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:

The currently available, most frequently used disease-modifying antirheumatic drugs (DMARDs) include auranofin, azathioprine. D-penicillamine, gold sodium thiomalate, hydroxychloroquine, methotrexate (amethopterin) and sulphasalazine. Controlled trials of these agents are reviewed to compare their relative efficacy and tolerability.Tender joint counts decreased with all drugs, as did joint swelling (measured as the percentage of patients with ≥ 50% improvement in joint swelling). Tender joint count decreased by 8 to 57% in drug-treated patients, compared with 3 to 30% (1 study exceeded this degree of placebo response) in the placebo groups. The ratio of drug to placebo improvement usually averaged greater than 2. A 50% improvement in joint swelling occurred in between 15 and 65% of drug-treated patients. Time to onset of response varied from 6 weeks (with methotrexate) to as long as 18 months (some patients on hydroxychloroquine). The remission rate was inconsistent and unusual in controlled studies (5 to 7%), but very high in some open studies (e.g. 43%). While up to 8% of patients on DMARDs stopped therapy secondary to unsatisfactory therapeutic response (with 1 exception) up to 43% of placebo patients discontinued therapy for this reason. The ratio of dropouts for unsatisfactory therapeutic response for DMARD compared to placebo was less than 1 in 16 of 22 studies, and it was usually less than 0.5.Laboratory data examined include ESR, rheumatoid factor (RF), immunoglobulins and radiographic data. Ratios of decreases in ESR, comparing drug and placebo, were usually greater than 2. ESRs decreased from 3.6 to 27 mm/h, with gold sodium thiomalate, auranofin and methotrexate being most effective relative to placebo. RF decreased by ≥ 2 tube dilutions in 15 to 53% of the DMARD groups but also decreased in up to 26% of placebo patients, with ratios of drug: placebo usually greater than 2. Immunoglobulins tended to decrease with DMARDs but the data are fragmentary.Radiographic evidence that a drug slows the rate of bony damage is strong evidence that it is a DMARD. These data, however, are not easily available because measurement of bony damage is insensitive and difficult. The best evidence of radiographic efficacy exists for gold, although the data are not uniform even here. Studies with other DMARDs suffer from lack of convincing control populations, methodological failures or small numbers, although trends exist showing that azathioprine and D-penicillamine (and perhaps sulphasalazine and methotrexate) may also slow bony deterioration.The other side of efficacy, of course, is tolerability. By examining dropouts resulting from adverse effects, it was discovered that hydroxychloroquine, sulphasalazine and auranofin were the best tolerated DMARDs, while D-penicillamine appeared most toxic. Finally, a clinically reasonable, although not scientifically or statistically exact, method for comparing DMARDs was developed. This approach was developeda prioriand resulted in the following conclusions: (a) for efficacy, gold sodium thiomalate and methotrexate were generally equivalent, D-penicillamine and azathioprine were marginally less effective, and hydroxychloroquine, sulphasalazine and auranofin were equal and less effective than the others; (b) on the other hand, hydroxychloroquine, azathioprine and methotrexate caused the least dropouts due to adverse reactions during these 6- to 12-month studies, while auranofin and sulphasalazine were equal and slightly less well tolerated; D-penicillamine and gold sodium thiomalate were most toxic.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Vasopressin is a potent vasoconstrictor which greatly reduces mesenteric blood flow. In patients with portal hypertension this results in decreased portal venous flow and portal pressure. Because of this property, vasopressin has been used for years in the therapy of variceal haemorrhage. A few controlled trials show that vasopressin causes a decrease in bleeding but has no effect on survival. It has been shown that intravenous vasopressin is just as effective as intra-arterial, and is associated with fewer complications.The inability to influence the outcome of variceal haemorrhage significantly may be related to suboptimal dosing due to the occurrence of systemic complications at higher doses. The combination of vasopressin with either sodium nitroprusside or nitroglycerin (glyceryl trinitrate) has resulted in a further decline of portal pressure, along with amelioration of most of the adverse haemodynamic effects of vasopressin. Whether or not clinical efficacy is increased when vasopressin is combined with sodium nitroprusside or nitroglycerin remains to be proven.Analogues of vasopressin, such as terlipressin, held early promise as agents which would be as effective as vasopressin, without the cardiac adverse effects. Recent data have not supported this and at present there is little to suggest any advantage of terli-pressin over vasopressin.Virtually no adequate studies have yet been performed to support the use of vasopressin in the treatment of non-variceal haemorrhages. There is reason to suspect that vasopressin can effectively control bleeding from haemorrhagic gastritis, but the subsequent results of inducing gastric ischaemia in an already damaged gastric mucosa are unknown.In summary, vasopressin appears to have little effect on the mortality of patients with variceal haemorrhage. It may, however, help control the haemorrhage in some patients by lowering the portal pressure. Cardiovascular complications limit the dose that can be used but it is hoped that by combining vasopressin with nitroglycerin, a more effective and safe therapy will be available for variceal haemorrhages.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

A number of diseases can cause recurrent intraoral ulceration. This review focuses principally on drug management of intraoral ulceration associated with local and systemic conditions most likely to be observed on an outpatient basis by the general practitioner. These consist of recurrent aphthous stomatitis, erosive lichen planus, benign mucous membrane pemphigoid (BMMP), erythema multiforme, Behcet's disease, allergic stomatitis and infection. Information is provided on a spectrum of medication found useful in ulcer management, including topical antimicrobial and antifungal agents, topical and systemic corticosteroids, topical and systemic analgesics, and systemic immunosuppressive and anxiolytic drugs, plus details of dosage, important adverse reactions and interactions. A treatment guide for management of recurrent aphthae is presented. The reader is presumed to be familiar with differential diagnosis and the importance of establishing an accurate impression before starting drug therapy.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Myasthenia gravis is an autoimmune disorder in which neuromuscular transmission is impaired by autoantibodies to the acetylcholine receptor (AChR). There are 3 varieties of generalised myasthenia with differing genetic susceptibilities. There is also a purely ocular form in which the weakness is confined to the extraocular muscles, and a neonatal variety which occurs in 20% of babies born to myasthenic mothers due to transplacental passage of the acetylcholine receptor antibody. Another variety of myasthenia occurs several months after treatment with D-penicillamine.The role of the thymus is suggested by abnormal histology in patients with myasthenia and by the beneficial effects of thymectomy in more than two-thirds of patients. Thymectomy is indicated in most patients unless the symptoms are minimal or the weakness is confined to the extraocular muscles.Most patients require treatment with anticholinesterase drugs to prolong the action of acetylcholine at the muscle end-plate. Overdosage of these drugs can provoke a cholinergic weakness.Remissions can be achieved with corticosteroids in 80% of patients. Immunosuppression with azathioprine is used mainly in patients who do not respond to thymectomy or in those patients who are considered unsuitable for operation. Plasma exchange can cause a rapid but temporary improvement in myasthenia, and has no long term place in its treatment.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Many drugs have been used in treating patients with postural hypotension but for a large number the evidence of benefit is small and the potential for adverse effects, particularly supine hypertension, is great. Full clinical assessment is essential at the outset to define the nature and extent of pathophysiological disturbance of autonomic function. Many patients can be treated adequately by sleeping with the head of the bed elevated, and the use of fludrocortisone. Patients without evidence of central neurological deficit may benefit from additional treatment with drugs which alter &bgr;-adrenoceptor tone. Patients who respond poorly to these measures should be admitted to hospital, and treatment with desmopressin initiated. Symptomatic postprandial hypotension should be identified early since the response to these measures alone is often poor; caffeine administered before eating, with abstinence for the rest of the day, may be very helpful.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisKetorolac is a non-steroidal agent with potent analgesic and moderate anti-inflammatory activity. It is administered as the tromethamine salt orally, intramuscularly, intravenously, and as a topical ophthalmic solution. Clinical studies indicate single-dose efficacy greater than that of morphine, pethidine (meperidine) and pentazocine in moderate to severe postoperative pain, with some evidence of a more favourable adverse effect profile than morphine or pethidine. In single-dose studies ketorolac has also compared favourably with aspirin, paracetamol (acetaminophen) and a few other non-steroidal anti-inflammatory drugs. If further investigation confirms the initially favourable findings regarding efficacy and tolerability, ketorolac will be a useful alternative to opioid agents in postsurgical pain. It may well also find use in acute musculoskeletal pain, where it appears at least as effective as other agents with which it has been compared. From the limited clinical data available, ketorolac also seems promising in the treatment of ocular inflammatory conditions. Additional multiple-dose studies are required to evaluate fully the potential of ketorolac in the management of chronic pain states where it has shown superior efficacy to aspirin.In summary, ketorolac offers promise as an alternative to opioid and to other non-steroidal analgesics in ameliorating moderate to severe postsurgical pain, and with wider clinical experience may find a place in the treatment of acute musculoskeletal and other pain states, and ocular inflammatory conditions.Pharmacodynamic StudiesKetorolac, in common with other non-steroidal anti-inflammatory drugs, is an inhibitor of prostaglandin synthesis. However, it possesses greater systemic analgesic than anti-inflammatory potency. In standard animal models of analgesic activity, ketorolac has exhibited up to 800 times the potency of aspirin (weight for weight). In all assays ketorolac was also more potent than indomethacin and naproxen, and demonstrated equal or greater potency than phenylbutazone. Animal models of systemic anti-inflam-matory activity have provided less consistent indications of the relative potency of ketorolac: ID50was 0.35 mg/kg in one assay, and intermediate between that of indomethacin and naproxen, while other assays indicate anti-inflammatory activity equal to or greater than that of indomethacin, greater than that of naproxen, and much greater than that of phenylbutazone. Tests of ocular anti-inflammatory activity indicate significant potency without exacerbation of underlying ocular infection. Antipyretic activity of ketorolac in rats was greater than that of aspirin and phenylbutazone, and equal to that of indomethacin and naproxen. Ketorolac appears to inhibit platelet aggregation induced by arachidonic acid and collagen, but not that induced by adenosine diphosphate (ADP), and to prolong mean bleeding time.Pharmacokinetic PropertiesThe single-dose pharmacokinetic properties of ketorolac have been investigated in several studies, but its pharmacokinetic properties after multiple doses have been less well studied.Ketorolac is rapidly absorbed, with a time to maximal plasma concentration (tmax) of as early as 30 to 40 minutes after oral administration to healthy volunteers, and of 45 to 50 minutes after intramuscular administration. The systemic availability of ketorolac is approximately 80% after oral administration. Food appears to reduce the rate. but not the extent, of absorption. Ketorolac is almost totally bound to plasma proteins. In healthy subjects, its apparent volume of distribution is 0.25 L/kg or less, its plasma clearance 0.021 to 0.037 L/h/kg, and terminal elimination half-life 4 to 6 hours. Ketorolac appears to cross the placenta, to the extent of approximately 10%, but is not found in breast milk in significant amounts.The major metabolic pathway in humans is glucuronic acid conjugation. Approximately 90% of the dose is recovered in urine, with the remainder in faeces. Preliminary studies report the percentage of the dose excreted as unchanged ketorolac to be approximately 60%.The rate of elimination of ketorolac appears to be reduced in the elderly and in patients with renal impairment, with plasma clearance reduced and elimination half-life prolonged. The influence of hepatic disease on the pharmacokinetics of ketorolac requires further investigation, but it seems that any alteration is unlikely to be clinically significant.Therapeutic TrialsKetorolac has been studied in a number of single-dose trials in patients with moderate to severe postsurgical pain. Ketorolac, usually 30 to 90mg intramuscularly, has shown analgesic efficacy superior to that of the opioid analgesics morphine (6 to 12mg), pethidine (meperidine) [50 and 100mg], pentazocine 30mg and ketobemidone. The lower 10mg dose of ketorolac is at least as effective as the opioid analgesics. A multiple-dose study showed ketorolac 30mg to be equivalent to morphine 12mg and superior to morphine 6mg when administered for up to 5 days.Similarly, the single-dose efficacy of ketorolac 5 to 30mg orally appeared equal or superior to that of aspirin 650mg, paracetamol (acetaminophen) 500 to 1000mg, glafenine 400mg and naproxen 550mg after major surgery. Ketorolac 10 or 20mg was superior to aspirin 650mg, paracetamol 500mg and ibuprofen 400mg in alleviating pain associated with oral surgery. A 5-day multiple-dose study which compared oral ketorolac 20 or 40mg daily with diflunisal 1000mg daily found ketorolac superior to placebo in the acute post-operative phase. However, no significant difference in pain relief between the active treatments or placebo was observed during the chronic phase of the study. Additionally, no differences in efficacy were found between ketorolac 10 or 20mg, aspirin 650mg, para-cetamol 500mg and ibuprofen 400mg when assessed on a repeated-dose basis.There have been a small number of single-dose comparisons of ketorolac with combinations of opioid and non-steroidal or simple analgesics, and in these studies ketorolac 20mg has demonstrated efficacy equal to or greater than that of either aspirin or para-cetamol plus codeine. A multiple-dose trial comparing ketorolac 10mg with paracetamol 1000mg + codeine 60mg up to 4 times daily showed both treatments to be similar in relieving pain. No differences in efficacy were found between ketorolac 10mg, dihydrocodeine 30mg or placebo, and repeated doses of ketorolac were equivalent to pentazocine 100mg.Oral ketoroloc 10mg 4 times daily for up to 7 days tended to relieve acute musculoskeletal pain better than ibuprofen 400mg, paracetamol 600mg + codeine 60mg or floctafenine 200mg in similar regimens, and was superior to diflunisal 500mg twice daily, Efficacy of ketorolac in other pain states, such as postpartum or labour pain, cancer pain, sciatica, renal colic or post-traumatic pain has not been fully investigated, although several preliminary single-dose or repeated dose comparisons with non-steroidal or opioid analgesics have been conducted. The limited experience with ketorolac in these indications at present does not permit any conclusions to be drawn regarding its efficacy.Ketorolac 10mg up to 4 times daily appears superior to aspirin 650mg in the same regimen in chronic pain (mostly osteoarthritis), as evidenced by a multicentre trial in more than 800 patients.In several studies of ketorolac ophthalmic solution administered after cataract surgery, marked anti-inflammatory efficacy was apparent in comparison with placebo and with dexamethasone. A further trial of ketorolac solution in cystoid macular oedema also indicated a potential role for ketorolac in this condition.Adverse EffectsThe overall incidence of adverse effects in published studies employing single intra-muscular doses of ketorolac 10 to 90mg has ranged from 17 to 41%, in comparison with 17 to 62% for morphine 6 to 12mg, and 59% for pethidine 50 and 100mg. In a 5-day trial of oral ketorolac 20 to 40mg daily, the incidence of adverse effects was approximately twice that observed with placebo. Single-dose comparison of oral ketorolac with para-cetamol has indicated a lower incidence of adverse effects overall with ketorolac (30 to 40% compared with 50 to 57%). Nausea and hedache were the unwanted effects most frequently reported by patients receiving ketorolac.Overall, oral and intramuscular ketorolac would appear to be at least as well tolerated as alternative analgesics used to treat moderate to severe pain. Adverse effects reported after multiple intramuscular doses of ketorolac include somnolence (7%), injection site pain (2%), increased sweating (1%) and nausea (1%). Headache, dizziness, vomiting, pruritus, vasodilatation, and dysgeusia have also been reported, each with an incidence of less than 1%. Similarly, after oral ketorolac 10mg 4 times daily for up to 10 days post-operatively, adverse events reported to occur with a probable causal relationship to treatment included: somnolence (4% incidence); nausea, gastrointestinal pain, dyspepsia, diarrhoea, headache, or dizziness (each 2% incidence); constipation, nervousness, dry mouth, increased sweating, abnormal dreams, hyperkinaesia, myalgia, asthenia, or palpitations (1% each event). The only adverse effects which appear to increase with time (after 30 mg/day for up to 1 year in patients with chronic pain) include gastrointestinal pain (12%), dyspepsia (11%), and nausea (7%).Dosage and AdministrationIn postoperative pain, single intramuscular doses of 10 to 90mg, and oral doses of 5 to 30mg, have usually been employed. A 4-times-daily regimen for longer term administration has been used. Ketorolac has also been administered topically in ocular inflammatory conditions in a 0.5% solution 3 or 4 times daily. It appears that systemic dosage should be reduced in the elderly and in patients with renal impairment; it is unclear whether hepatic disease necessitates dosage reduction.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisRamipril is a long acting angiotensin converting enzyme (ACE) inhibitor, which exhibits similar pharmacodynamic properties to captopril and enalapril. Like enalapril it is a prodrug, which is hydrolysed after absorption to form the active metabolite ramiprilat which has a long elimination half-life, permitting once daily administration. In hypertensive patients daily doses in the range 2.5 to 20mg are usually effective in reducing high blood pressure and maintaining satisfactory control during long term treatment. Patients who do not respond adequately to monotherapy with ramipril usually respond with the addition of a diuretic such as hydrochlorothiazide or piretanide. Ramipril 5 to 10mg once daily shows comparable antihypertensive efficacy to usual therapeutic dosages of captopril, enalapril and atenolol in patients with mild to moderate essential hypertension. Preliminary data indicate that ramipril may be effective in indications such as severe essential hypertension and renal hypertension. It has also displayed beneficial effects in patients with moderate to severe congestive heart failure. Ramipril has been well tolerated and exhibits an adverse effect profile typical of ACE inhibitors as a class.In conclusion, ramipril will likely represent a useful alternative ACE inhibitor for use in patients with hypertension or congestive heart failure.Pharmacodynamic StudiesRamipril is a prodrug which is hydrolysed after absorption to form the active angiotensin converting enzyme (ACE) inhibitor ramiprilat. Ramiprilat decreases plasma levels of angiotensin II and aldosterone and potentiates the effects of bradykinin. Most data support the hypothesis that the beneficial haemodynamic effects of ramipril are caused by ACE inhibition and the consequent reduction in angiotensin II, which either directly or indirectly results in dilatation of peripheral vessels and reduces vascular resistance. Cumulating evidence suggests that tissue ACE, particularly in the vasculature, rather than circulating ACE, is the primary target determining the haemodynamic effects.Ramipril is effective in lowering blood pressure in animal models of hypertension which are both renin-dependent and independent. The drug had little or no effect on blood pressure or heart rate in healthy human subjects, In patients with essential hypertension, single oral doses of ramipril 10 to 20mg reduced both supine and standing systolic and diastolic blood pressure maximally by 15 to 20% after about 4 hours, and the effects lasted for up to 48 hours. Heart rate was not significantly changed by single-dose or long term administration of ramipril in patients with hypertension. Prolonged treatment with ramipril caused a reversal of left ventricular hypertrophy in hypertensive patients without any deterioration of pump function.Animal studies have shown that ramipril improves cardiac function and metabolism, and exerts beneficial haemodynamic changes (improved preload and afterload) in acute ischaemic left ventricular failure. Beneficial acute haemodynamic effects were seen after oral administration of ramipril 5 to 20mg in patients with congestive heart failure. There was a reduction in peripheral resistance and mean arterial pressure, associated with a reduction in filling pressure (measured as pulmonary capillary wedge pressure and pulmonary artery pressure), and accompanied by increased cardiac output. There was only a slight effect on heart rate. Severe first-dose hypotension may occur with high doses.In healthy subjects and patients with hypertension single or repeated doses of ramipril had no significant effect on the excretion and plasma levels of sodium, potassium, urea and creatinine, but renal plasma flow was increased.Pharmacokinetic StudiesRamipril was designed as a prodrug to improve the systemic availability of the active ACE inhibitor ramiprilat, which is poorly absorbed in humans. About 60% of an oral dose of ramipril is absorbed in healthy subjects, and peak serum concentrations of ramipril are reached in about 1 hour. Ramipril undergoes de-esterification in the liver to form ramiprilat, which reaches peak serum concentrations about 3 hours after ramipril administration. Studies have shown the maximum serum concentration of ramiprilat to be directly related to dose, and absorption of the drug unaffected by coadministration with food. Ramipril and ramiprilat were shown to be about 73% and 56% protein bound, respectively. About 60% and 40% of a dose of radiolabelled ramipril were recovered in urine and faeces, respectively. The latter may represent both biliary excretion of metabolites and unabsorbed ramipril. The majority of renal excretion is accounted for by ramiprilat and its glucuronide conjugate. However, both ramipril and ramiprilat are metabolised to inactive diketopiperazine derivatives which are excreted in significant quantities in urine. The respective mean renal clearances of ramipril and ramiprilat were about 10 and 100 ml/min. Ramiprilat had polyphasic elimination kinetics: the half-life during the major distribution/elimination phase ranged between 1.1 and 4.5 hours. A prolonged terminal phase of elimination measured in days probably represents tight, saturable binding of ramiprilat to circulating ACE. Increased age and impaired renal function may decrease the urinary excretion of ramipril and its metabolites. Impaired hepatic function appears to result in increased maximum plasma ramipril concentrations and no change in those of ramiprilat, apart from a delay in reaching this parameter.Therapeutic TrialsDose-finding and placebo-controlled studies in patients with mild to moderate essential hypertension show that oral administration of ramipril 1.25 to 10mg once daily reduces supine or standing systolic and diastolic blood pressure by about 5 to 15%, with an adequate pressure control being achieved in about 50 to 70% of patients. The drug's efficacy is well maintained during 2 years of therapy at maintenance dosages of 2.5 or 5mg daily in the majority of patients. In mild to moderate essential hypertension, the antihypertensive efficacy of ramipril 10mg once daily was comparable to that of atenolol 100mg once daily and captopril 50mg twice daily, and ramipril 5 to 10mg once daily was comparable to enalapril 10 to 20mg once daily.The majority of patients who do not respond with an adequate reduction of blood pressure on ramipril monotherapy may be expected to achieve an adequate pressure reduction with the addition of hydrochlorothiazide or piretanide. Ramipril appears to be a suitable antihypertensive agent for use in patients with concomitant renal impairment or diabetes.In patients with moderate to severe congestive heart failure, ramipril has shown beneficial effects on relevant cardiovascular parameters. The drug may also be useful in other indications where ACE inhibitor therapy has proven effective, such as severe essential hypertension and renal hypertension.Adverse EffectsRamipril has been well tolerated, with a low incidence of adverse effects in clinical trials and during maintenance therapy for up to 1 year. Adverse effects were generally mild and transient, and only rarely severe enough to necessitate withdrawal of the drug. The nature, severity and frequency of adverse effects have been similar to those of captopril and enalapril. Dizziness/vertigo (3.4%), headache (3.2%), fatigue/weakness (1.9%) and nausea (1.7%) were the most frequently reported effects in clinical trials of ramipril. Of the class-specific adverse effects associated with ACE inhibitors, cough (0.9%), rash (0.6%), hypotension (0.4%), pruritus (0.3%), taste disturbance (0.1%) and angioneurotic oedema (0.05%) have been infrequently reported with ramipril. The available data indicate that ramipril possesses an adverse effect profile which is considered specific to ACE inhibitors.Dosage and AdministrationThe usual effective dosage range of ramipril in clinical trials of patients with mild to moderate essential hypertension has been 2.5 to 10mg once daily. In patients with congestive heart failure a starting dose of 1.25mg should be used to avoid the possibility of first-dose hypotension, and a lower daily dosage than used in hypertension would generally be expected to achieve maximum effects. The dosage of ramipril should be reduced in patients with renal insufficiency (creatinine clearance < 30 ml/min).

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisDuring the 20 years that have elapsed since clomipramine (chlorimipramine) was first marketed, it has become well established in the treatment of depressive illness, particularly treatment-resistant depression. However, in addition to its role as an antidepressant, attention is being focussed on the use of clomipramine in 2 other areas of psychiatry: obsessive compulsive disorder and panic disorder.Short term clinical trials have shown that clomipramine is generally more effective than amitriptyline, imipramine, desipramine, nortriptyline or clorgiline in reducing obsessive compulsive symptoms. Clomipramine appears to produce some short term benefit with exposure therapy in patients with obsessive compulsive disorder. However, the efficacy of the drug after long term follow-up has not been fully investigated. The antiobsessional efficacy of clomipramine appears to be independent of its antidepressant activity.In patients with panic disorder with or without agoraphobia (DSM-IIIR), clomipramine reduces the frequency and severity of panic attacks within 7 to 21 days of beginning treatment and efficacy is maintained for at least 12 months. Clomipramine is more effective than imipramine, the generally accepted standard treatment for patients with panic disorder after 2 weeks' treatment, but after 6 or 10 weeks both drugs are similarly effective. Other double-blind studies have shown that clomipramine is more effective than placebo and at least as effective as fluvoxamine and oxitriptan (5-hydroxytryptophan) in reducing panic attacks and associated anxiety.Adverse effects associated with clomipramine treatment are mild to moderate in nature and are predominantly a result of the drug's anticholinergic activity. The incidence of seizures is dose related, occurring in 0.48% of all patients receiving clomipramine ≥ 250 mg/day and 2.1% of patients receiving ≥ 300 mg/day.In conclusion, the available data indicate that clomipramine is a worthwhile addition to the limited treatments available for obsessive compulsive disorder and panic disorder, two psychiatric disorders which have previously been difficult to manage pharmacologically.Pharmacological PropertiesClomipramine is a potent inhibitor of serotonin (5-hydroxytryptamine) reuptakein vitro. In vivoadministration of the drug markedly reduces serotonin and 5-hydroxyin-doleacetic acid levels in cerebrospinal fluid and platelets from patients with depression or obsessive compulsive disorder. Receptor binding studies have shown that clomipramine has affinity for central dopamine-D2, histamine-H1, and &agr;1-adrenergic receptors, but the relevance of these findings to the pharmacological profile of the drug remains to be clarified. Clomipramine also has anticholinergic activityin vitroandin vivoand increases plasma prolactin levels in depressed patients. These effects may be responsible for some of the adverse effects associated with clomipramine treatment.Oral clomipramine is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of 41 to 81 &mgr;g/L are reached within 2 to 4 hours of a single oral 1 mg/kg dose in healthy volunteers. Steady-state plasma clomipramine concentrations of 20 to 275 &mgr;g/L were achieved within 7 to 14 days of oral clomipramine 100 to 200 mg/day in patients with depression or obsessive compulsive disorder. Steady-state plasma demethylclomipramine concentrations are generally higher, but reached later, than those of the parent drug. Most studies in patients with depression or obsessive compulsive disorder have failed to show a relationship between plasma clomipramine or demethylclomipramine concentrations and clinical response, but in 1 study an optimal therapeutic response was reported in patients with obsessive compulsive disorder with a plasma clomipramine concentration of 100 to 250 &mgr;g/L.Clomipramine is 98% bound to plasma protein and, because of its highly lipophilic nature, the drug would be expected to have a large volume of distribution.Only 1 to 3% of an oral or intravenous clomipramine dose is excreted unchanged. About 60% is excreted as urinary metabolites and about 30% is excreted via faeces. Demethylation is the major metabolic pathway but hydroxylation andN-oxidation also occur. Clomipramine undergoes extensive first-pass hepatic elimination after oral administration. Mean plasma elimination half-lives for clomipramine are 20 to 26 hours in healthy volunteers and 34 to 36 hours in depressed patients. Demethylclomipramine has an elimination half-life of 50 hours in depressed patients.Therapeutic UseDouble-blind studies spanning 5 to 16 weeks have shown the superiority of oral clomipramine in daily doses of 50 to 300 mg/day over placebo in reducing obsessive and compulsive symptoms. In one study, about three-quarters of children, previously unresponsive to other drug therapies, showed at least 25% improvement on the Obsessive Compulsive Rating scale. Similarly, in adult patients a superior effect over placebo was evident after 3 weeks of treatment and this persisted for up to 16 weeks. Data from 2 large multicentre studies have shown a mean improvement of 40 to 45% in obsessive compulsive symptoms after 10 weeks compared with 4 to 5% in patients administered placebo.Several studies have shown that clomipramine has a more pronounced effect on obsessive compulsive symptoms than desipramine, imipramine, amitriptyline, nortriptyline, or clorgiline. Generally, the superiority of clomipramine is evident 3 to 6 weeks after initiation of treatment and withdrawal of clomipramine treatment results in relapse within 3 days. Clomipramine reduced depressive symptoms occurring secondary to obsessive compulsive disorder to a greater extent than other antidepressants but in most comparative studies no significant correlation was seen between the antiobsessional and anti-depressant effects of clomipramine or between improvement in obsessive compulsive symptoms and initial severity of depression. The antiobsessional effect of clomipramine therefore appears independent of its antidepressant activity.Clomipramine appears to produce some short term benefit with exposure therapy in patients with obsessive compulsive disorder. However, the short term benefit of clomipramine was not apparent following change of exposure therapy in the longer term.In the treatment of panic disorder with or without agoraphobia (DSM-IIIR), non-comparative studies have shown that clomipramine resolves panic attacks in at least 75% of patients after 7 to 21 days of treatment and efficacy is maintained for at least 12 months. Clomipramine was as effective as imipramine after 6 to 10 weeks but, unlike imipramine, the efficacy of clomipramine was evident after only 2 weeks of treatment. Clomipramine was also comparable to fluvoxamine and superior to placebo and oxitriptan (5-hydroxytryptophan) in reducing anxiety symptoms, and had a superior effect on reducing associated depression in these patients.Adverse EffectsMost of the adverse effects associated with clomipramine treatment are extensions of its pharmacological properties, particularly its anticholinergic effects. The most frequently reported adverse effects associated with clomipramine therapy as reported in clinical studies up to 1988 are anticholinergic effects (43%), central nervous system effects (25%), gastrointestinal effects (10.5%), sexual dysfunction (8%), tremor (6%), cardiovascular effects (3%), and sleep disturbances (1.5%). The adverse effect profile in patients with obsessive compulsive disorder follows a similar pattern: in a study of 150 patients, the most common adverse effects were dry mouth (53%), excessive sweating (19%) and constipation (20%).The incidence of clomipramine-induced seizures appears to be dose-related: seizures were reported in 0.48% of patients (n = 2514) treated with a maximum dose of 250 mg/day and in 2.1% of patients (n = 472) treated with 300 mg/day or above.Clomipramine has a lower fatal toxicity index (defined as deaths per million pre-scriptions) after overdose than other tricyclic antidepressants. The incidence of overdose with clomipramine has not been reported, but fatalities have occurred.Dosage and AdministrationFor the treatment of obsessive compulsive disorder oral clomipramine administration should start at 25mg 2 or 3 times daily, before titrating up to a maximum of 250 mg/day. The usual maintenance dosage is 50 to 100 mg/day. Parenteral clomipramine should be administered as a 25 to 50 mg/day intramuscular dose or a 50 to 75mg infusion. Maintenance therapy with oral clomipramine can be substituted once clinical improvement has been achieved. In patients with panic disorder or agoraphobia with panic attacks, a low initial dosage (10 mg/day) is recommended. This should be increased gradually until an effective dosage (generally 50 to 100 mg/day) is achieved. The maintenance dosage is usually 25 mg/day or less.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS