ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Recently there has been extensive development of orally active angiotensin converting enzyme (ACE) inhibitors in addition to those already marketed, for example, captopril, enalapril, lisinopril and ramipril. It was initially thought that ACE inhibitors were likely to be most useful as antihypertensive agents in conditions in which circulating renin and angiotensin II were elevated. However, it is now clear that they can also lower arterial pressure when plasma renin is not high. In addition, they have beneficial effects in cardiac failure.Thus, captopril, enalapril, lisinopril and ramipril can be used in the treatment of mild to moderate hypertension either alone or in conjunction with diuretics or calcium antagonists. Broadly speaking, efficacy appears to be similar to that of &bgr;-blockers or diuretics. Unfortunately, however, there are no long term studies comparing one ACE inhibitor with another or with other classes of antihypertensive agents. Furthermore, there are no prognostic studies which show that use of ACE inhibitors reduces morbidity or mortality in hypertension.Many new ACE inhibitors are undergoing clinical assessment, including alacepril, cilazapril, fosenopril, perindopril, quinapril and ramipril. The drugs vary, in that some exist in the active form whereas others are prodrugs which are converted to the active agent following absorption. In addition they each possess one of several ligands, for example, carboxyl, phosphinyl or sulfhydryl groups, and so vary in their affinity for ACE. Although many of these agents are renally excreted, a small number are metabolised via the liver (e.g. quinapril and spirapril) and this may prove advantageous in the presence of renal impairment.In common with captopril and enalapril, the new ACE inhibitors inhibit the reninangiotensin system and initial results suggest that they are effective in lowering blood pressure in essential hypertension. Furthermore, they reduce systemic vascular resistance in the absence of a reflex tachycardia.There are a number of adverse effects which are attributable to the pharmacological mechanism of the ACE inhibitors as a group; these include hypotension, particularly in patients with high renin levels, prior diuretic use, renal impairment or in the elderly. Additional adverse effects may relate to chemical structure. The high incidence of adverse effects noted in early studies related to excess dosage and to the presence of a sulfhydryl group, which the more recently developed ACE inhibitors lack. The adverse effects most commonly reported with established and new ACE inhibitors include headache and fatigue, cough, skin rashes, hypotension and diarrhoea. As a group, ACE inhibitors have an acceptable but not negligible adverse effect burden. They need to be introduced cautiously if plasma renin is likely to be raised, and in the elderly, both circumstances in which first dose hypotension may occur. They can depress renal function in cases of bilateral renal artery stenosis and in cardiac failure.The ACE inhibitors have now been shown to be effective in the treatment of moderate hypertension, in supporting the ailing heart, and in combination with various other classes of antihypertensive drugs. While caution is needed with any new type of agent until wide experience has accumulated, ACE inhibitors clearly possess several features which make them attractive candidates for the initiation of antihypertensive therapy.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The decision to initiate total parenteral nutrition (TPN) in hospitalised patients should be based on the presence of clinically significant starvation and dysfunction of the gastrointestinal tract. It must also take into account the clinical status of the patient, considering major treatment strategies and the need for prolonged hospitalisation, the benefits of feeding and the attendant risks of central venous alimentation. Recent evidence in surgical patients in intensive care provides the impetus for early parenteral feeding; withholding TPN and inducing a cumulative caloric deficit of ≥ 10 000 calories has been associated with a survival disadvantage compared to those patients with a positive caloric balance. Moreover, the incidence of serious organ failure was consistently higher in the group with cumulative caloric deficits. Additional evidence favouring the provision of TPN exists, but the axiom ‘if the gut works, use it’ still prevails. Exceptions to this precept do exist, however, particularly in critically ill patients. The metabolic derangements encountered in these patients could be so severe that it may be impossible to correct the electrolyte and acid-base abnormalities via the enteral route. For example, such patients may have large potassium requirements and/or severe alkalaemia necessitating systemic acidification with hydrochloric acid, precluding enteral delivery due to gastrointestinal intolerance. In this setting, combined enteral feeding with 10 to 20 ml/h to maintain gut integrity (via a post-pyloric feeding tube) and TPN during the acute phases of illness is an exciting possibility.Once the decision to feed is made, the amount of nutrition prescribed may assume equal importance with respect to patient outcome. The frequent use of the Harris-Benedict equation, plus a multiplying factor for stress, may overestimate caloric requirements; this is particularly true during critical illness. The dangers of overfeeding may be just as harmful as not feeding at all. The use of indirect calorimetry provides the most accurate measurement of resting energy expenditure. However, in the absence of indirect calorimetry, modified equations to estimate caloric needs are available. Caution must be observed as caloric intakes exceeding the range of 25 to 35 kcal/kg may be dangerous, particularly in the severely ill patient with preexisting organ failure.The amount of protein and the ‘calorie-mix’ necessary for optimal nutritional support is open to debate. Recent