月经过多的药物治疗研究进展

月经过多首选药物治疗,最终目标是使经血减少到可接受的水平,尽可能减少不良反应。月经过多常用抗纤维蛋白溶解药、非甾体抗炎药、左炔诺孕酮宫内缓释系统、复方激素避孕药等药物治疗,也可用去氨加压素、口服孕酮化合物以及中医药等治疗。     

Benefits and risks of pharmacological agents used for the treatment of menorrhagia.

Menorrhagia affects the lives of many women. The assessment of menstrual flow is highly subjective and gauging the severity of the condition by objective assessment of menstrual blood loss is impractical. In treating menorrhagia, the primary aim should be to improve quality of life. Women are willing to undergo quite invasive treatment in order to achieve this. Drug therapy is the initial treatment of choice and the only option for those who wish to preserve their reproductive function. Despite the availability of a number of drugs, there is a general lack of an evidence-based approach, marked variation in practice and continuing uncertainty regarding the most appropriate therapy. Adverse effects and problems with compliance also undermine the success of medical treatment. This article reviews the available literature to compare the efficacy and tolerability of different medical treatments for menorrhagia. Tranexamic acid and mefenamic acid are among the most effective first-line drugs used to treat menorrhagia. Despite being used extensively in the past, oral luteal phase norethisterone is probably one of the least effective agents. Women requiring contraception have a choice of the combined oral contraceptive pill, levonorgestrel-releasing intrauterine system (LNG-IUS) or long-acting progestogens. Danazol, gestrinone and gonadotropin-releasing hormone analogues are all effective in terms of reducing menstrual blood loss but adverse effects and costs limit their long-term use. They have a role as second-line drugs for a short period of time in women awaiting surgery. While current evidence suggests that the LNG-IUS is an effective treatment, further evaluation, including long-term follow up, is awaited. Meanwhile, the quest continues for the ideal form of medical treatment for menorrhagia--one that is effective, affordable and acceptable.     

The problems and pitfalls of NSAID therapy in the elderly (Part II).

The elderly are most susceptible to pharmacokinetic drug interactions between various NSAIDs and anticoagulants, sulphonylurea hypoglycaemic agents, certain anticonvulsants, methotrexate, digoxin, aminoglycosides and lithium. Pharmacodynamic interactions between some NSAIDs and antihypertensive drugs, anticoagulants, sulphonylurea agents and other NSAIDs are also potentially significant in the elderly. Despite the finding that mean therapeutic responses of large groups of patients have been generally equivalent for the wide range of NSAIDs studied thus far, it is also apparent that marked variability exists in the response of individual patients to different NSAIDs. Subsequent dosage increments may predispose 'nonresponders' and some less sensitive 'responders' to toxicity from NSAIDs. This interindividual variability in response to NSAIDs may be contributed to by the differing physicochemical properties of NSAIDs, physician prescribing habits and patient expectations, variations in NSAID pharmacokinetics, and the differing effects of NSAIDs other than their common ability to inhibit prostaglandin synthesis. The principles for drug prescribing in the elderly are no different from those that should be applied to the prescribing of medication in any patient. The clinician should strive to make a diagnosis and should avoid treating symptoms in isolation. Critical assessment of the indication for prescribing NSAID therapy must include consideration of the available effective and safe alternatives. If an NSAID is commenced the lowest effective dose should be the desired goal, but after an appropriate trial it is acceptable clinical practice to employ an alternative NSAID. There is no justification for combination NSAID therapy. The progress of each patient must be carefully monitored, particularly during the first few months of treatment, while periodic review of the ongoing need for the NSAID is essential.     

Treatment options for rheumatoid arthritis beyond TNF-α inhibitors

The treatment of rheumatoid arthritis has changed over the last 15 years. Early and aggressive treatment, use of methotrexate as the anchor drug and combination treatment, with older disease-modifying drugs or biologics, have become the norm. TNF inhibitors were the first biologic agents available to rheumatologists and are still currently used as first-line biologics, in addition to other newer biologic agents. Abatacept, rituximab and tocilizumab are available biologics that use a different mode of action to TNF inhibitors, and can be used after a TNF inhibitor is tried. Abatacept is also currently used as a first-line biologic and others can also be used once data are available.     

Cyclooxygenase 2 selective inhibitors in cancer treatment and prevention

Prostaglandin synthesis by a number of enzymes is important at all stages during the genesis of cancer. The availability of prostaglandin H(2) as a substrate for prostaglandin production is a critical control point in its synthesis. Cyclooxygenase (COX) occurs in two forms (COX-1 and -2) and acts as the rate-limiting enzyme that generates prostaglandin H(2). COX-1 is produced as a steady-state enzyme, while COX-2 is heavily involved in inflammation and tumorigenesis. Differences in the catalytic sites of these enzymes are utilised to generate COX-2 selective inhibitors. Certain chemical characteristics of non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors make some of these inhibitors more effective against COX-2 than others. Epidemiological, animal and preclinical data demonstrate the promise of non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors as anticancer agents. Ongoing clinical trials are designed to determine the efficacy of non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors in the prevention and treatment of many types of cancer.     

Gastrointestinal effects of selective and non-selective non-steroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed group of drugs. Patients receiving NSAIDs often experience abdominal discomfort, and some of them develop serious gastrointestinal complications, such as ulceration, bleeding, perforation, or obstruction. Gastrointestinal side effects of NSAIDs are mostly attributed to cyclooxygenase (COX) inhibition resulting in reduction of prostaglandin in gastric mucosa. Topical irritant effects are also contributed to their systemic effect of prostaglandin inhibition. Anti-inflammatory effects of NSAIDs are mediated by COX-2 inhibition, while COX-1 inhibition is responsible for gastric prostaglandin inhibition. Management of gastrointestinal complications of NSAIDs is costly. In order to prevent or treat the gastrointestinal complications of NSAIDs, anti-ulcer drugs can be used concomitantly. Other alternative is the application or substitution of COX-2 selective inhibitors, which spare gastric mucosal prostaglandin synthesis and do not damage the gastric mucosa. Application of COX-2 selective inhibitors as a first line treatment for arthritic disorders may not be cost-effective, if patients do not have any risk factors including advanced age, history of complicating peptic ulcer, concomitant anticoagulant and corticosteroid medication. Patients with risk factors or those developing gastrointestinal complications during the course of NSAID treatment can be treated with COX-2 selective inhibitors if necessary.     

DNA synthesis inhibitors for the treatment of gastrointestinal cancer

Introduction: Intensive laboratory, preclinical and clinical studies have identified and validated molecular targets in cancers, leading to a shift toward the development of novel, rationally designed and specific therapeutic agents. However, gastrointestinal cancers continue to have a poor prognosis, largely due to drug resistance.

Areas covered: Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.

Expert opinion: Conventional agents, including DNA synthesis inhibitors such as fluoropyrimidines and platinum analogs, remain the most effective therapeutics and are the standards against which new drugs are compared. Novel DNA synthesis inhibitors for the treatment of gastrointestinal malignancies include a combination of the antimetabolite TAS-102, which consists of trifluorothymidine with a thymidine phosphorylase inhibitor, and a novel micellar formulation of cisplatin NC-6004 that uses a nanotechnology-based drug delivery system. The challenges of translational cancer research using DNA synthesis inhibitors include the identification of drugs that are specific to tumor cells to reduce toxicity and increase antitumor efficacy, biomarkers to predict pharmacological responses to chemotherapeutic drugs, identification of ways to overcome drug resistance and development of novel combination therapies with DNA synthesis inhibitors and other cancer therapies, such as targeted molecular therapeutics. Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.     

Cyclooxygenase 2 selective inhibitors in cancer treatment and prevention

Prostaglandin synthesis by a number of enzymes is important at all stages during the genesis of cancer. The availability of prostaglandin H₂ as a substrate for prostaglandin production is a critical control point in its synthesis. Cyclooxygenase (COX) occurs in two forms (COX-1 and -2) and acts as the rate-limiting enzyme that generates prostaglandin H₂. COX-1 is produced as a steady-state enzyme, while COX-2 is heavily involved in inflammation and tumorigenesis. Differences in the catalytic sites of these enzymes are utilised to generate COX-2 selective inhibitors. Certain chemical characteristics of non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors make some of these inhibitors more effective against COX-2 than others. Epidemiological, animal and preclinical data demonstrate the promise of non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors as anticancer agents. Ongoing clinical trials are designed to determine the efficacy of non-steroidal anti-inflammatory drugs and COX-2 selective inhibitors in the prevention and treatment of many types of cancer.     

Skeletal muscle digoxin binding in patients with renal failure.

The effect of inhibition of prostaglandin synthesis on the systemic clearance of indocyanine green and antipyrine was studied in seven subjects. Antipyrine clearance was not altered by indomethacin suggesting that oxidative metabolism was not affected. Both aspirin and indomethacin decreased the clearance of indocyanine green presumably by reducing liver blood flow. These results suggest that an effect of inhibitors of prostaglandin synthesis on hepatic drug clearance is likely to be confined to high clearance drugs when given systemically.     

Effects of glycosaminoglycan-polysulfate and two non-steroidal anti-inflammatory drugs on prostaglandin E2 synthesis in Chinese hamster ovary cell cultures

We have studied the influence of a polysulfated glycosaminoglycan (Arteparon) in comparison with indomethacin and piroxicam on the synthesis of prostaglandin E2 in Chinese hamster ovary cell cultures (CHO). The two non-steroidal anti-inflammatory drugs (NSAD) were found to be strong inhibitors of prostaglandin E2 (PGE2) synthesis. The inhibition was found to be dose-dependent. Arteparon, an antidegenerative drug for the treatment of osteoarthritis, was also found to inhibit PGE2 synthesis in the CHO cell cultures. The inhibition was not as strong as that of the NSAD and no correlation between the concentration of Arteparon and the inhibition of PGE2 synthesis could be demonstrated.     

Chromatography-mass spectrometry methods for the quantitation of statins in biological samples

The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, more commonly known as 'statins', are a novel class of drugs widely used for the treatment of hypercholesterolaemia in patients with established cardiovascular disease as well as those at high risk of developing atherosclerosis. Published chromatographic-mass spectrometric methods for the quantification of presently available seven statins, atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, rosuvastatin and pitavastatin are reviewed. High performance liquid chromatography (HPLC) in combination with tandem mass spectrometry (MS/MS) is the analytical technique of choice for the quantification of statins in biological samples. This review envisages that most of the methods used for quantification of statins are in plasma and they are suitable for therapeutic drug monitoring of these drugs.     

Inhibitors of de novo folate enzymes in Plasmodium falciparum

Antifolates, inhibitors of folate synthesis or folate conversion, are used for malaria treatment. They are developed as synergistic combinations of inhibitors of dihydrofolate reductase (DHFR) and of dihydropteroate synthase (DHPS). DHPS inhibitors are sulfur-based drugs, analogs of sulfanilamide. These compounds compete with para-aminobenzoic acid in the active site of DHPS. The discovery of new antifolates is based on the identification of DHFR inhibitors; little work has been done on sulfur-based drugs because of their toxicity. As a result, only a few sulfur-based drugs are available. In this review, the hypothesis that compounds that compete with pteridine derivatives in active sites of de novo folate enzymes can be used as synergizers of DHFR inhibitors is discussed. If correct, this could lead to the identification of a new family of synergizers of DHFR inhibitors.     

血脂异常的药物治疗

目的高血脂是导致冠心病的主要因素,调节血脂到适当范围,能显著降低心血管事件的发生率。本文综述了近年来用于临床的降脂药物,降脂药物的联合应用以及新的药物作用靶点。为临床合理选择提供参考。方法参阅国内外大量相关文献,进行归纳和总结。结果按药物不同的作用特点可分为:胆固醇生物合成酶抑制剂、苯氧酸类、烟酸类、胆固醇吸收抑制剂、胆酸螯合剂、多不饱和脂肪酸类、其他非中药类以及中药类的降血脂药物。他汀类药物使用广泛,占据降血脂药物市场的60%,它是血脂异常治疗的基线和主线药物。结论目前,临床调脂是以降低血浆LDL-C水平为第一目标,他汀类药物是降低LDL-C幅度最大的药物。贝特类是降低血中三酰甘油最显著的。在升高HDL-C水平方面,烟酸类仍然是效果最突出的药物。临床有他汀类联合贝特类、烟酸类或依折麦布应用,但目前的研究还不能证明联合应用较单用他汀,心血管事件发生率减少。联合用药只是二线选择。在生活方式的改善、饮食治疗、体育锻炼的基础上,有针对性的选用降脂药物,不仅医学指标显著降低,而且大大减少CV事件的发生。     

Pharmacologic management of glaucoma in childhood

An evidence-based review of the drugs available for the medical management of childhood glaucoma is presented; almost all of the drugs are not licensed for use in children. Despite this, most topical drugs are safe; however, there are some significant exceptions, such as brimonidine, which may cause apnea, among other life-threatening adverse events, in infants. Broad families of drugs are available including topical adrenoceptor antagonists, topical and systemic carbonic anhydrase inhibitors, prostaglandin analogs, adrenoceptor agonists, parasympathomimetics, and combination preparations. These drugs help to reduce intraocular pressure by reducing aqueous production or increasing the outflow facility. The variety of anti-ocular hypertensive medications for childhood glaucoma has increased in recent years. The vast majority of data on these medications are from adult studies but each year more experience of their use in pediatric glaucoma is gained. In general, topical treatment is well tolerated; however, the prescribing clinician and carers should be aware of potential adverse effects and how they may present.     

Benefit-risk assessment of treatments for heparin-induced thrombocytopenia.

Patients with heparin-induced thrombocytopenia (HIT) are at high risk of thrombosis and should be treated with alternative anticoagulant therapy to reduce complications. The current treatment of choice is one of the approved direct thrombin inhibitors, argatroban or lepirudin. These drugs have been proven to be safe and effective in multicentre clinical trials where dosage regimens have been established for prophylaxis and treatment of thrombosis. Argatroban has also been tested and approved for use in invasive cardiology procedures in the HIT patient. Dosage regimens for other clinical uses, such as cardiac surgery, have not yet been established for either drug. The safety and effectiveness of the thrombin inhibitors is dependent on their use according to established guidelines. Other treatment options that may be effective for the patient with HIT include dextran, plasmapheresis, intravenous gammaglobulin and aspirin (acetylsalicylic acid). Although used historically, these options have not been tested in rigorous clinical trials. For life- and limb-threatening thrombosis, thrombolytic agents and/or surgery may provide benefit. Because the risk of bleeding is high from these procedures, they should be performed only by an experienced practitioner. Several studies have shown that patients with HIT requiring continued anticoagulation are best managed with a warfarin derivative initiated while under full anticoagulation with a thrombin inhibitor. There is a risk of skin necrosis and bleeding if guidelines for dose administration and monitoring of warfarin are not followed. Subsequent use of heparin or a low molecular weight heparin after resolution of the clinical episode of HIT can be hazardous, particularly within the first 3 months. If laboratory testing is negative, heparin may be cautiously reinstituted for short-term use (1-2 hours) with monitoring for platelet count decrease and thromboembolism. The pregnant patient with HIT requiring anticoagulation represents a particular challenge, where there is no drug of choice at present. Although today there are realistic treatment options for the patient with HIT, the morbidity and mortality associated with this disease have not been eliminated. Awareness and early treatment of HIT remain important components of the clinical care for patients exposed to heparins. Future therapeutic developments based on a better understanding of the pathophysiology of HIT may further improve clinical outcomes. Despite some limitations, the current treatment options for patients with HIT provide unparalleled benefit compared with the treatment options available only a few years ago.     

Antiplatelet drugs: clinical pharmacology and therapeutic use.

Because platelets are so important in thrombus formation, drugs which inhibit platelet function (the 'antiplatelet drugs') have considerable potential as antithrombotic agents. Among the antiplatelet drugs, only aspirin, sulphinpyrazone, dipyridamole, hydroxychloroquine, and clofibrate have had wide clinical trial. Their effects on platelet metabolism differ. Aspirin prevents platelet prostaglandin synthesis by acetylating and irreversibly inactivating platelet prostaglandin synthetase, while sulphinpyrazone is a reversible inhibitor of the same enzyme. Both aspirin and sulphinpyrazone impair the platelet release reaction and reduce platelet aggregation, but neither prevents platelet adhesion to the subendothelium or to foreign surfaces. On the other hand, dipyridamole reduces platelet adhesion as well as aggregation, probably by inhibiting phosphodiesterase and so raising platelet cyclic AMP levels. The effects of hydroxychloroquine and clofibrate have been less well defined. As the antiplatelet drugs form a diverse group of substances with differing effects on platelet function, it is hardly surprising that every potential clinical application of each antiplatelet drug or drug combination has had to be tested separately, and that these drugs have not proved to be equally effective. One or more antiplatelet drugs have now been evaluated in each of the following situations.     

HIV-1 regulatory proteins: targets for novel drug development

Due to the development of HIV-1 resistance to current antiviral drugs and the known toxicity of many of these drugs, there is a clear need to identify and develop novel compounds for use in the treatment of HIV-1 infected patients. The HIV-1 regulatory proteins, Tat and Rev, are required for HIV-1 replication and therefore represent two important viral targets for drug development. Novel drugs that target these proteins would increase the number of available treatment strategies for HIV-1 infection. This could result in better combination therapies in which many different viral targets could be inhibited simultaneously, thereby decreasing the likelihood of selecting for drug-resistant viruses. This review outlines many of the ways that Tat and Rev can be targeted for drug development, describes recently reported lead compounds as inhibitors of these proteins and discusses strategies for implementing drug screens for identifying novel inhibitors.