Long-term complications of chemotherapy for germ cell tumours

Testicular cancer is the most common solid tumour among young males aged 15-35 years. Cisplatin-based combination chemotherapy has changed the outlook of this disease. Disseminated testicular cancer, once uniformly fatal, now has a cure rate of more than 80% with combination chemotherapy. Systematic randomised trials have shown that cisplatin, etoposide and bleomycin (PEB) combination chemotherapy remains the mainstay of treatment. While there is a high cure rate with chemotherapy in patients with this disease, some long-term complications from chemotherapy have now been recognised, including secondary leukaemia, therapy-related solid tumours, nephrotoxicity, neurotoxicity, pulmonary toxicity, vascular toxicity and infertility. Etoposide, a DNA topoisomerase II inhibitor, is a significant risk factor for developing leukaemia; the risk appears to be correlated with the total dose given. Patients receiving cisplatin-based combination chemotherapy for testicular cancer also appear to have a higher relative risk for developing second non-germ cell malignancies; the greatest risks for therapy-related solid tumours were seen with a combination of radiation therapy plus chemotherapy. Long-term vascular toxicities associated with chemotherapy include Raynaud's phenomenon, acute myocardial infarction and cerebrovascular events. Bleomycin is thought to be the most important drug in the pathogenesis of Raynaud's phenomenon, while cisplatin is the most likely agent involved in myocardial infarction. Peripheral neuropathy is the most common form of neurotoxicity observed with cisplatin-based chemotherapy. Risk factors for the development of neural damage include a high cumulative dose of cisplatin, the use of vinblastine and the concomitant development of Raynaud's phenomenon. Cisplatin is also well known to cause significant nephrotoxicity. Approximately 25% of patients present with azoospermia after undergoing combination chemotherapy with a follow up of 2-5 years. Physician awareness of complications associated with chemotherapy is vital to maximise efficacy, minimise toxicity, and preserve quality of life after treatment. Sperm cryopreservation should be considered for patients who desire children. Close monitoring during therapy allows for the early diagnosis of complications, and close follow up of patients after the completion of therapy is necessary to monitor for relapse and development of long-term complications such as myelodysplastic syndrome and leukaemia. Despite these complications, given the potential for cure rates in this young group of patients, the benefits far outweigh the risks.     

三种肺癌化疗方案的药物经济学分析

目的探讨肺癌不同治疗方案治疗效果的药物经济学分析。方法93例肺癌患者,根据不同治疗方案随机分为第一、第二和第三组。运用药物经济学成本-效果分析方法对3组治疗方案进行回顾性分析、评价。结果第一组(NP 250方案)显效率53.13%,一个疗程费用13683元;第二组(NP 500方案)和第三组(NP方案)显效率分别为64.52%和46.67%,一个疗程费用分别为13922元和13443元。第二组方案优于第一组和第三组。结论药物经济学在优化治疗方案,指导合理用药,提高经济效益,节约卫生资源方面具有重要意义。     

Comparative cytotoxicity of oxaliplatin and cisplatin in non-seminomatous germ cell cancer cell lines

Approximately 70-80% of patients with metastatic testicular cancer will become disease free with cisplatin-based chemotherapy and most of these patients will be longterm survivors. Despite these impressive results, the two limitations of cisplatin are its severe and potentially long-term side-effects, and the emergence of drug resistance which prevents a small proportion of these patients from achieving long-term remission. Oxaliplatin has an improved toxicity profile compared to cisplatin and contains the diaminocyclohexane (DACH) substituent known to be correlated with a lack of cross resistance with cisplatin. A phase II study has shown interesting activity when used in combination with cisplatin in cisplatin-refractory testicular cancer patients. Here we report the results of the first in vitro study investigating whether oxaliplatin as a single agent exhibits cross-resistance to cisplatin in a panel of non-seminomatous germ cell tumor (NSGCT) cell lines using short and long-term drug exposures in a five-day sulfhodamine B in vitro cytotoxicity assay. Oxaliplatin cytotoxicity was significantly superior to cisplatin in cell lines with both acquired (H12DDP) and intrinsic (1777NR Cl-A) intermediate level resistance to cisplatin. Following 24h or 96h drug exposure the fold resistance in H12DDP and 1777NR Cl-A was 1.7-2.2 with oxaliplatin compared to 3.9-6.1 with cisplatin. The cytotoxic activity of oxaliplatin was not significantly different from that of cisplatin in cisplatin-senstive cell lines or in cell lines with a high level (10-20 fold) of cisplatin resistance. The results of this study suggest that further pre-clinical studies in NSGCT are of interest, particularly in combination with cisplatin, ifosfamide and etoposide. Furthermore, the in vitro results support the use of an oxaliplatin administration schedules giving prolonged drug exposure, such as the flat or circadian rhythm-modulated schedule already under investigation for oxaliplatin.     

Comparative tolerability of therapies for ulcerative colitis.

This article reviews the clinical pharmacology, adverse events, and comparative tolerability of the drugs commonly available for treating ulcerative colitis. Synthetic glucocorticoids are the most commonly used conventional corticosteroids in the treatment of ulcerative colitis. Corticosteroids can be expected to impact on every organ system and most metabolic activities of the body. Suppression of the hypothalamic-pituitary-adrenal axis is common, but reversible, with conventional corticosteroids, but not with newer topically-acting corticosteroids. A serious complication of corticosteroids in children is growth retardation. The frequent adverse effects associated with the use of corticosteroids have prompted the development of a new group of rectal agents with equivalent efficacy and a more benign adverse event profile such as prednisolone metasulfobenzoate, fluticasone propionate, tixocortol pivalate, beclomethasone dipropionate and budesonide. The incidence of adverse effects related to the use of sulfasalazine (5-aminosalicylic acid plus sulfapyridine) is high and is dose related. The most frequently reported adverse effect is intolerance, not allergy, and relates to the sulfapyridine moiety correlating with the acetylator phenotype. Tolerance to 5-aminosalicylic acid by 80 to 90% of those patients allergic to, or intolerant of, sulfasalazine has given further evidence suggesting that the sulfa moiety is responsible for much of the toxicity of sulfasalazine. However, 10 to 20% of patients who are sulfasalazine intolerant have similar reactions to 5-aminosalicylic acid formulations, indicating that the 5-aminosalicylic acid moiety is responsible for adverse events in some patients taking sulfasalazine. Adverse effects resulting from treatment with azathioprine and mercaptopurine can be divided into two categories: allergic-type reactions that appear to be dose-independent and nonallergic-type reactions that are probably dose- and metabolism-dependent. It is well established now that genotype and thiopurine methyltransferase activity have an important impact on the rate of adverse effects during azathioprine or mercaptopurine therapy. Adverse effects resulting from high dose cyclosporin therapy for inflammatory bowel disease include: renal insufficiency, hypertension, opportunistic infections, seizures, paresthesias, tremor, headache, gingival hyperplasia, hypertrichosis, and anaphylaxis with intravenous cyclosporin. In contrast, the incidence of adverse events was relatively low when low-dose oral cyclosporin was used. The incidence of adverse events associated with any of the medications used in the treatment of ulcerative colitis is difficult to assess and it is therefore hard to make a comparative evaluation. The broadening of the drug regimen available to the clinician has advanced our knowledge about the disease, and further development of more effective, less toxic agents can be anticipated in the future.     

晚期非小细胞肺癌4种化疗方案的药物经济学评价

目的：探讨晚期非小细胞肺癌不同治疗方案的临床疗效和经济学效果。方法：收集某院2012-2015年99例符合要求的晚期非小细胞肺癌患者,根据不同治疗方法分为4组,用药物经济学对成本与效果进行分析,对4组治疗方案进行回顾性分析。A组：多西他赛+顺铂;B组：多西他赛+卡铂;C组：培美曲塞+顺铂;D组：培美曲塞+卡铂。结果：4组化疗方案的有效率分别为40.54%,31.58%,57.89%,54.17%。化疗一个疗程住院总费用分别为6 307.96元,5 356.51元,11 980.83元,11 387.94元。在B方案的基础上,每增加一个单位效果,A方案、C方案、D方案所需要的成本分别为106.19元,251.78,267.00元。结论：从成本-效果分析,A方案为治疗晚期非小细胞肺癌的较合理的方案。     

Comparative tolerability of therapies for cytomegalovirus retinitis.

Cytomegalovirus (CMV) retinitis is a potentially sight-threatening complication of advanced HIV infection. The acute infection can be controlled with one of several therapies, including intravenous ganciclovir, foscarnet or cidofovir, slow release ganciclovir intraocular implants or serial intraocular injections of ganciclovir or foscarnet. The initial induction course of therapy is typically followed by lifelong maintenance therapy. In addition to the aforementioned treatments, oral ganciclovir and intravitreal fomivirsen injections are other options for maintenance therapy. The choice of agent must take into consideration factors such as comparative short and long term toxicity of the agents, route of administration and the possible need for indwelling catheters, administration time, cost and protection afforded against systemic dissemination of CMV infection. Possible drug interactions and additive toxicities of other agents needed for the management of the underlying HIV infection must also be taken into consideration. These factors can affect the tolerability of therapy as well as the quality of life of the patient. Relapse or progression of CMV retinitis may be caused by either inadequate drug concentrations at the site of the infection or by drug resistance. This may necessitate either an increase in drug dosage, a change in route of administration or a change to an alternative agent. All of these approaches can increase the risk of toxicity of the therapy. With the initiation of highly active antiretroviral therapy and partial reconstitution of the immune system, some patients have been able to successfully discontinue anti-CMV maintenance therapy, thereby decreasing long term drug toxicity. Determination of the patient predictors of success of this approach is an active area of research.     

Current pharmacotherapy for testicular germ cell cancer

Introduction: With the implementation of platinum-based chemotherapy, germ cell tumors (GCTs) became a model for a curable solid tumor, with survival rates of 95% in all patients with >80% survival in metastatic stages.

Areas covered: Herein, the authors review the current standards of adjuvant chemotherapy for stage I GCTs as well as first-line and salvage treatments for metastatic disease. Novel approaches for refractory disease are also reviewed.

Expert opinion: Active surveillance should be considered for all stage I patients and is the preferred approach for stage I seminoma. In stage I non-seminomas with vascular invasion, one cycle of bleomycin, etoposide, and cisplatin (BEP) substantially reduces the relapse risk. For most advanced GCTs, BEP remains the first-line standard of care. For poor prognosis disease treatment, stratification according to tumor marker decline is recommended. The role of primary high-dose chemotherapy (HDCT) for selected very high-risk patients remains to be prospectively evaluated. Salvage HDCT at relapse seems superior to conventional chemotherapy, retrospectively. The treatment of multiply relapsed disease remains challenging. The gemcitabine/oxaliplatin/paclitaxel (GOP) protocol is considered the standard for refractory disease. However, overall, outcomes are poor and new treatment approaches are urgently needed with targeted therapies so far failing to yield relevant clinical activity.     

Comparative tolerability and efficacy of treatments for impotence.

Modern pharmacological treatment of impotence is determined by the presenting symptoms. Since this involves symptomatology with a heterogenous aetiology, many different drugs are involved in the treatment of impotence. Drugs used for libido and arousal problems include testosterone, yohimbine, trazodone and apomorphine. Since patient self-assessment is the only parameter that can be used to measure the result of treatment and positive results are seldom affirmed, no positive benefit of these agents can be assumed at present. Oral medications for erectile dysfunction include yohimbine, trazodone, apomorphine, phentolamine, arginine and sildenafil. Of these drugs, sildenafil has been the most systematically studied for effectiveness, but long term safety data await the results of post-marketing surveillance. Of the ejaculation disorder therapies, treatments for premature ejaculation are the best studied. Favourable results have been obtained with clomipramine, paroxetine and fluoxetine. The safety of these medications has been assessed through their long term use in psychiatry. Intracavernous self-injections for erectile disorders are performed using a variety of drugs and drug mixtures. Only alprostadil and the combination of papaverine with phentolamine are widely used. Alprostadil is very well tolerated; however, penile pain is a serious problem in a significant proportion of patients. Papaverine in combination with phentolamine is effective, but penile fibrosis and priapism occur more often than with the use of alprostadil. Several new developments in this area are currently under way. Alternative routes for medication for erectile dysfunction include ointments and patches to the penile skin and the glans. Only transurethral alprostadil, 'MUSE' (medicated urethral system for erection) has been shown to be effective in large trials. Long term safety still has to be demonstrated, but the 1-year safety profile is encouraging. In general, the end points of impotence treatment studies are very diverse so efficacy data can only be assessed in comparative studies. However, long term comparison studies have not been performed. Safety demands must be set very high for this type of treatment since the disorders being treated present no threat to the patient's health.     

Comparative tolerability of treatments for inflammatory bowel disease.

Despite limited understanding of therapeutic aetiopathogenesis of ulcerative colitis and Crohn's disease, there is a strong evidence base for the efficacy of pharmacological and biological therapies. It is equally important to recognise toxicity of the medical armamentarium for inflammatory bowel disease (IBD). Sulfasalazine consists of sulfapyridine linked to 5-aminosalicylic acid (5-ASA) via an azo bond. Common adverse effects related to sulfapyridine 'intolerance' include headache, nausea, anorexia, and malaise. Other allergic or toxic adverse effects include fever, rash, haemolytic anaemia, hepatitis, pancreatitis, paradoxical worsening of colitis, and reversible sperm abnormalities. The newer 5-ASA agents were developed to deliver the active ingredient of sulfasalazine while minimising adverse effects. Adverse effects are infrequent but may include nausea, dyspepsia and headache. Olsalazine may cause a secretory diarrhoea. Uncommon hypersensitivity reactions, including worsening of colitis, pancreatitis, pericarditis and nephritis, have also been reported. Corticosteroids are commonly prescribed for treatment of moderate to severe IBD. Despite short term efficacy, corticosteroids have numerous adverse effects that preclude their long term use. Adverse effects include acne, fluid retention, fat redistribution, hypertension, hyperglycaemia, psycho-neurological disturbances, cataracts, adrenal suppression, growth failure in children, and osteonecrosis. Newer corticosteroid preparations offer potential for targeted therapy and less corticosteroid-related adverse effects. Azathioprine and mercaptopurine are associated with pancreatitis in 3 to 15% of patients that resolves upon drug cessation. Bone marrow suppression is dose related and may be delayed. The adverse effects of methotrexate include nausea, leucopenia and, rarely, hypersensitivity pneumonia or hepatic fibrosis. Common adverse effects of cyclosporin include nephrotoxicity, hypertension, headache, gingival hyperplasia, hyperkalaemia, paresthesias, and tremors. These adverse effects usually abate with dose reduction or cessation of therapy. Seizures and opportunistic infections have also been reported. Antibacterials are commonly employed as primary therapy for Crohn's disease. Common adverse effects of metronidazole include nausea and a metallic taste. Peripheral neuropathy can occur with prolonged administration. Ciprofloxacin and other antibacterials may be beneficial in those intolerant to metronidazole. Newer immunosuppressive agents previously reserved for transplant recipients are under investigation for IBD. Tacrolimus has an adverse effect profile similar to cyclosporin, and may cause renal insufficiency. Mycophenolate mofetil, a purine synthesis inhibitor, has primarily gastrointestinal adverse effects. Biological agents targeting specific sites in the immunoinflammatory cascade are now available to treat IBD. Infliximab, a chimeric antibody targeting tumour necrosis factor-or has been well tolerated in clinical trials and early postmarketing experience. Additional trials are needed to assess long term adverse effects.     

Comparative tolerability of systemic treatments for plaque-type psoriasis.

Psoriasis is a chronic, debilitating skin condition that affects millions of people and is attributed to both genetic and environmental factors. Topical therapy is generally considered to be the first-line treatment of psoriasis. However, many patients do not respond to topical therapy or have disease so extensive that topical therapy is not practical. For these patients, systemic therapy is indicated. Presently, there are four available systemic treatments, psoralen with ultraviolet A (PUVA), methotrexate, oral retinoids (acitretin), and cyclosporin. Unfortunately, all of these treatments have significant potential adverse effects. PUVA may acutely cause nausea, pruritis and sunburn. More chronic and concerning is the development of PUVA lentigines, ocular complications and skin cancer. Non-melanoma skin cancer has been directly linked to PUVA; however, the association with melonoma is more elusive. Methotrexate use most notably carries the risk of hepatic fibrosis and cirrhosis, which is not always evident on liver function tests. Other more rare, but potentially life-threatening adverse effects include pancytopenia, lymphoproliferative disorders and acute pneumonitis. The addition of folic acid may help to reduce the risk of increasing liver enzymes and haematological toxicity seen in those taking methotrexate. Both methotrexate and oral retinoids are teratogenic and should never be used in pregnancy. Oral retinoids are probably the least effective available systemic medication for the treatment of plaque psoriasis. The effects are improved with the addition of other systemic therapies. Acitretin has replaced the formerly used etretinate primarily because of the significantly shorter half-life. The adverse effects are generally mild and reversible, making the drug fairly safe for long-term use. The most commonly seen adverse effects include elevated serum lipids, generalised xerosis and alopecia. Bony abnormalities, while somewhat controversial, have also been described and include diffuse idiopathic skeletal hyperostosis, skeletal calcifications and osteoporosis. Cyclosporin is the most recently approved systemic medication for plaque psoriasis. The nephrotoxicity associated with the use of cyclosporin can be minimised when used in lower doses and for a limited duration. Hypertension is usually mild and can be seen in up to about one-third of patients receiving long-term therapy. Cutaneous and internal malignancies have also been reported with cyclosporin and tend to be correlated with duration of treatment. In this review, we will examine the potential adverse effects with these US Food and Drug Administration-approved treatments in adults, with specific emphasis on the controversies that surround long-term therapy with these agents and their cumulative adverse effects.     

两种化疗方案对晚期宫颈癌的疗效观察

目的探究顺铂分别与多西它赛和紫杉醇联合对晚期宫颈癌的临床疗效。方法选取我院收治的80例局部晚期宫颈癌患者,采取随机数字表法将其分成A、B组,每组40例。A组患者采用多西它赛75mg/m2+顺铂50 mg/m2,B组患者采用紫杉醇60 mg/m2+顺铂50 mg/m2,分别化疗l~2个疗程,化疗间隔时间均为21 d,观察与比较2组患者经不同治疗方法后的临床疗效及不良反应等情况。结果 A、B组患者经不同用药方式后,疗效差异无统计学意义(P>0.05)。B组患者出现不良反应的例数明显高于A组患者,差异有统计学意义(P<0.05)。结论多西它赛75 mg/m2联合顺铂50 mg/m2对晚期宫颈癌临床作用显著,且不良反应较少,安全性高。     

两种新辅助化疗方案治疗乳腺癌的疗效比较

对比分析盐酸表柔比星联合环磷酰胺序贯多西他赛（EC→T）与盐酸表柔比星、环磷酰胺联合多西他赛（TEC）两种新辅助化疗方案治疗乳腺癌的疗效及不良反应。回顾性分析2013—2016年本院收治的Ⅱ～Ⅲ期乳腺癌新辅助化疗患者52例的临床资料,分别于术前接受3～4个周期的EC→T方案（n=22）或TEC方案（n=30）的新辅助化疗。EC→T方案的CR为 0例,PR为16例,有效率为72.73%;TEC方案的CR为2例,PR为24例,有效率为86.67%,两组有效率比较差异无统计学意义（P＞0.05）。EC→T组骨髓抑制及脱发程度均轻于TEC组（P＜0.05）。EC→T与TEC两种新辅助化疗方案近期疗效相似,但后者不良反应重于前者。EC→T方案在新辅助化疗中有一定的应用前景。     

Comparative tolerability of drug therapies for hypercalcaemia of malignancy.

The bisphosphonates are the treatment of choice in hypercalcaemia of malignancy. However, plicamycin (mithramycin) an calcitonin treatment may still be of value should bisphophonate treatment fail, and gallium nitrate has recently been introduced as an alternative therapy. We analysed the tolerability of different treatments based on articles identified in a Medline search covering the period 1979 through September 1998. Articles were included if they met two criteria: (i) quantitative assessment of adverse effects; (ii) inclusion of > or = 10 patients. Although bisphosphonates are generally well tolerated, elevation of serum creatinine level, nausea/vomiting and fever have been reported following their application. Patients receiving etidronate (n = 268) or clodronate (n = 127) more frequently experienced creatinine elevation (8 and 5%, respectively) than did patients receiving pamidronate (n = 424; 2%), aledronate (n = 79; 0%), or ibandronate (n = 203; <1%). The difference in the frequency of reported creatinine level elevations reached statistical significance only for etidronate (z-test: p < 0.001 versus pamidronate; p < 0.02 versus alendronate; p < 0.001 versus ibandronate). With regard to the frequency of creatinine level elevations, clodronate treatment did not differ significantly from treatment with pamidronate, alendronate and ibandronate. An exception among the bisphosphonates is tiludronate, which has been reported on s a treatment of hypercalcaemia in only 1 study (n = 19) resulting in 1 case of lethal and 1 case of manageable acute renal failure. Nausea and vomiting are rare adverse effects of bisphosphonate treatment but seem to be more frequent with first generation drugs: etidronate (8%) and clodronate (7%) versus pamidronate (2%) [p < 0.001 and 0.009, respectively] and versus ibandronate (<1%) [p< 0.002 and 0.02, respectively]. Bisphosphonates containing a nitrogen atom were associated with an acute phase reaction leading to reported fever in 16% of pamidronate, 20% of aledronate, and 11% of ibandronate-treated patients. The most frequently reported adverse effects of treatment with the cytostatic drug plicamycin were hepatotoxicity (26%), nausea/vomiting (23%), and serum creatinine level elevation (5%). Furthermore. plicamycin application was associated with bone marrow suppression and a bleeding tendency due to abnormalities in multiple clotting factors and platelet dysfunction. The use of calcitonin is limited more by the short duration of its therapeutic effect than by toxicities (most frequent: nausea/vomiting in 16% of treated cases). The few publications on gallium nitrate in the treatment of hypercalcaemia of malignancy characterise it as an efficient drug, which is, however, associated with a higher frequency of renal toxicity (10%) and of nausea and vomiting (14%) than are the bisphosphonates.     

Comparative tolerability of second generation antihistamines.

Second generation histamine H1 receptor antagonists, the so-called 'nonsedating' antihistamines, have high potency and additional antiallergic properties as well as H1 antagonism and are associated with fewer adverse effects compared with the first generation antihistamines. A number of drugs in this class are approved for use: acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, loratadine, mizolastine and terfenadine. All of them have a more favourable risk-benefit ratio with regard to the CNS adverse effects. Even those second generation antihistamines that are not actually 'nonsedating' are less impairing than their predecessors, but not one of them is entirely devoid of CNS activity. Under certain circumstances some antihistamines may affect cardiac repolarisation resulting in cardiovascular adverse effects. Serious cardiovascular effects have been reported with terfenadine and astemizole when they are used in high dosages or when they are given to 'at risk' patients. Animal models indicate that there might be a potential risk of cardiovascular adverse effects with other antihistamines as well. However, up to now there is no clinical evidence for this assumption, despite some confusing reports. Likewise there has been much discussion about a link between these agents and carcinogenicity. However, there is no evidence that any of the second generation antihistamines increase the risk of tumour growth in humans. Small children, elderly patients and persons with chronic renal or liver impairment are special groups in which the individual adverse effects of the second generation antihistamines must be kept in mind. The dosage for an individual has to be modified with respect to their metabolic situation. Despite the fact that some of the second generation antihistamines are listed in the US Food and Drug Administration pregnancy risk classification as class B, the use of second generation antihistamines should be avoided during pregnancy and they should never be administered to nursing mothers. Taking into account their negligible CNS activity, the low incidence of cardiovascular adverse effects, their lack of anticholinergic effects and other benefits, this class of antiallergic drugs represents a definite advance in therapy.     

Comparative tolerability of pharmacological treatments for patent ductus arteriosus.

The ductus arteriosus is a vascular channel which, although vital to the fetal circulation, rapidly becomes unnecessary and even deleterious after birth. As such, it is 'preprogrammed' to constrict within the first few hours of life. In infants born prematurely this natural closure is often delayed and/or ineffective. In this review, we summarise the current knowledge of the delicately orchestrated control of normal ductal closure, with emphasis on the role of various biochemical mediators. The major focus of this review, however, is on pharmacological approaches designed to prevent and/or treat the persistently patent ductus arteriosus (PDA) which often fails to constrict spontaneously in the premature infant. The standard treatment regimen is based on the administration of 3 doses of the nonselective cyclo-oxygenase inhibitor, indomethacin. We begin by examining, from the vantage point of the ductus, the use of this indomethacin as a tocolytic. It seems that antenatal administration of indomethacin can cause transient, reversible ductus constriction which renders the post-treatment ductus resistant to subsequent closure, both natural and therapeutic. We then review some of the pros and cons associated with the prophylactic administration of indomethacin. Although prophylactic indomethacin is aimed primarily at preventing intraventricular haemorrhages in premature neonates, it does tend to reduce the risk of PDA as well. We then describe some novel therapeutic approaches to effect ductal closure with indomethacin, including the use of continuous infusions to minimise toxic vasoconstrictive phenomena and the use of prolonged maintenance dose to prevent PDA recurrences. Finally we discuss some of the newer agents described more recently which play a role in closing the persistently patent ductus over the next decade. Most prominent of these is ibuprofen which some studies have shown to have less undesirable vasoconstrictive adverse effects. Studies which compare the use of ibuprofen to indomethacin are summarised.     

Comparative tolerability of contrast media used for coronary interventions.

Radiographic contrast media (CM) are necessary to provide x-ray absorption of the bloodstream; all other observed effects need to be regarded as adverse. Four types of CM are currently used in diagnostic and interventional cardiology: ionic high-osmolar CM (HOCM), either ionic or non-ionic low-osmolar CM (LOCM), and non-ionic iso-osmolar CM (IOCM). Focusing on the potential cardiovascular effects caused by the CM, there is a clear difference between HOCM and the LOCM or IOCM. HOCM have a poorer profile due to a higher incidence of hypotension and electrophysiological effects. To prevent contrast-induced nephropathy, HOCM should be avoided and patients should receive the minimal dose of LOCM or IOCM with intravenous hydration before and after the procedure. Clinical hyperthyroidism has been detected after CM use, but the condition appears, ultimately, to be self-limited and to occur mainly in elderly patients. When assessing the need for a CM in terms of improved patient safety, preventing serious complications should be the major factor determining the choice. CM should not be selected on the basis of minor adverse effects since these are, ultimately, of low clinical relevance. Thrombotic events, in contrast, carry a high clinical relevance and we consider that these should be the main issue governing current choice. Ionic LOCM appear to have better profile than other CM with respect to interaction with platelet function and coagulation. In relation to thrombotic events in randomised clinical studies, ionic CM have been associated, mainly, with favourable and some neutral results compared with non-ionic agents. Only one trial indicated a more pronounced antithrombotic effect of the non-ionic IOCM relative to the ionic LOCM. The antithrombotic advantages of ionic over non-ionic LOCM are, in part, balanced by a greater frequency of minor adverse effects such as nausea, vomiting or cutaneous rashes. A matter of concern is the delayed adverse effects observed with non-ionic IOCM. However, severe and life-threatening reactions are exceptional and there are probably no significant differences between IOCM and LOCM whether ionic or non-ionic. However, in patients with known allergies, non-ionic CM are to be recommended. On the basis of the available pre-clinical and clinical data, the ionic LOCM or the non-ionic IOCM are the agents to be recommended in percutaneous coronary interventions because of their antithrombotic advantages over non-ionic LOCM.     

Diagnosis and treatment of patients with testicular germ cell cancer.

Testicular germ cell tumours are a highly curable malignancy even in the presence of metastases, with an overall survival rate of approximately 90 to 95% when all stages are considered. Current therapeutic strategies aim at risk-adapted therapy, trying to maintain favourable overall results while reducing treatment-related toxicity, particularly in non-advanced disease. In stage I disease, unilateral inguinal orchiectomy represents the standard diagnostic and therapeutic approach. For patients with clinical stage I seminoma, prophylactic para-aortic radiotherapy with 26Gy is commonly employed. In patients with nonseminomatous germ cell tumours (NSGCT) at clinical stage I, the 3 options are: (i) retroperitoneal lymphadenectomy; (ii) a wait-and-see strategy; or (iii) 2 cycles of adjuvant chemotherapy. The individual risk profile for tumour recurrence, mainly based on histopathological criteria such as vascular tumour invasion, should guide treatment decisions in this group of patients. Radiotherapy is still the standard approach in clinical stage IIA/B seminoma, whereas in patients with a low tumour burden of NSGCT, retroperitoneal lymphadenectomy is frequently used followed by surveillance or adjuvant chemotherapy. Primary chemotherapy in these stages of disease may be at least equally successful. Major progress has also been achieved in the treatment of NSGCT patients with metastatic disease greater than clinical stage IIB, for whom primary chemotherapy represents the standard approach. After cisplatin-based combination chemotherapy, between 70 and 90% of patients will achieve a durable remission. In patients with 'good risk' metastatic disease, 3 cycles of cisplatin, etoposide and bleomycin (PEB) remain the standard treatment, despite several randomised trials trying to avoid the lung-toxic bleomycin or substituting cisplatin by carboplatin. In patients with 'intermediate' and 'poor prognosis' disease, 4 cycles of PEB given at 3-week intervals are considered routine treatment. The role of high dose chemotherapy with peripheral autologous blood stem cell transplantation is currently being investigated for patients presenting initially with advanced (poor prognosis) metastatic disease and for patients with relapse after previous chemotherapy, in whom conventional-dose salvage regimens will only result in 20% long-term survival. Because of the large group of patients with metastatic disease being cured, the possible long-term adverse effects of treatment have become important. Only a slightly elevated risk for therapy-related secondary malignancies has been identified. Long-term adverse effects associated with cisplatin may affect a larger proportion of patients. Further research should focus on reducing the risk of chemotherapy-related chronic toxicity.     

Comparative tolerability of the HMG-CoA reductase inhibitors.

The availability of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has revolutionised the treatment of lipid abnormalities in patients at risk for the development of coronary atherosclerosis. The relatively widespread experience with HMG-CoA therapy has allowed a clear picture to emerge concerning the relative tolerability of these agents. While HMG-CoA reductase inhibitors have been shown to decrease complications from atherosclerosis and to improve total mortality, concern has been raised as to the long term safety of these agents. They came under close scrutiny in early trials because ocular complications had been seen with older inhibitors of cholesterol synthesis. However, extensive evaluation demonstrated no significant adverse alteration of ophthalmological function by the HMG-CoA reductase inhibitors. Extensive experience with the potential adverse effect of the HMG-CoA reductase inhibitors on hepatic function has accumulated. The effect on hepatic function for the various HMG-CoA reductase inhibitors is roughly dose-related and 1 to 3% of patients experience an increase in hepatic enzyme levels. The majority of liver abnormalities occur within the first 3 months of therapy and require monitoring. Rhabdomyolysis is an uncommon syndrome and occurs in approximately 0.1% of patients who receive HMG-CoA reductase inhibitor monotherapy. However, the incidence is increased when HMG-CoA reductase inhibitors are used in combination with agents that share a common metabolic path. The role of the cytochrome P450 (CYP) enzyme system in drug-drug interactions involving HMG-CoA reductase inhibitors has been extensively studied. Atorvastatin, cerivastatin, lovastatin and simvastatin are predominantly metabolised by the CYP3A4 isozyme. Fluvastatin has several metabolic pathways which involve the CYP enzyme system. Pravastatin is not significantly metabolised by this enzyme and thus has theoretical advantage in combination therapy. The major interactions with HMG-CoA reductase inhibitors in combination therapy involving rhabdomyolysis include fibric acid derivatives, erythromycin, cyclosporin and fluconazole. Additional concern has been raised relative to overzealous lowering of cholesterol which could occur due to the potency of therapy with these agents. Currently, there is no evidence from clinical trials of an increase in cardiovascular or total mortality associated with potent low density lipoprotein reduction. However, a threshold effect had been inferred by retrospective analysis of the Cholesterol and Recurrent Events study utilising pravastatin and the role of aggressive lipid therapy is currently being addressed in several large scale trials.     

Comparative tolerability of drug treatment for nocturnal enuresis in children.

Primary nocturnal enuresis is one of the most frequent complaints in paediatric and urologic practice. Physicians face the dilemma of whether or not to treat primary nocturnal enuresis since the trend towards spontaneous remission is countered by social disadvantages and reduced self esteem of the children affected and their families. We reviewed randomised, controlled trials investigating efficacy and adverse effects of current medical treatment for primary nocturnal enuresis. Only desmopressin and imipramine displayed significant effects in reducing wet nights: when compared with baseline bedwetting or placebo controls, 30-70% of the studied children achieved therapeutic success. For drugs such as indometacin or oxybutynin, convincing studies displaying a significant positive effect are still needed. However, considering the adverse effects profiles of desmopressin and imipramine it can be seen that imipramine is associated with about twice as many unwanted reactions. More importantly, a serious adverse effect of imipramine is sudden cardiac arrest. In general, adverse effects with desmopressin are rare and mild, but there have been a number of case reports of hyponatraemic hypervolaemia associated with coma and seizures. Of these, many cases were attributed to excess water intake before taking the drug and all children recovered fully. In summary, if medical treatment is considered, preference should be given to desmopressin.