British Journal of Clinical Pharmacology

Paracetamol (acetaminophen) là một loại thuốc được sử dụng phổ biến nhất trên thế giới, với lịch sử lâu dài trong việc điều trị đau cấp tính và mãn tính. Trong những năm gần đây, lợi ích của việc sử dụng paracetamol trong các bệnh mãn tính bị đưa vào nghi vấn, đặc biệt trong các lĩnh vực như thoái hóa khớp và đau lưng dưới. Cùng lúc đó, sự lo ngại về các tác dụng phụ lâu dài của paracetamol đã gia tăng, ban đầu là trong lĩnh vực tăng huyết áp, nhưng gần đây đã mở rộng ra các lĩnh vực khác. Cơ sở bằng chứng về các tác dụng phụ của việc sử dụng paracetamol mãn tính bao gồm nhiều nghiên cứu đoàn hệ và quan sát, với ít thử nghiệm đối chứng ngẫu nhiên, trong đó nhiều nghiên cứu mâu thuẫn với nhau, vì vậy cần phải giải thích những nghiên cứu này một cách cẩn thận. Tuy nhiên, có một số lĩnh vực trong đó bằng chứng về tác hại là rõ ràng hơn, và nếu bác sĩ bắt đầu sử dụng paracetamol với kỳ vọng sử dụng dài hạn, có thể cần thảo luận trước những tác động phụ này với bệnh nhân. Đặc biệt, tăng nguy cơ chảy máu dạ dày và tăng huyết áp tâm thu nhỏ (~4 mmHg) là các tác dụng phụ trong đó bằng chứng đặc biệt mạnh mẽ và cho thấy sự phụ thuộc liều lượng. Khi sự ước tính về lợi ích giảm, đánh giá chính xác về các tác hại ngày càng trở nên quan trọng. Bài tổng quan này tóm tắt bằng chứng hiện tại về các tác hại liên quan đến việc sử dụng paracetamol lâu dài, tập trung vào bệnh tim mạch, hen suyễn và tổn thương thận, cũng như ảnh hưởng của việc tiếp xúc trong bụng mẹ.

1 The inter‐relationships among oral isosorbide dinitrate (ISDN) dose, drug pharmacokinetics and pharmacological effects were studied in 12 angina patients following single and chronic doses of 15, 30, 60 and 120 mg. 2 Significant accumulation of intact ISDN in plasma was observed after four times a day dosing at 30, 60 and 120 mg for 1 week. 3 The area under the plasma concentration v time curve (AUC), form 0‐6 h, was shown to be proportional to dose following single doses. In contrast, AUC increased disproportionately to dose after chronic dosing. 4 Pharmacokinetic correction provided modest improvements in the dose‐response relationships of ISDN. 5 Adverse hypotensive effects were observed in five patients after the single 60 mg dose. These patients showed statistically higher AUC and lower intrinsic clearance of ISDN at doses of 15, 30 and 60 mg compared to those who did not develop adverse effects. A possible relationship exists, therefore, between lower drug clearance and hypersensitivity to ISDN.

Drug‐induced liver injury (DILI) is a major challenge in clinical medicine and drug development. New models are needed for predicting which potential therapeutic compounds will cause DILI in humans, and new markers and mediators of DILI still need to be identified. This review highlights the strengths and weaknesses of using zebrafish as a high‐throughput in vivo model for studying DILI. Although the zebrafish liver architecture is different from that of the mammalian liver, the main physiological processes remain similar. Zebrafish metabolize drugs using similar pathways to those in humans; they possess a wide range of cytochrome P450 enzymes that enable metabolic reactions including hydroxylation, conjugation, oxidation, demethylation and de‐ethylation. Following exposure to a range of hepatotoxic drugs, the zebrafish liver develops histological patterns of injury comparable to those of mammalian liver, and biomarkers for liver injury can be quantified in the zebrafish circulation. The zebrafish immune system is similar to that of mammals, but the zebrafish inflammatory response to DILI is not yet defined. In order to quantify DILI in zebrafish, a wide variety of methods can be used, including visual assessment, quantification of serum enzymes and experimental serum biomarkers and scoring of histopathology. With further development, the zebrafish may be a model that complements rodents and may have value for the discovery of new disease pathways and translational biomarkers.

Self‐poisoning by ingestion or inhalation is common, and it is important to study its various epidemiological manifestations with clear definitions. Data on fatal self‐poisonings are recorded nationally within the UK and are codified according to the International Classification of Diseases (ICD) revision relevant at the time. Most fatal self‐poisonings are codified as suicides, accidental deaths or undetermined deaths (‘open verdicts’). Non‐fatal self‐poisoning data, whether accidental or as a manifestation of deliberate self‐harm, are recorded through hospital discharge information nationally but are not routinely published in the same way as mortality data. The bulk of the UK's published epidemiological information on nonfatal self‐poisoning episodes is largely based on individual hospitals’ admission or discharge records (‘special studies’). After establishing definitions for different self‐poisoning categories we discuss the published data on self‐poisoning as they relate to suicide, accidental self‐poisoning and deliberate self‐harm in the UK.

The field of bioinformatics has allowed the interpretation of massive amounts of biological data, ushering in the era of ‘omics’ to biomedical research. Its potential impact on pharmacology research is enormous and it has shown some emerging successes. A full realization of this potential, however, requires standardized data annotation for large health record databases and molecular data resources. Improved standardization will further stimulate the development of system pharmacology models, using translational bioinformatics methods. This new translational bioinformatics paradigm is highly complementary to current pharmacological research fields, such as personalized medicine, pharmacoepidemiology and drug discovery. In this review, I illustrate the application of transformational bioinformatics to research in numerous pharmacology subdisciplines.

1 Plasma levels and platelet 5‐HT uptake characteristics were determined at baseline and at various times during a long‐term study comparing fluvoxamine and lithium prophylaxis. 2 In the fluvoxamine‐ treated patients after 12 and 24 weeks of treatment, Km was significantly increased and y, the mean overall uptake, significantly decreased compared to the patients' own baseline values and to lithium treatment. No significant change was noted for Vmax. 3 For fluvoxamine, significant negative relationships were established between the Vmax of platelet 5‐HT uptake and plasma levels. 4 The trial had to be discontinued prematurely for some patients due to apparent lack of efficacy, unwanted effects or a combination of both in the fluvoxamine‐ treated patients. Low plasma levels of fluvoxamine may have contributed to the apparent lack of prophylactic efficacy of the drug. 5 Reference is made to the activity of receptor systems in patients receiving lithium and the consequent changes occurring after the administration of a potent 5‐HT re‐uptake inhibitor.

1 Fluvoxamine maleate is a compound from the series of 2‐ aminoethyloximethers of aralkylketones which possesses marked inhibition effects on 5‐hydroxytryptamine (5‐HT) uptake by blood platelets and brain synaptosomes. In contrast, it has no effect on noradrenaline uptake processes. 2 Fluvoxamine is completely absorbed in rats and dogs; the main metabolic path was similar in rat, dog, hamster, mouse and rabbit. The metabolites of fluvoxamine are inactive with regard to aminergic uptake processes. 3 Fluvoxamine is neither sedative nor stimulating, shows a very low cardiotoxic effect and no affinity for the cholinergic receptor. On the basis of the pharmacological profile, a highly favourable therapeutic ratio of antidepressant effects vs disturbing side‐effects is predicted.

Even‐number, medium‐chain dicarboxylic acids (DAs), naturally occurring in higher plants, are a promising alternative energy substrate. Unlike the homologous fatty acids, DAs are soluble in water as salts. They are β‐oxidized, providing acetyl‐CoA and succinyl‐CoA, the latter being an intermediate of the tricarboxylic acid cycle. Sebacic acid and dodecanedioic acid, DAs with 10 and 12 carbon atoms respectively, provide 6.6 and 7.2 kcal g⁻¹ each; therefore, their energy density is intermediate between glucose and fatty acids. Dicarboxylic acids have been proved to be safe in both experimental animals and humans, and their use has recently been proposed in diabetes. Studies in animals and humans with type 2 diabetes showed that oral administration of sebacic acid improved glycaemic control, probably by enhancing insulin sensitivity, and reduced hepatic gluconeogenesis and glucose output. Moreover, dodecanedioic acid intake reduced muscle fatigue during exercise in subjects with type 2 diabetes, suggesting an improvement of energy utilization and ‘metabolic flexibility’. In this article, we review the natural sources of DAs, their fate in animals and humans and their effect in improving glucose metabolism in type 2 diabetes.