ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Malaria has become an increasingly common health problem in the 1970s and 1980s, both in areas where infection is endemic and in travellers returning to non-endemic areas. The severity of infection varies widely, depending on the plasmodial species involved, and there is an extensive chemotherapeutic armamentarium currently available to combat malarial infection. Drug chemistry, pharmacokinetics, mechanism of drug action and resistance, and toxicities are outlined for the cinchona alkaloids (quinine and quinidine), chloroquine, amodiaquine, pyrimethamine, the sulphonamides, pyrimethamine/sulfadoxine, mefloquine, pyrimethamine/sulfadoxine/mefloquine, the sesquiterpene lactones, primaquine, and other drugs. A knowledge of the distribution of drug resistance is vital for the provision of effective antimalarial therapy, and current information in this area is outlined.Chloroquine remains the mainstay of treatment for the erythrocytic stages ofPlasmodium vivax, P. ovale, P. malariae,and chloroquine-sensitiveP. falciparummalaria. The dormant hepatic stages ofP. vivaxandP. ovalealso require further treatment with primaquine. Quinine, alone or in combination with other drugs, is the primary agent used to treat chloroquine-resistant falciparum malaria. Falciparum infection can rapidly become fatal, therefore its complications of multiple organ failure, heavy parasitaemias, cerebral malaria, and hypoglycaemia must be recognised and managed promptly. Because these protozoal parasitic infections are now encountered throughout the world and can become life-threatening, a wide variety of practitioners must become more familiar with their correct treatment.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

This review considers the definition of clinical diabetic neuropathy and the theoretical basis for the use of aldose reductase inhibitors in the treatment of distal sensorimotor neuropathy, the most common clinical problem. Myoinositol depletion is related to hyperglycaemia-induced polyol activity, changes which are associated with early functional deficits in acute experimental diabetes. These changes are reversible by the administration of aldose reductase inhibitors, and this provides the rationale for the treatment of human diabetic neuropathy with these agents. Many early trials of these drugs have produced some evidence of clinical benefit in patients with diabetic neuropathy, but interpretation of data is difficult as patient selection and neuropathy definition are not yet standardised. In addition, it is possible that once the neuropathic process is initiated, there is a point where it becomes irreversible, and treatment with aldose reductase inhibitors may therefore be of more relevance in early neuropathy. Long term double-blind multicentre trials are in progress, and preliminary data from some of these are reasonably encouraging. In conclusion, the results from clinical trials of the aldose reductase inhibitors in this difficult area are sufficiently encouraging to lead us to be optimistic about their future development, and continuing work should clarify their potential role with respect to the prophylaxis and treatment of diabetic neuropathy.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The potential benefits of estrogen replacement therapy (ERT) for postmenopausal women are now generally recognised, and no scientist involved in this field of research will deny the gratifying results of hormone therapy. However, in the risk-benefit equation the adverse effects of ERT must be carefully considered.Most of the harmful adverse effects of ERT have been related firstly to the absence of progestational balance, and secondly to the fact that most of the estrogens previously available for clinical use were artificial and administered orally, resulting in intensive hepatic metabolism, leading to metabolic disturbances. The need for the addition of progestogen leads also to consideration of the adverse effects of these substances.During the past decade therapeutic improvements have been achieved. Knowledge about the different types of steroids now available, the right choice of dosage and duration of therapy according to the needs of the patient, and the new alternative delivery systems improves day by day.Various steroids are now available for clinical use. Among the estrogens, orally administered drugs, natural derivatives of estradiol, and nonoral drugs delivered by injection, implant, vaginal ring or cream, ointment or transdermal system are at the prescriber's disposal. Among the progestogens available to the prescriber and recommended to be added to ERT, the molecules derived from testosterone [norethisterone (norethindrone), norgestrel] are less prescribed than the molecules derived from progesterone (didrogesterone) or from 17-hydroxyprogesterone (medroxyprogesterone acetate). In menopausal therapy the latter derivatives from progesterone or 17-hydroxyprogesterone are preferable, but low doses of any type of progestogen could be both protective of the target organs and devoid of harmful effects. Careful consideration of contraindications of treatment and regular follow-up are prerequisites for safe therapy.Recent epidemiological data now demonstrate clearly that the use of ERT under these conditions affords protection against osteoporosis and cardiovascular disease. Clear benefits to women's health may therefore be obtained from the adequate choice and surveillance of therapy.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Pruritus is an unpleasant sensation that provokes an urge to scratch. Many stimuli (notably histamine) are able to induce pruritus. The neural conduction of the itch sensation from the free unmyelinated nerve endings to the central nervous system mainly occurs on unmyelinated C fibres and the anterolateral spinothalamic tract.Pruritus is a common symptom in many skin or systemic diseases, but very little is known about the mechanism of the condition.Treatment evaluation is difficult; many methods do not evaluate the pruritus, but only the scratching, which is a consequence of pruritus. A number of asymptomatic treatments are only partially effective and we know little about their mechanism of action. Antihistamines remain the treatment of first choice for pruritus without known cause, but generally give incomplete relief. Whenever possible it is best to treat the underlying disease.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

This article examines the detection, assessment, and therapeutic modalities available for tuberculosis meningitis. Without appropriate treatment this disease is fatal within 2 months of development, and mortality is closely associated with the stage of disease upon initiation of chemotherapy. Initial lumbar puncture reveals smear-positive acid-fast bacilli in up to 40% in most series; however, repeat examinations increase the yield, via direct smear, to as high as 87%.Analysis of cerebrospinal fluid is described, along with advanced techniques for early detection of this infection. Eight antituberculosis agents have known penetration into the cerebrospinal fluid.The most important prognostic factor is the neurological stage at which the individual presents at the initiation of therapy. Various chemotherapeutic approaches are available but it appears the use of rifampicin (rifampin) with isoniazid-containing regimens gives the best results. Regardless of the therapy undertaken, a significant number of individuals are left with some degree of neurological deficit. The roles of bacillus of Calmette and Guérin (BCG) vaccine, steroids, and neurosurgery in the treatment of this disease are also discussed.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisDilevalol, the RR-stereoisomer of labetalol, is a non-cardioselective &bgr;-adrenoceptor antagonist with substantial partial &bgr;2-agonist and negligible &agr;1-blocking activity. Reduction in blood pressure during dilevalol administration is associated with peripheral vasodilatation, and heart rate remains essentially unchanged. Following oral administration, dilevalol is completely absorbed. Once-daily administration is possible, due to a long elimination half-life.Large well-controlled trials reveal that dilevalol is equivalent in antihypertensive efficacy to metoprolol, the ACE inhibitors captopril and enalapril, and the calcium antagonist nifedipine. Smaller noncomparative and comparative trials demonstrate the blood pressure-lowering effects of dilevalol and suggest an efficacy at least equivalent to that of the ‘pure’ &bgr;-blockers atenolol and propranolol and the &agr;1-blockers urapidil and doxazosin. Dilevalol appears to be well tolerated, the most frequent adverse effects being dizziness, headache and diarrhoea in only about 7% of patients each. Unlike &agr;1-blockers and labetalol, dilevalol is not commonly associated with orthostatic hypotension.Thus, data suggest that dilevalol, with its distinctive pharmacological profile, is likely to be a useful addition to the options currently available for treating patients with mild to moderate essential hypertension.Pharmacodynamic PropertiesIn vitroandin vivoanimal studies and results obtained in humans reveal that dilevalol is a nonselective blocker of &bgr;1- and &bgr;2-adrenoceptors, with a similar potency to propranolol, but has negligible antagonistic activity at &agr;1-receptors. As estimated from isoprenaline (isoproterenol)-induced haemodynamic effectsin vivoand in isolated animal tissues, dilevalol has 3 to 6 times the &bgr;-blocking activity of its parent racemate labetalol, but is less than 25% as effective as labetalol in inhibiting &agr;1-mediated changes induced by norepinephrine (noradrenaline) or phenylephrine. In humans, dilevalol is about 1.75 times more effective than labetalol in blocking the effects of isoprenaline at &bgr;1-receptors, and is significantly more potent in inhibiting stimulation of the &bgr;2-subtype by salbutamol (albuterol). It is almost devoid of &agr;1-blocking activity in humans.Dilevalol shows marked partial &bgr;2-agonist activity in animal models by producing ICI 118.551 and/or propranolol-sensitive tracheal relaxation and peripheral vasodilatation, and falls in systemic vascular resistance in humans.The haemodynamic profile of dilevalol is characterised by reductions in peripheral resistance and blood pressure without significant effects on heart rate in animals and in humans. Mean arterial blood pressure is reduced by 14 to 29%, and systolic and diastolic pressures by approximately 13 to 18% by dilevalol 100 to 1600 mg/day in patients with mild to moderate essential hypertension after 1 to 8 weeks of therapy (see also Therapeutic Use, below). The blood pressure lowering effects of dilevalol are maintained during the 24 hours after an oral dose in patients and in healthy subjects. A decrease in peripheral resistance of 13% is primarily responsible for the fall in blood pressure, since resting heart rate is generally unaffected or occasionally increased slightly. Although decreases in heart rate have occurred during dilevalol administration, the incidence and extent is not as great as with atenolol. Resting cardiac index is also unchanged. However, during exercise, increases in heart rate were blunted by up to 29% and cardiac index by 19%. Left ventricular function appears to improve during dilevalol treatment, as assessed by left ventricular mass index, ejection fraction and ejection time.In animals, dilevalol enhances nodal conduction but inhibits intraventricular conduction. Dilevalol protects against lethal ventricular fibrillation elicited by methylscopolamine in animals subjected to myocardial infarction, while the anticholinergic compensates for a relative excess in parasympathetic activity - and thus bradyarrhythmia and arrest - resulting from &bgr;-blockade by dilevalol.Glomerular filtration rate, filtration fraction and effective renal plasma flow are preserved in healthy volunteers, patients with essential hypertension and in those with renal dysfunction receiving dilevalol.There was no significant difference between the forced expiratory volume in 1 second following placebo or single oral doses of dilevalol 200 or 400mg in patients with reversible asthma, in contrast to a significant reduction of 16% observed with metoprolol 200mg. Furthermore, isoprenaline-induced bronchodilatation was re-established after 90 minutes during concomitant dilevalol, but not metoprolol, administration.Plasma renin activity is lowered and norepinephrine levels increased by dilevalol. There is a neutral or possibly beneficial effect on plasma lipids, with an increase in the high density lipoprotein fraction and a slight reduction in low density lipoprotein. Total cholesterol levels are unaltered by 1 month to 1 year of dilevalol therapy.In summary, dilevalol lowers blood pressure through a decrease in peripheral resistance, with perhaps a minor contribution from decreased cardiac output.Pharmacokinetic PropertiesIn healthy subjects, dilevalol is completely absorbed following oral administration. However, extensive first-pass metabolism occurs, with subsequent glucuronide conjugation such that the bioavailability of dilevalol is 30% or less, and only 1.25% of detectable urinary dilevalol is unchanged drug. Peak plasma concentrations (Cmax) of unchanged drug after a single oral 400mg dose are attained within 50 minutes, and vary among individuals between 220 and 485 &mgr;g/L. After a 200mg dose administered to healthy volunteers, Cmaxwas 61.5 &mgr;g/L after 1.4 hours, and in 15 patients with hypertension Cmaxvalues of 118, 226 and 545 &mgr;g/L occurred within 1 hour of the last dose following 5 days' administration of dilevalol 200, 400 and 800 mg/day, respectively. A Cmaxof 236 &mgr;g/L was detected in 6 renally impaired patients 46 minutes after a 400mg oral dose, and increased to 387 &mgr;g/L 1.5 hours after the same dose in 6 others maintained on haemodialysis. The area under the plasma concentration-time curve also varies considerably, but a dose-proportional increase in this parameter has been established.Although dilevalol is approximately 75% bound to human plasma proteins, it is extensively distributed into extravascular tissue, as shown by an apparent volume of distribution of about 25 L/kg following a 50mg intravenous dose in healthy subjects. In lactating women, the plasma concentration of unchanged dilevalol after a 400mg oral dose was 2 to 3 times that detected in breast milk. Over 48 hours, a total of 0.007% of the administered dose was excreted into the milk.At least 33% in total of an oral dose is recovered, mainly as conjugates, in the urine within 60 hours, representing the main route of excretion. Clearance of dilevalol from the plasma is essentially complete within 48 hours, with a total clearance of 23 ml/min/kg after an intravenous dose of 50mg, the main site of plasma clearance being the liver. In healthy subjects the elimination half-life of unchanged dilevalol after single doses and at steady-state is 8 to 12 hours, increasing to 19 hours in patients with severe renal dysfunction and to 29 hours in those maintained on haemodialysis.The blood pressure—lowering effects of dilevalol in hypertensive patients are related to plasma concentration of unchanged drug at steady-state.Therapeutic UseOnce-daily administration of dilevalol 200 to 1600mg was equivalent in efficacy to once-daily metoprolol 100 to 400mg or enalapril 20 or 40mg, and twice-daily therapy with captopril 50mg or nifedipine 20 or 40mg after 1 month to 1 year of treatment in large numbers of patients with mild to moderate hypertension participating in well designed double-blind comparative studies.Short term noncomparative studies involving small patient populations with essential hypertension show that dilevalol 100 to 800mg once or twice daily lowered systolic blood pressure by 8 to 13% and diastolic pressure by 11 to 16%. In most comparative trials, some of which were not strictly designed to assess antihypertensive efficacy and therefore included relatively few patients, diastolic blood pressure was reduced by 10mm Hg or more or to 90mm Hg or less in about 60% of patients receiving dilevalol. Dilevalol 50 to 1600mg once daily was superior to placebo and at least as effective as atenolol 50 to 150 mg/day, propranolol 40 to 320mg twice daily, and mean daily doses of acebutolol 444mg, tilisolol 21.7mg, urapidil 84mg and the rather low dose of doxazosin 1.7mg in these studies. Dilevalol was less effective in Black compared with White patients. Efficacy was estimated either in terms of the magnitude of the blood pressure reduction or the number of hypertensive patients achieving a diastolic pressure within normal limits.Dilevalol 400 to 450mg administered intravenously effectively reduced blood pressure in most patients with severe hypertension, but maintenance of this effect with subsequent oral therapy with dilevalol 200 to 800mg twice daily plus hydrochlorothiazide 25 or 50 mg/day was less successful.Adverse EffectsData from medium and long term comparative trials demonstrate that dilevalol 100 to 1600 mg/day is well tolerated, with an overall incidence of adverse effects similar to that of placebo and less than that of metoprolol 100 to 400 mg/day and propranolol 80 to 640 mg/day. Dizziness and headache are the most frequently reported reactions, each usually occurring in about 7% of patients. A similar percentage experience diarrhoea. Adverse effects associated with &bgr;2-blockade, such as cold extremities and dyspnoea, occur in less than 4% of recipients, and bradycardia and heart block from &bgr;1-blockade are encountered significantly less often than with metoprolol or propranolol. Since dilevalol's vasodilator activity is not mediated through &agr;1-blockade, overt orthostatic hypotension is unlikely to occur.Serum electrolytes are unaffected by dilevalol therapy. Serum transaminase levels are elevated in 2% of dilevalol recipients, and 3% have a positive antinuclear antibody (ANA) titre, but this is not uncommon with any &bgr;-blocker therapy.Dosage and AdministrationOnce-daily oral administration of 200 to 400mg, titrated up to 800mg if necessary, is the recommended dosage of dilevalol in adult patients with mild to moderate essential hypertension. Concomitant hydrochlorothiazide may also be required by some patients for adequate blood pressure control. In severe hypertension, intravenous injections of dilevalol 25 to 600mg have been used in the short term, with oral doses of 200 to 800mg twice daily plus hydrochlorothiazide 25 to 50 mg/day for longer term maintenance.Dosage reduction may only be necessary in those patients with renal dysfunction who are maintained on haemodialysis.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisClavulanic acid enhances the antibacterial spectrum of amoxicillin by rendering most &bgr;-lactamase-producing isolates susceptible to the drug. In clinical trials amoxicillin/clavulanic acid is clinically and bacteriologically superior to amoxicillin alone and at least as effective as numerous other comparative agents, such as orally administered cephalosporins, cotrimoxazole, doxycycline and bacampicillin, in the treatment of adults and children with the most common forms of infection encountered in general practice, i.e. urinary tract infections, upper and lower respiratory tract infections, otorhinolaryngological infections, and skin and soft tissue infections. It may also provide effective treatment for uncomplicated gonorrhoea, chancroid and gynaecological infections as well as acting as a prophylactic agent against surgical infection.Thus, in general practice environments where &bgr;-lactamase production has restricted the effectiveness of amoxicillin, the combination of clavulanic acid with amoxicillin has clearly extended the usefulness of a tried and proven first-line antibacterial agent.Antibacterial ActivityClavulanic acid is an irreversible ‘suicide’ inhibitor of intracellular and extracellular &bgr;-lactamases, effective against a wide variety of these enzymes including those of Richmond and Sykes classes II to V (but not class I cephalosporinases), staphylococcal &bgr;-lactamase, and &bgr;-lactamase produced byBacteroides fragilis.Clavulanic acid, therefore, protects amoxicillin from inactivation by many &bgr;-lactamases. As a consequence the antibacterial activity of amoxicillin has been restored at a time when the spread of resistance due to &bgr;-lactamase production severely threatened its usefulness.Clavulanic acid alone possesses only weak antibacterial activity, except againstLegionellaspp., and certain strains ofBranhamella catarrhalis, B. fragilisandNeisseria gonorrhoeae.However, the addition of clavulanic acid to amoxicillin increases the susceptibility to amoxicillin of amoxicillin-resistant strains of Gram-negative and Grampositive aerobic and anaerobic bacteria where resistance is caused by &bgr;-lactamase production. There includeStaphylococcus aureus(but not methicillin-resistant strains),Haemophilusspp.,Branhamella catarrhalis. Neisseria gonorrhoeae, Escherichia coli, Proteusspp.,Klebsiella pneumoniae, Citrobacter diversus, SalmonellaandShigellaspp.,Campylobacter jejuni, Bacteroidesspp., andMycobacteriumspp. The susceptibility of amoxicillin-sensitive strains is not generally affected by the addition of clavulanic acid.Amoxicillin/clavulanic acid is bactericidalin vitro,usually at concentrations no more than one dilution higher thanin vitroinhibitory concentrations. Thein vitrosynergy of clavulanic acid combined with amoxicillin has been confirmedin vivoin numerous experimental infections in animals. The combination of amoxicillin with clavulanic acid appears to suppress the development of resistance under experimental conditions.Pharmacokinetic PropertiesCombining clavulanic acid with amoxicillin causes no appreciable alteration of the pharmacokinetics of either drug compared with their separate administration. After oral administration, both components achieve maximum plasma concentrations in about 1 hour and these concentrations show a direct relationship to the dose administered. The absolute bioavailability of clavulanic acid is about 60%. Absorption is unaffected by concomitant administration of food, milk, ranitidine or pirenzepine and little affected by antacid administration, but cimetidine may increase the rate of absorption of both components. Probenecid increases the plasma concentration of amoxicillin but not clavulanic acid.Clavulanic acid has a volume of distribution of about 25% of bodyweight and is about 22% protein boundin vitro.The tissue and body fluid distribution of both components is generally adequate to achieve antibacterial levels, although concentrations may be somewhat low in bronchial secretions and cerebrospinal fluid. Both components transfer across the placenta but only very small quantities transfer into breast milk.Both clavulanic acid and amoxicillin possess a mean elimination half-life of about 1 hour and a mean total clearance of about 25 L/h in healthy subjects. The main route of elimination is via the urine, and 6-hour urinary recovery of intact drug after oral administration is about 60 to 80% for amoxicillin and 30 to 50% for clavulanic acid. Clavulanic acid is excreted mainly by glomerular filtration and amoxicillin by tubular secretion; thus, probenecid delays the excretion of amoxicillin but not clavulanic acid. While amoxicillin is mainly excreted unchanged, clavulanic acid is subject to hydrolysis and subsequent decarboxylation.Gastrointestinal disease may slow the rate of absorption of amoxicillin and clavulanic acid. The pharmacokinetic profile in children administered bodyweight adjusted dosages paralleled that in adults. Renal impairment decreases the clearance of amoxicillin and less markedly clavulanic acid: dosage reductions or increasing the dose interval are thus required. Both components are removed by haemodialysis and appropriate dose supplementation is therefore necessary at the end of a haemodialysis session.Therapeutic TrialsAmoxicillin/clavulanic acid has usually been administered empirically to patients with symptoms suggestive of bacterial infection without selection of patients according to the resistance or susceptibility of the pathogen. Dosages of amoxicillin/clavulanic acid were usually in the range 250/125 to 875/125mg 2 or 3 times daily in adults and bodyweight adjusted dosages were administered to children.In adult patients with complicated or uncomplicated urinary tract infection, amoxicillin/clavulanic acid was clinically and bacteriologically superior at a statistically significant level compared with amoxicillin alone and cefatrizine propylene glycol, and bacteriologically superior compared with cotrimoxazole. In addition, it was at least as effective as cefaclor, cefalexin and pivmecillinam/pivampicillin.In adult patients with upper or lower respiratory tract infections, amoxicillin/clavulanic acid was clinically more effective than amoxicillin alone or josamycin at a statistically significant level. Clinically and bacteriologically it was at least as effective as bacampicillin, pivmecillinam/pivampicillin, doxycycline, erythromycin, cefuroxime axetil, cefixime and cefaclor.Amoxicillin/clavulanic acid has been shown to be clinically more effective at a statistically significant level than amoxicillin alone in the treatment of acute otitis media in adults, but statistically significant differences were not identified in comparisons with amoxicillin in children with otitis media or maxillary sinusitis. Some studies have shown statistically significant superiority of amoxicillin/clavulanic acid over cefaclor or myringotomy both clinically and bacteriologically in children with acute otitis media.In skin and soft tissue infection amoxicillin/clavulanic acid produced a statistically significant higher bacteriological response rate and a tendency towards a higher clinical response rate compared with amoxicillin in adults with wound infection and children with nonbullous impetigo. In addition, in adults with wound infection amoxicillin/clavulanic acid was equivalent to cefuroxime axetil. In adults and children with skin and soft tissue infection, amoxicillin/clavulanic acid and cefaclor achieved similar clinical and bacteriological responses.In uncomplicated gonorrhoea, administration of 2 doses of amoxicillin/clavulanic acid 3000/125 or 3000/250mg 4 to 6 hours apart or a single dose concomitantly with probenecid 1g proved the most satisfactory and convenient regimens, with antibacterial activity extended to cover penicillinase-producingNeisseria gonorrhoeae.Amoxicillin/clavulanic acid 500/250mg 3 times daily for 3 days appears to provide an excellent treatment for chancroid.Amoxicillin/clavulanic acid may provide an effective and more manageable regimen than the standard triple combination of a &bgr;-lactam/an aminoglycoside/an imidazole in the treatment of obstetric and gynaecological infections but more study is required in this area before any definitive conclusions may be drawn. Amoxicillin/clavulanic acid has shown excellent results compared with other prophylactic regimens such as cephalosporins or aminoglycosides, and was superior to metronidazole at a statistically significant level, in the prevention of postoperative infectious complications following gynaecological, abdominal and vascular surgery.Adverse EffectsAbout 13% of patients report adverse effects with amoxicillin/clavulanic acid, requiring withdrawal of treatment in less than 3% of patients. The adverse effects are primarily mild gastrointestinal disturbances, including diarrhoea, nausea, vomiting and indigestion. Rash, andCandidavaginitis or stomatitis each occur in about 1% of patients. There have been isolated reports of urticaria, anaphylaxis, behavioural changes, and la-boratory test abnormalities.Gastrointestinal adverse effects may be reduced by taking the drug with food. Their frequency may be related to the dose of clavulanic acid and they may also occur considerably more frequently in children. Compared with other antibacterial agents, amoxicillin/clavulanic acid has usually been at least as well tolerated, although some orally administered cephalosporins (e.g. cefaclor) caused fewer gastrointestinal effects.Dosage and AdministrationThe usual dosage for routine oral use in adult infections is 250/125mg or 500/125mg 3 times daily, although in Italy the usual dose is 875/125mg twice or 3 times daily, depending on the severity of infection. A number of parenteral preparations are available which may be administered intravenously in cases of severe infection or as a prophylactic in patients undergoing surgery. The recommended daily dose in children is 20 to 40mg/kg, based on the amoxicillin component. Doses towards the lower end of this range should be adequate in mild to moderate infections while higher doses may be used against more severe infections. Dosage reductions are necessary in patients with renal failure. Amoxicillin/clavulanic acid should be administered with food and is contraindicated in patients with a known history of &bgr;-lactam hypersensitivity.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisDopexamine hydrochloride is a novel synthetic catecholamine, structurally related to dopamine, with marked intrinsic agonist activity at &bgr;2-adrenoceptors, lesser agonist activity at dopamine DA1- and DA2-receptors and &bgr;1-adrenoceptors, and an inhibitory action on the neuronal catecholamine uptake mechanism. The drug is administered by intravenous infusion, and is characterised by a rapid onset and short duration of action. Short term haemodynamic studies in volunteers and patients with severe chronic heart failure have indicated that dopexamine hydrochloride reduces afterload through pronounced arterial vasodilatation, increases renal perfusion by selective renal vasodilatation and evokes mild cardiac stimulation through direct and indirect positive inotropism. Preliminary smallscale noncomparative studies indicate that dopexamine hydrochloride displays beneficial haemodynamic effects in patients with acute heart failure and those requiring haemodynamic support following cardiac surgery, and that these effects are substantially maintained during longer term administration (≤ 24 hours). Dopexamine hydrochloride appears to be generally well tolerated. Nausea and vomiting are the most frequently reported adverse effects, and respond to dosage reduction. Occasional reports of chest pain/angina pectoris precipitated by tachycardia indicates the need for caution in the use of dopexamine hydrochloride in patients with ischaemic heart disease. Thus, dopexamine hydrochloride may prove to be a useful alternative to dopamine and dobutamine in the treatment of acute heart failure and the postoperative management of low cardiac output states, although controlled studies are required to establish its efficacy and tolerability with respect to that of established therapies.Pharmacodynamic StudiesDopexamine hydrochloride displays dopaminergic and &bgr;2-adrenergic agonist activity in isolated cardiac and vascular preparations, and produces a marked inhibition of neuronal catecholamine uptake. In dogs, dopexamine hydrochloride reduced blood pressure and afterload, increased heart rate and improved indices of myocardial contractility. The positive chronotropic and inotropic actions of the drug resulted from indirect &bgr;1-adrenoceptor stimulation, arising from baroreflex activation and inhibition of norepinephrine (noradrenaline) reuptake, and from direct cardiac &bgr;2-adrenoceptor stimulation. Dopexamine hydrochloride increased renal, myocardial and skeletal muscle blood flow. The drug displayed activity against ischaemic arrhythmias in the rat.In healthy volunteers, short term (≤ 3 hours) intravenous infusion of dopexamine hydrochloride resulted in dose-related increases in cardiac output and hear trate, reductions in renal vascular resistance and minimal changes in blood pressure. In patients with chronic congestive heart failure, dopexamine hydrochloride augmented left ventricular performance, producing a pronounced systemic vasodilatation, positive chronotropy and mild positive inotropy, and minimal changes in cardiac filling pressures and arterial blood pressure. Dopexamine hydrochloride-mediated improvements in isovolumic phase indices of left ventricular contractility were indicative of a direct positive inotropism. Blood flow to the hepatic-splanchnic and renal vascular beds was selectively increased, and accompanied by marginal increases in natriuresis and diuresis. Myocardial oxygen consumption and metabolic function were unaltered by dopexamine hydrochloride, while myocardial efficiency was slightly improved. Plasma norepinephrine levels were either unaffected or increased. Longer term (≤ 72 hours) intravenous infusion of high dose dopexamine hydrochloride was frequently characterised by a rapid and progressive attenuation of the haemodynamic response in patients with chronic congestive heart failure. Direct drug comparisons, performed in patients with chronic congestive heart failure, indicated that the acute haemodynamic effects of dopexamine hydrochloride were similar to those of dobutamine, with both drugs reducing preload and increasing cardiac output through enhanced inotropy and reduced afterload. Dopexamine hydrochloride had a comparable effect to sodium nitroprusside on loading conditions in chronic congestive heart failure, but displayed a more marked inotropic effect coupled with a less pronounced tachycardic action. In patients with left ventricular dysfunction, dopexamine hydrochloride showed greater chronotropism and preload-reducing properties than dopamine.Pharmacokinetic StudiesThere is little published information on the pharmacokinetic properties of dopexamine hydrochloride in animals or humans. Dose titration of dopexamine hydrochloride 1 to 4 &mgr;g/kg/min resulted in proportional increases in plasma drug concentrations in volunteers, with a peak of 124 mg/L after 1 hour. On termination of infusion, plasma drug concentrations declined rapidly and monoexponentially with an elimination halflife of 7 minutes (vs11 minutes in patients with low cardiac output) and a plasma clearance of 36 ml/min/kg (vs17 ml/min/kg in patients following cardiac surgery). Tissue distribution of dopexamine hydrochloride was extensive, with the drug acting as a substrate for the extraneuronal catecholamine uptake mechanism (Uptake2). Dopexamine hydrochloride was extensively metabolised byO-methylation and subsequent sulphate conjugation to yield 2 major products which were excreted with the parent drug in the urine and faeces. Urinary excretion was biphasic with a terminal half-life of 4 days; the 2-methoxy, 1-sulphate metabolite accounted for more than 90% of the excreted drug recovered from the urine. Over 12 days after administration, the urinary and faecal routes accounted for the elimination of more than 50% and 20%, respectively, of the original dose.Therapeutic TrialsNoncomparative dose-titration studies indicated that intravenous infusions of dopexamine hydrochloride 0.5 to 6.0 &mgr;g/kg/min produced a beneficial systemic and renal vasodilatation, in conjunction with enhanced diuresis and improvements in indices of myocardial function, in patients with acute heart failure. In contrast to its action in patients with chronic heart failure, dopexamine hydrochloride lacked significant preloadreducing properties in those with acute heart failure. Long term (24 hours) intravenous infusion of dopexamine hydrochloride in patients with acute heart failure following myocardial infarction was associated with sustained haemodynamic improvements, with no evidence of appreciable tolerance to the haemodynamic effects.Noncomparative dose-titration studies in patients with compromised left ventricular function subsequent to cardiac surgery reported that intravenous infusions of dopexamine hydrochloride 1.0 to 10.0 &mgr;g/kg/min produced dose-related increases in cardiac output and heart rate, reductions in afterload, but no changes in preload. These haemodynamic effects were associated with a tendency towards increased diuresis.Adverse EffectsDopexamine hydrochloride was well tolerated during short and extended term (≤ 72 hours) intravenous infusion at doses of 0.5 to 10.0 &mgr;g/kg/min. Nausea, vomiting, tachycardia, chest pain/angina pectoris, ventricular ectopy and tremor (which occurred in 2% to 5% of patients) accounted for the majority of reported adverse effects and responded rapidly to dose reduction or infusion termination. However, chest pain/angina pectoris precipitated by tachycardia have been chiefly encountered in patients with pre-existing ischaemic heart disease. In most patients, the dopexamine hydrochloride-induced tachycardia is within limits of clinical acceptability and there is no evidence of significant arrhythmogenic potential. Reversible reductions in neutrophil and platelet counts have been recorded in healthy subjects receiving short term intravenous infusions of dopexamine hydrochloride 1 to 4 &mgr;g/kg/min. There have been no reports of biochemical abnormalities following administration of the drug to normoglycaemic patients.Dosage and AdministrationFor the treatment of acute heart failure and haemodynamic support in patients following cardiac surgery, dopexamine hydrochloride should be infused intravenously at an initial dose of 0.5 &mgr;g/kg/min and then titrated upwards in dosage increments of 1.0 &mgr;g/kg/min, in accordance with haemodynamic response, to a maximum of 6.0 &mgr;g/kg/min. The use of dopexamine hydrochloride is contraindicated in patients with thrombocytopenia. Caution is advised in the case of patients with hyperglycaemia and hypokalaemia in view of the drug's &bgr;-adrenergic action.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS