Letter from the Editor

Antibacterials are frequently associated with idiosyncratic drug‐induced liver injury (DILI). The objective of this study was to estimate the risk of macrolides and amoxicillin/clavulanate (AMC) on DILI. We conducted a systematic review (SR) and meta‐analysis (MA) with studies retrieved from PubMed, Cochrane Library Plus, Web of Knowledge, clinicaltrials.gov, Livertox and Toxline (1980–2014). We searched for macrolides, AMC and MeSH and synonym terms for DILI. We included all study designs except case reports/series, all population ages and studies with a placebo/non‐user comparator. We summarized the evidence with a random‐effects MA. Quality of the studies was appraised with a checklist developed for SR of adverse effects. Heterogeneity and publication bias were assessed with different exploratory tools. We finally included 10 (two randomized clinical trials, six case–control, one cohort and one case–population studies) and 9 (case–population excluded) articles in the SR and MA, respectively. The overall summary relative risk of DILI for macrolides was 2.85 [95% confidence interval (CI) 1.81–4.47], p < 0.0001, I² = 57%. Three studies were perceived to be missing in the area of low statistical significance. Year of study and selected exposure window partly explained the variability between studies. For AMC, the risk of DILI was 9.38 (95% CI 0.65–135.41) p = 0.3, I2 = 95%. In conclusion, although spontaneous reports and case series have long established an association between macrolides and AMC with acute liver injury, these SR and MA have assessed the magnitude of this association. The low incidence of DILI and the therapeutic place of these antibiotics might tilt the balance in favour of their benefits.     

Letter from the Editor

Evocarpine, an isoquinolone alkaloid isolated from the fruit of Evodia rutaecarpa, was found to induce apoptotic cell death in promyelocytic leukaemia HL‐60 cells in dose‐ and time‐dependent manners. We investigated the involvement of protein kinase A during the evocarpine‐induced apoptotic cell death. Evocarpine‐induced apoptosis was markedly inhibited by treatment of the cells with dibutyryl‐cyclic adenosine monophosphate. Similar results were obtained with other commonly used cyclic adenosine monophosphate analogues, chlorophenylthio‐cyclic adenosine monophosphate and the intracellular cyclic adenosine monophosphate‐elevating agent, forskolin. In contrast, pretreatment of HL‐60 cells with KT5720, an inhibitor of cyclic adenosine monophosphate‐dependent protein kinase A, abrogated the protective effects of cyclic adenosine monophosphate analogues and forskolin on evocrpine‐induced apoptosis. These findings suggest that cyclic adenosine monophosphate‐dependent activation of protein kinase A plays a crucial role in protecting HL‐60 cells from the evocarpine‐induced apoptotic cell death.     

Letter from the Editor

This study investigated the antinociceptive and anti‐inflammatory activities of the ethanolic extract (EESAl), fractions and the compound 8‐methoxylapachenol (8ML) obtained from the tubers of Sinningia allagophylla. Male Swiss mice were treated with EESAl (3–300 mg/kg) or vehicle by oral route (p.o.) 1 hr before the injection of formalin 2.5% or carrageenan (Cg) into the hind paw. EESAl (3–30 mg/kg) reduced the inflammatory phase of the nociceptive behaviour induced by formalin (around 65% for all doses). EESAl (3–300 mg/kg, p.o.) also reduced Cg‐induced mechanical hyperalgesia and oedema in a dose‐dependent fashion but did not change the hot‐plate latency or the motor performance of the animals. Oral administration of petroleum ether fraction (PE, 3 mg/kg), but not in the methanolic fraction (30 mg/kg), reduced both Cg‐induced oedema and hyperalgesia. Compound 8ML isolated from PE (1.8 mg/kg, p.o.) abolished Cg‐induced hyperalgesia but also did not change hot‐plate latency or motor performance of the animals. 8ML administration into the paw (0.75–750 pg) dose‐dependently reduced Cg‐induced hyperalgesia. 8ML (750 pg) also blocked the hyperalgesia induced by tumour necrosis factor (TNF‐α), interleukin‐1β (IL‐1β) and prostaglandin E₂ (PGE₂) but failed to change the hyperalgesia induced by cytokine‐induced neutrophil chemoattractant‐1 (CINC‐1) and dopamine (Dopa). These results suggest that EESAl has an important antinociceptive and anti‐inflammatory activity, the former one related, at least in part, to the reduction in the hyperalgesia. Similarly, 8ML reduced Cg‐induced oedema and mechanical hyperalgesia and seems to act in peripheral sites and on the prostaglandin rather than on the sympathetic component of the Cg‐inflammatory hyperalgesia.     

Letter from the Editor

Abstract: Our study aimed to find more effective protective agents against mucosa toxicity induced by methotrexate and 5‐fluorouracil. We focused on the relationship between oral mucositis and keratinocyte injury and examined methotrexate and 5‐fluorouracil‐induced cytotoxicity in normal human epidermal keratinocyte cell lines. Cell viability and superoxide radical activity were measured based on converting WST‐1 (4‐[3‐(4‐indophenyl)‐2‐(4‐nitrophenyl)‐2H‐5‐tetrazolio]‐1,3‐benzen disulfonate) to a water‐soluble formazan dye. DNA synthesis by 5‐bromo‐2′‐deoxyuridine incorporation was measured as an indirect parameter of cell proliferation. Allopurinol and amifostine were used as the radical scavengers. l ‐glutamine was used as a mucosa‐protective agent. A cyclooxygenase inhibitor interrupting the production of hydroxyl radicals in the arachidonic acid cascade was also examined. 5‐fluorouracil and methotrexate caused cytotoxicity due to the activation of intracellular superoxide radicals specifically on normal human epidermal keratinocytes. From the electron spin resonance study, it was found that allopurinol was a superoxide radical scavenger, while amifostine was hydroxyl radical scavenger. Allopurinol showed no effect on the cytotoxicity due to 5‐fluorouracil and methotrexate. The cell injury induced by methotrexate was restored by amifostine. However, the cell injury induced by 5‐fluorouracil was markedly recovered by a selective cyclooxygenase‐1 inhibitor compared to amifostine. It was suggested that amifostine and cyclooxygenase‐1 inhibitor could be useful protective agents against methotrexate and 5‐fluorouracil chemotherapeutic toxicity. Additionally, this in vitro cell injury model using normal human epidermal keratinocytes may be useful for understanding the pathophysiology of oral mucositis induced by chemotherapeutic agents.     

Letter from the Editor

In vitro drug‐induced toxicity assessment demands the usability and validation of suitable cell models, obtained non‐invasively and pain‐free. Sperm suspensions, painlessly and easily obtained from breeding boars, have been proven as suitable biosensors for pre‐clinical toxicology screening and ranking of lead compounds in the drug development processes on a kinematics‐based assay. Having a limited number of mitochondria and depending on these mitochondria and on cytoplasmic glycolysis for the energy needed for motility and for plasma membrane functionality, spermatozoa become a suitable model for capturing multiple modes of action of drugs and other chemicals acting via measurements of sperm motility. In this MiniReview, the usability of boar spermatozoa as detectors of cytotoxicity based on sperm motility measurements is discussed.     

Letter from the Editor

Abstract Prostacyclin, nitric oxide and tissue plasminogen activator constitute a prominent triad of endothelial mediators. Prostacyclin is responsible mainly for maintaining vascular thromboresistance against platelet clumps, inhibits proliferation of vascular smooth muscle and modulates cholesterol turnover, tissue plasminogen activator is a fibrinolytic agent and nitric oxide controls vascular tone and structure. Receptor agonists such as acetylcholine, kinins, endothelins or adenosine diphosphate evoke a coupled release of mediators from endothelial cells. Prostacyclin and nitric oxide synergize in their antiplatelet, fibrinolytic and cardioprotective, but not in their hypotensive actions. Prostacyclin, but not nitric oxide, prevents paradox thrombogenic effects of tissue plasminogen activator. Filogenetically, prostacyclin and tissue plasminogen activator are younger brothers of nitric oxide from which they take over and perfect regulatory properties in circulation. Further studies on interactions of endothelial mediators may lead to a better understanding of mechanisms of thrombosis, atherogenesis, diabetic angiopathies, endotoxic shock and arterial hypertension.     

Letter from the Editor

Abstract: Certain types of neuronal ion channels have been demonstrated to be the major target sites of insecticides. The insecticide-channel interactions that have been studied most extensively are pyrethroid actions on the voltage-gated sodium channel and cyclodiene/lindane actions on the GABA_A receptor chloride channel complex. With the exception of organo-phosphate and carbamate insecticides which inhibit acetylcholinesterases, most insecticides commercially developed act on the sodium channel and the GABA system. Pyrethroids slow the kinetics of both activation and inactivation gates of sodium channels resulting in prolonged openings of individual channels. This causes membrane depolarization, repetitive discharges and synaptic disturbances leading to hyperexcitatory symptoms of poisoning in animals. Only a very small fraction (~1%) of sodium channel population is required to be modified by pyrethroids to produce severe hyperexcitatory symptoms. This toxicity amplification theory applies to pharmacological and toxicological actions of other drugs that go through a threshold phenomenon. Selective toxicity of pyrethroids between invertebrates and mammals can be explained based largely on the responses of sodium channels and partly on metabolic degradation. The pyrethroid-sodium channel interaction is also supported by Na⁺ uptake and batrachotoxin binding experiments. Cyclodienes and lindane exert a dual action on the GABA_A system, the initial transient stimulation being followed by a suppression. The stimulation requires the presence of the γ2 subunit. The suppression of the GABA system is also documented by CI^- flux and ligand binding experiments. It appears that the sodium channel and the GABA system merit continuing efforts for development of newer and better insecticides. Nitromethylene heterocycles including imidacloprid act on nicotinic acetylcholine receptors. Insect receptors are more sensitive to these compounds than mammalian receptors. Single-channel analyses of the nicotinic acetylcholine receptor of PC12 cells have shown that imidacloprid increases the activity of subconductance state currents and decreases that of main conductance state currents. This may explain the imidacloprid suppression of acetylcholine responses.     

Letter from the Editor

Abstract: The present article reviews the results of experimental studies on paraquat neurotoxicity, started by our group several years ago – when clinical and experimental reports had increased the interest for the possibility that environmental chemicals, including paraquat, may be related to the development of Parkinson's disease –, and which are still continuing since paraquat appears to be a promising tool to study the mechanisms of neuronal cell death in vivo. Our observations have demonstrated that paraquat causes evident neurotoxic effects after intracerebroventricular or intracerebral injection in experimental animals; however, it seems that the herbicide does not exibit a selective neurotoxicity towards the dopaminergic nigro-striatal system since potent behavioural and electrocortical changes are induced by paraquat after injection in brain areas other than the substantia nigra and caudate nucleus. By studying the mechanisms through which paraquat induces neurotoxic effects in vivo, it was shown that either free radical production and activation of cholinergic and glutamatergic transmission may be regarded as related events which play a crucial role in paraquat-induced neurotoxicity. In addition, it was observed that in rats paraquat penetrates the blood-brain barrier following systemic administration to give rise to a differential brain regional distribution; the latter observation rises some concern over the hazard of paraquat as a potential environmental neurotoxin. Indeed, paraquat, administered systemically in rats produces behavioural excitation and brain damage. The brain damage appears to be selective for the pyriform cortex and this does not seem to be strictly related to the high concentrations reached by the herbicide in this area but to the higher vulnerability of this cortical area to the enhanced cholinergic transmission. The recent observation that paraquat, injected into the rat hippocampus, induces the expression of apoptotic neuronal cell death, appears of valuable interest also with a view to paraquat as an useful experimental model in the development of neuroprotective drugs able to block the molecular events which, once activated, are responsible for the induction of neuronal cell death.