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

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The management of oesophageal reflux disease can and should be highly individualised, depending on the severity of the disease. Mild occasional symptoms of heartburn can often be controlled with conservative measures or changes in diet and antacids. For patients with erosive or ulcerative oesophageal disease, it is becoming clear that acid plays a crucial role in injury and that suppression of acid enhances healing. Antipeptic dosages of histamine receptor antagonists achieve good relief of symptoms but may not always heal erosive oesophagitis. Healing rates are improved with the use of new hydrogen-potassium adenosine triphosphatase (ATPase) pump inhibitors which suppress virtually all acid production. The recurrence of disease is common after acid suppression therapy is discontinued, suggesting the need for some form of long term maintenance therapy. Promotility drugs, which improve oesophageal motility, have inconsistent results in clinical trials and have been associated with a higher rate of adverse drug effects in comparison with acid-suppressive therapies. Surgical treatment should still be considered for patients with chronic recurrent disease who do not respond well to pharmacological therapies.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Acne may vary from a relatively trivial condition to a severe disfiguring disease and management must be tailored to suit individuals. Pathogenetic factors that may be addressed by treatment include increased sebum secretion, abnormal follicular keratinisation, bacterial colonisation and local inflammation.Mild acne can be controlled with topical preparations alone but many patients with more severe disease require oral therapy with antibiotics, antiandrogens or retinoids. Combinations of topical and systemic treatments are often appropriate. The choice of drug requires knowledge of their efficacy, ease of use and possible adverse effects.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisStreptokinase, the first of the thrombolytic agents to be used in acute myocardial infarction, has now been administered to many thousands of patients with this condition. Since early intervention and accessibility of care is paramount in these patients, intravenous infusion of streptokinase has largely replaced intracoronary use.Results of major trials (GISSI, ISIS-2 and ISAM) comparing streptokinase with standard treatment in more than 30000 patients prove convincingly that intravenous streptokinase increases patient survival after myocardial infarction. The largest trial, ISIS-2, demonstrated a 23% reduction in 5-week vascular mortality after streptokinase use. The greatest benefits occur where streptokinase infusion is initiated early after symptom onset, although late benefit has been observed in patients treated up to 24 hours after pain onset. Importantly, mortality is further decreased by combining streptokinase with aspirin, as shown by a 53% reduction in mortality using the combination in the ISIS-2 trial. Mortality has also been reduced in trials investigating the use of the thrombolytic agents rt-PA and anistreplase. Streptokinase and rt-PA produced similar reductions in mortality in the recent GISSI-2 and International t-PA/Streptokinase Mortality trials, findings which may be further clarified by ongoing comparative trials such as ISIS-3.Reperfusion of about 50 to 60% of occluded coronary arteries occurs with intravenous streptokinase, and left ventricular function is improved. Direct comparisons with rt-PA show a superior effect for the newer agent on early reperfusion, but a similar ability to salvage myocardial function. The complexities of the relationship between reperfusion, left ventricular function and mortality constitute an area of considerable clinical interest requiring further study to clearly differentiate between the drugs available to the physician.The most common adverse events observed during intravenous streptokinase infusion are bleeding complications. An incidence of 3.6% for minor bleeding and 0.4% for major haemorrhage (requiring transfusion) is derived from the combined results of the GISSI and ISIS-2 studies. Bleeding does not appear to be more frequent or severe with intravenous streptokinase than with the more fibrin-selective agent, rt-PA. While the risk to benefit ratio of sequential heparin following streptokinase therapy remains equivocal, the adjuvant use of aspirin confers a clinical advantage over streptokinase alone.In conclusion, streptokinase has now been proven to reduce mortality in patients with acute myocardial infarction, with an acceptable risk of bleeding complications. Given the substantial data that have now accumulated with extensive clinical experience, intravenous streptokinase should be considered a first-line agent in suitable patients. While current evidence suggests there is little difference among various thrombolytics in reducing mortality, this remains to be established definitively in large ongoing or planned comparative trials.Pharmacological PropertiesStreptokinase is a streptococcal protein of Lancefield group C &bgr;-haemolytic streptococci. It activates the fibrinolytic system by combining with plasminogen to form a plasminogen activator complex that is rapidly converted to a streptokinase-plasmin complex capable of converting plasminogen to plasmin. Insoluble fibrin within the thrombus is lysed by plasmin, resulting in dissolution of the thrombus. Streptokinase thus causes thrombolysis by indirect means or in 2 steps.Because of its low fibrin selectivity, streptokinase results in a systemic fibrinolytic state. However, decreased levels of plasma fibrinogen and plasminogen return to baseline within 48 hours after stopping streptokinase infusion, and the theoretical risk of increased bleeding complications relative to more fibrin-selective agents has not been seen (see Adverse Effects, below). A correlation has been observed in some instances between the extent of systemic fibrinolysis, as assessed by the decrease in fibrinogen, and the success of reperfusion; however, there is no conclusive evidence supporting a causal relationship between lytic state and reperfusion rate. The extent of systemic fibrinolysis with streptokinase appears to be similar to or marginally less than that which occurs with anistreplase, but is more extensive than with urokinase or fibrin-selective rt-PA.Reductions in plasma viscosity correlating with decreased plasma fibrinogen levels are apparentin vitroand in patients treated with streptokinase. Streptokinase, urokinase and rt-PA inhibited platelet aggregation in plasma from healthy volunteers.Levels of the cardiac enzymes creatine phosphokinase (CK) and creatine phosphokinase isoenzyme MB (CK-MB) achieve a peak earlier, but in general are not higher, in successfully reperfused patients compared with those who fail treatment. Similar patterns are seen with aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels. Levels of CK-MB peaked earlier with streptokinase treatment than with conventional treatment or placebo.Plasma levels of fibrinopeptide A, an indicator of thrombin activity, have decreased in some patients successfully reperfused with streptokinase, but have paradoxically increased in others. This latter effect may have been due to an insufficient dosage of streptokinase being administered. In the TIMI trial the magnitude rises in plasma fibrinopeptide A levels were similar in patients administered streptokinase or rt-PA.Like other foreign proteins streptokinase is antigenic. Antibody titres rise within several days after streptokinase infusion and may remain high for 6 months or longer. Streptokinase infusion may cause transient but significant hypotension through an unknown mechanism postulated to involve bradykinin production (see Adverse Effects, below).Little has been published regarding the pharmacokinetics of streptokinase. Peak plasma streptokinase activity has been reported as 175 U/ml after infusion of 1.5 million U. Mean apparent volume of distribution is reported as 1.10L, and total clearance as 0.65 L/h. Clearance of streptokinase occurs primarily via rapid combination with antibodies in the plasma. Differences in assay methods confound the determination of elimination half-life values for streptokinase; most reports indicate a value of 23 to 29 minutes, while in others the half-life is 83 minutes. The drug does not cross the placenta.Therapeutic UsePractical difficulties of widespread use of intracoronary streptokinase have resulted in a number of studies involving intravenous administration. This has the main advantages of decreasing the delay between onset of symptoms and infusion of streptokinase, and increased availability to patients with acute myocardial infarction. Initial comparative studies between intracoronary and intravenous streptokinase tended to show a slightly higher reperfusion rate with the intracoronary route, but low intravenous doses (≤ 750 000U) were used. The advantages of intravenous administration outweigh any differences, and intracoronary administration is not considered further in this review.Large randomised mortality trials - GISSI, ISIS-2 and ISAM - conducted in more than 30,000 patients in total have evaluated streptokinase as an intravenous infusion of 1.5 million U compared with standard treatment. These studies demonstrate a distinct benefit in reducing mortality with an intravenous infusion of streptokinase. The GISSI study showed that mortality was significantly reduced by streptokinase versus conventional treatment at 21 days (10.7vs13%) and one year (17.2vs19%). Similar results were found in the ISIS-2 trial, which demonstrated mortality rates of 9.2% for streptokinase compared with 12% for placebo at 5 weeks, and a significant (p < 0.01) reduction at a median follow-up of 15 months. The smaller ISAM study showed lower 21-day and 21-month mortality rates for streptokinase than for placebo (6.3vs7.1% and 14.4vs16.1%, respectively), although these differences were not statistically significant.At 21 days after therapy, the incidence of nonfatal reinfarction in the streptokinase group was twice that observed in the control groups of the GISSI and ISAM studies (about 4 to 6%vs2 to 4%). However, the incidence was 2.8% for streptokinase versus 2.4% for placebo in the ISIS-2 study. Ventricular arrhythmias and other rhythm disturbances were monitored in the ISAM trial and were not more frequent with streptokinase than with placebo.The GISSI study confirms that the sooner the intravenous infusion of streptokinase can be initiated after symptom onset then the greater is the overall benefit in reducing