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1. |
Over-the-Counter Histamine H2-Receptor AntagonistsHow will they Affect the Treatment of Acid-Related Diseases? |
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Drugs,
Volume 47,
Issue 1,
1994,
Page 1-11
Stephen Holt,
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ISSN:0012-6667
出版商:ADIS
年代:1994
数据来源: ADIS
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2. |
Leukotrienes as a Target in Asthma Therapy |
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Drugs,
Volume 47,
Issue 1,
1994,
Page 12-24
Nicholas Chanarin,
Sebastian L. Johnston,
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摘要:
Asthma is a chronic inflammatory condition characterised by bronchial hyper-responsiveness and reversible airways obstruction. Research has demonstrated that these effects are mediated by a wide range of compounds. In the last decade leukotrienes have been identified as products of arachidonic acid metabolism. Their effects mimic the pathological changes seen in asthma bothin vitroandin vivo. Further research has demonstrated increased production of leukotrienes both during episodes of asthma and in patients with stable asthma.The demonstration that leukotrienes have proinflammatory biological properties relevant to the pathogenesis of asthma has stimulated the development of many potential therapeutic compounds to block these actions. Early studies in laboratory-induced asthma in human volunteers have shown the efficacy of some of these compounds. They have been shown to attenuate the bronchoconstriction caused by allergen challenge, exercise, aspirin and exposure to cold air. Most encouraging of all have been recent placebo-controlled studies in clinical asthma where significant improvements in terms of spirometry, symptoms and &bgr;2-agonist use have been demonstrated.Leukotriene receptor antagonists and synthesis inhibitors are the first mediator antagonists to have been shown to be effective in treating clinical asthma and as such represent one of the most interesting new classes of antiasthma drugs in development at present.
ISSN:0012-6667
出版商:ADIS
年代:1994
数据来源: ADIS
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3. |
Methotrexate in Rheumatoid ArthritisAn Update |
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Drugs,
Volume 47,
Issue 1,
1994,
Page 25-50
Bernard Bannwarth,
Laurence Labat,
Yola Moride,
Thierry Schaeverbeke,
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摘要:
Methotrexate has been approved for the treatment of refractory rheumatoid arthritis by several regulatory agencies, including the Food and Drug Administration. The tendency is now to prescribe it at earlier stages of the disease.Methotrexate is a well known antifolate. Its exact mechanism of action in rheumatoid arthritis remains uncertain. The polyglutamated derivatives of methotrexate are potent inhibitors of various enzymes, including dihydrofolate reductase and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. Inhibitory effects on cytokines, particularly interleukin-1, and on arachidonic acid metabolism, as well as effects on proteolytic enzymes, have been reported. Some of them may be linked to the antifolate properties of methotrexate. Overall, the drug appears to act in rheumatoid arthritis as an anti-inflammatory agent with subtle immunomodulating properties. Direct inhibitory effects on rapidly proliferating cells in the synovium have also been suggested.Methotrexate is usually given orally. Marked interindividual variation in its bioavailability has been found. Food intake has no significant effect on the pharmacokinetics of oral methotrexate.Methotrexate undergoes significant metabolism. The functionally important metabolites are the polyglutamated derivatives of methotrexate, which are selectively retained in the cells. Less than 10% of a dose of methotrexate is oxidised to 7-hydroxy-methotrexate, irrespective of the route of administration. This metabolite is extensively (91 to 93%) bound to plasma proteins, in contrast to the parent drug (35 to 50% bound). Methotrexate is mainly excreted by the kidneys. It undergoes tubular secretion and may thereby compete with various organic acid compounds.Early placebo-controlled trials demonstrated that weekly low dosage methotrexate produced early symptomatic improvement in most rheumatoid arthritis patients. Two meta-analyses showed that methotrexate is among the most efficacious of slow-acting antirheumatic agents, together with parenteral gold (sodium aurothiomalate), penicillamine and sulfasalazine. Furthermore, in the short term context of clinical trials, methotrexate has one of the best efficacy/toxicity ratios.There is little evidence that methotrexate, or any available slow-acting antirheumatic agent, is a true disease-modifying drug. However, the probability that a patient will continue methotrexate therapy over time appears quite favourable compared with any other slow-acting antirheumatic drug. Combination therapy with slow-acting drugs has been advised for the management of rheumatoid arthritis, but the evidence currently available does not support general use of combination therapy including methotrexate.Almost all investigations indicated that toxic effects, rather than lack of response, were the major reason for discontinuing methotrexate therapy. An analysis of more than 3000 courses of therapy with 6 slow-acting drugs indicated that the overall toxicity of methotrexate was similar to that of penicillamine and azathioprine. Hydroxychloroquine was the least toxic, followed by sodium aurothiomalate, whereas auranofin was the most toxic.Few predisposing factors to methotrexate toxicity have been clearly identified, and individual susceptibility plays a primary role in determining toxicity. Folate supplementation may decrease the incidence of common adverse effects, but whether it prevents more serious adverse reactions remains to be answered. Gastrointestinal symptoms, stomatitis, increased levels of liver enzymes and mild cytopenia are frequent adverse effects associated with methotrexate therapy. Further-more, severe, and possibly life-threatening, complications have been reported. These include advanced liver fibrosis and cirrhosis, interstitial pneumonitis, severe neutropenia and pancytopenia, as well as opportunistic infections. Epstein-Barr virus-associated lymphomas have also been reported. Finally, a variety of other adverse events, such as central nervous system and cutaneous reactions, have been ascribed to methotrexate use.Numerous drug interactions may occur in patients receiving low dosage methotrexate. Most are probably not clinically significant. Conversely, methotrexate toxicity may be precipitated by concurrent use of cotrimoxazole (trimethoprim/sulfamethoxazole), probenecid, and possibly non-steroidal anti-inflammatory drugs (NSAIDs).On the basis of the available data, methotrexate should generally not be the first slow-acting antirheumatic drug to be used. However, unlike other cytotoxic agents, it should no longer be regarded as tertiary therapy for rheumatoid arthritis. Low dosage methotrexate may become one of the drugs considered earlier in the course of rheumatoid arthritis not controlled by NSAIDs alone.
