ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The study of chronic liver disease has been hampered by insufficient information relative to the pathogenesis of the many forms of hepatitis. Consequently, well-designed treatment strategies are frequently lacking. Wilson's disease is characterised by excessive copper accumulation in the liver and other organs. Whiled-penicillamine is clearly effective, many patients may not tolerate its many adverse effects. Trientine, oral zinc and unithiol have all shown promise as therapeutic alternatives.Autoimmune chronic active hepatitis responds well to prednisone and azathioprine. Cyclosporin has also produced clinical improvement in several case reports but no comparison has yet been made with the current standard therapy. Recombinant interferon-&agr; (IFN&agr;) has demonstrated the ability to inhibit hepatitis B viral replication, and the combination of oral corticosteroids followed by IFN&agr; is more effective than either agent alone in eliminating viral replication in patients with chronic active hepatitis B.Currently, primary sclerosing cholangitis (PSC) has no standard medical management, but corticosteroids and methotrexate may each have a future role in its treatment. Drug treatment for primary biliary cirrhosis (PBC) has been disappointing, and early reports of success withd-penicillamine were not confirmed in large well-controlled trials. While some reports of improvement with several agents have been described, larger studies are still needed.Alcoholic liver disease continues to be associated with significant morbidity and mortality and numerous investigators have researched several different medical avenues of treatment. Success reported with androgens and the antithyroid agent propylthiouracil in alcoholic liver disease will need confirmation by other research before these agents can be recommended for routine use. Finally, colchicine may prove to be effective in slowing the rate of fibrosis in cirrhosis, but this has yet to be conclusively proven.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Acid-base derangements are encountered frequently in clinical practice and many have life-threatening implications. Treatment is dependent on correctly identifying the acidbase disorder and, whenever possible, repairing the underlying causal process. Bicarbonate is the agent of choice for the treatment of acute metabolic acidosis. Controversy surrounds the use of alkali therapy in lactic acidosis and diabetic ketoacidosis, but bicarbonate should clearly be administered for severe acidosis. In most patients with mild to moderate chloride-responsive metabolic alkalosis, providing an adequate amount of a chloride salt will restore acid-base balance to normal over a matter of days. In contrast, therapy of the chloride-resistant metabolic alkaloses is best directed at the underlying disease. When alkalaemia is severe, administering hydrochloric acid or a hydrochloric acid precursor may be necessary.Treatment of respiratory acidosis should be targeted at restoring ventilation; alkali should be administered only for superimposed metabolic acidosis. The therapy of respiratory alkalosis is centred on reversal of the root cause; short of this goal, there is no effective treatment of primary hypocapnia.The coexistence of more than one acid-base disorder (i.e. a mixed disorder) is not uncommon. When plasma bicarbonate concentration and arterial carbon dioxide tension (paCO2) are altered in opposite directions, extreme shifts in pH may occur. In such cases, it is imperative that the nature of the disturbance is identified early and therapy directed at both disorders.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Toxic shock syndrome (TSS) is an acute febrile, exanthematous illness associated with multisystem failure including shock, renal failure, myocardial failure and adult respiratory distress syndrome (ARDS). It usually presents with fever, pharyngitis, diarrhoea, vomiting, myalgia, and a scarlet fever-like rash, and may progress rapidly (within hours) to signs of hypovolaemic hypotension such as orthostatic dizziness or fainting.The signs and symptoms of toxic shock syndrome should be recognised early to permit successful therapy. Patients are usually suffering from hypovolaemia due to leaky capillaries and fluid loss into the interstitial space, and consequently large volumes of fluid, both crystalloid (e.g. saline, electrolyte-solutions) and colloid (e.g. albumin, intravenous &ggr;-globulin), may be necessary to maintain adequate venous return and cardiac output. Patients with toxic shock syndrome usually have a focus of staphylococcal infection such as a surgical wound infection or soft tissue abscess, or they may have TSS associated with menstruation and use of a vaginal device such as tampons. The site of infection should be adequately drained and treated with antimicrobial therapy. Subacute complications including ARDS and myocardial failure require a thorough understanding of the underlying pathophysiology to ensure appropriate treatment. Recurrences of TSS can be avoided by appropriate antimicrobial treatment and avoidance of recurrent conditions which might favour staphylococcal toxin production (e.g. use of tampons during menstruation). More than 95% of patients survive toxic shock syndrome if appropriate therapy is instituted early.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

&bgr;-Blockers are effective in reducing the blood pressure of many patients with systemic hypertension. They differ in terms of the presence or absence of intrinsic sympathomimetic activity, membrane-stabilising activity, &bgr;1-selectivity, &agr;-blocking properties, and relative potency and duration of action. All &bgr;-blockers appear to have blood pressure lowering effects.The choice of which &bgr;-blocker to use in an individual patient is determined by the pharmacodynamic and pharmacokinetic differences between the drugs in conjunction with the patient's other medical condition(s). This review discusses the practical use of &bgr;-blockers and provides rational suggestions for which drug(s) to use in selected patient groups (Black, elderly, postinfarction, diabetes, renal disease, obstructive lung disease, elevated lipid levels, coexisting angina, and left ventricular hypertrophy).

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisFluconazole is a bis-triazole antifungal drug with novel pharmacokinetic properties (metabolic stability, relatively high water solubility) which contribute to its therapeutic activity. Clinical experience is limited to a relatively small number of mycoses and, as might be expected at this early stage of development, optimal dosage and duration of treatment for some serious mycoses is not yet established. Further study to evaluate higher dosages and to establish the efficacy of fluconazole relative to more established antifungal agents is required.In patients with oropharyngeal or oesophageal candidiasis, fluconazole produces rapid relief and eradicates the yeast in 50 to 90% of patients. Relapse of oral infection is common in chronically immunocompromised patients regardless of the antifungal used, and adequate primary therapy plus long term prophylaxis appears necessary in patients with AIDS. A single oral dose of fluconazole was comparable to standard topical azole therapy in women with acute vaginal candidiasis.Preliminary reports of success against deep-seated candidiasis are encouraging; moreover, experience in noncomparative clinical trials suggests that fluconazole 200 to 400mg once daily resolves infection in the majority of seriously ill patients. Clinical improvement has been reported in a few cases of pulmonary Aspergillus infection but the overall efficacy of conventional dosages of fluconazole in this mycosis has not been as impressive. Early experience in coccidioidosis, predominantly meningitis, suggests a beneficial clinical effect with oral fluconazole in this difficult to treat mycosis but relapse remains a problem.Fluconazole is a promising treatment of cryptococcal meningitis. The rate of clinical resolution and eradication ofCryptococcus neoformansfrom cerebrospinal fluid has been similar between fluconazole and amphotericin B treatment groups in comparative trials. Comparative trials of maintenance therapy indicate a similar low rate of relapse among patients given oral fluconazole once daily and intravenous amphotericin B once weekly. However, these results are preliminary and further study is required.Fluconazole has been well tolerated to date but wider clinical experience is needed, especially with regard to the rare occurrence of hepatotoxicity and exfoliative skin reactions.The promising clinical response of patients with various forms of candidiasis or cryptococcosis - together with convenient administration regimens - recommends fluconazole as a useful addition to currently available systemic antifungal therapies, in particular for the treatment of mycoses in patients with AIDS.Pharmacodynamic PropertiesResults ofin vitrosusceptibility tests do not accurately reflect the therapeutic efficacy of fluconazole. Relatively good activity against yeasts has been shown in specialised media (tissue culture agar and synthetic amino acid medium-fungal) but the MICs obtained in conventional media are generally many times greater for fluconazole than for ketoconazole. In contrast, fluconazole is the more potent azole in animal models of fungal infection. Studiesin vivohave shown fluconazole to improve the survival of animals challenged with lethal inocula ofCandida, Cryptococcus, Aspergillus, Blastomyces, Coccidioides, andHistoplasma.Fluconazole 40 to 120 mg/kg/day reduced the fungal burden of animals with systemic mycoses and lower dosages (25 to 10 mg/kg/day) cured 50 to 100% of animals with vaginal candidiasis or dermatophytoses.The antifungal activity of azole derivatives relates to their inhibition of membrane sterol synthesis by fungal cytochrome P450 enzymes. While ketoconazole also inhibits mammalian cytochrome P450 enzymes, supratherapeutic concentrations of fluconazole have a minimal effect on mammalian enzymes and, thus, fluconazole appears to be free of adverse effects on steroid hormone production.Pharmacokinetic PropertiesFluconazole is very well absorbed after oral administration even in the presence of food, or antacid or H2-receptor antagonist pretreatment, and its bioavailability exceeds 90%. The peak plasma concentrations achieved after single oral doses of fluconazole 100mg and 400mg are 1.9 mg/L and 6.7 mg/L, respectively, in healthy volunteers. Continued oral administration of fluconazole for 6 to 10 days leads to an increase in peak plasma concentration of 2.5 times that achieved after a single dose.Fluconazole is widely distributed and its apparent volume of distribution (0.8 L/kg) approximates that of total body water. Concentrations in cerebrospinal fluid, saliva, sputum and vaginal fluid approximate those attained in the plasma. In contrast to other azole antifungals which are highly bound, fluconazole is only 11% protein bound.The primary route of elimination is via renal excretion with up to 80% of the drug recovered in urine unchanged. The elimination half-life is approximately 30 hours and is prolonged in patients with decreased renal function, necessitating dosage modification. Fluconazole is removed by haemo- and peritoneal dialysis.Therapeutic UseThe majority of clinical experience with fluconazole has been in patients with candidiasis or cryptococcosis. Fluconazole 50 to 100mg daily produced rapid resolution of the signs and symptoms of oropharyngeal candidiasis associated with AIDS or the treatment of malignancy, 88 to 100% of patients were clinically cured and cultures became negative in 50 to 90% of patients. Comparisons of fluconazole 50 to 100 mg/day with ketoconazole 200 to 400 mg/day and clotrimazole troches 50 mg/day found a similar rate of clinical remission and mycological eradication between these azole antifungals. Relapse was common in patients with AIDS regardless of the success of acute therapy. Whether this reflects regrowth of sequesteredCandidaor new infection is not clear but antifungal maintenance therapy has been advocated for these patients. In patients with chronic atrophic oral candidiasis, lesions outside the denture-bearing mucosa responded well but palatal lesions tended to relapse. Soaking the dentures nightly in chlorhexidine 0.2% solution significantly reduced the rate of recolonisation. In large multicentre studies of acute vaginal candidiasis, fluconazole 150mg as a single oral dose resolved the signs and symptoms of infection in ≥ 80% of women evaluated 1 to 2 months post-treatment and was comparable to the efficacy of clotrimazole or econazole intravaginally for 3 and 6 days, respectively, and ketoconazole orally for 5 days.Oesophageal candidiasis responded well to treatment with fluconazole 50 or 100mg daily. Typically the drug eradicatedCandidafrom the oesophagus of evaluable patients and produced rapid resolution of pain and dysphagia. However, mycological cure did not improve oesophageal symptoms in patients with progressive systemic sclerosis in whom oesophageal dysmotility and antireflux medication predisposed to colonisation but not to invasive candidiasis. Preliminary results of a double-blind comparative trial suggest that fluconazole 100 to 200 mg/day produces mycological eradication rates equal to those of ketoconazole 200 to 400 mg/day and a greater degree of endoscopically confirmed healing.Symptomatic urinary tract infection responded well to fluconazole, generally 50mg daily, but urinary tract candidiasis is an ill-defined entity and controlled clinical studies are needed to evaluate the role of fluconazole in its management.Fluconazole 50mg daily was comparable to ketoconazole 200mg daily in a double-blind multicentre study of patients with various dermatophyte infections. Very few data are available on the efficacy of fluconazole in mycoses confined to keratinised tissue, including hair and nails, although therapeutic drug concentrations have been measured in skin and nail tissue.In noncomparative premarketing clinical trials fluconazole 50 to 400mg daily was used to treat a small number of patients with deep-seated candidiasis, and satisfactory clinical response and mycological eradication was achieved in approximately 85 and 76% of patients, respectively. Moreover, fluconazole was used successfully in many patients unresponsive to or intolerant of more established antifungal treatment. Fluconazole 100 to 300 mg/day proved useful in the few patients treated for pulmonary candidiasis or candidaemia associated with haematological malignancy, but there are insufficient data to generalise about the efficacy of fluconazole in neutropenic patients. Fluconazole 50mg daily was comparable to oral polyene prophylaxis in preventing the development of oropharyngeal candidiasis in patients at high risk of developing neutropenia but further study is needed to determine if fluconazole prophylaxis confers any protection against invasive fungal infection.Use of fluconazole has been particularly promising in patients with AIDS-related cryptococcal meningitis in whom conventional therapy with amphotericin B and flucytosine, while effective, is difficult to administer and carries considerable risk of toxicity. Success in individual patients and in noncomparative studies has prompted comparative studies between fluconazole and amphotericin B in patients with active cryptococcal meningitis. Preliminary analysis of ongoing trials found that fluconazole 200 to 400 mg/day cured or improved approximately 60% of patients treated to date and this response was similar to the success rate recorded for amphotericin B in all but 1 participating centre.Fluconazole (generally 100 or 200 mg/day) has also been evaluated as maintenance therapy in patients with AIDS who had negative cerebrospinal fluid cultures after primary treatment. The median follow-up period varied between 10 weeks and 11 months, during which 7 clinical relapses occurred in 59 patients. A comparison between daily oral fluconazole (200mg) and weekly intravenous amphotericin B (1 mg/kg) is continuing.Conventional dosages of fluconazole have been less impressive in pulmonaryAspergillusinfection although experience is limited to small Japanese trials. Clinical improvement was achieved with fluconazole 50 or 100mg daily alone or in addition to intrathecal antifungals in patients with coccidioidal meningitis; however, the problem of relapse with this mycosis remains.Adverse EffectsFluconazole has generally been well tolerated. In clinical trials utilising dosages between 50 and 400mg daily, the overall incidence of adverse reactions was approximately 16%, with nausea, headache, skin rash, abdominal pain, vomiting and diarrhoea being reported most commonly. Only 1.5% of patients discontinued treatment due to adverse reactions and 1.3% discontinued due to laboratory abnormalities - most frequently liver function test abnormalities. Rarely, patients with AIDS have developed exfoliative skin reactions during treatment, but the role of fluconazole in this reaction is uncertain. Hepatotoxicity has also been reported rarely in patients with serious underlying disease receiving fluconazole in addition to other potentially hepatotoxic agents. The causal association of these reactions with fluconazole is uncertain but, because of their potential seriousness, patients who develop liver function abnormalities or skin rash during treatment should be monitored closely.Dosage and AdministrationThe daily dosage of fluconazole is the same by oral or intravenous routes. The recommended dosage in patients with oropharyngeal or oesophageal candidiasis is 200mg on the first day followed by 100mg once daily for a minimum of 2 weeks in oropharyngeal infection and 3 weeks plus at least 2 weeks after symptoms resolve in oesophageal infection. A single oral dose of 150mg is recommended in women with acute vaginal candidiasis.For the treatment of serious candidiasis or cryptococcal meningitis, the recommended dosage is 400mg on the first day followed by 200mg once daily. The dosage should be increased to 400mg if clinically indicated. The minimum recommended treatment interval for patients with deep-seated candidiasis is 4 weeks. Patients with cryptococcal meningitis should receive active treatment for 10 to 12 weeks after cultures of cerebrospinal fluid become negative; thereafter fluconazole 200mg once daily is recommended for suppression of relapse in patients with AIDS.A small number of children greater than 3 years of age have been safely treated with 3 to 6 mg/kg/day.The following dosage modification is recommended in patients with impaired renal function: full dosage if creatinine clearance exceeds 0.8 ml/sec (50 ml/min), half recommended dosage if creatinine clearance is 0.35 to 0.8 ml/sec (21 to 50 ml/min), and one-quarter recommended dosage if creatinine clearance is 0.18 to 0.35 ml/sec (11 to 20 ml/min). The full recommended dose should be given after each session of regularly scheduled haemodialysis. No change is necessary for single-dose treatment.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisGuar gum is a dietary fibre advocated for use in lowering serum total cholesterol levels in patients with hypercholesterolaemia. Its mechanism of action is proposed to be similar to that of the bile-sequestering resins. Although guar gum is also employed as an adjunct in non-insulin-dependent diabetic patients this review is restricted to its efficacy as a hypolipidaemic agent. Clinical trials indicate that, when used alone, guar gum may reduce serum total cholesterol by 10 to 15%, although some studies show no significant response. An attenuation of this effect during longer term treatment has been seen but evidence of this effect is equivocal. As an adjunct to established therapies (bezafibrate, lovastatin or gemfibrozil) guar gum has shown some promise: it may produce a further reduction in total cholesterol of about 10% in patients not responding adequately to these drugs alone. Gastrointestinal effects, notably flatulence, occur relatively frequently and may be considered unacceptable by some patients. Standardisation of formulations and methods of administration of guar gum is required to clarify its pharmacological and clinical properties.Thus, on the basis of presently available evidence guar gum as monotherapy may be considered at most modestly effective in reducing serum cholesterol levels. Nonetheless, further investigation of guar gum is warranted, particularly its use as an adjunct to produce additional reductions in serum cholesterol in patients not responding optimally to other lipid-lowering agents.Pharmacological PropertiesGuar gum is a dietary fibre obtained from the endosperm of the seeds of the Indian cluster bean (Cyamopsis tetragonolobus), which forms a highly viscous gel on contact with water, and undergoes colonic fermentation to short-chain fatty acids. It may significantly delay gastric emptying time and/or gastrointestinal transit and reduce small intestinal absorption, although this appears highly dependent on the nature of the diet. While this action may in part explain the mechanism of action whereby it reduces blood glucose and insulin levels, and consequently its use as an adjunct in the treatment of non-insulin-dependent diabetic patients, this has not generally been accepted as part of the mechanism of action in reducing cholesterol levels. Guar gum has been shown to reduce serum total cholesterol (by about 10 to 15%) and low density lipoprotein (LDL)-cholesterol (by about 15 to 25%) in hypercholesterolaemic animals, healthy subjects and diabetic patients, without producing any significant effect on serum high density lipoprotein (HDL)-cholesterol or triglyceride levels. These effects are also seen in patients with hyperlipidaemia (see below). More generally accepted hypothese concerning its antihypercholesterolaemic mechanism of action include reduced cholesterol absorption and increased bile acid excretion, leading to increased hepatic cholesterol turnover. It is also proposed that appetite and dietary intake may be affected since significant weight loss has occurred in some, although not the majority, of patients treated with guar gum.Therapeutic TrialsThere have been relatively few clinical trials of guar gum in the treatment of patients with hypercholesterolaemia, and few of these included comparison with placebo and/or appropriate controls to reduce bias and variation. Indeed, double-blind conditions may be difficult to maintain because of the high frequency of unwanted gastrointestinal effects with some formulations. These studies usually included small numbers of patients (generally 10 to 30). When used alone, guar gum 15 to 30g daily reduced serum total cholesterol by 10 to 15% and LDL-cholesterol by 10 to 20%, although some studies showed a lack of any clinically or statistically significant effect. Serum HDL-cholesterol levels were not significantly affected, and most studies found no change in triglyceride levels. Evidence of attenuation of the antihypercholesterolaemic effect of guar gum is equivocal: rises in cholesterol levels toward baseline values have occurred after 8 to 12 weeks' therapy, but significantly reduced levels have also been measured after 9 to 12 months.The addition of guar gum to bezafibrate, gemfibrozil or lovastatin monotherapy has resulted in a further reduction of 7 to 13% in total cholesterol and 14 to 19% in LDL-cholesterol. Further investigation of such strategies seems warranted.Adverse Effects and Drug InteractionsThe tolerability of guar gum may vary greatly depending on many factors including dosage, formulation and method of administration. As it is not absorbed from the gastrointestinal tract guar gum does not appear to produce systemic adverse effects. Unwanted effects are thus restricted to the gastrointestinal tract and include flatulence, pain or discomfort, nausea and diarrhoea. Although the severity of these effects may necessitate a reduction in dosage or withdrawal from treatment, usually they are transient or diminish during continued treatment. While some trials have reported a low incidence of mild, transient adverse effects, others have reported flatulence in up to 50%, and sometimes 100%, of patients, with dosage reduction sometimes necessary.Guar gum may affect the absorption of certain concomitantly administered drugs: often only the rate of absorption is affected [e.g. paracetamol (acetaminophen), digoxin, bumetanide] and this is consequently of little clinical significance. However, the extent of absorption of certain drugs (e.g. phenoxymethylpenicillin, metformin, oral contraceptives and some galenic formulations of glibenclamide) may be reduced by a clinically significant degree.Dosage and AdministrationGuar gum should be administered initially at a dosage of 2.5g 2 or 3 times daily during the first week of treatment. Thereafter, the dosage may be increased gradually to 5g 3 times daily, to reduce the possibility of unwanted gastrointestinal effects. Numerous formulations are available including powder and coated granules, but plain granules have been used most frequently and appear more palatable. Guar gum has also been incorporated into various foodstuffs including bread, crispbread, pasta and snack bars. The effects of the source, formulation and method of administration of guar gum on its efficacy and tolerability have not been well studied.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

SynopsisPinacidil is an orally administered antihypertensive drug that acts via direct relaxation of vascular smooth muscle to produce peripheral vasodilatation and a reduction in blood pressure without significant direct effects on cardiac electrophysiology. Pinacidil is unrelated to other antihypertensive drugs in clinical use, either in structure or mechanism of action. It belongs to a new class of agents called ‘potassium channel openers’ which act via potassium efflux to hyperpolarise cell membranes, indirectly causing a net reduction in intracellular calcium that leads to relaxation of vascular smooth muscle.Pinacidil is indicated in the management of essential hypertension. In clinical trials of up to 1 year, duration, pinacidil administered twice daily in a controlled release capsule formulation has been shown to achieve adequate blood pressure control both in previously untreated patients and in those with blood pressure inadequately controlled by &bgr;-adrenoceptor blocking drugs or thiazide diuretics. In long term (up to 1 year) comparative studies pinacidil was at least as effective as hydralazine, prazosin or nifedipine in maintaining blood pressure control. Pinacidil may also have a potential use in the treatment of patients with secondary renal hypertension.Clinical trials to date have usually allowed the addition of a thiazide diuretic and/or &bgr;-adrenoceptor blocking drug to enhance the efficacy of pinacidil and/or to reduce the incidence of adverse effects.The main adverse effects of pinacidil treatment, which result from its peripheral vasodilator activity, are headache, oedema, palpitations and tachycardia. Although the over-all incidence of adverse effects is quite high, they are usually mild, transient in nature and respond to a reduction in dose. Nevertheless, these effects may occasionally be severe, necessitating withdrawal from therapy.Thus, pinacidil is an effective antihypertensive drug for the treatment of mild to moderate essential hypertension. Despite its novel mechanism of action pinacidil causes adverse effects typical of peripheral vasodilators; during long term use with twice daily administration of the controlled release capsule formulation, the addition of a diuretic is often necessary to attenuate peripheral oedema and maintain adequate control of blood pressure. Further long term controlled trials are needed to determine the precise role of pinacidil relative to that of the angiotensin converting enzyme (ACE) inhibitors and calcium channel blocking drugs.Pharmacodynamic PropertiesPinacidil is a peripheral vasodilator belonging to a novel class of drugs known as ‘potassium channel openers’. The opening of potassium channels in smooth muscle cells results in potassium efflux and a negative shift in the resting membrane potential, causing hyperpolarisation of the cells at rest. The net result is a decrease in intracellular calcium and relaxation of smooth muscle, particularly in the vasculature.The primary haemodynamic effect of pinacidil is peripheral vasodilatation leading to significant decreases in both systolic and diastolic blood pressures and a reflex increase in heart rate. These effects are dose related over the range of oral doses of pinacidil of 10 to 37.5mg. Administration of a conventional tablet formulation provides a rapid onset of action, with a maximum antihypertensive effect in 1 to 3 hours and a return to baseline values within 6 hours. This short duration of action prompted the development of a controlled release capsule formulation containing micropellets of pinacidil, which extends the duration of the antihypertensive effect to between 8 and 12 hours. Pinacidil in this formulation has been administered twice daily in most of the clinical trials.Single dose intravenous administration of pinacidil (0.2 mg/kg) to patients with hypertension or cardiovascular disease produced a significant decrease in systemic vascular resistance (28 to 40%), resulting in a decrease in systolic and diastolic blood pressures in the order of 20%, and reflex increases in heart rate (11 to 36%) and cardiac index (25 to 29%). The effects on cardiac haemodynamics could be abolished by &bgr;-adrenoceptor blockade, indicating that they are the result of arteriolar vasodilatation and not of any direct cardiostimulatory effect of pinacidil. Cardiac haemodynamic effects appear to be attenuated during long term oral therapy. Although pinacidil has demonstrated negative inotropic activity in animal models, the plasma concentrations required would probably not be achieved clinically and thus any marked effect on action potential duration or cardiac contractility would be unlikely.The potent effect of pinacidil in reducing systemic vascular resistance would be expected to result in a reflex increase in sympathetic outflow, an increase in plasma renin and aldosterone release and retention of sodium and water. In hypertensive patients such effects have been demonstrated following acute administration of the drug. However, the effects of long term therapy are more variable and their quantification is confounded by the frequent concomitant administration of both thiazide diuretics and &bgr;-adrenoceptor blocking drugs. Thus, the extent of the effect of long term pinacidil monotherapy on these parameters remains unclear.Pharmacokinetic PropertiesThe oral bioavailability of the controlled release capsule formulation of pinacidil in healthy volunteers is 57%. The parent compound undergoes rapid metabolism with 25% of a systemically available dose found in plasma as the major metabolite, pinacidil-N-oxide, and 17% found as other unidentified metabolites. TheN-oxide metabolite also has blood pressure-lowering activity but has approximately one-quarter the potency of pinacidil.The maximum plasma concentration of pinacidil increases linearly with dose in the range 12.5 to 75mg, the ‘average’ plasma concentration being 268 &mgr;g/L for each 1 mg/kg bodyweight of pinacidil administered. The peak plasma concentration of the rapidly released pellets occurs at approximately 1 hour, with a further peak from the slow release portion of the formulation at 4 to 6 hours. The area under the plasma concentration-time curve (AUC) is also linearly related to dose. Accumulation of pinacidil has not been demonstrated with long term administration of the drug.The volume of distribution of pinacidil after an intravenous infusion is in the order of 1.1 to 1.4 L/kg, and plasma protein binding was approximately 39% over a range of plasma pinacidil concentrations of 43 to 435 &mgr;g/L in one study, although binding of 60 to 65% was reported in another.Metabolism and elimination of pinacidil involve hepatic biotransformation via the cytochrome P450 enzyme system followed by renal excretion of metabolites. The appearance in plasma of the major metabolite, pinacidil-N-oxide, is rapid, with a peak plasma concentration (at 4 hours) and AUC which are linearly related to dose. The accumulation of theN-oxide metabolite has been demonstrated in both healthy volunteers and in hypertensive patients during long term pinacidil therapy and is directly related to increasing age and deteriorating renal function.The 24-hour urinary excretion values range from 1.3 to 6.9% for pinacidil and 25.1 to 68.3% for the metabolite. Faecal excretion as determined from animal data appears not to be significant.The elimination half-lives of pinacidil and pinacidil-N-oxide with the controlled release formulation are in the order of 1 to 3 and 4 hours, respectively. The clearance of both parent compound and major metabolite is reduced with increasing age and the peak plasma concentration of metabolite rises as creatinine clearance decreases. Liver disease also increases the plasma concentration and the elimination half-life of pinacidil and pinacidil-N-oxide, and impaired hepatic oxidising ability leads to reduced recovery of metabolite in the urine.A linear correlation between plasma concentration of pinacidil and decrease in blood pressure has been demonstrated in several studies using single oral doses of pinacidil and in some long term trials over 1 to 3 months. However, other studies have not confirmed this relationship, indicating that other factors may be involved in the determination of antihypertensive response in the long term.Therapeutic TrialsThe efficacy of pinacidil in the treatment of mild to moderate essential hypertension has been demonstrated in several short term noncomparative and controlled clinical trials and in a few longer studies of more than 12 months' duration. Some studies utilised pinacidil as monotherapy, although in the great majority a diuretic and/or &bgr;-adrenoceptor blocking drug was added. These drugs had failed to control blood pressure adequately in most patients prior to the studies. The daily dose of pinacidil in individual studies ranged from 20 to 100mg (mean range 32 to 57mg) and the average reduction in pressures achieved ranged from 9 to 44mm Hg systolic and 7 to 25mm Hg diastolic in the supine position and from 25 to 37mm Hg systolic and 13 to 24mm Hg diastolic in the erect position. The duration of effect with the controlled release formulation appeared to make twice daily dosing practicable, although continuous ambulatory blood pressure recording demonstrated a gradual rise in blood pressure from 6 hours after the dose of pinacidil and a loss of blood pressure control prior to the next dose in some patients. The addition of a thiazide diuretic was found to improve efficacy and to alleviate the common adverse effects of oedema and weight gain. Tolerance to the antihypertensive effects of pinacidil did not occur during the studies and there was no rebound hypertensive effect when therapy with pinacidil was abruptly withdrawn, blood pressure readings slowly returning toward pretreatment levels over a 1- to 2-week period.Blood pressure control with pinacidil, usually combined with a diuretic and/or adrenoceptor blocking drug, was also achieved over a prolonged period (mean 43 weeks) in a small number of patients with hypertension secondary to renal disease. No tolerance occurred and tachycardia, oedema and weight gain were not a problem.When compared with placebo pinacidil monotherapy was significantly more effective, controlling blood pressure to target levels in 67 to 87% of patients. Concomitant administration of pinacidil with hydrochlorothiazide was also more effective than the diuretic plus placebo. Furthermore, the incidence of adverse effects of the combination of pinacidil with a diuretic was less than that when pinacidil was administered alone.Pinacidil has been compared with hydralazine in a number of randomised double-blind parallel or crossover trials. Pinacidil was at least as effective, and in some studies was more effective than hydralazine in providing continued blood pressure control for periods of up to 12 months. All of the studies allowed the concomitant use of a thiazide diuretic and/or &bgr;-adrenoceptor blocking drug to enhance efficacy or reduce adverse effects. Indeed, in some studies only a limited response was noted with pinacidil monotherapy, the success rate rising markedly with the addition of the allowed medications. In a comparative trial, however, these drugs were added more frequently to pinacidil treatment to control adverse effects, while they were more often added to hydralazine therapy to enhance efficacy.In studies comparing pinacidil and prazosin the drugs were generally of similar efficacy in achieving blood pressure control. While monotherapy did achieve adequate results in most patients, the response to pinacidil was limited by the appearance of adverse effects related to vasodilatation, necessitating the addition of hydrochlorothiazide or propranolol to maintain efficacy. Similar results have been found in a small number of trials comparing pinacidil with nifedipine, verapamil or methyldopa, although no firm conclusions concerning relative efficacy can be drawn until further studies in large groups of patients have been conducted. Studies comparing pinacidil with ACE inhibitors have not been reported.Because pinacidil has often been combined with a thiazide diuretic the antihypertensive efficacy of combination therapy relative to that of either drug alone has specifically been addressed. Both hydrochlorothiazide and pinacidil administered as monotherapy were capable of lowering blood pressure, while the combination was more effective in this regard than either agent alone. Overall, the optimum daily dosage range of pinacidil alone was 25 to 50mg; this could be reduced by the addition of hydrochlorothiazide 25mg daily. The incidence of oedema was clearly reduced by combination therapy.Adverse EffectsThe most commonly reported adverse effects of pinacidil - headache, palpitations, tachycardia and dizziness - are related to its potent peripheral dilating properties. These effects, which are common, occur early in treatment and are dose related. They are alleviated by a reduction in dosage, and sometimes resolve spontaneously. Peripheral oedema, occurring later in treatment, has been reported in 25 to 50% of patients and is also related to dose. Addition of a thiazide diuretic markedly decreases the incidence of these vasodilatory effects and usually allows treatment with pinacidil to continue, although patient withdrawals of 11 to 20% have been reported in studies which enrolled reasonable numbers of patients.Other relatively common adverse effects of pinacidil therapy include weight gain, asymptomatic T wave changes on the electrocardiogram (31%) and hypertrichosis (6.4%) which resolves once the drug is discontinued. Other adverse effects noted sporadically include tiredness, postural hypotension, flushing, nasal congestion and depression.Few changes attributable to the drug have been noted in biochemical or haematological parameters during treatment with pinacidil. The development of positive antinuclear factor antibodies (ANA) has occurred in a number of patients but was not accompanied by any clinically obvious adverse effects. Pinacidil appears to have a salutary effect on serum lipids, reducing total cholesterol and triglycerides and the low density lipoprotein (LDL) fraction, while increasing the high density lipoprotein (HDL) fraction. This effect is blunted by the addition of hydrochlorothiazide and/or propranolol such that the overall effect of the combination on lipid levels is usually not significant.Drug InteractionsDrugs such as cimetidine which inhibit the enzymes of the hepatic cytochrome P450 system may delay the elimination of pinacidil, while enzyme-inducing drugs such as phenytoin and phenobarbital can increase the rate of elimination of pinacidil. Probenecid also may delay the excretion of pinacidil and pinacidil-N-oxide.Dosage and AdministrationThe initial dosage of pinacidil in the treatment of mild to moderate essential hypertension should be 12.5mg twice daily, with slow increases until the desired antihypertensive effect is achieved. The maximum daily dose varies in different countries, being 25mg twice daily in the US and 37.5mg twice daily in Europe. The usual maintenance dose is 12.5 to 25mg twice daily. It is seldom necessary to increase the total dose above 100mg daily. Dosage adjustment may be necessary in elderly patients, in those with renal or hepatic dysfunction and in patients receiving concomitant diuretics and/or &bgr;-adrenoceptor blocking drugs.The addition of a thiazide diuretic is recommended to ensure the maintenance of blood pressure control throughout the dosing interval with a twice daily dosage regimen and to control vasodilatory adverse effects.

ISSN:0012-6667    

出版商:ADIS    

年代:1990

数据来源: ADIS