mortality. Overall reductions in 21-day mortality were 47% in patients treated with streptokinase within 1 hour of symptom onset, 23% in those treated within 3 hours and 18% in patients treated within 12 hours. The ISIS-2 results showed no distinct advantage of administering streptokinase within 3 hours of infarct compared with between 3 and 6 hours, but there was a trend to greater benefit with earlier treatment. Although the GISSI study did not show a mortality reduction in patients treated 6 or more hours after pain onset, a significant reduction was found in the ISIS-2 trial in patients treated between 6 and 24 hours after symptom onset. This suggests that thrombolytic therapy should not necessarily be restricted to patients presenting early.Addition of aspirin to streptokinase therapy provides an even greater reduction in mortality than streptokinase alone, as demonstrated by a 53% reduction in the odds of death for patients treated within 4 hours in the ISIS-2 trial, and negates the increased rate of reinfarction seen with streptokinase alone.On present evidence it appears that the various thrombolytic agents produce similar decreases in mortality. Streptokinase and rt-PA were comparable in the GISSI-2 study, and in the International t-PA/Streptokinase Mortality Trial (which included GISSI-2 patients). Mortality rates with streptokinase, anistreplase and rt-PA appear similar in comparative trials not designed to assess mortality as a primary endpoint. However, the question of whether differences do indeed exist among the thrombolytics is being addressed further in the ISIS-3, TEAM-3 and other planned comparative trials.Reperfusion rates of occluded coronary vessels are about 50 to 60% for intravenous streptokinase in comparative trials including angiography to confirm vessel occlusion. A tendency for a lower patency rate with streptokinase than with anistreplase in 2 trials not including pretreatment angiography reached statistical significance in 1 study, but patency rates were similar in a third trial. Analysis of combined data from 2 directly comparative trials shows a greater early reperfusion rate (90 minutes after initiating infusion) with rt-PA than with streptokinase. The thrombolytic effect of either drug lessens as the time interval from onset of symptoms to treatment increases. Importantly, it is unclear whether differences in reperfusion rates among thrombolytic agents will translate into comparable reductions in mortality.Streptokinase improves left ventricular function, and increases of 3 to 6% in ejection fraction are seen relative to placebo or conventional therapy. On the whole, streptokinase and rt-PA appear to have similar effects on left ventricular function as assessed by directly comparative trials. The complexities of the relationship between reperfusion, left ventricular function and mortality remain to be elucidated.Reocclusion rates with intravenous streptokinase have not been specifically investigated using serial coronary angiography, but averaged 18% in an overview of several trials and 16% for both streptokinase and rt-PA in a more recent overview. The TIMI-I study reported reocclusion rates of 30% with streptokinase and 29% with rt-PA at hospital discharge, but these values appear to overestimate the reocclusion rates for both drugs. At present, neither coronary artery bypass surgery nor coronary angioplasty can be recommended as routine adjuvant treatment following streptokinase therapy. Immediate angioplasty after thrombolysis offers no advantage over thrombolysis plus conservative strategies, although selected patients may benefit.The benefit to risk ratio of sequential heparin following streptokinase infusion has not been satisfactorily established. In the SCATI trial heparin prevented the development of mural thrombi, but the use of streptokinase plus heparin in the GISSI-2 trial was not more effective than streptokinase alone. Streptokinase plus aspirin 160 mg/day confers significant clinical advantages over streptokinase alone, as discussed above.Adverse EffectsBoth intravenous and intracoronary streptokinase cause a peripheral lytic state which theoretically carries an increased risk of bleeding complications. The most common adverse effect is haemorrhage, with an incidence of 3.6% and 0.4% for minor (not requiring transfusion) and major bleeding episodes, respectively, as reported in the GISSI and ISIS-2 trials. In the ISIS-2 study the overall incidence for intracranial bleeding in the streptokinase group was 0.1%, and for stroke was 0.8% in patients who were scanned. Compared with placebo, streptokinase was associated with a higher number of ‘early’ haemorrhagic or other strokes on the first 2 days of treatment, but thereafter the rate was significantly lower with streptokinase. There does not appear to be an appreciable difference between streptokinase or rt-PA in producing bleeding.Transient hypotension and bradycardia are observed during or after intravenous streptokinase infusion, with an incidence of 10% versus 2% with placebo in the ISIS-2 study. As streptokinase is a streptococcal protein, allergic reactions are possible. Shivering, pyrexia or rashes were noted in 4.4% of ISIS-2 patients administered streptokinase versus 0.9% of placebo recipients, and 99 patients (1.7%) who experienced allergic reactions were withdrawn from streptokinase therapy in the GISSI