ISSN:0012-6667
出版商:ADIS
年代:1994
数据来源: ADIS
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4. |
Torsade de PointesMechanisms and Management |
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Drugs,
Volume 47,
Issue 1,
1994,
Page 51-65
Carlo Napolitano,
Silvia G. Priori,
Peter J. Schwartz,
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摘要:
Torsade de pointes is a polymorphic ventricular tachycardia showing a peculiar electro-cardiographic pattern characterised by a continuous twisting in QRS axis around an imaginary baseline.An abnormally prolonged QT interval is actually associated with torsade de pointes and it is constantly observed in the sinus beats preceding the onset of the arrhythmic event. Prolongation of ventricular repolarisation associated with the development of torsade de pointes can be observed in many clinical conditions, commonly referred to as prolonged QT syndromes, which can be divided into two major groups: (a) idiopathic long QT syndrome (LQTS), which include the Jervell-Lange-Nielsen and the Romano-Ward syndromes; and (b) acquired prolonged QT syndromes, which are largely iatrogenic and may follow treatment with antiarrhythmic drugs, tricyclic antidepressants, phenothiazines or macrolide antibiotics, and may be associated with metabolic disturbances (hypokalaemia, hypocalcaemia and hypomagnesaemia).Clinical studies have provided criteria for the definition and guidelines for the management of torsade de pointes, while the electrophysiological mechanisms responsible for its onset are still unclear. Two pathogenetic hypotheses have been proposed to account for the electrophysiological mechanisms underlying the condition: (a) re-entry due to a dispersion of refractory periods; and (b) triggered activity initiated by either early or delayed after-depolarisations. Both mechanisms are supported by clinical and experimental observations but a conclusive answer is not yet available.
ISSN:0012-6667
出版商:ADIS
年代:1994
数据来源: ADIS
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5. |
Benign Prostatic HyperplasiaCurrent Pharmacological Treatment |
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Drugs,
Volume 47,
Issue 1,
1994,
Page 66-81
Morten Jønler,
Morten Riehmann,
Reginald C. Bruskewitz,
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摘要:
During the past decades, pharmacological treatment of symptomatic benign prostatic hyperplasia (BPH) has become a fairly established modality. Approaches include blockade of &agr;-adrenoreceptors and suppression of androgens. Patients eligible for drug treatment are those with mild to moderate symptoms of BPH and no strong indications for surgery.&agr;-Receptor blockers generally improve urinary symptoms and peak urinary flow rates 2 to 4 weeks after introduction of therapy. Because of minor adverse effects, selective &agr;1-blockers are preferred over nonselective drugs. Prazosin, terazosin and alfuzosin are extensively studied and widely used in BPH treatment. Terazosin might be preferred to prazosin and alfuzosin because it can be administered once daily, but a disadvantage is higher cost. Doxazosin and tamsulosin (amsulosin; YM 617) are drugs currently under clinical investigation in the treatment of BPH.Antiandrogen therapy induces reduction in prostate volume and relief in symptoms of bladder outlet obstruction. However, the only drug which seems to be of major interest in BPH treatment is finasteride. Other drugs [gonadotrophin-releasing hormone (GnRH) agonists, progestogens and flutamide] are associated with frequent and sometimes severe adverse effects, such as impotence, flushing and loss of libido. Finasteride has fewer adverse effects and is well tolerated, but needs to be administered for at least 6 to 12 months to obtain maximum effect.Future approaches in medical treatment of BPH might be combination therapy of &agr;1-blockers and finasteride.
ISSN:0012-6667
出版商:ADIS
年代:1994
数据来源: ADIS
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6. |
Treatment Recommendations for Osteosarcoma and Adult Soft Tissue Sarcomas |
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Drugs,
Volume 47,
Issue 1,
1994,
Page 82-92
Piero Picci,
Stefano Ferrari,
Gaetano Bacci,
Franco Gherlinzoni,
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摘要:
During the past 20 years, dramatic improvements have been obtained in the treatment of localised osteosarcoma of the extremities, both in the rates of disease-free survival and in quality of life.Twenty years ago 80 to 90% of the patients died, in spite of mutilating surgery, but now about 75% survive and avoid the necessity of amputation. This is due to the introduction of very effective combined treatments, mostly also using preoperative chemotherapy.One of the major issues is that of intensive preoperative chemotherapy, which improves both limb salvage and survival. A multidisciplinary approach is necessary to obtain good results.When the role of adjuvant or neoadjuvant chemotherapy is not accurately defined for soft tissue sarcomas, particular emphasis is given to the staging of the diseases and to the important role of local treatment in the survival of these patients. A combination of radiation therapy and surgery is strongly recommended.
ISSN:0012-6667
出版商:ADIS
年代:1994
数据来源: ADIS
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7. |
GallopamilA Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Ischaemic Heart Disease |
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Drugs,
Volume 47,
Issue 1,
1994,
Page 93-115
Rex N. Brogden,
Paul Benfield,
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摘要:
SynopsisGallopamil is a methoxy derivative of verapamil. As is typical of the phenylalkylamine class of calcium antagonists, it acts on the vascular system, and on the heart and its nodal structures. In the treatment of stable angina pectoris, gallopamil is at least as effective as nifedipine and diltiazem, though apparently better tolerated than nifedipine. Typical of calcium antagonists there is little or no tolerance to the antiischaemic effects of gallopamil.Preliminary studies indicate that gallopamil, like other calcium antagonists, has cardioprotective potential. However, further investigation is required to explore the clinical relevance of the improved myocardial regional perfusion and free fatty acid utilisation in reversibly ischaemic regions, and the potential of delayed ischaemia during angioplasty that is observed during gallopamil administration.Gallopamil is well tolerated, exhibiting a low propensity for causing cardiovascular and gastrointestinal adverse effects, thus making it a suitable alternative to other calcium antagonists for the treatment of patients with ischaemic heart disease.Pharmacodynamic PropertiesGallopamil, a phenylalkylamine calcium antagonist, is typical of its class in acting on the vascular system, and the heart and its nodal structures. When administered at usual oral therapeutic dosages, gallopamil generally caused little change in resting heart rate, reduced the gain in heart rate during exercise, and decreased systolic and diastolic blood pressure in patients with coronary artery disease, particularly those who developed ischaemia, both at rest and during exercise. The effect of gallopamil on rate-pressure product has varied between studies, but this parameter decreased or remained unchanged more frequently than it increased.In animal studies, gallopamil inhibited contraction of major extramural and peripheral arteries induced by potassium, acetylcholine or adrenaline (epinephrine), as well as autoregulatory constriction of peripheral resistance vessels, with a potency intermediate between those of verapamil and nifedipine. The concentration of gallopamil required to relax potassium-induced contracture of canine veins was much lower than that