Background & Aims Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods We performed a genome-wide association study using 822,927 single-nucleotide polymorphism (SNP) markers from 201 White European and US cases of AC-DILI and 532 population controls, matched for genetic background. Results AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with a human leukocyte antigen (HLA) class II SNP (rs9274407, P=4.8×10−14), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10−4). An independent association was observed in the class I region (rs2523822, P=1.8×10−10), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=0.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10−6) and HLA-DQB1*0602 (P=5×10−10), and their interaction (P=0.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of auto-immunerelated genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10−4). Conclusions Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI, but have limited utility as predictive or diagnostic biomarkers because of the low positive-predictive values.

BACKGROUND & AIMS We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS We performed a GWAS of 862 persons with DILI and 10588 population-matched controls. The first set of cases was recruited prior to May 2009 in Europe (n=137) or the USA (n=274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the USA and South America. For the GWAS, we included only cases of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs). After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% CI, 1.9–3.8; P=2.4×10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6–2.5; P=9.7×10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant, genome wide, for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the LRBA gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6–2.7; P=4.8×10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR=5.4; 95% CI, 3.0–9.5; P=7.1×10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non–drug-specific risk factors.

Aims Cutaneous manifestations are frequently reported in association with drug use. The aim of this study was to analyse the skin reactions reported to the spontaneous surveillance systems of four Italian regions (Friuli Venezia Giulia, Lombardy, Sicily and the Veneto), and correlate the reports with estimated drug consumption during the same period, paying particular attention to the reactions to antimicrobial agents and nonsteroidal anti-inflammatory drugs (NSAIDs). Methods All of the adverse drug reactions (ADRs) reported spontaneously between January 1996 and December 1997 to the surveillance systems of four Italian regions (a total population of about 20 million people) were analysed by a panel of experts including dermatologists. On the basis of the Critical Term List of the World Health Organization (WHO), the reactions were classified as either serious or nonserious events. Drug consumption was expressed as a daily defined dose (DDD)/1000 inhabitants/day. Results A total of 2224 adverse skin reaction reports (44.7% of all of the reported ADRs) were identified, making a reporting rate of about 5.5 per 100 000 inhabitants/year. The female/male ratio was 1.58, and the reporting rate progressively increased with age. The drug categories with the highest number of cutaneous reactions were antimicrobials, followed by NSAIDs, analgesics and radiology contrast media. There was a total of 372 (16.9%) serious reaction reports, the most frequent being angioedema (171 cases), erythema multiforme (68 cases) and photosensitivity (37 cases). Co-trimoxazole, followed by the cephalosporins and fluoroquinolones, were associated with the highest consumption-related reporting rate among the antimicrobials, and aspirin and dipyrone among the NSAIDs and analgesics. Conclusions Spontaneous reports from four Italian regions revealed that the skin was the organ most frequently affected by ADRs. The paper shows the validity of a regional decentralized system in Italy. health service use and costs [4, 6]. Keywords

IntroductionThis study was designed to investigate the putative anxiolytic-like activity of ultra-low doses of Gelsemium sempervirens (G. sempervirens), produced according to the homeopathic pharmacopeia.MethodsFive different centesimal (C) dilutions of G. sempervirens (4C, 5C, 7C, 9C and 30C), the drug buspirone (5 mg/kg) and solvent vehicle were delivered intraperitoneally to groups of ICR-CD1 mice over a period of 9 days. The behavioral effects were assessed in the open-field (OF) and light–dark (LD) tests in blind and randomized fashion.ResultsMost G. sempervirens dilutions did not affect the total distance traveled in the OF (only the 5C had an almost significant stimulatory effect on this parameter), indicating that the medicine caused no sedation effects or unspecific changes in locomotor activity. In the same test, buspirone induced a slight but statistically significant decrease in locomotion. G. sempervirens showed little stimulatory activity on the time spent and distance traveled in the central zone of the OF, but this effect was not statistically significant. In the LD test, G. sempervirens increased the % time spent in the light compartment, an indicator of anxiolytic-like activity, with a statistically significant effect using the 5C, 9C and 30C dilutions. These effects were comparable to those of buspirone. The number of transitions between the compartments of the LD test markedly increased with G. sempervirens 5C, 9C and 30C dilutions.ConclusionThe overall pattern of results provides evidence that G. sempervirens acts on the emotional reactivity of mice, and that its anxiolytic-like effects are apparent, with a non-linear relationship, even at high dilutions.