study. Nonfatal anaphylactic reactions occurred in 7 patients in the GISSI study but none were reported in the ISIS-2 study.Dosage and AdministrationThe currently recommended dosage of intravenously administered streptokinase in patients with acute myocardial infarction is 1.5 million U infused over 30 to 60 minutes, although an optimum dosage has not yet been established. The infusion should be started as soon as possible after onset of symptoms, preferably within 6 hours, but patients presenting up to 24 hours should not necessarily be excluded.Contraindications to streptokinase include active internal bleeding, intracranial neoplasm, severe uncontrolled hypertension, and recent cerebrovascular accident or intraspinal or intracranial surgery. The risk to benefit ratio of streptokinase should be carefully considered when other conditions are present, including: recent major surgery; serious gastrointestinal bleeding; organ biopsy; obstetrical delivery or previous puncture of noncompressible vessels; sustained hypertension; recent trauma; infectious endocarditis; pregnancy; cerebrovascular disease; diabetic haemorrhagic retinopathy and haemostatic defects.Patients should be monitored for possible bleeding complications, particularly when anticoagulant or antiplatelet drugs are also administered. Patients with elevated levels of streptococcal antibodies because of recent streptococcal infections or previous exposure to streptokinase may be resistant to therapy.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisAcecainide(N-acetylprocainamide), theN-acetylated metabolite of procainamide, is a Class III antiarrhythmic agent. It can be given either intravenously or orally, and is eliminated primarily by renal excretion. In a small number of noncomparative and placebo-controlled short term therapeutic trials acecainide markedly reduced premature ventricular beats and prevented induction of ventricular tachycardia in more than 70% of patients following intravenous administration and in about 50% after oral administration. Acecainide was effective in about one-quarter of patients refractory to other antiarrhythmic drugs. Interpretation of its effectiveness following long term oral therapy is complicated by the limited number of patients, and patients discontinuing due to adverse effects or lack of efficacy. However, about 40% of the small number treated for extended periods were controlled for periods of 6 months to 3 to 4 years. Comparative studies with other antiarrhythmic drugs have not been undertaken apart from a small study in atrial flutter where acecainide was better than quinidine plus digoxin. Thus, although further clinical experience is required before the relative place of acecainide in therapy can be determined, the drug nevertheless appears to offer advantages over procainamide, particularly with respect to the reduced formation of antinuclear antibodies.Pharmacodynamic PropertiesThe predominant effect of acecainide in isolated tissue and animal studies is a dose-dependent lengthening of the action potential duration and effective refractory period, indicating Class III antiarrhythmic activity (Vaughan Williams classification) with little or no effect on resting membrane potential, action potential amplitude or upstroke velocity (therefore apparently devoid of Class I activity). In patients with coronary artery disease, acecainide significantly increased corrected QT interval (QTc by 14%) and atrial (15%) and ventricular (8%) effective refractory periods. No changes occurred in sinus cycle length, sinus node recovery time, atrioventricular nodal conduction time, His-Purkinje conduction time, right intra-atrial conduction time, QRS conduction interval, atrioventricular nodal functional refractory period or Wenckebach cycle length; similar results were observed in patients with arrhythmias in whom increases in QTc ranged from 6 to 21%. In patients with bundle branch block or conduction dysfunction no worsening occurred, although 1 group of investigators suggested caution in patients with pre-existing His-Purkinje system disease.Haemodynamic studies in isolated and intact animal preparations demonstrated that acecainide has a small and short term positive inotropic effect at therapeutic plasma concentrations. These results were essentially confirmed in patients, with acecainide having no effect on heart rate and systolic blood pressure either at rest or during exercise, and no change in echocardiographic measurements of end diastolic dimension, end-systolic dimension, left ventricular internal diameter shortening, cardiac output or pulmonary artery pressure. The ratio of pre-ejection period to left ventricular ejection time (an indicator of left ventricular performance) was constantly reduced; this was accompanied by a significant decrease in pre-ejection period index, an increase in ejection time index and a decrease in systolic time intervals index. These results are compatible with acecainide being relatively free of myocardial depressant activity.Pharmacokinetic PropertiesIn healthy subjects, mean peak plasma concentrations following single oral doses of acecainide 1000mg were about 5.4 mg/L and were usually attained about 2.5 hours after administration. Similar values were reported in patients with cardiomyopathy. Plasma concentrations increased almost linearly with increasing dosages between 500 and 2500mg. Bioavailability in healthy subjects was 85%. At steady-state, volume of distribution was between 1.25 and 1.7 L/kg in healthy subjects and patients. Acecainide is 10% bound to plasma proteins. Some studies have noted that a small proportion of acecainide is converted to procainamide but this has not been a consistent finding. Acecainide, unlike procainamide, does not form a reactive metabolite, considered the initial step in procainamide-induced lupus. Renal clearance is generally reduced in patients with cardiomyopathy and ventricular arrhythmias and is dependent on creatinine clearance. Consequently, the elimination half-life has tended to be prolonged in patients relative to that in healthy subjects. Optimum therapeutic plasma concentrations have not been established.Therapeutic UseAcecainide has been investigated in a small number of noncomparative trials as well as in a few which were placebo controlled and has been compared with quinidine and procainamide in preliminary trials. Following intravenous administration spontaneously occurring premature ventricular contractions were significantly reduced in most patients and ventricular tachycardia abolished in about half of those treated. Arrhythmias following programmed electrical stimulation were prevented in about one-third of patients (2 studies) and ventricular tachycardia was induced at a slower rate. After short term oral administration, ventricular arrhythmias (premature ventricular contractions and ventricular tachycardia) were significantly reduced in about half of the patients including some of those patients whose arrhythmias were refractory to other antiarrhythmic drugs. Acecainide was effective in about one-quarter of the latter group of patients. Following long term administration of acecainide for periods ranging from 3 months to 3 to 4 years in responsive patients selected from previous short term studies, assessment of efficacy was complicated by the small numbers of patients, withdrawals, lack of continued efficacy in some cases, and a high incidence of sudden death. Results from the few long term studies reported indicate that about 40% of the patients involved remained controlled for periods of 6 to 48 months. However, the use of antiarrhythmic therapy in patients with asymptomatic arrhythmias is controversial.A preliminary short term comparative study suggested that acecainide was better tolerated and had greater efficacy than procainamide, while combined efficacy and tolerability with acecainide was significantly better than with quinidine plus digoxin in patients with atrial flutter. Acecainide has not been compared with other antiarrhythmic drugs and the dosage required to maintain antiarrhythmic effects is still not clear.Adverse EffectsThe predominant noncardiac adverse effects associated with acecainide administration involved the gastrointestinal tract (nausea, vomiting, diarrhoea) and the central nervous system (paraesthesias, fatigue, vivid dreams, light-headedness); the overall incidence ranged from 0 to 68%. Visual disturbances were also reported in 18% of patients. Systemic lupus erythematosus was not a common adverse effect with acecainide in comparison to the previously reported high incidence with procainamide. Worsening of arrhythmias, including the development of torsade de pointes, occurred in a small number of patients. There was a high incidence of sudden death among patients on long term oral therapy, although any direct association with acecainide therapy is unproven.Dosage and AdministrationThe dose of acecainide should be adjusted to control patients' arrhythmias with regard to their clinical state including age, renal function and concurrent administration of other drugs. Intravenous infusions of 0.45 mg/kg/min or 15 to 20 mg/kg appear to be effective in suppressing arrhythmias. For short term oral administration 1.5 to 2.0g as a single daily dose, or given as divided doses, appears to be satisfactory. However, in long term studies and in patients refractory to other antiarrhythmic drugs, doses were increased to 7.5 g/day. A number of studies indicated that tolerance developed and that higher doses were required with long term therapy. In those patients with decreased renal function, and possibly in the elderly, the dose should be decreased.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisPentamidine is an aromatic diamidine derivative which has become one of the standard therapies forPneumocystis cariniipneumonia (PCP), particularly in patients with acquired immunodeficiency syndrome (AIDS). However, with parenteral administration of the drug there is a high risk of toxicity. Inhaled pentamidine produces much higher concentrations of drug on the bronchoalveolar surface with minimal systemic absorption. It has been used successfully for the treatment of PCP in AIDS patients, but its most valuable contribution has been as prophylaxis in AIDS patients at high risk of developing PCP. In prospective controlled studies there has been > 80% reduction in relapse rate with pentamidine. The reduction in relapse rate among patients who have experienced one previous episode of PCP has been 50 to 100% compared with historical control groups, over a follow-up period averaging about 6 months. Significant systemic adverse effects to inhaled pentamidine are rare. Respiratory effects associated with inhalation are common but usually controllable without treatment discontinuation. The ideal particle size for even distribution of pentamidine throughout the lung is considered to be 1 to 2&mgr;m. Jet nebulisers such as the ‘Respirgard II’ system produce a mass median aerodynamic diameter (MMAD) of particles in this range. Ultrasonic nebulisers produce larger particles. The implication from this difference is that while ultrasonic nebulisers may have poorer alveolar distribution and the incidence of local side effects (common with all formulations) may be higher, total drug delivery may be more efficient allowing effective PCP prophylaxis with lower dosages (120mgvs300mg monthly). However, there are no data available comparing the efficacies and tolerabilities of the different formulations of inhaled pentamidine. Nevertheless, inhaled pentamidine would seem poised to become routine prophylaxis in patients with AIDS or AIDS-related complex at risk of developing PCP.Antiprotozoal and Pharmacokinetic PropertiesPentamidine has been reported to have a destructive action againstP. carinii in vitro, reducing its viability to a similar extent as trimethoprim-sulfamethoxazole.After parenteral administration pentamidine becomes widely distributed and is strongly tissue bound, with highest concentrations achieved in the liver and kidney and lower levels in the lung and other tissues but not in the brain. Pentamidine is detectable in some tissues up to a year after the last dose of a course of parenteral therapy. After aerosol administration pentamidine is rarely detectable in the plasma, but bronchoalveolar concentrations are 5 to > 10 times higher than after intravenous administration.A variety of jet and ultrasonic nebulisers have been used to administer aerosolised pentamidine. Important differences between them would seem to be the mass median aerodynamic diameter of particles produced and the efficiency of total drug delivery. Smaller particles (<2&mgr;m) have a more uniform distribution throughout the lung, while greater deposition of larger particles in the large airways may be associated with bronchospasm.Therapeutic TrialsFor the treatment of mild PCP (usually first episodes) in AIDS patients the results of clinical trials with inhaled pentamidine have been encouraging, particularly with the ‘Respirgard II’ nebuliser, 300 or 600mg daily for up to 21 days; the success rate has ranged from 81% to 100%.There is considerably more evidence available to support the use of inhaled pentamidine as prophylaxis in patients at high risk of developing PCP. Many of the reported studies have included over 100 patients, with the mean follow-up time ranging from 4 to 10 months, and follow-up continuing for 18 months in some patients. Maintenance dosages of pentamidine ranged from 60 to 300mg per month delivered through a variety of aerosol formulations. The incidence of PCP recurrence during pentamidine prophylaxis was consistently low (6 to 16%). In two prospective studies which included control groups there was over 80% suppression of PCP episodes with pentamidine. A dose comparison study using the ‘Respirgard II’ nebuliser revealed significantly better prophylaxis with a dose of 300mg once monthly (6.2% recurrence) than with 30mg bimonthly (18.8%). However, using the ‘Fisoneb’ formulation or other ultrasonic nebulisers, dosages of ≤ 120mg monthly (usually 60mg every 2 weeks) provided effective prophylaxis with PCP recurrence rates in the range 5.9 to 16%.Adverse EffectsNo significant systemic effects definitely attributable to inhaled pentamidine have been reported in clinical trials, in marked contrast to the poor toxicity profile of parenterally administered pentamidine. However, there have been isolated reports of pancreatitis, maculopapular rash, hypoglycaemia and pneumothoraces. Also, there have been reports of atypical pulmonaryP. cariniiinfection and extrapulmonary pneumocystosis in patients receiving inhaled pentamidine. Cough and bronchospasm have been common during inhalation, but can usually be controlled by reducing the delivery rate or intensity of the aerosol stream and/or by pretreatment with a bronchodilator.Dosage and AdministrationVarious ultrasonic and jet (flow rate about 6 L/min) nebulisers have been used successfully for prevention of PCP in high-risk human immunodeficiency virus (HIV)-positive patients. The recommended dosage of inhaled pentamidine, employing a jet nebuliser delivering particles of small size (e.g. ‘Respirgard II’), is a single 300mg dose every 4 weeks. However, with ultrasonic nebulisers delivering larger particles successful prophylaxis has been demonstrated with a dosage of 60mg twice monthly.