required to relax arteries from the same body region.In patients with normal coronary arteries, intracoronary administration of gallopamil 1.5 or 3 &mgr;g/kg produced dose-related coronary vasodilatation, while a 26% increase in the calibre of stenosed arteries followed intravenous administration of a 2mg dose. When administered orally or intravenously, gallopamil does not significantly influence normal or mildly impaired left ventricular function in patients with coronary artery disease, and improves relaxation and left ventricular filling in patients with acute myocardial infarction or hypertrophic cardiomyopathy, reflecting improved left ventricular diastolic function.Changes in intracellular calcium may be a primary event in the sequence of metabolic and ionic changes that characterise acute ischaemia. In animal studies, gallopamil attenuated the release of creatine phosphokinase and noradrenaline (norepinephrine) during reperfusion, maintained mitochondrial function, reduced microcirculatory changes induced by repetitive ischaemia, and limited the extent of myocardial necrosis when administered soon after the beginning of occlusion.Initial studies in patients with coronary artery disease suggest that oral treatment with gallopamil 50mg 3 times daily improves regional myocardial perfusion and fatty acid utilisation, and myocardial microperfusion in previously ischaemic areas of left ventricle, similarly to verapamil 80mg, diltiazem 180mg and nifedipine 60mg (all 3 times daily).Electrophysiological investigations during His bundle electrocardiography revealed that within 20 minutes of intravenous administration of gallopamil 0.06 mg/kg there was an increase in sinus rate, nodal conduction time, Wenckebach point, and functional and effective refractory period of the AV node. Sinoatrial node recovery time was prolonged only in patients thought to have sick-sinus syndrome.Oral administration of gallopamil to obese males with hypertension and impaired glucose tolerance did not influence glucose metabolism, whereas gallopamil 1mg intravenously delayed the release of insulin and C peptide after an oral glucose load in healthy volunteers.Pharmacokinetic PropertiesThe pharmacokinetic properties of gallopamil administered as the racemate have been studied in small groups of healthy volunteers and in patients with chronic stable angina pectoris. Single dose administration of gallopamil 50 and 100mg as conventional tablets resulted in mean maximum plasma concentrations (Cmax) of about 30 and 50 &mgr;g/L, respectively. Mean Cmaxvalues increased to 68.3 &mgr;g/L in healthy volunteers receiving 50mg 3 times daily for 12 days. In a comparison of single doses of conventional (50mg) and sustained release (SR) tablets (100mg), mean Cmaxand area under the plasma concentration-time curve (AUC) were 21.3 &mgr;g/L and 66.8 &mgr;g/L · h, respectively, after the conventional preparation, and 13 &mgr;g/L and 161.7 &mgr;g/L · h after the sustained release tablet. Mean trough plasma concentrations were 20.3 and 33.7 &mgr;g/L in patients treated twice daily with SR gallopamil 75 and 100mg, respectively. Despite almost complete oral absorption, systemic availability is low at 15% after a single dose and about 23% after repeated doses, due to extensive first-pass hepatic metabolism.Protein binding of gallopamilin vitroin serum of healthy volunteers is about 93% and independent of drug concentration over a range of 10 to 100 &mgr;g/L, but is influenced by pH.Gallopamil is largely eliminated by metabolism. The principal metabolite is norgallopamil, which is thought to be pharmacologically inactive. Mean total plasma clearance is 66 to 72 L/h after intravenous administration. Reported values for mean terminal elimination half-life were between 2.5 and 5.5 hours or between 4 and 8 hours after oral administration of conventional tablets, depending on assay method. Following administration of SR gallopamil, elimination half-life was reported to be between 5.3 and 8 hours. After oral administration of radiolabelled gallopamil, about 48 to 55% of cumulative14C excretion appeared in the urine and 40 to 50% in faeces in the form of metabolites. Only 0.2 to 2% of a dose was excreted unchanged in the urine.Preliminary studies in patients with liver cirrhosis given a single oral dose of gallopamil indicated that total plasma clearance was reduced, absolute bioavailability increased, and elimination half-life prolonged to an extent suggesting the need for a dosage reduction in patients with liver cirrhosis.Therapeutic EfficacyThe therapeutic efficacy of gallopamil administered orally as a conventional or sustained release product has been studied in double- or single-blind short term trials involving generally small numbers of patients with confirmed coronary artery disease and stable exertional angina pectoris. Gallopamil 50mg 3 times daily or 100mg twice daily (SR) is more effective than placebo in improving exercise time and tolerance, delaying the ischaemic threshold and decreasing the extent of ST-segment depression at comparable and maximum workload during exercise tests. Relative to placebo, gallopamil increased the duration of exercise by 9 to 44%, exercise tolerance by 24 to 57%, and decreased the ST-segment depression by 42 to 70%, Treatment with conventional or SR gallopamil reduces the mean incidence of spontaneous asymptomatic as well as exercise-induced episodes of ischaemia during 24-hour ambulatory electrocardiographic monitoring.In small numbers of patients studied for periods of 1 to 4 weeks, the overall efficacy of gallopamil 50mg 3 times daily was generally similar to that of nifedipine 10mg 3 times daily, although in one study gallopamil tended to be more effective. SR gallopamil (100mg twice daily) was superior to SR nifedipine 20mg twice daily in delaying the onset of ST segment depression. In some of the small number of crossover trials conducted, gallopamil 50mg 3 times daily was more effective than diltiazem 60mg 3 times daily in improving exercise duration, the extent of ST-segment depression and anginal attack frequency.Long term noncomparative studies of up to 2 years' duration indicated that objective and subjective improvement achieved in the first 1 to 3 months of gallopamil therapy was maintained for the duration of the study.Preliminary studies suggest the potential of intravenously administered gallopamil for the symptomatic control of unstable and variant angina.TolerabilityIn the treatment of patients with coronary artery disease, therapeutic dosages of gallopamil have been well tolerated by most patients. In large short term noncomparative trials involving a total of over 33 000 patients, gastrointestinal symptoms, including nausea, constipation, epigastric pain and other complaints, occurred in 4.4 to 8.3% of patients. Orthostatic hypotension, flushing and peripheral oedema were reported in 2 to 2.4%. Other cardiovascular complaints included bradycardia (0.5%), first and second degree AV block (0.3%), and tachycardia (0.2%). Aggravation of existing heart failure occurred in only 0.03% of patients. Adverse effects necessitated withdrawal of gallopamil in 1.4 to 3% of patients.Dosage and AdministrationThe usual oral dosage of gallopamil in the treatment of patients with chronic stable angina pectoris is 50mg 3 times daily when administered as a conventional tablet and 100mg once or twice daily as a sustained release preparation, although individualised dosages have ranged from 75 to 200mg and 100 to 200mg daily administered as conventional and sustained release preparations, respectively. In patients with unstable or variant angina, an intravenous bolus of gallopamil 30 to 60 &mgr;g/kg has been followed by continuous intravenous infusion of 0.3 to 1 &mgr;g/kg/min. Dosage should be reduced in patients with liver cirrhosis.
ISSN:0012-6667
出版商:ADIS
年代:1994
数据来源: ADIS
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8. |
CisaprideAn Updated Review of its Pharmacology and Therapeutic Efficacy as a Prokinetic Agent in Gastrointestinal Motility Disorders |
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Drugs,
Volume 47,
Issue 1,
1994,
Page 116-152
Lynda R. Wiseman,
Diana Faulds,
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摘要:
SynopsisCisapride is an orally administered prokinetic agent which facilitates or restores motility throughout the length of the gastrointestinal tract. It is a substituted piperidinyl benzamide, chemically related to metoclopramide, but unlike metoclopramide, cisapride is largely devoid of central depressant or antidopaminergic effects.In placebo-controlled trials, cisapride improved healing rates and symptoms in both adults and children with reflux oesophagitis. Maintenance therapy with cisapride at half the healing dose is effective in reducing the incidence of relapse. Symptoms are also alleviated in patients with functional dyspepsia, and gastric emptying and symptoms are improved in most patients with gastroparesis, an effect which is sustained during long term administration. However, the efficacy of cisapride in end-stage gastroparesis remains less clear. Cisapride increases stool frequency in patients with chronic constipation, and limited data suggest that the drug may also be beneficial in treating chronic intestinal pseudo-obstruction and irritable bowel syndrome. Cisapride demonstrated efficacy comparable with or superior to that of metoclopramide, and was at least as effective as cimetidine and ranitidine in patients with reflux disease. In patients with functional dyspepsia, cisapride has shown at least equal efficacy to domperidone, metoclopramide and ranitidine, and superior efficacy to cimetidine in the small comparative trials conducted to date.Adverse effects in patients receiving cisapride are generally transient and mild, with abdominal cramping, borborygmi, diarrhoea or loose stools most frequently reported. Central nervous system adverse effects are rare.Thus, with its favourable tolerability profile and demonstrated efficacy in a variety of gastrointestinal motility disorders, the position of cisapride as a valuable agent in the management of patients with gastrointestinal motility disorders is strengthening. However, larger well-controlled comparative trials of the drug with other agents are necessary before the relative position of cisapride in therapy can be categorically defined.Pharmacological PropertiesCisapride stimulates gastrointestinal motor activity through an indirect mechanism involving the release of acetylcholine mediated by postganglionic nerve endings in the myenteric plexus of the gut. It is an agonist of serotonin (5-hydroxytryptamine; 5-HT) at the 5-HT4receptor as well as an antagonist at the 5-HT3receptor. Studies indicate that the intestinal effect is most likely to result from activation of 5-HT4receptors, although other, as yet unidentified serotonin receptors may also be involved.Cisapride has been shown to reduce the exposure of the oesophagus to gastric acid - an action which can be attributed to its effects on the lower oesophageal sphincter pressure (LOSP), oesophageal clearing peristalsis and gastric emptying. Cisapride administration generally increases LOSP and oesophageal motility by about 20 to 50% in healthy adult volunteers and patients with gastro-oesophageal reflux disease (GORD). Increases in LOSP and oesophageal motility have also been found in infants with GORD after administration of the drug and in some patients with systemic sclerosis. Cisapride reduces the duration of oesophageal pH < 4 in adults and children during both day and night.In comparative studies, cisapride demonstrated an efficacy similar or superior to that of metoclopramide in reducing oesophageal acid exposure in patients with GORD, and had a more prolonged effect. When administered together with ranitidine, cisapride caused a significantly greater reduction in acid reflux than ranitidine alone.Cisapride accelerated gastric emptying of both solids and liquids to a significantly greater extent than placebo in healthy adults, and patients with idiopathic or diabetic gastroparesis, or GORD. In children with GORD and delayed gastric emptying of solids, final gastric emptying time was significantly reduced from 145 to 95 minutes after 8 weeks' treatment with cisapride 0.3 mg/kg 3 times daily. An improvement in gastric emptying has been observed in adults with intestinal pseudo-obstruction and in patients with primary anorexia nervosa after cisapride administration. Cisapride was more effective than metoclopramide in accelerating gastric emptying in patients with diabetic gastroparesis and demonstrated similar efficacy to that of domperidone. Increased gastric emptying was sustained in patients with idiopathic or diabetic gastroparesis treated with cisapride and followed for up to 3 years.Antroduodenal motility and its coordination were improved following single or multiple doses of cisapride in healthy volunteers and patients with dyspepsia during fasting and fed conditions. Antroduodenal coordination was enhanced in patients with diabetic gastroparesis and the post-prandial duodenal motility index improved in children with chronic intestinal pseudo-obstruction.Cisapride reduced transit time through the small and large bowel in healthy volunteers and patients with deficiencies in propulsive activity, including patients with diabetic autonomic neuropathy, quadriplegics and patients with gas bloat syndrome. Colonic transit time was reduced by cisapride in healthy volunteers and patients with diabetes and in patients following cholecystectomy, and the number of bowel movements increased in healthy volunteers and patients with constipation.Peak plasma concentrations of cisapride are achieved 1 to 2 hours after oral administration of a single 5 to 20mg dose. The absolute bioavailability of the oral formulation of the drug is 40 to 50%. The volume of distribution is 2.4 L/kg and cisapride is 98% bound to plasma proteinsin vitro.The drug is extensively metabolised; however, the metabolites do not appear to contribute significantly to the pharmacological activity of the drug. An elimination half-life of approximately 10 hours has been found in healthy volunteers, which may be prolonged in patients with hepatic disease and in the elderly. Renal dysfunction does not appear to affect the pharmacokinetics of cisapride and the drug is not removed by haemodialysis.Therapeutic EfficacyIn patients with GORD, endoscopically confirmed response rates after administration of cisapride 10mg 4 times daily or placebo ranged from 57 to 73% and from 12 to 53%, respectively, Cisapride therapy was associated with greater symptomatic improvement than placebo, with good or excellent responses in 57 to 91% and in 13 to 52% of patients, respectively. Cisapride 10mg 4 times daily or 20mg twice daily demonstrated similar efficacy to cimetidine 400mg 4 times daily or ranitidine 150mg twice daily in comparative trials. No significant differences were found in mucosal healing rates or symptomatic improvement between cisapride and histamine H2receptor antagonists, whereas metoclopramide 10mg 3 times daily appeared less effective in healing mucosal lesions. Coadministration of cisapride 40mg daily with ranitidine or cimetidine improved healing ratesvseither agent as monotherapy.Cisapride treatment may be beneficial in children with reflux disease, with studies showing greater improvement in reflux parametersvsplacebo and further improvement when cisapride was administered in combination with postural and dietary therapy. In preliminary comparative studies, cisapride demonstrated similar efficacy to cimetidine or a combination of Gaviscon® and Carobel®, and its efficacy was similar or superior to that of metoclopramide, although the onset of symptom relief was more rapid in cisapride recipients. Cisapride improved symptoms in some children with cystic fibrosis-associated reflux; however, further larger trials of the drug in this disease are warranted.Long term treatment with a low dosage of cisapride was effective in prolonging the duration of symptomatic and endoscopic remission, consequently reducing the incidence of relapse after endoscopically-proven healing of oesophagitis with cisapride or histamine H2receptor antagonists. After 12 months, relapse rates were significantly lower in patients treated with cisapridevsplacebo (32vs51%; p < 0.01). The duration of remission tended to be longer in patients with a lower initial degree of oesophagitis.Cisapride is effective in alleviating symptoms of functional dyspepsia (epigastric discomfort or pain, belching, bloatedness, abdominal distension, early satiety). Good or excellent responses have been reported in 63 to 86% of patients in clinical trials after treatment with cisapride 5 or 10mg 3 times daily for 3 to 6 weeks. Cisapride was superior to placebo in alleviating dyspeptic symptoms in most studies, although the placebo response was generally high in patients with functional dyspepsia (20 to 55%). In some trials the superior efficacy of cisapridevsplacebo was confined to the subgroup of patients with severe symptoms, or to the first 2-week observation period. Cisapride was more effective than placebo in improving symptoms in patients with dyspepsia refractory to metoclopramide or domperidone. In comparative studies, cisapride demonstrated similar efficacy to metoclopramide, domperidone, clebopride, ranitidine and tripotassium dicitrato bismuthate (bismuth subcitrate) in alleviating dyspeptic symptoms, and was superior to cimetidine in the subgroup of patients with dysmotility-like dyspepsia. In large-scale noncomparative trials, response rates to cisapride were good or excellent in about 80% of patients, generally irrespective of dyspepsia subgroup, concomitant disease and co-medication, but were lower in patients receiving nonsteroidal anti-inflammatory drugs. Dyspeptic symptoms recurred in about 30% of patients during a 6-month follow-up in 1 trial and were associated with pretreatment duration of dyspepsia and mean symptom score at the end of treatment.Improved gastric emptying after cisapride administration in patients with gastroparesis of various origins was associated with symptom improvement in most short and long term studies. Cisapride was generally superior to placebo in improving symptoms (mainly epigastric pain, bloating and prolonged digestion) although its efficacy in patients with severe disease remains unclear. Long term treatment with cisapride 10 to 20mg 3 times daily generally sustained accelerated gastric emptying and symptom improvement in patients followed for 2 years. Clinical studies indicate that cisapride may be effective in improving gastrointestinal atony in the postoperative phase, accelerating gastric emptying and facilitating bowel recovery; however, further studies are necessary to clarify its role in this indication.An increase in stool frequency with reduced laxative use has been found in some patients with chronic constipation following treatment with cisapride 5 to 10mg 3 times daily or 20mg twice daily. A significant increase in stool frequency has been reported in children following administration of cisapride 0.2mg/kg 3 times daily for 12 weeks, whereas placebo did not have a significant effect. The efficacy of the drug in alleviating chronic constipation in paraplegic patients remains unclear. Similarly, the possible beneficial effect of cisapride in treatment of chronic intestinal pseudo-obstruction, irritable bowel syndrome and gastric ulcer remains to be defined.TolerabilityCisapride is well tolerated by the majority of patients during short and long term treatment, and cessation of therapy due to adverse effects is rarely necessary. Transient abdominal cramping, borborygmi and diarrhoea or loose stools, the most frequently reported adverse events, are extensions of the pharmacological profile of cisapride. The drug is also well tolerated by infants and children, with an incidence of adverse effects similar to that reported in adults. Notably, central nervous system effects, such as somnolence or fatigue, are rare and extrapyramidal reactions do not occur with cisapride. Small trials suggest the incidence of adverse events reported during cisapride therapy is similar to that with cimetidine or ranitidine, but cisapride may be better tolerated than metoclopramide and clebopride.The acceleration of gastric emptying by cisapride may affect the absorption of other drugs. Concomitant administration of cisapride with ranitidine or cimetidine significantly increases the rate of absorption of the H2antagonists and the bioavailability of cisapride is increased by cimetidine administration. Cisapride also accelerates absorption of disopyramide, flecainide, cyclosporin, alcohol and morphine, and may increase coagulation time in patients receiving anticoagulant agents concomitantly.Dosage and AdministrationPatients with functional dyspepsia or constipation should receive oral cisapride 5mg 3 times daily, increasing to 10mg 3 times daily if necessary. Cisapride should be administered at the higher dosage of 10mg 4 times daily to patients with GORD or gastroparesis; 0.2 mg/kg (increased to 0.3 mg/kg if necessary) 3 to 4 times daily (suspension formulation) is recommended in infants and children with GORD. The recommended dosage for maintenance treatment of GORD is half that recommended for healing i.e. 10mg twice daily or 20mg once daily, which may be increased to 20mg twice daily. A 50% reduction in initial dosage is recommended in patients with renal or hepatic impairment. In all instances, cisapride should be taken 15 to 30 minutes prior to a meal.
ISSN:0012-6667
出版商:ADIS
年代:1994
数据来源: ADIS
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9. |
AciclovirA Reappraisal of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy |
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Drugs,
Volume 47,
Issue 1,
1994,
Page 153-205
Antona J. Wagstaff,
Diana Faulds,
Karen L. Goa,
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摘要:
SynopsisAciclovir (acyclovir) is a nucleoside analogue with antiviral activityinvitro against the herpes simplex viruses (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6).Topical, oral or intravenous aciclovir is well established in the treatment of ophthalmic, mucocutaneous and other HSV infections, with intravenous aciclovir the accepted treatment of choice in herpes simplex encephalitis. The efficacy of aciclovir is increased with early (preferably during the prodromal period) initiation of treatment but, despite significant clinical benefit, viral latency is not eradicated, and pretreatment frequencies of recurrence usually continue after episodic acute treatment is completed. Intravenous administration has also shown benefit in the treatment of severe complications of HSV infection in pregnancy, and neonatal HSV infections. Recurrence of HSV has been completely prevented or significantly reduced during suppressive therapy with oral aciclovir in immunocompetent patients.Use of oral aciclovir is effective but controversial in the treatment of otherwise healthy individuals with varicella (chickenpox), and in some countries it has been recommended for use only in cases which may be potentially severe. The development of rash and pain associated with herpes zoster (shingles) is attenuated with oral or intravenous aciclovir therapy, ocular involvement is prevented, and post-herpetic neuralgia appears to be decreased. Similarly, in a few patients with zoster ophthalmicus, oral aciclovir has reduced the frequency and severity of long term ocular complications and post-herpetic neuralgia, and herpes zoster oticus is improved with intravenous aciclovir.Oral aciclovir has prevented recurrence of HSV genital or orofacial infections during suppressive therapy in > 70% of immunocompetent patients in most clinical trials. Suppression of latent HSV, VZV and CMV infections has been achieved in many immunocompromised patients receiving the oral or intravenous formulations. Aciclovir also appears to offer partial protection from invasive CMV disease in CMV-seropositive bone marrow transplant recipients.The few comparative trials published have shown aciclovir to be at least as effective as other investigated antivirals in the treatment of HSV infections in immunocompetent patients, and more effective than inosine pranobex in the prophylaxis of genital herpes. Similarly, in isolated clinical trials, oral aciclovir appears as effective as topical idoxuridine and oral brivudine in some parameters in immunocompetent patients with VZV infections, and the intravenous formulation appears at least as effective as oral brivudine and intravenous vidarabine in treating these infections in immunocompromised patients. Investigations of a regimen of aciclovir plus zidovudine in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) suggest some advantage for the combination over zidovudine monotherapy in reducing the incidence of opportunistic infections and mortality. However, patient numbers were limited and these preliminary results require substantiation.Aciclovir is well tolerated. Mild gastrointestinal effects may occur with the oral formulation in a few patients, and acute reversible renal failure and neurotoxicity has been associated with high peak plasma aciclovir concentrations, usually in patients receiving intravenous administration.Thus, aciclovir in intravenous, oral and to a lesser extent topical formulations retains its secure position as an effective agent in the therapy and prophylaxis of HSV and VZV infections in immunocompetent and immunocompromised patients, with no clear advantages shown for newer agents over aciclovir in limited comparisons. The role of aciclovir in the prevention of CMV infections in immunocompromised patients is also generally accepted, but its use in diseases caused by other herpes viruses such as EBV and HHV-6 has not been supported in clinical investigations to date. Nonetheless, there appears to be potential for further growth in the role of aciclovir if combination regimens become more accepted in the treatment of viral infections, and if its efficacy in reducing opportunistic infections and associated mortality in patients with AIDS or ARC is confirmed.Antiviral ActivityAciclovir (acyclovir) selectively inhibits DNA replication of herpes viruses, with low host cell toxicity. The antiviral is preferentially activated in infected cells; initial phosphorylation occurs via viral thymidine kinase, and aciclovir triphosphate (the active derivative obtained from the monophosphate via host cell enzymes) inhibits viral DNA polymerase more readily than the cellular enzyme, thus preventing viral replication. Although Epstein-Barr virus (EBV) appears to have only minimal thymidine kinase activity, EBV DNA polymerase is very susceptible to inhibition by aciclovir triphosphate. Since cytomegalovirus (CMV) does not code for thymidine kinase, and CMV DNA polymerase is poorly inhibited by aciclovir triphosphate formed by cellular enzymes, CMV is less susceptible to aciclovir than are herpes simplex virus (HSV), varicella zoster virus (VZV) and EBV.In descending order of susceptibility, the viruses against which aciclovir exhibitsin vitroantiviral activity are HSV-1 and 2, VZV, EBV, human herpesvirus 6 (HHV-6) and CMV. Thein vitroactivity of aciclovir was generally similar to or greater than that of most other antiviral agents tested against HSV and VZV; ganciclovir, idoxuridine and vidarabine are more potent than aciclovir against CMV; ganciclovir and foscarnet appear to be more potent against HHV-6; and aciclovir appears to have greater activity than penciclovir against EBV. Combination of aciclovir with various antiviral compounds has resulted in synergistic or additive antiviral activityin vitroagainst HSV, VZV and CMV. Although part of the latent HSV reservoir is eradicated by aciclovir in ganglionic or tissue cultures and replication is readily interrupted, reversion to latency occurs after several days of exposure.Thein vivoactivity of aciclovir was demonstrated in animal models of HSV ocular, cutaneous, genital, CNS and neonatal infections. Initiation of aciclovir administration within 24 hours of viral challenge can reduce the establishment of viral latency following primary infection, but eradication of established latent virus has not been achieved. Activity as a prophylactic agent has been demonstrated in rabbits with HSV keratitis. Combination with other antiviral agents, such as vidarabine, ribavirin or ribonucleotide reductase inhibitors, has resulted in synergistic effects against HSV infections in animals.Most aciclovir-resistant strains of HSV and VZV have mutations in the thymidine kinase gene which result in little or no production of the enzyme. Resistant HSV strains occur infrequently in immunocompetent patients, and reactivation of these strains from latency is rare. However, aciclovir-resistant HSV strains causing clinical disease are becoming increasingly common among the immunocompromised population. Reports of aciclovir-resistant strains of other herpes viruses are comparatively rare.Pharmacokinetic ProfileThe pharmacokinetic disposition of intravenous aciclovir is not affected by dose, duration or frequency of administration. Steady-state plasma aciclovir concentrations in immunocompromised patients (6.7 to 20.6 mg/L after intravenous doses of 2.5 to 15.0 mg/kg every 8 hours) are similar to those obtained with equivalent single doses. Absorption of oral aciclovir is slow and variable, with a bioavailability of 15 to 30%. There is no systemic absorption of topical aciclovir from the ointment, but 30 to 50% of the drug reaches the basal epidermis in cutaneous infections treated with the cream formulation, and substantial intraocular penetration occurs with the ophthalmic ointment.Orally or intravenously administered aciclovir is distributed to a wide range of tissues and fluids, crosses the placenta and accumulates in breast milk. Plasma protein binding is 9 to 33%, and is independent of plasma aciclovir concentrations. Drug interactions appear to be scarce. Area under the plasma concentration-time curve values and elimination half-life are increased when aciclovir and probenecid are coadministered.The main metabolite, 9-carboxymethoxymethyl guanine, accounts for about 14% of a dose and is pharmacologically inactive. Since the main route of elimination is via renal excretion, kidney dysfunction affects plasma concentrations, extent of metabolism and rate of elimination of the drug. The elimination half-life in adults with normal renal function is 2 to 3 hours, extending to about 20 hours in patients with end-stage renal failure. The half-life in dialysis patients is 6 to 10 hours, but is prolonged to 13 to 18 hours during continuous ambulatory peritoneal dialysis. In neonates, total body clearance is reduced and elimination half-life is increased to up to 5 hours.Therapeutic EfficacyIn Immunocompetent PatientsDouble-blind placebo-controlled studies in immunocompetent patients have demonstrated the efficacy of intravenous (5 mg/kg 3 times daily), oral (200mg 5 times daily) and topical (applied 4 to 6 times daily) aciclovir initiated within 4 days of the first symptoms of HSV perigenital infection. The duration of viral shedding and time to complete healing of lesions are significantly reduced, particularly in the primary episode. Topical aciclovir is less effective in ameliorating symptoms than are the other formulations. Comparison of topical aciclovir and intramuscular interferon-&agr; has demonstrated no significant differences in the treatment of primary genital herpes infection, with a trend in favour of aciclovir in parameters involving time to healing, pain, and viral response. The rate of recurrence of infection is not affected by initial treatment with aciclovir.Most well-controlled trials have shown complete suppression of genital herpes recurrence in 71 to 88% of immunocompetent patients, using prophylaxis with oral aciclovir 800 to 1000 mg/day for up to 2 years. Pretreatment recurrence rates returned on discontinuation of aciclovir. Complete suppression of recurrence for 5 years has been achieved in 20% of patients on aciclovir prophylaxis (800 to 1600 mg/day). Two well-controlled trials have demonstrated a clear advantage for oral aciclovir over oral inosine pranobex in the suppression of recurrent genital HSV infection.Oral aciclovir therapy causes significant improvements in recurrent orofacial and cutaneous infections if begun as early as possible after reactivation. Prophylaxis with topical, and especially oral, aciclovir reduces the severity and frequency of orofacial and cutaneous HSV recurrence during treatment. Reductions in symptoms are small with topical treatment of recurrent orofacial herpes in immunocompetent patients.Aciclovir 3% ophthalmic ointment 5 times daily eliminates 95 to 100% of herpetic dendritic corneal ulcers in 5 to 9 days, and is at least as effective as idoxuridine 0.5 and 1.0%, trifluridine 2% and vidarabine 3% ointments. The ophthalmic ointment is also as effective as vidarabine in treating geographic corneal ulcers. Combination of aciclovir with topical interferon-&agr; shortens the time to healing of superficial herpetic keratitis by several days compared with aciclovir alone. Oral administration of aciclovir appears to be equivalent or superior to topical administration in the treatment of herpetic disciform keratitis. Addition of topical corticosteroids to the ophthalmic ointment has proved effective in treating herpetic disciform keratitis and necrotising stromal keratitis unresponsive to single agent therapy.Aciclovir ophthalmic ointment is as effective as vidarabine ophthalmic ointment in herpetic disciform keratitis and trifluridine ophthalmic solution in herpetic kerato-uveitis, when cortico-steroids are included in the regimens. However, corticosteroids may not be necessary in patients with HSV uveitis previously untreated with corticosteroids if oral aciclovir is added to topical aciclovir therapy. Prophylaxis with oral aciclovir 800 to 1000 mg/day for 12 to 15 months completely prevented HSV keratitis recurrence in all patients undergoing penetrating keratoplasty, compared with a recurrence rate of 44% in an untreated group.The treatment of choice for HSV encephalitis, intravenous aciclovir 10 mg/kg every 8 hours for at least 10 days, improves survival rates and reduces the incidence of serious sequelae to infection. Addition of interferon-&bgr; to the regimen provided no advantage in most patients. A placebo-controlled trial of oral aciclovir prophylaxis (800 mg/day for 26 weeks) in HSV erythema multiforme has substantiated previous reports of efficacy. Case studies have reported successful intravenous aciclovir treatment and prophylaxis in patients with HSV meningitis, and successful treatment of HSV-associated encephalitis, disseminated infection and hepatitis in pregnant women, followed by survival of mothers and infants without complications. Intravenous aciclovir and vidarabine appear equally effective in the treatment of neonatal HSV infections including mucocutaneous infection, encephalitis and disseminated disease.There is some controversy over the role of aciclovir in treating varicella (chickenpox) in otherwise healthy individuals, since the disease is usually self-limiting. Nonetheless, oral aciclovir initiated within 24 hours of the appearance of the rash associated with varicella (chickenpox) has resulted in decreased numbers of lesions, duration of new lesion formation, severity or duration of pruritus, time to healing and duration of fever in otherwise healthy children, adolescents and adults in several well-designed studies. Clinical improvement has been noted in a few adults with varicella pneumonia receiving intravenous aciclovir, and maternal mortality rates associated with this complication have been decreased during pregnancy.In patients with herpes zoster (shingles), intravenous (5 mg/kg every 8 hours for at least 5 days) or oral (4000 mg/day for 7 days) aciclovir treatment begun within 72 hours of exanthem onset attenuates the development of rash and pain, offers protection against ocular involvement and appears to decrease the duration of post-herpetic neuralgia. Topical idoxuridine was superior to oral aciclovir in some parameters in one double-blind study, but efficacy was similar in time to disappearance of papulopustules, appearance of first scabs, loss of all scabs, and disappearance of erythema or pain. Oral brivudine was associated with significantly greater reductions in pain and new lesion formation compared with intravenous aciclovir in elderly cancer patients with severe herpes zoster, but there were no differences in time to loss of vesicles or time to full crusting.Although the immediate efficacy of aciclovir ophthalmic ointment in the treatment of zoster ophthalmicus is equivocal, oral aciclovir begun within 72 hours of skin eruption produces significant reductions in the longer term (up to 12 months) in frequency and severity of ocular complications such as dentriform keratopathy, stromal keratitis and anterior uveitis in these patients.Case reports and one small placebo-controlled trial have demonstrated rapid improvement of facial function grade in patients with herpes zoster oticus treated with intravenous aciclovir, and success is also reported in isolated cases of patients with herpes zoster-associated encephalitis, myelitis, idiopathic vocal cord paralysis and Rosai Dorfman disease. Recurrence of severe almost constant aphthae has been prevented or decreased with oral aciclovir 1600 mg/day for 10 weeks.Although trends towards faster improvement have been recorded in 2 double-blind trials of aciclovir versus placebo in patients with infectious mononucleosis, no statistically significant differences were seen. Addition of aciclovir to interferon-&agr; therapy in patients with chronic hepatitis B appears to offer some advantages over monotherapy, but no significant differences in the rate of seroconversion were demonstrated. Aciclovir has prevented postsurgical recurrence of laryngeal papillomatosis in 3 children and improved symptoms of epilepsia partialis continua in 4 patients.In Immunocompromised PatientsThe efficacy of intravenous (250 mg/m2every 8 hours) or oral (2000 mg/day) aciclovir is well established in the treatment of immunocompromised patients with HSV infections. Severe infections refractory to normal dosages of aciclovir (such as HSV hepatitis, or infections caused by viruses deficient in thymidine kinase activity) may respond to higher dosages, as demonstrated in case reports. Topical administration (5% in polyethylene glycol) reduced the period of viral shedding in renal transplant recipients, but the value of topical aciclovir is limited in severely immunocompromised patients.Viral shedding and/or scabbing time, deterioration in clinical condition and progression of the disease are reduced in immunocompromised patients with VZV infections treated with intravenous aciclovir (500 mg/m2every 8 hours for 5 to 8 days). In this setting aciclovir appears as effective as oral brivudine and at least as effective as intravenous vidarabine. Oral aciclovir is also effective in promoting healing and preventing dissemination of varicella in immunocompromised patients, and topical aciclovir reduced time to pustulation, crusting and healing in immunocompromised patients with localised herpes zoster.Virtually complete suppression of latent HSV or VZV infections during intravenous or oral aciclovir prophylaxis has been demonstrated in most patients at increased risk of recurrence because of bone marrow transplantation, radiotherapy or cytotoxic chemotherapy, while up to 50% of infections which did recur involved asymptomatic viral shedding only. While protection was confined to the period of therapy in most patients, there is evidence that long term prophylaxis may also result in a reduction in the rate of HSV infections, compared to that seen in placebo recipients, after discontinuation of therapy. Oral aciclovir prophylaxis has provided protection against HSV and VZV infections in patients receiving renal transplants, and against HSV infections in liver and heart transplant recipients, with complete suppression of clinical symptoms during treatment in most patients. The incidence of HSV infection was also reduced in renal and heart transplant patients for up to 12 months following withdrawal of aciclovir prophylaxis.High dose oral or continuous infusion of intravenous aciclovir have resulted in resolution of EBV infections such as oral hairy leucoplakia in immunocompromised patients, but reactivation of latent infection occurs frequently on discontinuation of the drug. Similarly, although aciclovir treatment of symptomatic CMV infection in immunocompromised patients has generally resulted in little clinical improvement, continuous infusion has resolved the infection in isolated cases.Aciclovir prophylaxis appears to decrease CMV shedding, and reduce the incidence of clinically evident and invasive CMV disease, and possibly that of associated mortality, in immunocompromised patients with haematological disorders, despite decreased activity compared with prophylaxis against HSV and VZV. The rate of CMV infection after treatment was decreased in some patients. The incidence of CMV infection was reduced by about half (to 36%) during 1 year of observation after a 12-week course of oral aciclovir prophylaxis (800 to 3200 mg/day) in a double-blind trial in renal transplant recipients, and by half to two-thirds (to 18.3 to 30.8%) in liver transplant recipients after a 12-week course of oral aciclovir (2000 to 3200 mg/day) in several trials. Oral aciclovir plus CMV-specific immunoglobulin prophylaxis appears to offer some advantage in preventing CMV infection in patients receiving heart or lung transplants but controlled double-blind trials have not been performed in this patient population.The effects of aciclovir alone or combined with zidovudine on laboratory measures of human immunodeficiency virus infection are equivocal, but recent double-blind studies have suggested that combined therapy may offer an advantage over zidovudine monotherapy in terms of survival and incidence of opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex.TolerabilityAciclovir is well tolerated whether administered by ocular, topical, oral or intravenous routes. Adverse reactions to topical preparations have been mainly limited to mild local effects. The incidence of most adverse events, such as gastrointestinal symptoms, rash and headache, occurring during oral aciclovir therapy is similar to that seen in patients receiving placebo. There have been occasional reports of acute, usually reversible, renal failure and neurotoxicity associated with the oral formulation, but these occur more often with intravenous administration, usually in patients with high peak plasma aciclovir concentrations. Slow infusion rates, adequate hydration and lower dosages of aciclovir are recommended in patients with renal dysfunction. The effects of aciclovir on immune function have not yet been clarified. Depression of the immune response to herpesvirus antigens associated with oral and intravenous aciclovir treatment or prophylaxis in some studies is postulated to be a result of viral inhibition rather than a direct immunosuppressant effect.Dosage and AdministrationTherapy with aciclovir should be initiated as soon as possible after the onset of signs or symptoms. For dosage recommendations in specific herpesvirus infections see table XI on page 192. Dosage reductions proportional to the degree of impairment are necessary in patients with moderate to severe renal dysfunction.
ISSN:0012-6667
出版商:ADIS
年代:1994
数据来源: ADIS
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