Several lines of evidence suggest that homeopathic high dilutions (HDs) can effectively have a pharmacological action, and so cannot be considered merely placebos. However, until now there has been no unified explanation for these observations within the dominant paradigm of the dose-response effect. Here the possible scenarios for the physicochemical nature of HDs are reviewed. A number of theoretical and experimental approaches, including quantum physics, conductometric and spectroscopic measurements, thermoluminescence, and model simulations investigated the peculiar features of diluted/succussed solutions. The heterogeneous composition of water could be affected by interactive phenomena such as coherence, epitaxy and formation of colloidal nanobubbles containing gaseous inclusions of oxygen, nitrogen, carbon dioxide, silica and, possibly, the original material of the remedy. It is likely that the molecules of active substance act as nucleation centres, amplifying the formation of supramolecular structures and imparting order to the solvent. Three major models for how this happens are currently being investigated: the water clusters or clathrates, the coherent domains postulated by quantum electrodynamics, and the formation of nanoparticles from the original solute plus solvent components. Other theoretical approaches based on quantum entanglement and on fractal-type self-organization of water clusters are more speculative and hypothetical. The problem of the physicochemical nature of HDs is still far from to be clarified but current evidence strongly supports the notion that the structuring of water and its solutes at the nanoscale can play a key role.

The pharmacodynamics aspects of homeopathic remedies are appraised by laboratory studies on the biological effects at various levels (cellular, molecular and systemic). The major question is how these medicines may work in the body. The possible answers concern the identification of biological targets, the means of drug-receptor interactions, the mechanisms of signal transmission and amplification, and the models of inversion of effects according to the traditional 'simile' rule. These problems are handled by two experimental and theoretical lines, according to the doses or dilutions considered (low-medium versus high dilutions). Homeopathic formulations in low-medium dilutions, containing molecules in the range of ultra-low doses, exploit the extreme sensitivity of biological systems to exogenous and endogenous signals. Their effects are interpreted in the framework of hormesis theories and paradoxical pharmacology. The hypotheses regarding the action mechanisms of highly diluted/dynamized solutions (beyond Avogadro-Loschmidt limit) variously invoke sensitivity to bioelectromagnetic information, participation of water chains in signalling, and regulation of bifurcation points of systemic networks. High-dilution pharmacology is emerging as a pioneering subject in the domain of nanomedicine and is providing greater plausibility to the puzzling claims of homeopathy.

The foundation of homeopathic medicine is the ‘Similia Principle’, also known as the ‘Principle of Similarity’ or also as the ‘Simile’, which reflects the inversion of pharmacological effects in healthy subjects as compared with sick ones. This article describes the inversion of effects, a widespread medical phenomenon, through three possible mechanisms: non-linearity of dose–response relationship, different initial pathophysiological states of the organism, and pharmacodynamics of body response to the medicine. Based on the systemic networks which play an important role in response to stress, a unitary and general model is designed: homeopathic medicines could interact with sensitive (primed) regulation systems through complex information, which simulate the disorders of natural disease. Reorganization of regulation systems, through a coherent response to the medicine, could pave the way to the healing of the cellular, tissue and neuro-immuno-endocrine homeodynamics. Preliminary evidence is suggesting that even ultra-low doses and high-dilutions of drugs may incorporate structural or frequency information and interact with chaotic dynamics and physical-electromagnetic levels of regulation. From the clinical standpoint, the ‘simile’ can be regarded as a heuristic principle, according to which the detailed knowledge of pathogenic effects of drugs, associated with careful analysis of signs and symptoms of the ill subject, could assist in identifying homeopathic remedies with high grade of specificity for the individual case.

Objectives: To analyse an Italian database of spontaneous reporting of suspected adverse drug reactions in order to compare the safety profile of amoxicillin and amoxicillin/clavulanic acid.Methods: Data were retrieved from the spontaneous reports collected by six Italian regions (the GIF database) from January 1988 to June 2005. Drug utilization data were also available for the two drugs. The comparison between amoxicillin and amoxicillin/clavulanic acid was made using the x 2 or Student's t-test, when appropriate. Disproportionality in reporting of adverse events was assessed using reporting odds ratio methodology.Results: Up to June 2005, the GIF database collected 37 906 reports, of which 1088 were related to amoxicillin/clavulanic acid and 1095 to amoxicillin. The percentage of skin reactions was statistically higher for amoxicillin (82%) than for amoxicillin/clavulanic acid (76%); on the contrary, the percentage of gastrointestinal, hepatic and haematological reactions was significantly higher for amoxicillin/ clavulanic acid (13%, 4% and 2%, respectively) than for amoxicillin (7%, 1% and 1%, respectively). Amoxicillin/clavulanic acid seems to be associated with a higher risk of Stevens-Johnson syndrome, purpura and hepatitis than amoxicillin alone. In particular, the reporting rate of hepatitis is on average 9-fold higher for amoxicillin/clavulanic acid than for amoxicillin.Conclusions: Analysis shows a different safety profile for the two selected drugs. The combination of amoxicillin/clavulanic acid has been increasingly used in Italy and now represents the most frequently antibiotic prescribed by Italian general practitioners. Given the documented level of inappropriate use of b-lactams in Italy, these results should be taken into account by physicians before prescribing amoxicillin/clavulanic acid to patients.