evidence has demonstrated no additional benefit to nitrogen balance in severely septic patients when protein was given at a level exceeding 1.5 g/kg/day. Similarly, protein intakes > 1.75 g/kg/day in patients with advanced gastrointestinal cancer did not achieve a state of net protein synthesis. Therefore, for most patients with moderate to severe degrees of stress, a level of protein intake up to 1.75 g/kg/day is reasonable, since levels above this offer no additional benefits and most likely lead to ureagenesis.Carbohydrate intake is important for a number of vital physiological functions, and it is an essential macronutrient. However, excessive glucose administration is associated with a number of adverse effects. In general, glucose infusion rates should not exceed 4 mg/kg/min for 2 reasons: first, this rate is equal to its optimal infusion rate, and dosages above this level increase the rate of lipogenesis; and second, even doubling its optimal infusion rate has not been shown to improve protein-sparing in severely stressed patients. Hence, the carbohydrate content should generally not exceed 4 mg/kg/min (i.e. approximately 400g in the reference 70kg man) with the balance of the calories provided as lipids. When given as long chain triglycerides (LCT), lipids should preferably be given continuously as a 3-in-1 or total nutrient admixture.Finally, we recommend that nutrition support teams take an aggressive approach to the management of severely ill patients. Manipulations that reduce volume burdens, such as concentrating all separate (i.e. piggyback) infusions, as well as using the TPN as a drug vehicle (where appropriate), will afford greater likelihood of providing the necessary protein and calories. Furthermore, managing the plethora of metabolic derangements frequently encountered in the intensive care unit (i.e. acid-base and electrolyte disturbances) via the TPN should reduce the dangers of protracted imbalances. It is obvious that professional training of pharmacists and physicians specialising in clinical nutrition is needed to achieve optimal care of these patients.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Infections in burn patients continue to be the primary source of morbidity and mortality. Topical antimicrobial therapy remains the single most important component of wound care in hospitalised burn patients. The goal of prophylactic topical antimicrobial therapy is to control microbial colonisation and prevent burn wound infection. In selected clinical circumstances topical agents may be used to treat incipient or early burn would infections. At the present time silver sulfadiazine is the most frequently used topical prophylactic agent; it is relatively inexpensive, easy to apply, well tolerated by patients, and has good activity against most burn pathogens. In patients with large burns the addition of cerium nitrate to silver sulfadiazine may improve bacterial control. Mafenide acetate has superior eschar-penetrating characteristics, making it the agent of choice for early treatment of burn wound sepsis. However, the duration and area of mafenide application must be limited because of systemic toxicity associated with prolonged or extensive use. Other agents, such as nitrofurazone or chlorhexidine preparations, may be useful in isolated clinical situations. The undesirable side effects of silver nitrate solution limit its use by most clinicians at the present time.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisAs a member of the class Ib antiarrhythmic drugs mexiletine's primary mechanism of action is blocking fast sodium channels, reducing the phase 0 maximal upstroke velocity of the action potential. It increases the ratio of effective refractory period to action potential duration, but has little effect on conductivity. Unlike quinidine it does not prolong QRS and QT (QTc) intervals.In the dosage range 600 to 900mg daily mexiletine effectively suppresses premature ventricular contractions (PVCs) in 25% to 79% of patients, with or without underlying cardiac disease. In comparative studies the response rate was comparable to that with quinidine or disopyramide. However, the use of antiarrhythmic therapy in patients with asymptomatic arrhythmias is controversial. More importantly, mexiletine abolishes spontaneous or inducible ventricular tachycardia or fibrillation in the short term in 20% to 50% of patients with refractory arrhythmias. Arrhythmia suppression is maintained in 57% to over 80% of these early therapeutic successes in the long term, with mexiletine alone or in combination with another antiarrhythmic drug. As with other antiarrhythmic drugs, there is no substantial evidence that administration of mexiletine after acute myocardial infarction improves long term prognosis.Although the incidence of adverse effects associated with mexiletine is high, the majority are minor gastrointestinal or neurological effects which can be adequately controlled through dosage adjustment. Furthermore, mexiletine has minimal effects on haemodynamic variables, or on cardiac function in patients with or without pre-existing deterioration of left ventricular function, and it appears to have a low proarrhythmic potential. Thus, while the therapeutic efficacy of mexiletine for the prevention or suppression of symptomatic ventricular arrhythmias may be no greater than that of other antiarrhythmic drugs, and less than that of some (e.g. amiodarone), it is effective in a significant proportion of patients refractory to other treatments and can be administered without causing adverse haemodynamic effects to patients with complicating factors such as acute myocardial infarction or congestive heart failure.Pharmacodynamic PropertiesMexiletine is an orally active class Ib antiarrhythmic drug. It blocks the fast sodium channel, reducing the rate of depolarisation of the cardiac action potential. In preclinical studies it enhanced the threshold of excitability, decreased conduction velocity and shortened the effective refractory period, but most importantly it increased the ratio of effective refractory period to action potential duration. Clinical studies show little influence of mexiletine on atrial refractoriness or AV nodal function. There are reports of lengthening of the ratio of His-bundle to ventricular muscle conduction time in patients with impaired conduction, but this has not been confirmed in other studies. The electrophysiological effects of mexiletine are more pronounced in diseased (e.g. ischaemic) than healthy tissue, and in patients with conduction disorders than in healthy volunteers. Both preclinical and clinical studies have demonstrated additive or synergistic electrophysiological effects with the combination of mexiletine and quinidine. Mexiletine, unlike quinidine has no significant effect on QRS duration, PR interval or QTc interval.Mexiletine has a minimal effect on haemodynamic variables. There is evidence of a minor negative inotropic effect in healthy volunteers receiving acute administration of mexiletine 3 mg/kg intravenously or 200mg four times daily orally. This effect is equivalent to that with propafenone but less than that with disopyramide. However, radionuclide ventriculography revealed that acute or long term oral therapy with mexiletine (up to 1200mg daily) had no significant effect on cardiac function in patients with ventricular arrhythmias whether or not they had pre-existing impairment of ventricular function.Pharmacokinetic StudiesAfter intravenous administration of mexiletine there is extensive tissue uptake with an initial rapid and subsequent slow distribution phase. The volume of distribution is over 600L in healthy subjects. The bioavailability after oral administration in healthy volunteers is about 90%. Peak plasma concentrations are achieved in 2 to 4 hours and there is a linear dose-plasma concentration relationship in the dose range 100 to 600mg. With multiple oral administration steady-state is achieved after 4 or 5 days with no evidence of accumulation.There is extensive hepatic metabolism of mexiletine to inactive metabolites, and only about 8 to 15% of an administered dose is eliminated unchanged in the urine. At physiological pH the elimination half-life has been reported in the range 7.5 to 11.3 hours, but this is prolonged in the presence of alkaline urine. A sustained release formulation of mexiletine (360mg capsules) has equivalent bioavailability to the standard preparation but produces lower peak plasma concentrations at 4 to 6 hours after administration and maintains higher trough concentrations.Patients with recent acute myocardial infarction (AMI) have delayed absorption of mexiletine. They also have an increased volume of distribution and prolonged elimination. In contrast there is very little variation in the pharmacokinetics of mexiletine in patients with renal disease, even those on dialysis, or in elderly patients. Patients with hepatic disease may have a markedly prolonged elimination half-life and reduced rate of clearance of mexiletine, resulting in plasma concentrations above the therapeutic range of 0.5 to 2 mg/L in some.Therapeutic UseFor suppression of premature ventricular complexes (PVCs) in patients with or without underlying cardiac disease, orally administered mexiletine, usually at dosages in the range 600 to 900mg daily for < 1 to 12 weeks, produces response rates in the range 25% to 79%. The wide variation in response results from the variations in definition of response, trial population, study design, dosage and duration of treatment. Mexiletine 600mg daily for 2 weeks produced ≥ 75% PVC suppression in 72 to 82% of 144 patients in a placebo-controlled crossover trial. In a large comparative, parallel design study mexiletine 600 to 1200mg daily and quinidine 800 to 1600mg daily for 12 weeks, each in about 245 patients, produced ≥ 70% PVC suppression in 31% and 32% of patients, respectively. Other small parallel design studies revealed response rates of 54 to 69% with mexiletine, similar to those with quinidine. In short term crossover studies involving small numbers of patients mexiletine 300 to 1000mg daily consistently produced more strictly defined response rates (≥ 75% to ≥ 90% PVC suppression) of about 30%, which were comparable with the response rate to disopyramide 300 to 800mg daily but less than that with propafenone 900mg daily or intravenous lidocaine (lignocaine) 20mg then 2.75 mg/min. PVC suppression by mexiletine is similar in patients with or without organic heart disease. Controlled trials have shown that sustained release mexiletine 360mg twice daily produces equivalent PVC suppression to conventional mexiletine 200mg 3 or 4 times daily.Mexiletine (usually 600 to 900mg daily) abolished spontaneous or inducible VT or VF in the short term in 10% to 20% of patients with refractory arrhythmias in most studies which employed programmed electrical stimulation (PES). The response rate and tolerability can be improved with the addition of a class Ia antiarrhythmic drug or amiodarone, although further controlled trials are necessary to delineate the role of mexiletine in combination with other antiarrhythmic drugs. Long term maintenance therapy with mexiletine 600 to 900mg daily in patients whose refractory ventricular arrhythmias responded to initial treatment prevented arrhythmia recurrence in 57% to over 80% for periods of up to 6 years. Sustained therapeutic response is more predictable when initial success is defined, and mexiletine dosage determined by PES than ambulatory ECG monitoring. However, between 20% and 40% of patients might be expected to have arrhythmia recurrence or develop intolerable adverse effects during mexiletine maintenance therapy.Intravenous and/or oral administration of mexiletine is effective at suppressing ventricular arrhythmias complicating the early or late stages of AMI. Despite this mexiletine did not reduce mortality. In fact, medium term mortality (3 to 12 months) was slightly higher with mexiletine than with placebo. Any benefit on long term prognosis after AMI has yet to be proven, either with mexiletine or other class I antiarrhythmic drugs, and in view of the preliminary findings of the Cardiac Arrhythmia Suppression Trial, routine prophylactic PVC suppression cannot be recommended in asymptomatic or mildly symptomatic patients.Adverse EffectsThere is a particularly high incidence of adverse effects after acute intravenous administration of mexiletine. With lower initial doses or oral administration the incidence can be reduced, but adverse effects are still reported in 43 to 88% of patients receiving long term maintenance therapy. Nevertheless, most are not serious and can be controlled by dosage reductions or administration with food. In the largest placebo-controlled trial, including over 250 patients per treatment group, the overall incidence of adverse effects was over 80% in each group, but there were significantly more reports of tremor, loss of consciousness, nausea and constipation with mexiletine than with placebo, and more withdrawals or dosage reductions for adverse effects. Gastrointestinal disturbance and neurological side effects are the most frequently reported adverse effects with mexiletine. Such symptoms occurred more frequently with mexiletine than quinidine in one study: upper gastrointestinal distress in 38%vs22% of patients, tremor in 12%vs2% and coordination problems in 11%vs1%. Diarrhoea occurred more frequently with quinidine (7%vs35%).Adverse effects to mexiletine are dose-related and reversible following treatment withdrawal. In many patients they can be controlled by dosage reduction and/or administration with food. Administering mexiletine at lower dosages in combination with other antiarrhythmic drugs may also improve tolerability.The potential to aggravate or induce arrhythmias is a characteristic of antiarrhythmic drugs. The frequency of proarrhythmia with mexiletine appears to be relatively low.Drug InteractionsIn contrast with some other antiarrhythmic drugs, mexiletine has no significant effect on plasma digoxin concentrations. Drugs which interfere with hepatic function such as rifampicin and phenytoin may influence the rate of metabolism and excretion of mexiletine, although cimetidine - which can be of benefit for reducing the incidence of gastrointestinal disturbance with mexiletine - has no significant effect on its pharmacokinetics.Mexiletine appears to reduce the rate of clearance of methylxanthines, and there have been reports of theophylline toxicity and enhanced proarrhythmic effects in patients receiving mexiletine and theophylline concurrently.Dosage and AdministrationThe therapeutic serum concentration range for mexiletine is between 0.5 and 2.0 mg/L. Thus, careful dosage titration is necessary to establish the optimum dosage in each individual. The usual oral dosage is between 200 and 300mg three times daily administered with food, and the maximum recommended daily dosage is 1200mg. A more rapid onset of action can be achieved with an initial loading dose of 400mg orally, or by commencing therapy with an intravenous infusion.The sustained release formulation, containing 360mg of mexiletine, can be administered twice daily but this regimen allows little flexibility for dosage titration.Particular care is required during dosage titration in patients with AMI or hepatic disease in view of the influence of these conditions on the pharmacokinetics of mexiletine.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisKetotifen is an orally active prophylactic agent for the management of bronchial asthma and allergic disorders. Accumulated evidence indicates that after 6 to 12 weeks of administration, ketotifen significantly reduces respiratory symptoms and the need for concomitant antiasthmatic drugs in about 70% and 50%, respectively, of patients with mild to moderate bronchial asthma. However, absolute improvement in lung function is generally slight. Ketotifen also has pronounced antihistaminic and antianaphylactic properties which result in moderate to marked symptom improvement in the majority of patients with atopic dermatitis, seasonal or perennial rhinitis, allergic conjunctivitis, chronic or acute urticaria or food allergy.Comparative trials with established agents - notably sodium cromoglycate (cromolyn sodium) in asthma and histamine H1-antagonists in allergic disorders - indicate that ketotifen has comparable clinical utility. Unlike inhaled sodium cromoglycate, ketotifen ameliorates the symptoms of asthma, rhinitis and dermatitis when present together in atopic patients.Patient acceptance of ketotifen is good, although sedation can be troublesome in older children and adults for the initial 2 weeks of treatment. Weight gain is another notable effect in a small percentage of patients.Thus, ketotifen appears to be a useful agent for the management of allergic disorders and bronchial asthma, particularly in patients for whom oral therapy is preferred. Although a lengthy run-in period is needed in the treatment of asthma, in those patients who respond, continued reduction in the frequency and severity of symptoms and in the use of additional antiasthmatic drugs can be anticipated.Pharmacodynamic PropertiesKetotifen inhibits the bronchial response to inhaled histamine, allergen or aspirin, and the ocular, nasal and dermal responses to applied allergen in sensitised subjects. Ketotifen and clemastine have similar protective effects against histamine challenge, and ketotifen is generally as effective as sodium cromoglycate against both early and late reactions precipitated by inhalation of allergen extract in patients with extrinsic asthma. In contrast, ketotifen does not protect against methacholine- or exercise-induced bronchoconstriction.Chronic inflammatory changes associated with the recruitment and activation of eosinophils within the tracheobronchial tree appear to underlie the changes in airway patency and reactivity in chronic asthma. Prior treatment with ketotifen attenuated airway eosinophilia and the ensuing hyperreactivity in animals, but similar data in humans are currently lacking. Inhibition of the release and/or activity of proinflammatory mediators, which has been demonstratedin vitroor in animals for histamine, platelet-activating factor (PAF), arachidonic acid metabolites, neutrophil chemotactic factor, and the cytotoxic oxygen intermediate O2-, may contribute to the prophylactic effect of ketotifen. Calcium may be integral to the generation and/or release of some of these compounds and a number of studies suggest that ketotifen interferes with calcium flux. It does not appear to affect smooth muscle contraction. Additional possible modes of action of ketotifen include its ability to reverse &bgr;2-agonist-induced reductions in &bgr;-adrenoceptor density and to alter the affinity of these receptors and increase intracellular concentrations of cyclic adenosine monophosphate (cAMP).Exposure to ketotifenin vitroorin vivohad no clinically important effect on the number or function of lymphocytes in asthmatic children but the drug has been reported to decrease serum IgE levels and eosinophil counts in patients with bronchial asthma.Pharmacokinetic PropertiesKetotifen is well absorbed after oral administration, achieving peak plasma concentrations within 2 to 4 hours of administration in conventional dosage forms. However, information regarding absorption from the once-daily slow-release tablet is lacking. Due to a ‘first pass’ effect, bioavailability of the drug is only about 50%. Peak plasma concentrations after multiple oral doses of 1mg twice daily were 1.92 mg/L in adults and 3.25 mg/L in children, with corresponding areas under the concentration-time curve of 16.98 mg/L · h and 20.72 mg/L · h. The drug is reported to be 75% protein bound.Ketotifen is extensively metabolised to the inactive ketotifen-N-glucuronide and the pharmacologically activenor-ketotifen, and recovery of these metabolites in urine accounts for 50% and 10% of the administered dose, respectively. Only 1% is retrievable as the parent compound. Clearance of the drug from plasma is biphasic, with a half-life of distribution of 3 hours and a half-life of elimination of 22 hours in adults. Children exhibit a similar pattern of elimination. No data are available with regard to the effect of advanced age or disease on the pharmacokinetic profile of ketotifen.Therapeutic UseAlthough there is a large body of data available on the clinical use of ketotifen, poor study design, critical to the evaluation of a prophylactic drug, limits the usefulness of some studies. In well-designed trials the drug improved respiratory symptoms in about 70% of adults with asthma, based on patient diaries and physician assessment, and permitted a reduction in concomitant antiasthmatic drug requirements in about 50% of patients. The effects were apparent after 6 to 12 weeks and responding patients continued to improve with long term treatment. When initiated 6 to 8 weeks prior to peak pollen season, ketotifen attenuated the symptoms associated with seasonal asthma. Lung function, most frequently measured as peak expiratory flow, did not markedly improve in most studies but did remain stable as bronchodilators were withdrawn. Well-designed comparative trials are divided on whether ketotifen or sodium cromoglycate is statistically superior in patients with asthma. In general, the improvements in respiratory symptoms and bronchodilator requirements are clinically equivalent for these 2 agents and the preference of the individual and subsequent response will be the best guide when deciding on long term treatment. Limited comparative experience with ketotifen, azelastine and picumast suggests these 3 oral agents are similarly effective in the management of asthma.Although some investigators reported ketotifen to be no more effective than placebo when used to treat children with asthma, when studies permitting concomitant sodium cromoglycate were excluded from analysis significant reductions in asthma symptoms and bronchodilator or theophylline requirements were demonstrated with the active drug. Well-designed comparisons with sodium cromoglycate are sparse but suggest that, in children as in adults, ketotifen reduces symptoms and drug requirements to a similar degree.Several studies have addressed the possibility of corticosteroid withdrawal in ketotifen-treated patients with more severe steroid-dependent asthma. The results suggest that reduction in steroid dosage is possible in selected patients but there is currently little evidence that ketotifen can replace oral or inhaled corticosteroids in dependent patients.Prevention of asthma with ketotifen would be ideal; studies in at-risk infants hint at a protective effect for ketotifen and its use in this setting merits further study.Ketotifen is effective in relieving the nasal and ocular symptoms of perennial and seasonal rhinitis in adults and children, the improvement being most pronounced in children with seasonal symptoms. The drug was at least as effective as clemastine, chlorpheniramine (chlorphenamine), terfenadine, loratadine or insufflated sodium cromoglycate in comparative trials but was less effective than astemizole in 1 study.Good and sometimes dramatic improvement was noted in patients with chronic or cold- or exercise-induced urticaria treated with ketotifen for 1 to 4 weeks. The response in patients with urticaria pigmentosa or systemic mastocytosis was less impressive although good responses have been reported in individuals with this disorder and in small groups of patients with neurofibromatosis. Despite the variable nature of atopic dermatitis, a good response has been clearly demonstrated for ketotifen, including a decrease in skin lesions and pruritus over the course of 4 to 9 weeks' treatment.Food intolerance or allergy often appear as symptoms in several body systems (e.g. skin, gastrointestinal tract, lungs), and while elimination of the offending food(s) is effective it may impose unacceptable lifestyle and nutritional hardships. Prophylactic use of ketotifen appears to prevent bronchospasm, urticaria, skin lesions and gastrointestinal upset invoked by food allergens and may allow the reintroduction of poorly tolerated foods.Adverse EffectsKetotifen is generally well tolerated, especially in young children. The most frequent adverse effect is sedation, which occurs in about 10 to 20% of patients but declines after 1 to 2 weeks of continued use. Other reactions including dizziness, dry mouth, nausea and headache have been reported in 1 to 2% of patients after initiating therapy but do not appear to persist in patients continuing with long term treatment (up to 12 months). Weight gain may also occur in a small percentage of patients.Dosage and AdministrationFor adult patients with bronchial asthma or allergic disease, the recommended dosage of ketotifen is 2 mg/day divided into 2 doses or given as a single slow-release tablet. Patients should be cautioned against operating machinery or performing tasks requiring psychomotor skills until the sedative effects of the drug, if any, are known. If sedation is considered a problem, therapy should be initiated at half the daily dose or the drug should be given at bedtime.Children aged 6 months to 3 years should be given ketotifen (tablet or syrup) in a dosage of 0.5mg twice daily, but older children should receive the full adult dose.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisTeicoplanin is a glycopeptide antibiotic with a molecular structure which is related to that of vancomycin. Gram-positive bacteria such as staphylococci (including methicillin-resistant strains), streptococci, enterococci and many anaerobic Gram-positive bacteria are susceptible to teicoplaninin vitro.Teicoplanin has an exceptionally long half-life, allowing once-daily intramuscular or intravenous administration.Teicoplanin is clinically and bacteriologically effective against a wide variety of Grampositive infections such as septicaemia, endocarditis, skin and soft tissue infections and infections associated with venous catheters. The drug is equally efficacious against methicillin-resistant and -susceptible staphylococci. Adverse effects with teicoplanin are generally limited to local effects or hypersensitivity reactions. While teicoplanin has the potential for ototoxicity and nephrotoxicity, the incidence appears to be quite low when recommended serum concentrations are maintained.Teicoplanin is a valuable alternative to vancomycin, and providing controlled comparative studies prove equivalent safety and efficacy between the 2 glycopeptides the more easily administered teicoplanin should become the preferred antibacterial agent.Antibacterial ActivityGram-positive bacteria, including staphylococci (S. aureus, S. epidermidis, S. hominis, S. haemolyticus, S. saprophyticus), streptococci (S. pyogenes, S. pneumoniae, S. agalactiae, S. bovis, S. milleri, S. mitis, S. sanguis,viridans Group streptococci, and Groups B, C, F and G streptococci), enterococci and many anaerobic Gram-positive bacteria (Clostridium difficile, Clostridium perfringens, Propionibacterium acnes, Listeria monocytogenesandCorynebacterium jeikeium) are susceptible to teicoplaninin vitro[minimum inhibitory concentration (MIC) ≤ 4 mg/L]. &bgr;-Lactamase-producing and/or methicillin-resistant strains of staphylococci are generally equally susceptible to teicoplanin as are nonresistant strains. In general, MIC90values for teicoplanin are the same or a 2-fold dilution lower than those of vancomycin against most susceptible species. However, teicoplanin is several times more potent an inhibitor of enterococci than is vancomycin, although vancomycin-resistant enterococci may be cross-resistant to teicoplanin. In some studies reduced susceptibility of coagulase-negative staphylococci to teicoplanin was observed, with 2 to 4 times more teicoplanin than vancomycin required for inhibition. Most such strains have proved to beS. haemolyticuswhen full identification has been performed.Gram-negative bacteria are not susceptible to teicoplanin and vancomycin because these large polar molecules cannot penetrate the external lipid membranes of Gramnegative organisms to bind with the terminal acyl-D-alanyl-D-alanine of cell wall peptidoglycan building blocks. Inhibition of peptidoglycan polymerisation of susceptible species results in cell wall damage and eventually cell death, probably through the activities of cell wall hydrolytic enzymes. Surprisingly, several vancomycin-resistant strains of pigmentedBacteroidesspecies (Gram-negative anaerobic bacteria) are highly susceptible to teicoplanin, and some strains ofNeisseria gonorrhoeaeare also susceptible.The apparentin vitroactivity of teicoplanin is more affected by changes in inocula, media and testing conditions than is that of vancomycin. Higher teicoplanin MICs are recorded for Gram-positive cocci in media containing serum, presumably because of differences in protein binding, and there is greater variation in apparent activity in agar than in broth/media. Coagulase-negative staphylococci are less susceptible when tested in Diagnostic Sensitivity Test agar than in Iso-Sensitest or Mueller-Hinton agar.In general, teicoplanin is bactericidal against most species of Gram-positive cocci. However, results varied between studies depending on whether activity was assessed by minimum bactericidal activity or killing curves, with several reports suggesting that teicoplanin may be primarily bacteriostatic against coagulase-negative staphylococci.As seen with vancomycin, synergy studies have shown that the combination of teicoplanin with rifampicin is generally additive or subadditive, and that teicoplanin antagonises ampicillin. However, aminoglycosides, imipenem, fosfomycin and several other antibacterial drugs are synergistic with teicoplanin against some strains of Gram-positive cocci, the percentages of such strains so affected varying widely between studies.The relative immunity of vancomycin to development of resistance in bacterial isolates encountered clinically, and the difficulty with which resistance to teicoplanin is inducedin vitro,has suggested that resistance would not be a problem with these glycopeptide antibacterials. Unfortunately, more recent reports of teicoplanin and vancomycin resistance developingin vitroandin vivoto enterococci and coagulase-negative staphylococci have tempered this impression. More worrying still is the identification of a plasmid fromEnterococcus faecium,which has the potential ability to self-transfer toE. faecalis, L. monocytogenesand several species of streptococci (S. sanguis, S. pyogenes, S. lactis), thus conferring glycopeptide resistance.Pharmacokinetic PropertiesIntravenous injection of teicoplanin 3 mg/kg and 6 mg/kg produced peak plasma concentrations of 53.5 and 111.8 mg/L, respectively, with similar dosage proportionality demonstrated in the areas under the concentration-time curves. Plasma concentrations decreased to approximately 4 mg/L at 24 hours and were still detectable (0.4 mg/L) at 10 days. Bioavailability following intramuscular injection of 3 mg/kg was 90%, with a peak plasma concentration of 7.1 mg/L at 2 hours and a trough of 2.3 mg/L at 24 hours. Teicoplanin was not significantly absorbed from the gastrointestinal tract.A 3-compartment analysis has been most frequently utilised to describe teicoplanin pharmacokinetics, giving mean volumes of distribution at steady state ranging from 40 to 77L. Teicoplanin is approximately 90% protein bound. Following bolus administration of single 400mg intravenous doses, concentrations likely to be inhibitory to susceptible bacterial strains have been reported in blister fluid, gall bladder wall, bile, tonsils, cartilage, mucosa, liver, pancreas and bone; lower concentrations were achieved in fat, skin and cerebrospinal fluid. Urinary concentration was high (16 to 156 mg/L) during multiple-dose administration (200mg 12- or 24-hourly) and the drug was still detected (0.9 to 9 mg/L) the second week following discontinuation.Teicoplanin is eliminated almost entirely by renal mechanisms and does not appear to undergo extensive metabolism. Total clearance and renal clearance are both consistently lower than that of creatinine, suggesting renal tubular reabsorption or a protein binding associated limitation of the fraction of free drug available for elimination. The elimination half-life varied widely depending on the pharmacokinetic model used and the duration of the sampling interval, but a value of 45 to 70 hours after single-dose administration is probably most accurate.With decreasing renal function both total and renal clearances are reduced, and the elimination half-life is increased, but the volume of distribution is not affected. Teicoplanin is not removed by haemodialysis, and has a low clearance in continuous ambulatory peritoneal dialysis, failing to attain concentrations in peritoneal effluent which are likely to be inhibitory to bacteria implicated in peritonitis. However, intraperitoneal administration of teicoplanin 3 mg/kg into the dialysate resulted in approximately 70% absorption through noninflamed peritoneum during a 6-hour dwell time, with peak serum concentrations of 2.8 to 5.5 mg/L. Teicoplanin pharmacokinetics in elderly patients reflect the reduced renal function in this population, with reduced clearance of the drug and increased elimination half-life. Similarly, in neonates immaturity of renal and extrarenal excretory functions may result in decreased clearance and prolonged elimination half-life, although a recent study suggested an increased teicoplanin dosage may be required in this group. Pharmacokinetics in children aged 2 to 12 years are probably similar to those in normal adults, although an increased rate of total clearance (but not renal clearance) has been reported, with a correspondingly decreased elimination half-life.Therapeutic UseA large multicentre study assessing more than 1300 patients with Gram-positive infections reported teicoplanin clinical efficacy rates of 90% or more in infections of skin and soft tissue, urinary tract, upper and lower respiratory tract, gastrointestinal tract and in meningitis. Clinical efficacy was also achieved in 89% of patients with septicaemia, 87% with bone and joint infections and 83% with endocarditis. In this study, the overall clinical efficacy of teicoplanin, generally administered as a loading dose of 400mg on the first day followed by 200 to 400mg daily, was 92%. Efficacy was similar in adults, children and the elderly, and between those administered teicoplanin monotherapy and combination antibacterial therapy, but was lower in patients with diabetes mellitus, immunosuppression, malignant diseases and in the presence of foreign bodies. A teicoplanin dosage of at least 400mg daily was more effective (p < 0.05) than a lower dosage in patients with endocarditis. Bacteriological cure was achieved in 79% of the 1333 patients.A few studies have assessed the efficacy of teicoplanin in comparison with other antibacterials. An early study comparing teicoplanin 400mg initially, then 200mg daily, with flucloxacillin 2g 6-hourly in severe staphylococcal infections (most with concomitant septicaemia) was terminated after 0 of 9 patients who received teicoplanin, responded clinically (vs8 of 9 flucloxacillin patients). In contrast, clinical efficacy rates of 92% and 100%, respectively, occurred with a higher dosage of teicoplanin (400mg daily) or vancomycin 1g twice daily in patients with severe methicillin-resistantS. aureusinfections, most of whom had concomitant septicaemia.This apparent correlation of teicoplanin dosage with efficacy is further illustrated by the results of a noncomparative study in severely debilitated septicaemic patients, mostly with concomitant infective endocarditis or with an infected Hickman catheter, all 7 patients with streptococcal septicaemia were cured with a dosage of 400mg followed by 200mg daily, including 2 due toE. faecalis,but only 11 of 18S. epidermidisand 2 of 6S. aureusinfections were cured. In a noncomparative study in endocarditis, teicoplanin 200mg daily was successful in the treatment of streptococcal but not staphylococcal infections, while teicoplanin 200 to 400mg daily and vancomycin 1g twice daily were both 100% effective in patients with septicaemia associated with indwelling venous catheters.Similarly, all 19 immunocompromised patients with staphylococcal Hickman catheter infections, 9 of which were associated with concomitant septicaemia, were cured with a teicoplanin dosage of 400mg initially, then 200mg daily; only 2 catheters had to be removed because of persistence of infection. Teicoplanin (400 or 800mg loading dose followed by 200 or 400mg daily) was of similar clinical efficacy to vancomycin 1g twice daily, alone or in combination with gentamicin plus piperacillin in the treatment of Grampositive (mostly coagulase-negative staphylococci) Hickman catheter-associated infections in neutropenic patients with haematological malignancy. All septicaemias and most exit site infections were cured, but 60% of tunnel infections responded to teicoplanin and none to vancomycin.Teicoplanin has also proven advantageous as part of an antibacterial regimen for empirical treatment of fever and suspected infection in immunologically compromised patients. Patients obtaining the greatest advantage from the addition of ‘antistaphylococcal’ coverage are those with profound and persistent neutropenia. Furthermore, in several case reports teicoplanin administered intraperitoneally in CAPD peritonitis, and intraventricularly in ventriculitis associated with neuroshunts, has demonstrated clinical efficacy.Perioperative prophylaxis with teicoplanin alone (400mg at induction followed by 200mg at 24 hours or two 400mg doses within 24 hours) in cardiac surgery was not associated with the emergence of Gram-negative skin flora, but the lower dosage regimen was less effective than flucloxacillin plus tobramycin in preventing Gram-positive wound infections, despite being active against all of the organisms isolated, and was associated with a higher incidence of Gram-negative chest and urinary tract infections. The higher dosage teicoplanin regimen was associated with a similar incidence of wound and respiratory tract infections compared with flucloxacillin plus tobramycin, but even greater teicoplanin dosages may be justified in this indication. In prophylaxis of infection in orthopaedic implant surgery, preliminary results of a comparative study did not reveal statistically significant differences between a single preoperative dose of teicoplanin 400mg intravenously and 3 perioperative injections of cefuroxime 750mg.In prophylaxis of septicaemia in dental patients, rates of bacterial isolation from blood cultures were greater in patients administered teicoplanin 200mg intramuscularly than in those administered amoxicillin 3g orally, but in a second study prophylaxis with teicoplanin 400mg intravenously was superior to amoxicillin 1g intramuscularly. Differences in achievable antibacterial serum concentrations related to dosage and to route and timing of administration probably explain the differing results.Although findings in only small numbers of patients have been reported, teicoplanin 200mg orally 2 to 4 times daily for 3 to 12 days has been highly successful in the treatment of antibiotic-associated colitis andC. difficile-associated diarrhoea.Adverse EffectsAdverse effects most frequently associated with teicoplanin are injection site intolerance and hypersensitivity, the latter usually limited to skin reactions but in some instances progressing to bronchospasm and anaphylactoid reaction. However, unlike vancomycin, teicoplanin may be administered rapidly without severe anaphylactoid effects; cross-reactivity between teicoplanin and vancomycin remains controversial. Teicoplanin also has the potential to cause ototoxicity and nephrotoxicity, although to date the incidence in teicoplanin patients not receiving concomitant oto- and/or nephrotoxic drugs is quite low and less than that associated with vancomycin. Similarly infrequent are reports of nonspecific adverse events such as tremor, tachycardia, headache, fatigue and diarrhoea. Transient elevation of liver enzymes may also occur.Dosage and AdministrationTeicoplanin is administered intramuscularly or intravenously (either rapid injection over 1 minute or more slowly by infusion) at a dosage sufficient to maintain trough serum concentrations of greater than 10 mg/L in severe infections. In adults with normal renal function a loading dose of 400mg (approximately 6 mg/kg) is administered on the first day, followed by once daily doses of 200 or 400mg on subsequent days; in life-threatening infections 6 to 12 mg/kg should be administered 12-hourly for the first day, followed by 6 mg/kg daily on subsequent days.In children under 12 years, 3 doses of 10 mg/kg should be administered 12-hourly, followed by 6 mg/kg or 10 mg/kg daily according to the severity of infection. Doses of up to 12 mg/kg are recommended in granulocytopenic patients. Recent results have suggested teicoplanin 15 mg/kg on day 1 then 8 mg/kg/day may be required to maintain trough serum concentrations above 10 mg/L in neonates but this remains to be confirmed.In acute or chronic renal impairment the normal recommended dosage of teicoplanin should be administered for the first few days, after which the dosage interval is modified to maintain trough serum concentrations of greater than 10 mg/L; 200 or 400mg daily or every 2 days in mild to moderate renal insufficiency, and 200 to 400mg every 2 to 3 days in severe renal insufficiency, should be adequate.Peritonitis in patients undergoing CAPD is treated with teicoplanin 50mg in each 2L bag for the first 48 hours, then 25mg per 2L bag thereafter.For prophylaxis of surgical infections, teicoplanin 400mg is administered intravenously at the induction of anaesthesia. In cardiac surgery additional 400mg doses are administered at the end of surgery and 24 hours later, although recent evidence suggests a higher dose regimen may be required for prophylactic efficacy in this indication.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS