ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Non-insulin-dependent diabetes mellitus (NIDDM) is being increasingly diagnosed as its importance as a risk factor for the development of cardiovascular disease continues to be recognised. Good metabolic control remains a major goal of drug therapy as it decreases the severity and incidence of diabetic complications. Many drugs have been known to interfere with glucose control, either in a beneficial or, more commonly, in a deleterious fashion. Unfortunately in many instances drug-induced effects have not been looked at specifically in NIDDM.Thiazide diuretics have been shown to cause a deterioration in glucose control not only in the general population but especially in patients who have impaired glucose tolerance. While the effect appears less with potassium supplementation and the lower dosage employed nowadays, thiazide diuretics are best avoided in diabetic patients. Loop diuretics have been reported to reduce glucose control to a lesser extent than thiazides. Although indapamide would appear not to interfere with blood sugar control in NIDDM, higher doses that cause potassium loss may cause a deterioration.&bgr;-Adrenoceptor antagonists have been reported to cause a rise in blood sugar and glycosylated haemoglobin in NIDDM. The effect may be more marked in patients on oral hypoglycaemic agents as opposed to diet alone and in those on concomitant thiazide diuretics. The greatest effect was seen with propranolol, and the least with cardioselective and the less lipophilic &bgr;-blockers. It is of interest that &agr;-blockade with prazosin seems to antagonise &bgr;-adrenoceptor blocker-induced deterioration in glucose control.The calcium antagonists have differing effects which may be structure related. In some, but not all, studies use of the dihydropyridines such as nifedipine has been associated with a deterioration in glucose control in NIDDM. Long term studies are needed to assess definitively their effect on glucose control. Verapamil, on the other hand, has in 1 small study been found to have a beneficial effect on glucose control in NIDDM.Centrally acting &agr;-agonists such as the antihypertensive drug clonidine have not been shown to result in a deterioration in glucose control when used in NIDDM, although there are isolated case reports. Long term therapy with the more specific agonist guanfacine was reported in 1 uncontrolled study to have a beneficial effect on glucose tolerance in NIDDM. Uncontrolled studies suggest that phenothiazines may aggravate diabetic control.The significance of a number of recent observations is not fully clear. The balance of endogenous opioid influences over pancreatic &bgr;-cell function in NIDDM patients favours the inhibitory effects ofmet-enkephalin, and the opiate antagonist naloxone partially restores the acute insulin response to glucose. Aspirin appears to have a dual effect in NIDDM - decreased insulin clearance and tissue sensitivity - with no resultant overall change in glucose levels.There are also a number of drugs that may improve glucose tolerance in NIDDM. A number of studies have reported a fall in glycosylated haemoglobin and 2-hour plasma glucose during treatment with the angiotensin converting enzyme (ACE) inhibitors captopril (post glucose load) and enalapril (postprandial), although the effect is relatively small and nonsignificant in some studies. There are also reports of a reduction in fasting plasma glucose and insulin levels during treatment with the lipid-lowering fibric acid derivatives (clofibrate, bezafibrate and fenofibrate) and possibly nicotinic acid derivatives, suggesting increased tissue sensitivity to insulin. The effect was not seen with gemfibrozil and other lipid-lowering agents.Mebendazole, through insulin secretion, and chloroquine, through reduced hepatic degradation of insulin, have been shown in 2 small studies to improve glucose tolerance in NIDDM. While induction of hepatic drug metabolising enzyme activity has been advanced as a means of improving glucose control, possibly through enhanced peripheral glucose utilisation, studies to date in NIDDM have produced contradictory results. A number of uncontrolled studies suggest that both monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants may improve glucose tolerance.Close monitoring of glucose and glycosylated haemoglobin is recommended where the abovementioned drugs are used in NIDDM. There is evidence that possible effects of new drugs in NIDDM are being recognised increasingly as a requirement in new drug development, particularly with cardiovascular agents.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Renal disease is common in patients with systemic lupus erythematosus and may run an extremely variable course. Specific therapy is not necessary in patients with mild kidney involvement but a careful surveillance is needed to recognise possible transfor-mations to more severe disease classifications or flare-ups. Vigorous treatment must be started early in patients with nephritic syndrome and/or active lesions at renal biopsy, i.e. glomerular cell proliferation, necrosis and inflammation. Corticosteroids remain the cornerstone for treating lupus nephritis. However, every attempt should be made to minimise their possible toxic effects.A short course of intravenous high-dose methylprednisolone followed by moderate doses of prednisone is a relatively nontoxic regimen which is generally effective in reversing the flare-ups of the disease. Once the activity is quenched the maintenance dosage of steroids should be reduced to the lowest possible dose, trying to switch the patient to an alternate-day regimen whenever possible. In patients with persisting activity the administration of a cytotoxic agent may obviate the need for protracted high-dose corticotherapy. Intermittent intravenous cyclophosphamide pulses may be considered in nonresponding patients. Other approaches, with cyclosporin, lymphoid irradiation, etc. although promising, are still preliminary. Although we are still far from an optimal treatment of lupus nephritis, the refined use of corticosteroid and cytotoxic agents and a careful monitoring of patients may allow excellent patient and kidney survival rates for 10 or more years.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisIsradipine, a dihydropyridine derivative, inhibits the inward calcium flux through ‘slow’ channels of cardiac and vascular tissue, thereby eliciting potent coronary, cerebral and peripheral vasodilatation. In comparison with other calcium channel blockers the drug offers the advantages of minimal cardiodepressant activity, a selective action on the coronary and skeletal muscle vasculature, and a prolonged vasodilatory action. Clinical trials indicate that isradipine is an effective antihypertensive agent, suitable as monotherapy or in combination with &bgr;-blockers, diuretics or ACE inhibitors, for long term treatment of mild to moderate hypertension. Preliminary findings suggest that the drug has a potential role in the treatment of chronic stable angina and, possibly, congestive heart failure. Adverse effects associated with the vasodilatory action of isradipine are generally mild, transient and well-tolerated, and are similar to those encountered with other calcium channel blockers. Thus, isradipine appears to offer a useful alternative to other dihydropyridine derivatives currently employed for the treatment of mild to moderate hypertension and, to a lesser extent, chronic stable angina. While its relative freedom from serious adverse effects may prove of value, its place in therapyvis-à-visthe established calcium channel blockers requires further clarification.Pharmacodynamic PropertiesIsradipine, in common with other calcium channel blockers, produces preferential blockade of voltage-operated calcium channels, thereby inhibiting the ‘slow’ channel influx of calcium into cardiac and vascular tissue. Its high degree of selectivity for coronary, cerebral and skeletal muscle vasculature confers potent vasodilatory activity, particularly on the arterial side of the circulation, and accounts for the drug's pronounced antihyper-tensive action.In vitroanimal studies indicate that isradipine has a selective depressant effect on sinoatrial node automaticity, a less pronounced inhibitory action on atrioven-tricular node conduction and no effect on intraventricular conduction, while its negative inotropic actions are manifest at substantially higher concentrations than its electrophysiological actions. In humans, isradipine has minimal depressant activity on sinoatrial node automaticity and negligible negative chronotropic, dromotropic and inotropic actions.In vitroinvestigations in animal tissues indicate that, of the calcium channel blockers, isradipine is inferior only to nifedipine and darodipine in its coronary vasodilator potency, while its selectivity for coronary over cardiac tissues is more marked than that of nicardipine, nisoldipine, nimodipine and darodipine. Similarly, isradipine shows marked selectivity for vascular smooth muscle over cardiac tissue.In vivoanimal experiments indicate that the effects of isradipine on regional circulation are consistent with the general pattern observed with other dihydropyridine derivatives (viz. increased coronary, brain and skeletal muscle blood flow and reduced renal blood flow) but are typically longer lasting.Acute haemodynamic studies in humans suggest that isradipine induces selective arterial vasodilatation, reducing blood pressure and systemic vascular resistance without altering cardiac filling pressures, and produces secondary increases in cardiac output and stroke volume as the result of afterload reduction. Reflex tachycardia is either slight or absent, and the negative inotropic effects, which are counterbalanced by the reflex sympathetic activation associated with isradipine-induced vasodilatation, are less marked than with nifedipine. Short and long term isradipine administration is accompanied by sustained diuretic and natriuretic effects in hypertensive patients. Plasma renin activity is variously increased or unaltered by isradipine administration in these patients, and the antihypertensive efficacy of isradipine is not obviously related to pretreatment plasma renin activity.Isradipine shows antiatherogenic effects in the cholesterol-fed rabbit at doses in the therapeutic range of human use and, moreover, does not appear to have a detrimental effect on the serum lipid profile in man. The question of whether isradipine can retard the progression of atherosclerotic lesions in humans is currently under investigation.Pharmacokinetic PropertiesIsradipine is rapidly and virtually completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass hepatic metabolism, resulting in a bioavailability of approximately 17% with oral doses of 5 to 20mg. The pharmacokinetics of isradipine are linear in this dose range, and peak plasma levels (˜ 2 to 10 &mgr;g/L with capsule formulations) are attained within 2.5 hours of oral administration.Isradipine is a lipophilic compound which is approximately 97% bound to plasma proteins (predominantly &agr;1-acid glycoprotein). Information regarding its tissue distribution is limited. The volume of distribution of the drug is ˜ 2.9 L/kg at steady-state.Isradipine undergoes extensive hepatic biotransformation to yield pharmacologically inactive metabolites which remain detectable in the urine for up to 96 hours following a single oral dose. The urine: faeces excretion ratio is 70:30, with approximately 10% of the parent compound being excreted unchanged in the faeces. Isradipine shows a biphasic elimination pattern; the effective elimination half-life of isradipine is 8.8 hours, and appears unrelated to dose.The bioavailability of isradipine is enhanced in elderly subjects and in patients with impaired hepatic (but apparently not renal) function, indicating that dosage modification may be appropriate in these subgroups.Therapeutic TrialsOpen and placebo-controlled trials of up to 2 years duration have suggested that isradipine (typically in doses of 2.5 to 10mg twice daily) normalises systolic and diastolic blood pressure in up to 85% of patients with mild to moderate hypertension. The drug's antihypertensive efficacy appears to be unrelated to patients' age or race. Results from comparative studies indicate that the medium term antihypertensive efficacy of isradipine is comparable to that of nifedipine and hydrochlorothiazide, and possibly superior to that of propranolol atenolol, prazosin and diltiazem. In combination with the &bgr;-blocker pindolol or the ACE inhibitor captopril, isradipine is effective in restoring blood pressure to normotensive levels in patients inadequately controlled by monotherapy.Comparative trials of 4 to 6 weeks duration, albeit limited in number, have indicated that isradipine (2.5 to 7.5mg 3 times daily) is of similar efficacy to nifedipine and isosorbide dinitrate in improving exercise performance and reducing the frequency of anginal attacks in patients with chronic stable angina.Adverse EffectsThe majority of reported adverse effects of isradipine - headache, flushing, ankle oedema, dizziness and palpitations/tachycardia - are related to the drug's vasodilatory action and are commonly encountered with other calcium channel blockers. These side effects are generally mild, dose-related and transient, occurring most frequently during the initial weeks of therapy and subsiding with continued treatment. The incidence of adverse effects with low dose isradipine therapy (≤ 5mg twice daily) is comparable to that seen with placebo, ranging from 15 to 30% of patients; facial erythema and hot flushes in particular are more frequent with higher doses (> 15 mg/day). The overall tolerability of isradipine has been assessed as good or very good in 86% of patients, and compares favourably with that of nifedipine.Drug InteractionsSteady-state digoxin concentrations are not significantly altered by isradipine pretreatment and no special precautions appear to be necessary when the 2 drugs are jointly administered. Peak plasma propranolol concentrations are elevated by concomitant isradipine administration, although the clinical significance of this observation is unclear.Dosage and AdministrationIn patients with mild to moderate hypertension, the optimum response, both with isradipine monotherapy and with &bgr;-blocker combination therapy, occurs with doses ranging from 2.5 to 7.5mg twice daily. Doses should be titrated to individual patient responses, commencing with an initial dose of 2.5mg twice daily, and dose increments should be performed at intervals of at least 4 weeks to avoid unnecessarily high doses. For patients with chronic stable angina, a regimen of isradipine 2.5 to 7.5mg 3 times daily appears appropriate.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisBetaxolol is a lipophilic &bgr;-adrenoceptor antagonist relatively selective for &bgr;1-adrenoceptors with only weak &bgr;2-blocking activity. Used topically in glaucoma and ocular hypertension, betaxolol 0.5% solution produces a reduction in intraocular pressure of between 13 and 30%, an effect comparable with that of ocular timolol. It may usefully be combined with other types of anti-glaucoma agents. The most notable feature of its adverse effect profile is transient local stinging or irritation, occurring in 25 to 40% of patients. Following ocular administration, betaxolol appears to be largely devoid of adverse bronchopulmonary or cardiac effects, in comparison with nonselective ocular &bgr;-adrenoceptor antagonists, which may be more likely to exert systemic effects. Betaxolol has negligible local anaesthetic activity, so that corneal desensitisation does not occur with its use. Thus, betaxolol is an alternative therapeutic option available to the physician for the management of chronic open-angle glaucoma and ocular hypertension. Its apparently lower propensity to affect the cardiopulmonary system represents a significant advantage over other ocular &bgr;-adrenoceptor antagonists.Pharmacodynamic PropertiesBetaxolol is a lipid-soluble (lipophilic) &bgr;-adrenoceptor antagonist which is relatively cardioselective, with no intrinsic sympathomimetic activity and little or no membrane stabilising activity. In common with other ocular &bgr;-adrenoceptor antagonists, the mechanism of the reduction in intraocular pressure observed with betaxolol is generally considered to be decreased production of aqueous humour by the ciliary body, with no apparent effect on aqueous outflow. The precise mechanism of this effect remains to be elucidated. Retinal and ciliary perfusion pressures in patients have been reported to be unaltered by betaxolol treatment. Betaxolol 0.5% was less toxic to regenerating corneal epithelium in rabbits than was timolol 0.5% or levobunolol 0.5%. Similarly, corneal healing rates were faster with betaxolol (and levobunolol) than with timolol.Although ocularly administered betaxolol may be absorbed from the nasopharyngeal and conjunctival mucosa into the systemic circulation, betaxolol appears to possess minimal systemic &bgr;-blocking activity - approximately 5% that of timolol in 1 radioreceptor assay in rabbits. Ocular betaxolol also failed to antagonise the isoprenaline-induced increase in heart rate in monkeys, an index of systemic &bgr;-blockade.Betaxolol appears to have less propensity for adverse effects on pulmonary function than nonselective ocular &bgr;-adrenoceptor antagonists. In studies in patients with respiratory disease or timolol-induced bronchoconstriction, betaxolol has not had any effect on FEV1, forced vital capacity, or relative forced expiratory volume. However, in an investigation in 85 patients followed for up to 2 years, symptomatic pulmonary obstruction was apparent in 5 patients after 1 to 554 days' betaxolol treatment. All patients had glaucoma and chronic obstructive pulmonary disease, asthma, or timolol-induced bronchoconstriction at baseline. In 1 study, no statistically significant difference was apparent between betaxolol and placebo in the histamine concentration necessary to produce a 15 to 20% reduction in FEV1.Despite its cardioselectivity, betaxolol has had minimal effects on resting or exercise heart rate, blood pressure or double product, after ocular administration, in several placebo-controlled studies. This is in contrast to timolol, which effects significant reductions in these parameters. In 1 study in healthy volunteers, the incidence of CNS effects, including insomnia, depression, hypochondriasis and hysteria, tended to be less with betaxolol than with timolol. In 2 further studies, 16 of 18, and 5 of 7 patients experiencing CNS effects while receiving timolol improved after betaxolol treatment.Pharmacokinetic PropertiesThere are no published data detailing the pharmacokinetic properties of betaxolol following ocular administration in humans; such information is important to assess the extent of systemic availability.The bioavailability of oral betaxolol is 80 to 90% - it does not undergo extensive first pass metabolism. Excretion is mainly viaO-dealkylation followed by aliphatic hydroxylation, yielding 2 major inactive metabolites. Betaxolol and its metabolites are excreted renally with an elimination half-life of between 14 and 22 hours, which is prolonged in neonates and the elderly. Total body clearance does not appear to be affected by liver disease but is reduced in patients with severe renal failure.Therapeutic TrialsIn comparisons with placebo, betaxolol has proven superior in reducing intraocular pressure. Mean reductions have ranged between 13 and 27% with betaxolol compared with about 2 to 13% with placebo. Trials comparing betaxolol with timolol reported reductions in intraocular pressure at the end of 6 months' treatment of between 26 and 36% with betaxolol, and between 29 and 37% with timolol. These 3 trials involved a total of 101 patients.In a noncomparative trial a reduction of intraocular pressure was obtained within several hours of instillation of betaxolol 0.25%, was maximal at 2 weeks, at 30 to 35%, and was sustained for the duration of the study (1 year). In a second noncomparative trial, patients previously administered pilocarpine showed a nonsignificant reduction in intraocular pressure of 8.4% following substitution with betaxolol; in newly diagnosed patients, mean diurnal intraocular pressure was significantly reduced with betaxolol by 17%. In 17 of 20 patients with open-angle glaucoma or ocular hypertension receiving betaxolol 0.5% alone (n = 15) or in combination with pilocarpine (n = 5), who had been treated with timolol, an additional mean reduction in intraocular pressure of 2.4mm Hg was apparent after 2 weeks, and was maintained for the 12 weeks of study. In specific investigations of combination use, betaxolol therapy resulted in small incremental reductions in intraocular pressure over those obtained with other monotherapies.After 2 weeks' treatment with dipivefrine 0.1% alone, intraocular pressure was reduced by 12%, and addition of betaxolol resulted in a total reduction of 15% at 4 weeks. Betaxolol 0.5% twice daily added to oral acetazolamide resulted in an incremental reduction in outflow pressure (intraocular pressure minus an episcleral venous pressure assumed to be 10mm Hg) of 17.6%. With acetazolamide alone the reduction was 42.5%. With betaxolol alone the reduction was 27.3% below baseline, decreased by an additional 35.1% with acetazolamide.Adverse EffectsThe most frequent adverse effect of topical betaxolol treatment is transient local irritation, which occurs in 25 to 40% of patients. A double-blind comparison indicated a higher incidence of ocular symptoms with betaxolol (89%), than with timolol (48%). Ocular symptoms reported include burning, stinging or irritation, pruritus, hyphaemia, vitreous separation and blurred vision. As a cardioselective agent, betaxolol is less likely to be associated with adverse respiratory effects than nonselective &bgr;-adrenoceptor antagonists. While adverse respiratory effects have been observed in a small number of patients with underlying respiratory disease followed for up to 2 years on betaxolol, their relationship to treatment is uncertain. Of a total of 56 spontaneous reports of adverse drug experience attributed to betaxolol during its first year of marketing in the US, postmarketing surveillance identified 11 cases of asthma, 8 requiring hospitalisation.During a clinical trial in 101 patients treated with betaxolol for up to 2 years, cardiac arrhythmia and shortness of breath occurred in 1 patient and bundle branch block in a second. There are case reports describing myocardial infarction, sinus arrest, and congestive heart failure in association with ocular betaxolol. Of the 56 spontaneous reports mentioned above, there were 4 instances of bradycardia, 1 with syncope, and 1 of cardiac arrhythmia. Other adverse effects reported in association with ocular betaxolol include depression, disorientation, vertigo and sleepwalking; and rhinitis, dysuria, alopecia, and prolonged prothrombin time.Dosage and AdministrationThe recommended dosage of ocular betaxolol in glaucoma or ocular hypertension is one droip of 0.5% solution in each eye twice daily.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisNaproxen is a nonsteroidal anti-inflammatory drug (NSAID) advocated for use in painful and inflammatory rheumatic and certain nonrheumatic conditions. It may be administered orally or rectally using a convenient once or twice daily regimen. Dosage adjustments are not usually required in the elderly or those with mild renal or hepatic impairment although it is probably prudent to start treatment at a low dosage and titrate upwards in such groups of patients.Numerous clinical trials have confirmed that the analgesic and anti-inflammatory efficacy of naproxen is equivalent to that of the many newer and established NSAIDs with which it has been compared. The drug is effective in many rheumatic diseases such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and nonarticular rheumatism, in acute traumatic injury, and in the treatment of and prophylaxis against acute pain such as migraine, tension headache, postoperative pain, postpartum pain and pain associated with a variety of gynaecological procedures. Naproxen is also effective in treating the pain and associated symptoms of primary or secondary dysmenorrhoea, and decreases excessive blood loss in patients with menorrhagia. The adverse effect profile of naproxen is well established, particularly compared with that of many newer NSAIDs, and the drug is well tolerated.Thus, the efficacy and tolerability of naproxen have been clearly established over many years of clinical use, and it can therefore be considered as a first-line treatment for rheumatic diseases and various pain states.Pharmacodynamic PropertiesNaproxen possesses the typical pharmacodynamic properties of the nonsteroidal class of anti-inflammatory drugs. In animal studies it exhibits dose-related anti-inflammatory, analgesic and antipyretic effects: on a weight-for-weight basis it is more potent than aspirin and phenylbutazone, and equal to or less potent than indomethacin. Its anti-in-flammatory effects are still apparent in adrenalectomised animals, indicating a nonsteroidal mechanism of action. The anti-inflammatory effects of naproxen, and most of its other pharmacological effects, are generally thought to be related to its inhibition of cyclo-oxygenase and consequent decrease in prostaglandin concentrations in various fluids and tissues, including the gastric mucosa, synovial fluid, urine and blood.In common with other NSAIDs naproxen may induce gastrointestinal microbleeding and endoscopically proven gastrointestinal lesions: it generally produces less effects than aspirin and indomethacin but more than diflunisal, etodolac, nabumetone and sulindac. In clinical practice, however, while the gastrointestinal tolerability of naproxen is better than that of aspirin and indomethacin, there is no definitive evidence to suggest significant differences in tolerability (minor complaints, bleeding or ulceration) between naproxen and other NSAIDs.Naproxen, like other NSAIDs, is a potent inhibitor of the secondary phase of platelet aggregation. However, at usual therapeutic dosages it has little effect on bleeding time in humans. In general, naproxen does not produce detrimental renal effects in patients with normal renal function although a few changes were reported in some patients with preexisting renal impairment or heart failure. Naproxen does not exert a uricosuric effect.In normal animals naproxen does not affect collagen metabolism but can inhibit cartilage and bone erosions in animals with adjuvant-induced arthritis. There is no definitive evidence in humans with rheumatic disease that naproxen or any other NSAID can inhibit the progression of cartilage or bone destruction. As occurs with other NSAIDs, naproxen affects leucocyte function reducing chemotaxis, and lysosomal and neutral protease, and collagenase activities in animals.Pharmacokinetic PropertiesNaproxen is available in 2 forms: the free acid or the sodium salt. Naproxen and naproxen sodium are pharmacologically and therapeutically equivalent at comparable dosages (naproxen 500mg equals naproxen sodium 550mg). The only difference between the 2 forms is their rate of absorption; naproxen sodium dissolves more rapidly in gastric juice and consequently produces earlier and higher plasma concentrations. Peak plasma concentrations are achieved in about 1 hour with naproxen sodium and 2 hours with naproxen. It is possible that this may provide a faster onset of action with the sodium salt after an initial dose; this would be of relevance in the treatment of acute pain states. Apart from this difference, the post-absorption phase pharmacokinetics of the sodium salt and its parent acid are identical.Naproxen is completely absorbed after oral and rectal administration. Concomitant administration of food may delay the absorption of orally administered naproxen but does not reduce the extent. Absorption is slower after rectal compared with oral administration, leading to a delay in and lower peak plasma concentrations. Plasma concentrations rise proportionately with dose after oral administration of single doses up to 500mg, but thereafter the increase is less than linear. This is related to increased clearance caused by saturable protein binding. Naproxen is highly protein bound (> 99.5%); the free fraction, however, increases significantly at higher plasma concentrations. The volume of distribution of naproxen is small, being about 10% of bodyweight. The drug readily reaches the synovial fluid and synovial membrane. Naproxen crosses the placental barrier, and minimal transfer occurs to breast milk (about 1% of maternal plasma samples). Approximately 95% of a radiolabelled dose of naproxen is recovered in urine and 3% or less in faeces. 70% of the drug is excreted as unchanged naproxen and the remainder is metabolised to an inactive 6-demethyl metabolite, probably by hepatic microsomal oxidation. The parent compound and metabolite are excreted free or as glucuronide or sulphate conjugates. The elimination half-life is about 12 to 15 hours.The pharmacokinetic profile of naproxen is generally unaffected to any clinically significant extent by age or the presence of disease. However, free plasma concentrations of naproxen may be increased in elderly patients with rheumatoid arthritis and in patients with hepatic impairment, due to decreased plasma albumin levels. Renal insufficiency has little effect on the pharmacokinetics of naproxen until it is severe. When creatinine clearance is less than 10 ml/min there is a significant decrease in plasma naproxen concentration but an increase in metabolite concentrations. Naproxen is not removed by haemodialysis. Dosage reductions are not therefore required in patients with mild to moderate renal impairment and neither is dose supplementation after haemodialysis.Therapeutic UseNaproxen, usually 500 to 1000 mg/day on a once or twice daily basis, administered orally or rectally, has been well studied in controlled clinical trials in patients with rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. The drug shows similar analgesic and anti-inflammatory efficacy to usual therapeutic dosages of other commonly used NSAIDs (e.g. aspirin, diclofenac, ibuprofen, indomethacin, ketoprofen, piroxicam), and other less frequently used or newer NSAIDs. As would be expected in such a large number of comparisons, statistically significant differences were found for some assessment parameters but these differences were not of clinical significance and usually related to comparison of therapeutically nonequivalent dosages. With appropriate dosage titration, clinical response to NSAIDs generally appears equivalent (although individual patients may inexplicably respond to or tolerate one NSAID and not others). The therapeutic efficacy of naproxen is maintained during long term treatment up to several years and is associated with a steroid-sparing effect in patients with rheumatoid arthritis.Several studies have shown that naproxen is effective in the treatment of acute gout and juvenile arthritis but further study is required to allow any definite conclusions concerning its efficacy and tolerability compared with other commonly used agents. Naproxen up to 1000 mg/day has been demonstrated to be an effective analgesic and anti-inflammatory agent for the treatment of acute or chronic nonarticular rheumatic conditions and soft tissue injuries. Its efficacy in these conditions is comparable to that of other commonly used agents. Naproxen is a useful analgesic in a variety of acute pain states, such as migraine, tension headache, postoperative pain, postpartum pain and pain associated with a variety of gynaecological procedures. In the treatment of acute migraine naproxen was comparable to ergotamine. In other acute pain states naproxen was at least as effective as some of the more commonly used ‘pure’ analgesics or their combinations [e.g. paracetamol (acetaminophen), codeine, dextropropoxyphene]. Naproxen has also been used successfully in the prophylaxis of migraine, reducing the severity and frequency of migraine attacks to a similar extent as pizotifen and propranolol.Naproxen is a well studied agent in the treatment of primary and secondary dysmenorrhoea, alleviating pain and associated symptoms. It reduces symptoms at least as well as other NSAIDs with which it has been compared. In addition, naproxen reduces blood loss and anaemia consequent to menorrhagia.Naproxen appears to be a particularly effective agent in the control of neoplastic fever and has been used to differentiate between neoplasm-related and infection-related pyrexia in cancer patients with fever of unknown origin. It may also be effective as a general antipyretic agent although further study is required to compare its efficacy relative to that of other standard treatments.Adverse EffectsThe tolerability profile of naproxen is well established, as extensive experience has been gained with the drug over many years. The drug is generally well tolerated. In common with other NSAIDs the most frequent adverse effects include mild gastroin-testinal disturbances and CNS effects, followed by occasional mild skin reactions. Increased age does not appear related to any increase in unwanted effects and there is little evidence to suggest that the nature, severity or frequency of adverse effects is any different with naproxen compared with other NSAIDs. Despite some claims of improved tolerability with some newer NSAIDs, there are no definitive findings to show this. Aspirin and indomethacin may produce a higher frequency of gastrointestinal symptoms and CNS effects compared with naproxen.As with any drug which has been used so extensively in clinical practice, a number of rare serious adverse effects have been associated with naproxen, which have also been associated with other NSAIDs. They include: gastrointestinal bleeding or ulceration, pseudoporphyria and other severe cutaneous reactions; acute renal failure including papillary necrosis, interstitial nephritis and hyperkalaemia; hepatitis; pulmonary infiltrates with eosinophilia; agranulocytosis; aplastic anaemia; haemolytic anaemia; peripheral neuropathy; aseptic meningitis; and corneal opacity. Patients exhibiting aspirin hypersensitivity may show cross-reactivity with naproxen.Dosage and AdministrationThe following dosage schedule refers to naproxen administered as the free acid. If naproxen sodium is used, the dosage is increased by 10% to achieve bioequivalence (naproxen 500mg = naproxen sodium 550mg).The usual adult maintenance dosage of naproxen in patients with chronic rheumatic disease or chronic pain is 375 to 1000 mg/day after food and on a once or twice daily basis. This may be increased to 1500 mg/day in divided doses for up to 2 weeks to treat acute exacerbations of the disease. For children with juvenile arthritis the recommended dosage is 10 mg/kg in 2 divided doses; a suspension formulation is available to aid administration. In patients with acute conditions such as tendinitis, bursitis, dysmen-orrhoea and mild to moderate pain an initial loading dose of 500mg should be administered and followed by 250mg every 6 to 8 hours as required (up to a maximum of 1250 mg/day).

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisMoricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal re-entry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death.Pharmacodynamic StudiesThe predominant cellular electrophysiological effect of moricizine is a frequency-de-pendent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class 1 antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine.In vivoanimal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal. His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased antero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node.Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function.Although a phenothiazine derivative, moricizine displays low affinity for striatal DA1-dopamine receptorsin vitro,and correspondingly lacks significant psychotropic effects in humans.Pharmacokinetic StudiesAlthough rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (˜95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg.In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s).Therapeutic TrialsPlacebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous anti-arrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45).Adverse EffectsThe predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasive monitoring in 3.2% of 908 patients with ventricular arrhythmias, and were confined to those with potentially lethal or lethal ventricular tachycardias. Moricizine has minimal effect on the QTc interval, and a low propensity to provoke torsade de pointes. The drug is devoid of significant cardiodepressant activity in patients with normal or mildly to moderately impaired left ventricular function. The incidence of moricizine-induced aggravation or provocation of congestive heart failure is low (< 1%), and the phenomenon appears to be confined to patients with pre-existing severely depressed left ventricular function.Dosage and AdministrationDose titration should be performed, where feasible, in conjunction with inpatient ECG monitoring, commencing with an oral dose of 600 mg/day administered on a thrice-daily regimen; this may be increased to a maximum of 900 mg/day. Caution in the use of moricizine is required in patients with cardiac conduction abnormalities, severe impairment of left ventricular function, and renal or hepatic dysfunction.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS