Risk-benefit assessment of tocolytic drugs

beta 2-Mimetics are the principal agents used for myometrial relaxation. As all the available drugs also have beta 1-stimulant effects, the various side effects (cardiovascular, pulmonary and metabolic) require a critical consideration of the clinical indications, thorough supervision and combined therapeutic concepts. With regard to clinical indications, 'prophylactic tocolysis' frequently turns out to be unnecessary, as does the treatment of physiological uterine contractions during pregnacy which have no effect on the cervix. The benefit of tocolysis must be seen not so much in a reduction of preterm labour but in enabling the obstetrician and neonatologist to optimise the handling of the premature baby, e.g. by allowing lung maturation or by enabling the patient to reach a centre for perinatal medicine before the birth. Labour-dependent fetal distress situations during birth at term can also be managed successfully. Supervision involves thorough control of both mother (especially of cardiovascular and metabolic parameters, electrolyte and water balance) and fetus (cardiotocography, fetometry) in order to decide individually when possible benefits are outweighed by maternal or fetal risks. Combination of beta 2-mimetic treatment with magnesium therapy reduces the beta-mimetic dosage required, has a cardioprotective action, and reduces the development of drug tolerance and the risk of lung oedema. This combination, therefore, should become routine in tocolytic therapy. If further protection against cardiovascular and risk of lung oedema is required, administration of beta 1-blockers is advisable.     

Risk-benefit effects of tocolytic therapy

Tocolytics are potent drugs that are used to interdict preterm labour. Although all of these agents have some side effects, if not frankly adverse effects under certain clinical situations, two of these drugs, the beta-mimetics and magnesium sulphate (MgSO(4)), have been found to have considerable potential for adverse maternal cardiovascular and respiratory effects. Furthermore, magnesium sulphate has been shown to have harmful, indeed, sometimes lethal, effects in some babies. Although less well established, NSAIDs, the most common example of which is indomethacin, also have some important adverse effects in fetuses. Within the limits of contemporary scientific knowledge, calcium channel blockers, such as nifedipine, appear to be among the more efficacious and safer drugs that are currently being used for tocolysis.     

Risk-benefit assessment of carbamazepine in children

Carbamazepine is an effective antiepileptic drug for the treatment of partial and convulsive generalised epilepsy in adults and children. The pharmacokinetic profile in children is similar to that in adults, but the half-life in long term paediatric therapy is between 6 and 12 hours, compared with 15 hours in adults. Autoinduction is present. The most common adverse effects are neurological and dose-related, and occur in up to 50% of patients treated, usually on dosage initiation or dose elevation. Most dissipate over time and require no alteration in dosage. Idiosyncratic effects include hypersensitivity, hepatic and haematological reactions. A benign leucopenia occurs in 10 to 12% of adults and children and appears to be unrelated to aplastic anaemia which occurs in approximately 1 in 575,000 treated patients per year. Carbamazepine is reported to have cognitive and behavioural advantages over other antiepileptic drugs. Overall, carbamazepine has become a major antiepileptic drug in children as well as adults.     

Risk-benefit assessment of angiotensin II receptor antagonists

Inhibiting the renin-angiotensin-aldosterone system through the use of angiotensin-converting enzyme (ACE) inhibitors has proven very useful in the treatment of hypertension, congestive heart failure (CHF) and progressive renal failure. More recently, agents that directly block the angiotensin II Type 1 (AT(1)) receptor--angiotensin II receptor antagonists (AIIRAs)--have been developed. These agents are thought to have a more specific mechanism of action since they do not affect other hormone systems as do the ACE inhibitors. Whether such specificity results in a different efficacy profile is still being determined. However, these drugs are extremely well-tolerated and very safe. AIIRAs are effective in the reduction of both systolic and diastolic blood pressure and compare favourably to other classes of agents. Recent results indicate that at least one AIIRA has a favourable effect on stroke in hypertensive patients with left ventricular hypertrophy. Additional studies with other members of the class will provide further information on similar outcomes. In CHF patients, ACE inhibitors remain the drug of choice and AIIRAs are best utilised in patients who cannot tolerate an ACE inhibitor or in those receiving an ACE inhibitor who cannot tolerate a beta-blocker and need additional therapy. AIIRAs are effective in slowing the progression of renal failure in patients with Type II diabetes and may be effective in other proteinuric conditions. Whether they are more or less effective than ACE inhibitors is unknown. Overall, AIIRAs represent an important addition to the armamentarium of cardiovascular therapies with an excellent safety record and an emerging profile of utility in multiple cardiovascular conditions.     

Risk-benefit assessment of angiotensin II receptor antagonists

Inhibiting the renin-angiotensin-aldosterone system through the use of angiotensin-converting enzyme (ACE) inhibitors has proven very useful in the treatment of hypertension, congestive heart failure (CHF) and progressive renal failure. More recently, agents that directly block the angiotensin II Type 1 (AT₁) receptor – angiotensin II receptor antagonists (AIIRAs) – have been developed. These agents are thought to have a more specific mechanism of action since they do not affect other hormone systems as do the ACE inhibitors. Whether such specificity results in a different efficacy profile is still being determined. However, these drugs are extremely well-tolerated and very safe. AIIRAs are effective in the reduction of both systolic and diastolic blood pressure and compare favourably to other classes of agents. Recent results indicate that at least one AIIRA has a favourable effect on stroke in hypertensive patients with left ventricular hypertrophy. Additional studies with other members of the class will provide further information on similar outcomes. In CHF patients, ACE inhibitors remain the drug of choice and AIIRAs are best utilised in patients who cannot tolerate an ACE inhibitor or in those receiving an ACE inhibitor who cannot tolerate a β-blocker and need additional therapy. AIIRAs are effective in slowing the progression of renal failure in patients with Type II diabetes and may be effective in other proteinuric conditions. Whether they are more or less effective than ACE inhibitors is unknown. Overall, AIIRAs represent an important addition to the armamentarium of cardiovascular therapies with an excellent safety record and an emerging profile of utility in multiple cardiovascular conditions.     

Risk-benefit assessment of anaesthetic agents in the puerperium

A critical evaluation of anaesthetic agents in the puerperium is difficult because systematic, relevant studies are still lacking. Current knowledge of the effects of different agents used in labour and caesarean section indicates that significant residual effects on the mother and newborn are limited. In the early puerperium, based on physiological and/or hormonal changes, the mother could be more sensitive to inhalational anaesthetic agents and local analgesics. To date there is no evidence that any anaesthetic agent is excreted in breast milk in clinically significant amounts when given as a single dose. The only exception is perhaps in the case of very premature neonates whose mothers have had multidrug therapy before labour. Even then the importance of breast milk should be carefully assessed against possible adverse drug effect. However, repeated administration of long-acting benzodiazepines and continuous epidural administration of pethidine (meperidine) can have adverse effects on the neonate. The essential conclusion of this review is that breast-feeding is best. The different anaesthetic agents are excreted in the milk in amounts so low that detrimental effects on the neonate should not be expected.     

Risk-benefit assessment of anticonvulsants in women of child-bearing potential

Problems with anticonvulsants in women of child-bearing potential include potential adverse effects on appearance, contraception and pregnancy. These effects must be weighed against the overwhelming benefits of anticonvulsant treatment in the majority of women with epilepsy. Coarsened features, hirsutism and acne may occur in both men and women, particularly if they are exposed to phenytoin. Valproic acid may cause weight gain and hair loss, while carbamazepine treatment carries a significant risk of skin rashes. Anticonvulsants which are liver enzyme inducers (phenytoin, phenobarbital, primidone and carbamazepine) reduce the efficacy of the oral contraceptive pill. No 'pill failure' has been reported with valproic acid. There is a risk of increased seizure frequency in pregnancy irrespective of whether anticonvulsant treatment is taken. Individual seizures carry little risk to the mother or the fetus but status epilepticus has a significant maternal and fetal mortality. The risk of status epilepticus must be taken into account when deciding whether to stop anticonvulsant treatment before pregnancy. There is a 2 to 3 times increased malformation rate in the offspring of epileptic women on treatment. This is primarily due to the drug treatment, but epilepsy itself may also increase the malformation rate. Most malformations are mild and include facial clefts, congenital heart disease and skeletal abnormalities. Valproic acid, however, carries a 1% risk of causing neural tube defects: women receiving this drug who become pregnant should have an ultrasound and alpha-fetoprotein estimation at 16 to 18 weeks of pregnancy. If any abnormality is detected then amniocentesis should be carried out. Women with epilepsy should be counselled before conception and during pregnancy. Before achieving pregnancy a women should be on optimum treatment, preferably on one anticonvulsant. Consideration should be given to withdrawal of anticonvulsant drugs in any woman who has been seizure free for 2 years or who has only mild and infrequent seizures. Folate supplementation should be started prior to conception and should continue during pregnancy. There is a tendency for anticonvulsant drug concentrations to fall during pregnancy, and the dose may need to be increased if clinically indicated. Over 90% of epileptic women who become pregnant will have uneventful pregnancies and will produce healthy infants.     

Risk-benefit assessment of glatiramer acetate in multiple sclerosis.

Glatiramer acetate, formerly known as copolymer 1, is a mixture of synthetic polypeptides composed of four amino acids. Glatiramer acetate has been shown to be effective in preventing and suppressing experimental autoimmune encephalitis (EAE), the animal model of multiple sclerosis (MS). Therefore it was tested in several clinical studies, where it was found to slow the progression of disability and to reduce the relapse rate and the magnetic resonance imaging (MRI)-defined disease activity and burden in relapsing-remitting MS. As a daily standard dose, 20mg of glatiramer acetate is injected subcutaneously. After injection, glatiramer acetate undergoes rapid degradation to amino acids and shorter peptides; so it is not possible to measure any systemic plasma concentrations or excretion rates. Two major mechanisms have been proposed to explain the effects of glatiramer acetate in EAE and MS: the induction of glatiramer acetate-reactive T helper 2 (Th2)-like regulatory suppressive cells and the interference with T cell activation as an altered peptide ligand. The most common adverse effects were mild injection site reactions (erythema, inflammation and induration). The most remarkable adverse event is the acute and transient immediate postinjection reaction manifested by flushing, chest tightness, palpitations and dyspnoea. Other reported adverse effects are transient chest pain and lymphadenopathy. Antibodies to glatiramer acetate induced during treatment do not interfere with its clinical effects. In several controlled clinical studies, glatiramer acetate has been shown to provide consistent, reproducible clinical benefits in the target population of patients with relapsing-remitting MS. The safety profile and risk-benefit ratio are excellent. Overall, glatiramer acetate is very well tolerated and has an excellent risk-benefit profile in patients with relapsing-remitting MS.     

Risk-benefit assessment of opioids in chronic noncancer pain.

Opioids have been accepted as appropriate treatment for acute and cancer pain, but their role in the management of chronic nonmalignant pain is the subject of much debate, mainly due to concerns about waning efficacy, the potential for neuropsychological impairment and the development of drug addiction. Controlled clinical trials demonstrated that opioids may be effective in both nociceptive and neuropathic noncancer pain, although the former responded more consistently than the latter. Gastrointestinal and CNS adverse effects were frequent in most studies. Observational studies have generated contradictory findings regarding efficacy and safety as well as the risk of drug addiction in patients with chronic noncancer pain receiving long term opioid therapy. However, they suggest that opioids may be effective in individual cases, whichever the pathophysiological mechanism of pain. Taken together, the available data indicate that the outcomes associated with opioid therapy vary markedly across patients experiencing chronic nonmalignant pain. The main consensus is that a subset of these patients may gain substantial benefit from opioid analgesics without requiring rapidly escalating doses or developing intolerable adverse effects or drug addiction. Prescribing guidelines have been developed to assist practitioners in selecting the appropriate patients and ensuring an acceptable risk : benefit ratio of opioid therapy. Finally, it must be emphasised that chronic pain is a complex entity wherein analgesics, including opioids, are only part of the treatment.     

Risk-benefit assessment of amiodarone in the treatment of cardiac arrhythmias

Cardiac arrhythmias are a cause of significant morbidity and mortality in patients with cardiac disease, and thus represent a major management problem. The recognition that antiarrhythmic drugs have the potential to aggravate as well as to attenuate arrhythmias has prompted clinicians to reconsider treatment strategies and weight the benefits of treatment against the risks. In this context, amiodarone has emerged as an effective antiarrhythmic agent and when used at the lowest effective dose has an acceptable side effect profile. This review focuses on the current clinical usage of amiodarone in a broad variety of cardiac arrhythmias, and addresses the risk-benefits arising from its use. It further discusses the current position of amiodarone in the management of sudden cardiac death.     

Risk-benefit assessment of therapies for Mycobacterium avium complex infections.

Mycobacterium avium complex (MAC) is an important pathogen that can cause chronic lung disease in immunocompetent patients and disseminated disease in patients with the acquired immunodeficiency syndrome (AIDS). Treatment of MAC with antituberculosis drugs was unsatisfactory, but the introduction of the newer macrolides, clarithromycin and azithromycin, and of rifabutin has greatly improved the outcome of treatment regimens for MAC. However, these agents are also associated with many new treatment-related adverse effects and potential drug-drug interactions. Rifamycins [rifampicin (rifampin) more than rifabutin] induce cytochrome P450 enzymes and accelerate the metabolism of clarithromycin and HIV protease inhibitors. Conversely, clarithromycin inhibits these enzymes, resulting in increased rifabutin toxicity. The net results are treatment regimens that may be extremely difficult to tolerate, especially for elderly or debilitated patients. Clarithromycin and azithromycin must be administered in combination with other agents such as ethambutol to prevent the emergence of macrolide resistance. Unfortunately, not all patients respond to the combination of a macrolide, rifabutin and ethambutol, and many have significant adverse effects (mostly gastrointestinal) with this regimen. For some patients the treatment is worse than the disease. The same 3-drug regimen is also effective therapy for disseminated MAC in AIDS patients, in whom the additional problem of a rifamycin/protease inhibitor interaction may be present. Fortunately, as opposed to pulmonary MAC disease in immunocompetent patients, disseminated MAC disease is a diminishing problem because of effective prophylactic regimens for MAC and improved antiretroviral therapy for HIV. Significant progress has been made in the treatment of MAC disease with the introduction of the newer macrolides. It is to be hoped that even better drugs that are more active against MAC and are associated with less toxicity and drug-drug interactions will be introduced in the future.     

Risk-benefit assessment of drugs used for the treatment of menstrual disorders

This article considers the benign yet debilitating conditions of menorrhagia, dysmenorrhoea and irregular menstrual bleeding. Surprisingly little has been reported in the literature concerning these common ailments which can detract from the quality of female life during the reproduction years. Both dysmenorrhoea and menorrhagia are subjective complaints, but despite accurate means of measuring menstrual blood loss such quantification is rarely performed. This lack of diagnostic accuracy is a cause for concern, especially as both medical and surgical treatment are not without risk. The therapeutic alternatives which are commonly prescribed in an attempt to rectify such menstrual disorders are discussed. These include the nonsteroidal anti-inflammatory agents, the combined oral contraceptives, danazol, progestogens, antifibrinolytics, haemostatics, luteinising hormone releasing hormone analogues and clomiphene. The results of clinical trials which have utilised these various agents are considered in terms of both the effectiveness of treatment and its potential adverse effects.     

Reversing anticoagulant therapy

For more than 50 years, heparin(s) and warfarin have been the most important anticoagulant agents, and clinicians are accustomed to their specific antidotes (protamine sulfate and vitamin K/plasma [or factor concentrates], respectively). Recently, there has been an explosion of novel anticoagulant development: ideally, these newer agents should have advantages over traditional anticoagulants, such as fewer side effects, a more predictable pharmacokinetic profile (and potentially no need for monitoring), minimal drug-drug interactions, and so forth. But, unlike the older agents, the newer anticoagulants do not have specific antidotes. There is increasing focus on the use of nonspecific procoagulants, such as non-activated and activated prothrombin complex concentrates (PCCs) and recombinant factor VIIa (rFVIIa), to manage major bleeding or need for emergency invasive procedures. This paper reviews several of the novel anticoagulants and presents the available evidence for their "reversal". Based on extrapolation from animal models, clinical anecdote, and an understanding of their mechanism of action, we recommend treating major bleeding complications of DTIs, as follows (in descending order of preference): activated PCCs; rFVIIa; and (non-activated) PCCs. For management of fondaparinux-associated bleeding, rFVIIa has some rationale (for which we provide an illustrative case). The increasing use of novel anticoagulants will require physicians to have an understanding of rational approaches to "reverse" their anticoagulant effects when true antidotes do not exist.     

Risk-benefit assessment of drugs used in the treatment of inflammatory bowel disease.

Although the aetiology of inflammatory bowel disease remains elusive, many agents are available for the control of symptoms and inflammation. Knowledge of drug pharmacology, indications and side effects is essential to ensure the best possible clinical care while minimising toxicity and inappropriate use. Sulfasalazine consists of sulfapyridine linked to mesalazine (5-aminosalicylic acid) via an azobond. Its use is indicated in the treatment of mild to moderately active ulcerative colitis and in the prevention of relapse in patients with quiescent disease. Patients with mild to moderate colonic or ileocolonic Crohn's disease also benefit from this drug, as do a proportion of patients with isolated small bowel disease. Sulfasalazine has not been uniformly effective in preventing relapse in Crohn's disease, although many clinicians continue its use in patients who respond initially. A high incidence of side effects which limit therapy include intolerance, hypersensitivity reactions and impairment of male infertility. The newer aminosalicylates offer targeted delivery of mesalazine to the bowel, with fewer side effects. Topical mesalazine has proved extremely effective in patients with distal ulcerative colitis; oral forms are effective in the treatment of mild to moderately active ulcerative colitis and in relapse. Both types appear to be effective in the treatment of Crohn's disease, and possibly in preventing relapse. There is no current clinical advantage of one mesalazine preparation over another, nor is there an indication for their use in sulfasalazine-treated patients who have satisfactory response without adverse effects. Corticosteroids are indicated for more severe disease activity where the aminosalicylates have limited efficacy-specifically to induce remission in patients with severe or refractory ulcerative colitis or Crohn's disease. They should not be used to maintain disease remission or in the prevention of postoperative recurrence. Topical corticosteroids allow their local use in distal colitis with minimal systemic side effects. Long term use is limited by side effects, many of which are dose related, although alternate-day therapy may lessen the incidence. Immunosuppressive agents are beneficial for the treatment of refractory inflammatory bowel disease unresponsive to other medications, and may also facilitate the withdrawal of steroids in refractory patients. Mercaptopurine has an added benefit in the treatment of Crohn's disease fistulae; the role of cyclosporin in bowel disease has not been established and its use cannot currently be recommended. The potential toxicity of immunosuppressive agents warrants careful consideration of their use by both physician and patient. Metronidazole is indicated for the treatment of mild to moderate Crohn's disease, including perineal disease. Common side effects include peripheral neuropathy and nausea.(ABSTRACT TRUNCATED AT 400 WORDS)     

抗凝治疗新进展

抗凝治疗在预防和治疗血栓栓塞性疾病中发挥重要作用。肝素和华法林是最经典的抗凝药物。近年来新的抗凝药物进展很快。新的抗凝药物的优点是:(1)有的经静脉应用,起效快;有的口服,使用方便。(2)可用于肾功能不全患者。(3)使用剂量较稳定,不需实验室监测。(4)出血不良反应小。AVE5026、艾比肝素、奥米沙班、RB006、达比加群酯、AZD0837、利伐沙班、阿哌沙班、依度沙班等为目前研究和临床应用较多的新的抗凝药物。     

Individualisation of oral anticoagulant therapy.

The hepatic synthesis of vitamin K dependent coagulation factors is modified by oral anticoagulant drugs, resulting in the release of functionally deficient coagulation factors into the circulation and consequently anticoagulation. Since their introduction into clinical medicine over 30 years ago, both clinical and scientific evidence has demonstrated the value of oral anticoagulants in the treatment and prophylaxis of venous thrombosis. In the treatment of arterial disease, however, both the indications for and usefulness of oral anticoagulants remain very much in doubt despite their widespread use in the 1950s and 1960s and in numerous clinical trials. The initiation and continuation of oral anticoagulant therapy is a co-operative venture involving the patient, the clinician and the laboratory. The clinician must have a thorough knowledge of the indications for and contraindications to the use of these drugs, and regular, accurate laboratory control is essential if haemorrhage, the major side effect, is to be avoided or reduced to a minimum. The patient must bear the responsibility for regular clinic attendance, abstinence from proprietary medications, and must immediately seek medical advice if any sign of haemorrhage occurs.