Drugs

Dexrazoxane has been used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced breast cancer). The drug is thought to reduce the cardiotoxic effects of anthracyclines by binding to free and bound iron, thereby reducing the formation of anthracycline-iron complexes and the subsequent generation of reactive oxygen species which are toxic to surrounding cardiac tissue. Clinical trials in women with advanced breast cancer have found that patients given dexrazoxane (about 30 minutes prior to anthracycline therapy; dexrazoxane to doxorubicin dosage ratio 20: 1 or 10: 1) have a significantly lower overall incidence of cardiac events than placebo recipients (14 or 15% vs 31%) when the drug is initiated at the same time as doxorubicin. Cardiac events included congestive heart failure (CHF), a significant reduction in left ventricular ejection fraction and/or a ≥2-point increase in the Billingham biopsy score. These results are supported by the findings of studies which used control groups (patients who received only chemotherapy) for comparison. The drug appears to offer cardiac protection irrespective of pre-existing cardiac risk factors. In addition, cardiac protection has been shown in patients given the drug after receiving a cumulative doxorubicin dose ≥300 mg/m2. It remains to be confirmed that dexrazoxane does not affect the antitumour activity of doxorubicin: although most studies found that clinical end-points (including tumour response rates, time to disease progression and survival duration) did not differ significantly between treatment groups, the largest study did show a significant reduction in response rates in dexrazoxane versus placebo recipients. Dexrazoxane permits the administration of doxorubicin beyond standard cumulative doses; however, it is unclear whether this will translate into prolonged survival. Preliminary results (from small nonblind studies) indicate that dexrazoxane reduces cardiac toxicity in children and adolescents receiving anthracycline-based therapy for a range of malignancies. The long term benefits with regard to prevention of late-onset cardiac toxicity remain unclear. With the exception of severe leucopenia [Eastern Cooperative Oncology Group (ECOG) grade 3/4 toxicity], the incidence of haematological and nonhaema-tological adverse events appears similar in patients given dexrazoxane to that in placebo recipients undergoing anthracycline-based chemotherapy. Although preliminary pharmacoeconomic analyses have shown dexrazoxane to be a costeffective agent in women with advanced breast cancer, they require confirmation. Conclusions: Dexrazoxane is a valuable drug for protecting against cardiac toxicity in patients receiving anthracycline-based chemotherapy. Whether it offers protection against late-onset cardiac toxicity in patients who received anthracycline-based chemotherapy in childhood or adolescence remains to be determined. Further clinical experience is required to confirm that it does not adversely affect clinical outcome, that it is a cost-effective option, and to determine the optimal treatment regimen. The use of anthracyclines is significantly limited by cardiac toxicity, which occurs in 1 to 2% of patients given a cumulative doxorubicin dose < 450 mg/m2. This increases to 20 to 40% at cumulative doses >600 mg/m2. Children appear to be more susceptible to the cardiotoxic effects of this class of drugs than adults, although toxicity may not become apparent until years after cessation of therapy. Cardiac toxicity is thought to occur principally as a result of oxidative stress placed on cardiac myocytes by reactive oxygen species (generated by the stable complex formed between anthracyclines and iron). Consequently, the ability of free-radical scavengers and metal-chelating agents to reduce cardiac toxicity has been investigated. Dexrazoxane, a cyclic derivative of edetic acid (EDTA), provides cardiac protection from anthracyclines primarily through its metal-chelating activity. The hydrolysis products of dexrazoxane have been shown to chelate both free and bound intracellular iron, including iron that is bound in anthracycline complexes, thereby preventing the generation of cardiotoxic reactive oxygen species. The hydrolysis products are thought to be responsible for most of the activity of the drug. The cardioprotective activity of dexrazoxane has been demonstrated in animal models of anthracycline-induced cardiac toxicity. Dexrazoxane administration was associated with a significant reduction in the number of cardiac lesions and increased survival after toxic doses of anthracyclines. In studies in beagle dogs and rats, the drug appeared more effective when administered prior to or simultaneously with the anthracycline. In addition, delayed administration until after the sixth dose of doxorubicin was less effective than administration at the time of the initial doxorubicin dose (in contrast, delayed administration did not appear to reduce dexrazoxane's cardioprotective effect in patients). Studies in patients receiving anthracycline therapy for cancer indicate that the pharmacokinetic properties of dexrazoxane fit a 2-compartment model with first-order elimination kinetics. Absorption is linear within the dose range 60 to 900 mg/m2: the mean peak plasma concentration is 36.5 mg/L after a 15-minute intravenous infusion of dexrazoxane 500 mg/m2. The distribution half-life is about 15 minutes and the steady-state volume of distribution has been estimated to be about 1.1 L/kg. Protein binding is usually <2%. Dexrazoxane is hydrolysed to its active ring-opened forms by the enzyme dihydropyrimidine amidohydrolase (DHPase). Unchanged dexrazoxane, a diacid-diamide cleavage product and 2 monoacid-monoamide ring products have been detected in the urine. Total body clearance is about 0.29 L/h/kg. Most of the drug is eliminated in the urine (about 50% over 24 hours), the elimination half-life ranging from 2 to 4 hours. A study comparing the pharmacokinetic properties of dexrazoxane in adults and children found that the steady-state volume of distribution was higher in children, as was the total body clearance rate. There are no data at present on the properties of the drug in patients with renal or hepatic impairment. The pharmacokinetic properties of doxorubicin (60 mg/m2) are generally unchanged when the drug is administered 15 to 30 minutes after dexrazoxane (600 o 900 mg/m2) intravenous infusion. However, the properties of epirubicin may be altered by dexrazoxane when the drug is administered at doses ≥100 mg/m2. Clinical trials have shown dexrazoxane to significantly reduce the incidence of cardiac toxicity in patients receiving anthracycline-based chemotherapy for advanced breast cancer. Cardiac events indicative of cardiac toxicity included congestive heart failure (CHF), a reduction in the resting left ventricular ejection fraction (LVEF) to <45% or a ≥20% reduction in LVEF from baseline and/or a ≥2 point increase in the Billingham biopsy score. In these studies, the dexrazox-ane to doxorubicin dosage ratio was 10: 1 or 20: 1. In 2 multicentre double-blind comparative studies, the incidence of doxorubicin (50 mg/m2)-induced cardiac toxicity was 15 and 14% in patients given dexrazoxane (500 mg/m2 about 30 minutes prior to each dose of the anthracycline) versus 31% in both groups of placebo recipients. CHF occurred in 15% of placebo recipients but in no patients treated with dexrazoxane in one of these studies. Where reported in comparative studies, clinically relevant reductions in LVEF were less common in patients treated with dexrazoxane than in dexrazoxane-untreated control patients or placebo recipients. In most studies, dexrazoxane therapy was started at the same time as anthracycline therapy; however, it may also be cardioprotective when administration is delayed until a cumulative dose of doxorubicin ≥300 mg/m2 has been given (incidence of cardiac events 60% in patients given placebo throughout (for up to 13 cycles of chemotherapy) versus 25% in patients initially given placebo (for 6 cycles of chemotherapy) then switched to dexrazoxane according to protocol amendment). The extent of cardiac protection offered by dexrazoxane appeared similar in patients with or without pre-existing cardiac risk factors. Dexrazoxane did not affect the clinical outcome of anthracycline therapy in most studies. However, the largest study did show a significantly lower rate of tumour response to doxorubicin therapy in patients given dexrazoxane versus that in placebo recipients (46.8 vs 60.5%). Other studies (including one by the same investigators) have failed to show any detrimental effect of dexrazoxane on the antitumour activity of anthracyclines. The cardiac protection offered by dexrazoxane permits the administration of doxorubicin beyond standard cumulative doses. However, it remains unclear whether this will prolong the time to disease progression or the overall survival duration. While there was a trend towards prolonged survival in dexrazoxane recipients in most studies, the difference did not reach statistical significance (except in a retrospective analysis of patients given placebo or placebo followed by dexrazoxane as a result of protocol amendment). Preliminary results (from small nonblind studies) indicate that dexrazoxane is also an effective cardioprotective agent in children and adolescents receiving anthracycline-based chemotherapy for a range of malignancies: the incidence of cardiac toxicity was 22 vs 67% in dexrazoxane-treated and -untreated patients in one study. Further investigation in this high-risk patient group, with regard to long term benefit, is warranted. Available data from clinical trials in women with advanced breast cancer indicate that coadministration of dexrazoxane with anthracycline-based chemotherapy does not compromise tolerability in most patients. As expected, haematological toxicity was common in all treatment groups, but was generally more frequent in patients given dexrazoxane than in control groups (either placebo or no additional treatment). In comparisons with placebo, the incidence of severe leucopenia [Eastern Cooperative Oncology Group (ECOG) grade 3/4] at nadir was significantly higher in dexrazoxane recipients (78 vs 68%; p < 0.01). However, the incidences of severe granulocytopenia and thrombocytopenia did not differ significantly between treatment groups. The incidence and nature of other adverse events including vomiting, mucositis, infection, fever with neutropenia, alopecia, diarrhoea, fatigue, anaemia, haemorrhage, sepsis and stomatitis were similar between treatment groups. Pain on injection was more common with dexrazoxane than with placebo, whereas severe nausea (ECOG grade 3/4) appeared more common with placebo in comparative trials. Limited data indicate that the drug has similar tolerability in children and adolescents to that observed in women with advanced breast cancer. Pharmacoeconomic analyses [based on data from a retrospective study of patients with breast cancer given placebo for up to 13 cycles of chemotherapy or placebo for 6 cycles then dexrazoxane (as a result of protocol amendment in 2 phase III studies)] indicate that the administration of dexrazoxane to prevent anthracycline-induced cardiac toxicity was cost-effective. Dexrazoxane cost $US5662 per cardiac event prevented and $US12 992 per CHF event prevented (based on 1995 costs). It was also found to cost $US2809 per life-year gained; however, survival data used in this analysis require confirmation. The investigators concluded that dexrazoxane compared well in terms of cost-effectiveness with other medical interventions in routine use in the US and Canada, including invasive cardiac monitoring to prevent heart failure. For protection against anthracycline-induced cardiac toxicity, the recommended dexrazoxane to anthracycline dosage ratio is 10: 1 in the US (i.e. 500 mg/m2 for a 50 mg/m2 doxorubicin dose) or 20: 1 in Europe. Dexrazoxane should be administered by intravenous infusion (slow push or rapid drip infusion), starting approximately 30 minutes before anthracycline infusion. In Europe, dexrazoxane should be initiated at the same time as anthracycline therapy whereas in the US delayed administration until a cumulative dose of 300 mg/m2 doxorubicin is given is recommended. The maximum dose given in any cycle should not exceed 1000 mg/m2. Dexrazoxane may potentiate haematological toxicity induced by chemotherapy or radiation; thus monitoring of haematological parameters is recommended. The drug should not be given to pregnant or breast-feeding women, and caution is required in patients with renal or liver impairment.

Regdanvimab (Regkirona™) is a recombinant human monoclonal antibody targeted against the severe acute respiratory syndrome coronavirus 2. It is being developed by Celltrion Inc. for the treatment of coronavirus disease 2019 (COVID-19). In September 2021, regdanvimab received full approval in South Korea for the treatment of COVID-19 in elderly patients aged > 50 years with at least one underlying medical condition (obesity, cardiovascular disease, chronic lung disease, diabetes, chronic kidney disease, chronic liver disease, and patients on immunosuppressive agents) and mild symptoms of COVID-19 and in adult patients with moderate symptoms of COVID-19. This article summarizes the milestones in the development of regdanvimab leading to this first approval for COVID-19.

Since its discovery in 1982, neuropeptide Y (NPY) has been shown to have numerous effects mediated by a growing number of NPY receptors in both the CNS and peripheral nervous system. Perhaps best appreciated is the role of NPY in the control of systemic blood pressure, together with its effects on feeding, anxiety and memory. However, recent evidence increasingly supports an important role for NPY in mediating analgesia and hyperalgesia by distinct central and peripheral mechanisms. In this review we concentrate on this important aspect of NPY pharmacology and consider mechanisms controlling the expression of NPY and its receptors. In addition, we also present the more recent data describing the other possible roles for NPY. NPY agonists and antagonists may be useful in the treatment of conditions as varied as anorexia, epilepsy, anxiety, depression, hypertension and heart failure.

Diabetic ketoacidosis is an all too frequent and sometimes preventable complication of Type I diabetes mellitus, responsible for significant morbidity and mortality within the diabetic population. Precipitating diseases account for the majority of deaths occurring in patients admitted in diabetic ketoacidosis, but some deaths are still attributable to ketoacidosis alone, despite recent advances in therapy and management. Recognition of the ketoacidotic state is paramount to optimal therapy, and often hinges on the diagnostic acumen of the physician. Since 20 to 30% of patients presenting in diabetic ketoacidosis do so as the initial manifestation of their previously undiagnosed disease, physicians must maintain a high level of suspicion for this condition. Understanding the pathogenetic mechanisms leading to and prevailing in diabetic ketoacidosis will allow physicians to intervene in a rational manner, approaching therapy with specific end-points in mind: (a) restoration of optimal volume status; (b) reversal of acidosis; (c) reduction of serum glucose levels; (d) replacement of specific electrolytes in a timely manner; (e) institution of appropriate therapy for any precipitating cause; and, (f) careful monitoring of the patient’s biochemical, physical and mental parameters to allow adjustment in therapy as necessary. The mainstay of treatment for diabetic ketoacidosis is appropriate fluid and insulin therapy. Low-dose intravenous infusion is now the accepted mode of insulin delivery for patients with this condition. Potassium replacement is almost always necessary, often requiring massive amounts of this ion due to the total body depletion seen with the development of ketoacidosis. Controversy still surrounds routine use of phosphate in diabetic ketoacidosis but replacement may be needed if serum levels fall toward the lower limits of normal values, to avoid the potential adverse effects of phosphate depletion. Administration of bicarbonate is also controversial and should be reserved for patients whose pH is less than 7.0 to 7.1 and then it should be added to intravenous fluids, not given as an intravenous bolus. Efforts toward preventing diabetic ketoacidosis should be of prime importance to physician and patient alike. Preventive measures should include patient education about diabetes mellitus, precipitating factors of diabetic ketoacidosis, signs and symptoms of early metabolic decompensation, rational insulin therapy during minor illness and appropriate timing of physician contact to help avoid this serious and sometimes fatal complication of diabetes mellitus.

Các NSAID thường được sử dụng trong thực hành lâm sàng và chiếm khoảng 5–10% tổng số đơn thuốc. Việc sử dụng NSAID đã được liên kết với nguy cơ xảy ra các sự kiện bất lợi, có tác động đáng kể đến tỷ lệ bệnh tật và tử vong, đồng thời làm tăng chi phí chăm sóc sức khỏe. Các sự kiện bất lợi liên quan đến NSAID ít phổ biến hơn nhưng có liên quan lâm sàng, đó là sự suy giảm chức năng thần kinh trung ương, đặc biệt là sự xuất hiện của các triệu chứng tâm thần. Những triệu chứng này bao gồm thay đổi nhận thức, trạng thái tâm trạng và thậm chí là sự khởi phát hoặc trầm trọng thêm các rối loạn tâm thần đã có trước đó. Bài báo này nhằm xem xét tài liệu y khoa về các báo cáo đã công bố về các sự kiện bất lợi tâm thần liên quan đến NSAID, xác định các yếu tố nguy cơ cho những sự kiện này và mô tả các cơ chế có thể liên quan đến sự khởi phát của chúng. Chúng tôi đã xác định được 27 báo cáo với dữ liệu về 453 trường hợp sự kiện bất lợi tâm thần liên quan đến NSAID. Dữ liệu cho thấy những cá nhân có khả năng nhạy cảm với những sự kiện như vậy bao gồm bệnh nhân có tiền sử bệnh tâm thần và có thể cả sản phụ. Indometacin và các thuốc ức chế chọn lọc COX-2 là những loại thuốc được báo cáo thường xuyên nhất; tuy nhiên, không rõ liệu điều này có phản ánh tỷ lệ xảy ra cao hơn với những loại thuốc này so với các NSAID khác hay các yếu tố như mẫu sử dụng hoặc báo cáo. Một lời giải thích có thể cho hiệu ứng tâm thần của NSAID nằm ở sự điều chỉnh của truyền dẫn thần kinh trung ương bởi prostaglandin, việc tổng hợp của các chất này bị ức chế bởi NSAID. COX-2 là một enzym then chốt trong quá trình này vì hoạt động của nó được tìm thấy ở các nhánh xa và gai nhánh, những đặc điểm tế bào tham gia vào tín hiệu synap. Dopamine được coi là chất truyền dẫn thần kinh có liên quan nhất trong hiện tượng này. Các triệu chứng tâm thần là một biến chứng hiếm nhưng có liên quan của việc sử dụng NSAID. Hiệu ứng này có thể là hậu quả của sự suy giảm trong truyền dẫn thần kinh được điều chỉnh bởi prostaglandin khi NSAID được sử dụng bởi những cá nhân nhạy cảm. Những loại thuốc này nên được sử dụng cẩn thận ở những cá nhân có nguy cơ cao với bệnh tâm thần đã có từ trước, và cũng nên thận trọng trong thời kỳ hậu sản. Tính đến nay, các báo cáo về sự kiện bất lợi tâm thần liên quan đến NSAID chủ yếu liên quan đến indometacin và các thuốc ức chế chọn lọc COX-2. Những người kê đơn nên xem xét cảnh báo bệnh nhân về khả năng xảy ra sự kiện thần kinh tâm lý cấp tính khi kê đơn NSAID thông thường hoặc các thuốc ức chế COX-2 chọn lọc.

Serplulimab (汉斯状®) là một kháng thể chống PD-1 được tiêm tĩnh mạch đang được phát triển bởi Công ty TNHH Công nghệ Sinh học Thượng Hải Henlius để điều trị các khối u rắn. Các liệu pháp miễn dịch chống PD-1, chẳng hạn như serplulimab, có thể kích thích phản ứng miễn dịch bằng cách giảm thiểu tình trạng ức chế miễn dịch liên quan đến PD-1. Serplulimab đã nhận được phê duyệt đầu tiên vào ngày 25 tháng 3 năm 2022 tại Trung Quốc để điều trị cho bệnh nhân trưởng thành mắc khối u rắn có độ bất ổn microsatellite cao (MSI-H) không thể cắt bỏ hoặc di căn và đã không phản hồi với các phương pháp điều trị tiêu chuẩn trước đó. Bài báo này tổng hợp những dấu mốc trong quá trình phát triển serplulimab dẫn đến phê duyệt đầu tiên trong điều trị khối u rắn MSI-H ở người lớn.

The recently published Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) provides interesting evidence for the use of statins in hypertensive patients with average cholesterol concentrations and other cardiovascular risk factors. The clinical benefit of atorvastatin in these patients is probably explained by both lipid-dependent and lipid-independent effects of the drug. Many of these effects are related to inhibition of the synthesis of isoprenoid, which serves as lipid attachment for a variety of proteins implicated in intracellular signalling. These proteins have an important role in cell growth, actin cytoskeleton organisation, membrane trafficking, gene expression, cell proliferation/migration and programmed cell death. In this article we summarise the different effects of statins in relation to the results observed in the ASCOT-LLA study.

Despite the effectiveness of anticoagulant therapy for the treatment of acute venous thromboembolism and the prevention of recurrent venous thromboembolism, existing antithrombotic therapies are suboptimal. Unfractionated heparin, low-molecular-weight heparin (LMWH) and warfarin have practical limitations and carry the risk of treatment-related adverse events that restrict their clinical benefits and reduce cost-effectiveness. Efforts to achieve optimal venous thromboembolism prophylaxis by modifying the intensity of oral warfarin treatment have produced equivocal results, and there is a need for new, efficacious antithrombotic drugs providing predictable, well-tolerated oral dosing without the need for coagulation monitoring. Such agents would ideally have no significant food or drug interactions, and be suitable for both short- and long-term treatment. Ximelagatran, the first oral direct thrombin inhibitor, has the potential to fulfill many of the unmet needs in the management of venous thromboembolism.