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisDiltiazem is a calcium antagonist effective in the treatment of stable, variant and unstable angina pectoris and mild to moderate systemic hypertension, with a generally favourable adverse effect profile.It is also effective in terminating supraventricular tachycardia and in controlling the ventricular response to atrial fibrillation/flutter. Atrioventricular block, the risk of which may be exacerbated by concomitant &bgr;-adrenoceptor antagonist therapy, occurs rarely as an adverse effect of diltiazem treatment.Diltiazem appears to exert complex cardioprotective effects which have been of benefit after intracoronary administration to patients undergoing coronary angiography and by-pass procedures. In addition, long term diltiazem treatment has produced a significant reduction in subsequent cardiac events in patients with non-Q wave myocardial infarction.Thus, diltiazem is an effective and well-tolerated first-line or alternative treatment of patients with ischaemic heart disease, systemic hypertension, and supraventricular arrhythmias, with possible potential in limiting ischaemia-induced myocardial damage.Pharmacodynamic PropertiesAlthough diltiazem is a potent vasodilator, the reduction in blood pressure that accompanies its use is usually accomplished without reflex tachycardia, probably because the drug suppresses sinoatrial node stimulation. As a result, the double product (an indirect measure of myocardial oxygen demand) is reduced. In hypertensive patients, the fall in blood pressure, with regular administration, is sustained over 24 hours relative to natural circadian variation. Diltiazem has mild negative inotropic effects at clinically useful dosages but may improve myocardial relaxation and diastolic function together with decreases in afterload to produce a net improvement in left ventricular performance. In addition to reducing peripheral vascular resistance, diltiazem decreases coronary resistance. Total coronary flow is generally unchanged but there is evidence in some instances of improved patency of stenotic lesions during exertion and improved perfusion of myocardium supplied by occluded vessels. However, in some patients with complete occlusion of the left anterior descending coronary artery and distal collaterals, diltiazem may worsen flow dynamics. In common with other calcium antagonists, it is effective in preventing coronary artery spasm in patients susceptible to ergometrine (ergonovine).Work in animal heart preparations indicates that the presence of diltiazem prior to occlusion and reperfusion conserves high energy phosphates within the cell and reduces myocardial damage. Cardioprotective activity in intact animals may also involve improving the coronary vasodilatory response to ischaemia and stabilising cardiac conduction in the early phase.The response of vascular smooth muscle to diltiazem varies somewhat according to the anatomical origin of the tissue. In humans, increased blood flow has been demonstrated in the fingers and forearm, and in the splanchnic circulation only when preconstricted by digoxin. Diltiazem neither reduces renal blood flow nor alters glomerular filtration rate despite significant reductions in mean arterial pressure and systemic vascular resistance. Renal function may improve in patients with dysfunction related to hypertension. In the short term, urine flow rate and sodium excretion may increase but no effect on serum electrolyte levels or fluid retention has been observed long term. Evaluation of glucose and lipid homeostasis in diabetic and nondiabetic subjects treated with calcium antagonists indicates that diltiazem does not affect energy metabolism in the majority of individuals.Pharmacokinetic PropertiesAfter oral administration, peak plasma diltiazem concentrations are achieved within 1.5 hours for the fast release formulation and 3 to 4 hours for the slow release formulation. 90% of the administered dose is absorbed but extensive first-pass metabolism limits the absolute bioavailability to 30 to 40%. Absolute bioavailability is dose related but does not depend on dose formulation.Peak plasma concentrations of diltiazem are approximately 0.04 to 0.07 mg/L after 60mg, 0.09 to 0.12 mg/L after 90mg and 0.06 to 0.15 mg/L after 120mg. A minimum plasma diltiazem concentration of 0.10 mg/L is associated with haemodynamic change and clinical improvement. Marked individual variation occurs in plasma concentrations, particularly for the slow release formulation of diltiazem, and accumulation occurs after multiple doses. Steady-state plasma concentrations are achieved after 3 to 5 days.The mean volume of distribution is 5 L/kg. The drug is highly lipophilic and appears in cerebrospinal fluid (as studied in rabbits) and breast milk. Diltiazem is highly protein bound (80 to 90%) and binding is unaffected by its most active metabolite, deacetyl diltiazem, which is itself 60 to 75% protein bound.Diltiazem is metabolised to several metabolites, the most important beingN-monodemethyl diltiazem with 20% of the potency of diltiazem, deacetyl diltiazem with 50% of the potency of the parent drug, andN-demethyl deacetyl diltiazem. These metabolites are detectable in plasma within 30 minutes, reaching concentrations of 30 to 50%, 10 to 30% and 10 to 20% of the parent drug, respectively.The elimination half-life of orally administered diltiazem averages about 4.5 hours, with a range of 2 to 5 hours reported for intravenously administered drug. The half-lives of theN-monodemethyl and deacetyl diltiazem metabolites are approximately 7 and 8 hours, respectively. Elderly subjects demonstrate a prolonged half-life although peak plasma concentrations and total clearance of diltiazem may not be altered in the aged. Renal dysfunction does not affect diltiazem pharmacokinetics.Therapeutic UseThe effectiveness of diltiazem in patients with mild to moderate systemic hypertension (diastolic pressure ≥ 90 or 95mm Hg but ≤ 110 or 115mm Hg) has been proven in double-blind comparisons with placebo. Compared with other antihypertensive drugs [e.g. hydrochlorothiazide, &bgr;-adrenoceptor antagonists, other calcium antagonists, angiotensin converting enzyme (ACE) inhibitors] diltiazem was as effective when titrated according to diastolic blood pressure. Studies conducted over 12 to 20 months found no evidence of tolerance. When results of comparative trials were reanalysed by race and age, no trends strong enough to support the use of 1 agent over another were apparent although patient numbers were relatively small. Diltiazem was effective when given intravenously to patients with severe malignant hypertension and to patients with postoperative hypertension.In patients with stable exertional angina, short and long term diltiazem reduced the frequency of spontaneous anginal attacks and significantly improved exercise tolerance compared with placebo. The anti-ischaemic activity of diltiazem was equivalent to that of &bgr;-adrenoceptor antagonists and nifedipine or verapamil. In contrast to propranolol, diltiazem has been shown to improve left ventricular function in patients with ischaemic heart disease. When maximally tolerated propranolol (with and without long-acting nitrates) was not effective, the addition of diltiazem generally resulted in improvement. Diltiazem plus nifedipine was also an effective combination in patients unresponsive to either monotherapy. The use of diltiazem plus long acting nitrates is not extensively reported but does not appear to be particularly beneficial.Diltiazem has been shown to be effective in treating unstable angina - a condition with aspects of exertional and vasospasm-induced ischaemia. It compared favourably with intravenous nitroglycerin (glyceryl trinitrate) and oral propranolol in directly comparative trials. The potential of diltiazem in silent myocardial ischaemia remains to be clarified. Nonsignificant reductions in incidence of reinfarction have been described in patients with acute myocardial infarction treated with short term oral diltiazem; a significant protective effect was apparent in patients with angina associated with transient ST-T interval changes. In a further study among long term diltiazem recipients, there was a significantly higher rate of cardiac events in patients with pulmonary congestion, while those without pulmonary congestion had a lower rate. A similar but nonsignificant relationship was observed between ejection fraction (< 40%) and diltiazem treatment. In a cohort of patients with non-Q wave infarction, a significant reduction in cardiac events of 40% was observed.Diltiazem inhibits the slow inward calcium current, prolonging the effective and functional refractory periods of the atrioventricular node and intranodal (A-H) conduction. It was effective in terminating supraventricular tachycardia and in slowing the ventricular response to atrial fibrillation and flutter. A therapeutic role for diltiazem in the management of ventricular arrhythmias is unlikely. The role of diltiazem in treatment of Raynaud's phenomenon, oesophageal motility disorders, migraine and cardiomyopathy, and its use as an adjunct to cardioplegia, requires further investigation.Adverse EffectsDiltiazem treatment appears to be associated with a low incidence of adverse effects. The principal adverse effects are predictable given the vasodilating properties of the drug and include oedema (2.4%), headache (2.1%), nausea (1.9%), dizziness (1.5%), rash (1.3%) and asthenia (1.2%). The most frequent serious adverse event is atrioventricular block, which occurs in approximately 0.2% of patients overall; patients receiving concurrent &bgr;-adrenoceptor antagonists may be at increased risk of developing conduction disturbances.Dosage and AdministrationOral dosages recommended for the treatment of systemic hypertension and angina pectoris vary between countries and may reflect genetic differences as well as local medical practice. In patients with systemic hypertension, oral dosages of 120 to 360 mg/day are used in the United States, 180 to 360 mg/day in France and West Germany and 90 to 180 mg/day in Japan and Southeast Asia. The dosage in angina pectoris ranges between 120 to 360 mg/day in the United States, 120 to 180 mg/day in France, 90 to 180 mg/day in Japan and is 90 mg/day in Southeast Asia.Intravenous diltiazem has been effective in unstable angina (0.3 mg/kg bolus followed by 0.2 mg/min infusion) and in controlling paroxysmal supraventricular tachycardia and atrial fibrillation/flutter (generally 0.1 to 0.3 mg/kg bolus injection). Diltiazem 1mg intracoronarily has been employed to prevent vasospasm during coronary angioplasty.Since diltiazem is metabolised, dosage reductions may be necessary in patients with hepatic impairment; however, no dosage adjustment is required in patients with renal dysfunction.Diltiazem is contraindicated in sick sinus syndrome or second or third degree atrioventricular block (except in the presence of a functioning ventricular pacemaker). It should be administered with caution in the presence of atrioventricular conduction delays or transient sinus pauses. It is contraindicated in hypotension and in patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.Coadministration of diltiazem with cyclosporin increases plasma concentrations of cyclosporin; similarly, diltiazem increases digoxin concentrations.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS