasis include bone marrow suppression, gastrointestinal symptoms and hepatotoxicity. Liver damage is a major concern in long term methotrexate therapy and thus liver biopsies are warranted to monitor any pathological changes. The drug is a known teratogen and should be avoided in pregnant patients. Women of childbearing age should use reliable contraception during therapy.Patients should be made aware of the signs and symptoms of methotrexate toxicity and inform their physicians promptly as most adverse effects can be ameliorated with appropriate dosage adjustment. Methotrexate will continue to play a major role in the treatment of psoriasis and it is thus important that it be used safely.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

This article highlights the choices and the arguments in the selection of appropriate contrast materials in radiological examinations - nonionic versus ionic contrast material - and aims to assist the physician in decision-making.Various authors have raised questions concerning the proposed advantages of nonionic contrast material. However, studies in low risk patients have shown more complications with the use of ionic contrast than nonionic contrast materials; this is the important group of patients since in high risk patients nonionics are used almost exclusively.The important factor that increases the controversy is cost, which is significant since nonionic agents cost 10 to 15 times more than ionic agents in the USA. Thus, costbenefit considerations are important because price sensitivity and cost may determine fund availability for equipment or materials that also may be necessary or important in improving patient care.In magnetic resonance imaging (MRI), as in computed tomography (CT), the use of contrast material has improved diagnostic accuracy and the ability to reveal lesions not otherwise easily detected in brain and spinal cord imaging. These include separating scar from disc, meningitis, meningeal spread of tumour, tumour seeding, small metastases, intracanalicular tumours, separating major mass from oedema, determining bulk tumour size and ability to demonstrate blood vessels so dynamic circulatory changes may be revealed.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisClozapine, an antipsychotic agent of the dibenzodiazepine class, is characterised by relatively weak central dopaminergic activity and displays atypical pharmacological and clinical properties in relation to the classic antipsychotics. Clinical studies have shown clozapine to be effective in suppressing both the positive and negative symptoms of schizophrenia and to be associated with an extremely low incidence of extrapyramidal side effects. Clozapine has been shown to be of comparable, or on some criteria superior, therapeutic efficacy to perphenazine, levomepromazine, haloperidol and chlorpromazine in several short term comparative studies in patients with schizophrenia of predominantly acute symptomatology. Moreover, clozapine is effective in a substantial proportion (30 to 50%) of schizophrenic patients who are refractory to or intolerant of classic antipsychotic therapy. Despite its promising therapeutic potential, the relatively high incidence of clozapine-induced agranulocytosis (1 to 2% of patients) is a major factor restricting the drug's wider use in psychiatric practice. In accordance with current guidelines, clozapine therapy, performed in conjunction with close haematological monitoring, is indicated for the management of severe and chronic schizophrenia refractory to classic antipsychotic therapy, and in those unable to tolerate such therapy. In such appropriately selected patients, clozapine represents an important alternative to the classic antipsychotics.Pharmacodynamic PropertiesIn comparison with the classic antipsychotics, clozapine is a relatively weak antagonist at striatal dopamine D2-receptors, and produces a more potent blockade of central dopamine D1-, cholinergic, serotonergic S2-, histamine H1-, and &agr;1- and &agr;2-adrenergic receptors. In patients with schizophrenia, clozapine appears to induce a comparablein vivoblockade of striatal dopamine D1- and D2-receptors; at clinically effective doses central dopamine D2-receptor blockade is less pronounced with clozapine than with classic antipsychotics. On long term administration clozapine selectively enhances central dopamine D1-receptor function and produces down-regulation of serotonergic S2-receptors in rodents. Biochemical and neurophysiological studies indicate that clozapine may act preferentially on mesolimbic and amygdaloid rather than neostriatal dopaminergic pathways, and that this site specificity may underlie the dissociation between clozapine's marked antipsychotic activity and its relative absence of extrapyramidal side effects. Clozapine is only marginally effective in several animal behavioural models (e.g. induction of catalepsy, inhibition of dopamine-induced stereotypy) mediated via neostriatal dopaminergic pathways which are considered predictive of antipsychotic activity, but antagonises those behaviours (e.g. dopamine-induced locomotion) mediated via mesolimbic dopaminergic pathways. In contrast to the prolonged stimulation of prolactin secretion observed with the classic antipsychotics, clozapine has minimal effects on plasma prolactin levels in humans.Pharmacokinetic PropertiesPeak plasma concentrations of clozapine are reached at 1 to 4 hours after oral administration, before declining in a biphasic manner (terminal elimination half-life 6 to 30 hours). Orally administered clozapine undergoes moderate hepatic first-pass metabolism; systemic bioavailability is approximately 50%. The pharmacokinetics of clozapine are consistent with a model of first-order absorption and are linear over plasma concentrations of 10 to 1000 &mgr;g/L (corresponding to daily doses of ≈ 0.5 to 12.0 mg/kg). Maximum and minimum plasma clozapine concentrations and AUC values at steady-state are positively correlated with dosage over the range 75 to 300 mg/day. Large intersubject variation in steady-state plasma clozapine concentrations is attributable to factors of age, sex, bodyweight and smoking behaviour. Clozapine is approximately 95% bound to plasma proteinsin vitro.In humans, clozapine undergoes extensive metabolism viaN-oxidation,N-demethylation and dehalogenation, with unchanged clozapine accounting for 2 to 5% of the excreted drug. Excretion is predominantly by the urinary route (≈ 50% of administered dose) and the faecal route (35% of administered dose).Therapeutic UseNoncomparative studies in hospitalised patients with schizophrenia have indicated that clozapine produces symptomatic improvement in 60 to 80% of cases, with the benefit being most evident in those with acute schizophrenia. Typically, the response to clozapine is characterised by an initial sedative/anxiolytic effect which is followed after 1 to 2 weeks of therapy by the development of an antipsychotic action and a subsequent gradual alleviation of behavioural disturbances leading to restoration of social skills. Long term clozapine maintenance therapy (≤ 6.5 years) has been associated with a sustained therapeutic effect in 50 to 80% of patients with chronic schizophrenia.Short to medium term (3 to 12 weeks) comparative studies in small groups of patients with schizophrenia of predominantly acute symptomatology have demonstrated that the antipsychotic efficacy of clozapine (≤ 1000 mg/day) is at least equal to, and on some criteria greater than, that of classic antipsychotics such as perphenazine (mean 18 to 64 mg/day), levomepromazine (mean 135 to 220 mg/day), chlorpromazine (≤ 1600 mg/day) and haloperidol (3 to 40 mg/day). In comparison with chlorpromazine, clozapine displayed more pronounced sedation, a broader spectrum of antipsychotic effects, greater improvement in the ‘psychomotor plus’ symptoms of schizophrenia (tension, hostility and excitement) and a more rapid onset of action, thereby allowing a higher proportion of patients to meet hospital discharge criteria and experience disease remission. Similarly, in this group of patients with schizophrenia, clozapine proved superior to haloperidol on short to medium term (6 to 12 weeks) therapy, displaying a broader antipsychotic spectrum and more marked antidelusional, anxiolytic/sedative and contact-promoting effects. The antipsychotic superiority of clozapine was particularly evident in severely disturbed patients with additional symptoms of anxiety, tension and psychomotor agitation, and those with prominent negative symptoms.Retrospective and prospective noncomparative studies have indicated that clozapine is of benefit in a substantial proportion (30 to 50%) of patients with treatment-resistant schizophrenia (those refractory to or intolerant of classic antipsychotics), producing improvements in both florid and autistic symptoms and the quality of disease remission after 1.5 to 6 months of therapy, and promoting social adaptation and integration on maintenance therapy (≥ 2.5 years). The aetiological/clinical factors predictive of therapeutic benefit with clozapine in this subgroup of schizophrenic patients remain to be elucidated. Short to medium term (6 to 8 weeks) comparative studies in patients with treatment-resistant schizophrenia have demonstrated the superior antipsychotic efficacy of clozapine (≤ 900 mg/day) versus that of chlorpromazine (≤ 1800 mg/day) in terms of physicians' and ward nurses' ratings of symptoms, the rapidity of onset of clinical response, and the proportion of patients showing clinical improvement.Adverse EffectsSedation, hypersalivation, tachycardia, postural hypotension and dizziness constitute the most frequently reported adverse effects of clozapine, occurring in up to 40% of patients. These effects are generally dose related, arise on initiation of therapy and tend to subside as tolerance develops, although tachycardia, hypersalivation and sedation may be persistent. Less frequent adverse effects include constipation (14%), nausea/vomiting (11%), hyperthermia (5%) and seizures (3%). Serious adverse effects attributable to clozapine and necessitating its withdrawal (predominantly toxic delirium and sedation) occurred in 6% of 959 treatment-resistant schizophrenics prospectively monitored over a 10-year period.Agranulocytosis is the most serious adverse effect of clozapine, occurring in 1 to 2% of patients and requiring immediate discontinuation of the drug once it is detected. Onset is gradual, with the period of maximum risk occurring during the initial 18 weeks of clozapine therapy. The phenomenon does not appear to be dose related, and predisposing factors are unknown.Clozapine is distinguished from the traditional antipsychotics by its relatively low propensity to induce extrapyramidal symptoms (0 to 20% of patients), among which akathisia, akinesia and tremor appear to predominate over dystonia. There have been no confirmed cases of induction of tardive dyskinesia on long term clozapine therapy.Dosage and AdministrationClozapine may be administered orally or intramuscularly. The manufacturer recommends initiation of clozapine therapy with 25 to 75 mg/day administered in 2 or 3 divided doses, followed by titration in 25 to 50 mg/day increments to achieve a target dose of 300 to 450 mg/day after 2 weeks. Subsequent dosage increases of ≤ 100 mg/day should be performed no more than twice weekly, to a maximum dose of 900 mg/day. After initial titration, the dose should be progressively reduced to the minimum level necessary to maintain clinical remission. In view of the continuing risk of agranulocytosis, weekly haematological surveillance is essential during the initial 18 weeks of clozapine administration; thereafter monthly monitoring is considered satisfactory. Clozapine is contraindicated in conjunction with drugs with the potential to depress bone marrow function/induce agranulocytosis, as well as in patients with severe CNS depression, myeloproliferative disorders or a history of drug-induced agranulocytosis.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisTerodiline has both anticholinergic and calcium antagonist properties and, as a result, effectively reduces abnormal bladder contractions caused by detrusor instability. When administered to adult patients with urge incontinence (generally as a 25mg twice-daily dose) terodiline reduces diurnal and nocturnal micturition frequency and incontinence episodes. In studies also assessing cystometric parameters, bladder volume at first urge and bladder capacity are increased. Children with diurnal enuresis respond similarly to a daily 25mg dose.Several studies have shown that terodiline 50 mg/day is preferred by patients when compared with emepronium 600 mg/day or flavoxate 600 mg/day, and tends to reduce voluntary micturition frequency and episodes of incontinence more effectively than these drugs.Terodiline is well tolerated in short and long term (up to 3.5 years) studies. Anticholinergic effects are most commonly reported; other adverse effects occur equally during terodiline and placebo treatment.Thus, terodiline is effective and well tolerated in patients with urge incontinence or neurogenic bladder dysfunction, and will claim an important place in the treatment of such patients in light of the limitations of alternative therapies.Overview of Pharmacological PropertiesIn vitrostudies in isolated animal and human detrusor muscle have shown that terodiline possesses anticholinergic activity at concentrations of 5 &mgr;mol/L or less: it inhibits carbachol-induced muscle contractions in a concentration-dependent manner. An interaction between terodiline and muscarinic receptors has also been demonstratedin vitro.In addition, at higher concentrations terodiline inhibits calcium-induced contractions in depolarised rabbit aorta and pregnant human uterus, and reduces potassium-induced contraction in isolated rabbit detrusor muscle, indicating a calcium antagonist effect. Unlike verapamil and nifedipine, terodiline showed specific calcium antagonism in bladder tissue. Terodiline exhibits local anaesthetic and spasmolytic activity which may also contribute to its overall clinical efficacy.After oral administration, terodiline is rapidly absorbed: a mean absolute bioavailability of 92% and a mean peak plasma concentration of 32 &mgr;g/L were reached 4 hours after a 12.5mg dose in healthy volunteers. Steady-state terodiline concentrations are dose related, and are achieved after 10 to 14 days of administration because of its slow elimination (mean elimination half-life is about 60 hours but this increases to about 130 hours in elderly inpatients).Terodiline is extensively metabolised, mainly via hydroxylation, with only 15% of a dose excreted unchanged in urine. The major metabolite in humans is parahydroxyterodiline; this compound is pharmacologically active but is present in small quantities only. The reduced elimination of terodiline in elderly inpatients resulting in increased serum drug levels for a given dose suggests that a reduced dosage is warranted in these patients.Therapeutic UseNoncomparative studies in patients with urge incontinence have shown that terodiline 37.5 to 50 mg/day reduces the number of day- and night-time voluntary micturitions and episodes of incontinence, and improves bladder volume at first urge and bladder capacity. These changes were noted over treatment periods of up to 3.5 years duration. Furthermore, over 70% of patients preferred terodiline therapy to the pretreatment runin period. Japanese studies have demonstrated similar benefits in patients with idiopathic or neurogenic urinary incontinence using daily doses of 24mg.Compared with placebo, terodiline consistently improves subjective and objective symptoms of urge incontinence. In the largest study, a typical 50mg daily dose administered for 8 weeks was significantly superior to placebo with regard to reducing 24-hour micturition frequency and incontinence episodes, daytime micturitions and average voided volume, and increasing bladder capacity. Similar benefits have been noted in children with diurnal enuresis treated with terodiline 25 mg/day; in children with subnormal (< 150ml) bladder capacity, terodiline resulted in an increase of 32ml, compared with 16ml with placebo.Comparative studies in adult patients with urge incontinence have shown that terodiline 50 mg/day is preferred by patients, and in most studies tended to be superior to emepronium 600 mg/day or flavoxate 600 mg/day.In the few studies that have investigated the efficacy of terodiline in patients with bladder dysfunction resulting from neurological damage, terodiline 50 mg/day (except in 1 Japanese study where 24 mg/day was used) reduced day- and night-time micturitions, and incontinence episodes, although not all improvements were significant compared with placebo.Adverse EffectsTerodiline 25mg twice daily has been generally well tolerated in clinical trials. Adverse effects are mild and transient and withdrawal from therapy is rarely required. The most frequently reported adverse events include dry mouth, blurred vision, tremor and nausea. Clinical evidence suggests that terodiline is generally well tolerated in children and in elderly patients.Dosage and AdministrationThe dosage of terodiline must be individualised. When used to treat adults with urinary incontinence the recommended initial dosage of oral terodiline is 25mg twice daily. Elderly inpatients and children should begin with 25mg daily in 2 divided doses. Dosages of 24 mg/day have been used in Japanese patients in clinical trials.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisCetirizine, a piperazine derivative and carboxylated metabolite of hydroxyzine, is a potent histamine H1-receptor antagonist with antiallergic properties. It has marked affinity for peripheral histamine H1-receptors and, at the standard dose of 10mg daily, lacks the CNS depressant effects of standard antihistamines. In addition, it inhibits histamine release and eosinophil chemotaxis during the secondary phase of the allergic response. Results from controlled clinical trials indicate that cetirizine is an effective and well tolerated treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria. Cetirizine appears to be as effective as conventional dosages of terfenadine, chlorpheniramine and hydroxyzine in relieving symptoms associated with these disorders and produces a markedly lower incidence of sedation than chlorpheniramine, hydroxyzine and several other standard antihistamines. Thus, cetirizine appears to provide a useful alternative to other ‘nonsedating’ antihistamines; cetirizine may also have a future role in the treatment of allergic asthma and certain forms of physical urticaria.Pharmacodynamic PropertiesCetirizine demonstrates similar affinity to terfenadine forin vitrobinding to peripheral histamine H1-receptors. However, it is highly selective for histamine H1-receptors, possessing less affinity than terfenadine or hydroxyzine for calcium channel receptors, adrenergic &agr;1-, dopamine D2-, serotonin 5-HT2receptors and muscarinic receptors.Standard tests of antihistaminic activity in animals have shown cetirizine to have greater potency on a weight-to-weight basis than other antihistamines such as clemastine, mepyramine, terfenadine and hydroxyzine. In human studies, suppression of the weal response to intradermally injected histamine was greater with cetirizine 10mg than with placebo, peaking at 4 to 8 hours and lasting up to 24 hours. Cetirizine 10mg had a similar potency to diphenhydramine 50mg, hydroxyzine 25mg and terfenadine 180mg, but was more potent than terfenadine 60mg with a more rapid onset and longer duration of action, more potent than loratadine 10mg, chlorpheniramine 6mg or mequitazine 5mg, and more rapid in onset than astemizole 10mg.Cetirizine 5 to 20mg also provided a dose-dependent protective effect from bronchospasm induced by inhaled histamine in asthmatics: a 20mg dose was superior in activity to hydroxyzine 25mg.Antiallergic activity has been shown in models using allergens and other inflammatory agents. Cetirizine had little effect on mast cells and the release of mediators of immediate hypersensitivity. However, eosinophil chemotaxis in response to allergens was inhibited in atopic subjects. An inhibitory effect on the responses of neutrophils and platelets in allergy has also been demonstrated in experimental models and human volunteers.In psychomotor performance studies, cetirizine 10mg did not significantly affect subjective or objective assessments of drowsiness, or objective assessments of cognitive impairment in volunteers.Pharmacokinetic PropertiesCetirizine is rapidly absorbed, reaching peak plasma concentrations of 257 &mgr;g/L within 1 hour of administration of 10mg oral doses to healthy volunteers (980 &mgr;g/L in children); AUC was 2.87 mg/L · h with this dose (6.37 mg/L · h in children). Plasma concentrations and AUC increase linearly with dose. Food does not affect the extent of absorption, but may slightly reduce the rate.The volume of distribution of cetirizine at steady-state is 30 to 40L. Animal studies indicate that peak concentrations in the brain are less than 10% of plasma concentrations.The terminal phase elimination half-life is 7 to 10 hours. Approximately 70% of a dose of cetirizine is excreted in the urine, mainly as unchanged drug, although small amounts of unidentified metabolites are found. Approximately 10% of the total dose is excreted in the faeces. The apparent total body clearance is 0.04 to 0.05 L/h/kg (0.06 to 0.07 L/h/kg in children).In patients with even mild impairment of renal function, the terminal elimination half-life of cetirizine is increased to approximately 20 hours. Half-life is also prolonged in elderly volunteers, an effect independent of ageper se, but dependent on renal function. The elimination half-life is somewhat shorter in children, being 6 to 7 hours.Therapeutic EfficacyA number of randomised double-blind studies, most placebo controlled and many crossover in design, have established the efficacy of cetirizine 5mg to 20mg daily in the treatment of seasonal and perennial allergic rhinitis, and chronic idiopathic urticaria. In addition, several reports suggest a role for cetirizine 15 to 20mg daily, administered in 2 divided doses, in the treatment of pollen-associated asthma in atopic individuals.Comparisons with other histamine H1-receptor antagonists generally indicate similar symptomatic control, as well as patient and investigator acceptance, between cetirizine 5mg to 10mg daily, terfenadine 60mg twice daily and chlorpheniramine 8mg twice daily in seasonal allergic rhinitis; cetirizine 10mg daily and terfenadine 60mg twice daily in perennial allergic rhinitis; and cetirizine 5mg to 20mg daily, terfenadine 60mg twice daily and hydroxyzine 25mg once to 3 times daily in chronic idiopathic urticaria. A single brief report indicated that cetirizine 10mg twice daily alleviated asthmatic symptoms more successfully than did terfenadine 60mg twice daily in patients with pollen-associated asthma.Adverse EffectsIn the comparative studies discussed above, the incidence of sedation and/or somnolence was generally similar between cetirizine and terfenadine, and not significantly different from that reported with placebo. In contrast, the incidence reported with chlorpheniramine 8mg twice daily in patients with seasonal allergic rhinitis, and with hydroxyzine 25mg to 75mg daily in patients with chronic idiopathic urticaria, was significantly greater than that reported with placebo. Collated results from 1502 patients who received cetirizine 10mg in double-blind placebo-controlled clinical trials conducted in Europe indicate an incidence of sedation similar to that of other ‘nonsedating’ antihistamines, such as astemizole and terfenadine, and substantially less than that with ketotifen, clemastine, chlorpheniramine or mequitazine. In these collated results, there was no significant difference between cetirizine and placebo treatment in the incidence of headache, gastrointestinal disturbance, anticholinergic effects, dizziness or cardiovascular effects.Dosage and AdministrationThe recommended dosage of cetirizine in adults and children over the age of 12 is one 10mg tablet daily (Europe) or one 5 or 10mg tablet daily, up to a maximum of 20mg once daily (USA and Canada). In the elderly and in patients with even a mild degree of renal impairment dosage should be reduced.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS