Machine learning-based prediction of adverse drug effects: An example of seizure-inducing compounds.

Various biological factors have been implicated in convulsive seizures, involving side effects of drugs. For the preclinical safety assessment of drug development, it is difficult to predict seizure-inducing side effects. Here, we introduced a machine learning-based in vitro system designed to detect seizure-inducing side effects. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices, while 14 drugs were bath-perfused at 5 different concentrations each. For each experimental condition, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which indeed were reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to detect the seizure-inducing side effects of preclinical drugs.

[Machine Learning-based Prediction of Seizure-inducing Action as an Adverse Drug Effect].

　During the preclinical research period of drug development, animal testing is widely used to help screen out a drug's dangerous side effects. However, it remains difficult to predict side effects within the central nervous system. Here, we introduce a machine learning-based in vitro system designed to detect seizure-inducing side effects before clinical trial. We recorded local field potentials from the CA1 alveus in acute mouse neocortico-hippocampal slices that were bath-perfused with each of 14 different drugs, and at 5 different concentrations of each drug. For each of these experimental conditions, we collected seizure-like neuronal activity and merged their waveforms as one graphic image, which was further converted into a feature vector using Caffe, an open framework for deep learning. In the space of the first two principal components, the support vector machine completely separated the vectors (i.e., doses of individual drugs) that induced seizure-like events, and identified diphenhydramine, enoxacin, strychnine and theophylline as "seizure-inducing" drugs, which have indeed been reported to induce seizures in clinical situations. Thus, this artificial intelligence-based classification may provide a new platform to pre-clinically detect seizure-inducing side effects of drugs.

Profiles of hepatic and dysrhythmic cardiovascular events following use of fluoroquinolone antibacterials: experience from large cohorts from the Drug Safety Research Unit Prescription-Event Monitoring database.

OBJECTIVE: To investigate how frequently serious dysrhythmic cardiovascular, and hepatotoxic events are reported during routine clinical use of fluoroquinolones (quinolones) in general practice. DESIGN: Cohorts prescribed quinolones (cohort sizes: ciprofloxacin 11 477; enoxacin 2790; ofloxacin 11 033 and norfloxacin 11 110; mean age in each cohort of 48.6 to 57.0 years) were selected from the Drug Safety Research Unit's Prescription-Event Monitoring (PEM) database. The monitoring periods were November 1988 to January 1989 for ciprofloxacin; April 1989 to January 1991 for enoxacin; May 1991 to December 1991 for ofloxacin and October 1990 to October 1991 for norfloxacin. Data collected over the total PEM surveillance period on selected gastrointestinal events were extracted and reviewed to identify possible hepatic events, together with selected cardiovascular events associated with dysrhythmias. For each quinolone, times to onset of the event and patient-months of observation (denominator values) were calculated. The analysis was based on two observation periods: rate of event during the first 7 days following dispensing of a prescription for each drug (W(1)), and rate of event during the second to sixth week inclusive (W(2)). RESULTS: Scrutiny of original green forms revealed no evidence of drug-induced hepatic dysfunction within 42 days of drug administration for any of the quinolones monitored. No evidence was found of drug-induced dysrhythmic events associated with enoxacin within 42 days of drug administration. Of the other quinolones, 'atrial fibrillation' was reported most often within 42 days following ciprofloxacin administration, with no change in event rate over that time, crude relative risk (CRR)[W(1)/W(2)] 1.0 [95% confidence interval (CI) 0.02 to 8.92]. Other less serious events associated with dysrhythmia were reported with varying incidence within 42 days of quinolone administration. The crude rate of palpitation did not change significantly over that time for ciprofloxacin, ofloxacin and norfloxacin: CRR 0.83 (95% CI 0.02 to 6.86), 2.00 (95% CI 0.19 to 12.20) and 4.99 (95% CI 0.06 to 391.94), respectively. Syncope and tachycardia were also reported for ofloxacin [CRR 9.99 (95% CI 0.52 to 589.49 for both events)] and ciprofloxacin [1.0 (95% CI 0.02, 8.92)] and 2.50 (95% CI 0.04, 47.96) for syncope and tachycardia, respectively]. CONCLUSION: It cannot be ruled out that some rare hepatic and dysrhythmic events associated with quinolones may be drug related. The primary purpose of PEM is signal generation. Compared with the other quinolones, ciprofloxacin was associated with the highest number of reports of dysrhythmic cardiovascular events occurring within 42 days of administration. This requires further investigation by other types of epidemiological study.

Comparison of enoxacin versus trimethoprim-sulfamethoxazole in the treatment of patients with complicated urinary tract infection.

Given the prevalence of complicated urinary tract infection (UTI) and the resistance patterns of common uropathogens, antimicrobial therapy for complicated UTI must be carefully selected. For patients with complicated UTI who can be treated with oral medication, the quinolones or trimethoprim-sulfamethoxazole (TMP-SMX) are reasonable treatment choices. Enoxacin and TMP-SMX were compared for efficacy, safety, and bacteriologic response in this study. A total of 260 patients with complicated UTI were enrolled in a multicenter, open-label, randomized study and received enoxacin or TMP-SMX. Short-term assessments 5 to 9 days posttherapy and long-term assessments 4 to 6 weeks posttherapy included physical and clinical evaluations, laboratory testing, urine cultures, and susceptibility testing. Although enoxacin and TMP-SMX demonstrated comparable short-term efficacy rates, enoxacin exerted a potent, long-term bacteriologic response, particularly against Escherichia coli. Enoxacin therapy achieved a 94.7% long-term eradication rate against E coli compared with a 76.0% eradication rate against this pathogen with TMP-SMX. Most adverse events were mild, and a comparable incidence (approximately 17%) occurred in both treatment groups. These data indicate that enoxacin is an excellent addition to the armamentarium of agents commonly used in the treatment of patients with complicated UTI.

[Comparison of fluoroquinolones (norfloxacin, enoxacin, ofloxacin) in the therapy of lower urinary tract infections]. / Fluorochinoloni a confronto (norfloxacina, enoxacina, ofloxacina) nella terapia delle infezioni delle basse vie urinarie.

The present study was carried out to assess comparatively the effectiveness and tolerance of norfloxacin, enoxacin and ofloxacin in the treatment and prophylaxis of infections of the low urinary tract in non-hospitalised patients. Thirty patients presenting positive uroculture on clinical evidence of ongoing infection were treated. Doses were 400 mg b.i.d. for norfloxacin, and 300 mg b.i.d. for ofloxacin and enoxacin; duration of treatment was 7 days in treatment. The pathogen was eradicated in 94% of cases at the control carried out after 5 days from the end of treatment; in the follow-up at 20 days, recurrences or reinfections were observed in 30% of the cases, almost all of them consisting of complicated infections. Slight side-effects were observed in 8 patients. No significant differences in effectiveness or tolerance were reported between the 3 quinolones under study which are therefore considered reliable overall for urological treatment. The absence of greater side-effects is related to the restriction of indications and the brevity of the therapeutic cycles.

[Effect of fluoroquinolones made in China in the treatment of acute bacillary dysentery. A report of 212 cases].

212 cases of acute bacillary dysentery were treated with enoxacin and norfloxacin, another 15 cases were treated by chujunsheng. The cure rate in enoxacin group was 99.1%, in norfloxacin group 98.04% and in chujunsheng group 63.64%. The isolated pathogens were tested for susceptibility with disk diffusion and MIC determination. The results showed that both enoxacin and norfloxacin are better than gentamycin, ampicillin, chloramphenicol and trimethoprim-sulfamethoxazole. Side effects of enoxacin group and norfloxacin were noted in are 2.7% and 3.0% of the patients respectively. This study suggests that enoxacin and norfloxacin are highly effective, quite convenient for use and have few adverse reactions. They are considered to be drugs of choice for the treatment of acute bacillary dysentery.

[Clinical experience of enoxacin complicated urinary tract infection].

Enoxacin (ENX) was administered to 69 patients with complicated urinary tract infections (UTI). Clinical efficacy and safety were evaluated by the criteria proposed by the UTI Committee, Japan. The overall clinical efficacy was excellent in 60.9%, moderate in 10.1% and poor in 29% of the patients. Of the 76 strains isolated from the patients 61 strains (80.3%) were eradicated. Subjective side effect was observed in one patient who complained of slight nausea. No drug-related aggravation in the laboratory test was observed. These results showed that ENX was effective and safety for the treatment of complicated urinary tract infection.

[Convulsion following the combination of single preoperative oral administration of enoxacine and single postoperative intravenous administration of flurbiprofen axetil].

We experienced a case of convulsion following the combination of single oral administration of enoxacine before an emergency operation and single postoperative intravenous administration of flurbiprofen axetil. The patient was an 87-year-old female referred to our hospital for severe abdominal pain. She was diagnosed as having the strangulation ileus, then underwent the emergent operation of partial resection of the necrotic small intestine under general anesthesia. Unfortunately we did not know that she had temporarily received oral enoxacine 200 mg, a new quinolone, administered by the previous doctor on the day before the operation. After the operation, flurbiprofen axetil 50 mg, a nonsteroidal anti-inflammatory drug, was given intravenously in thirty seconds due to postoperative pain. One minute after administration of the drug, she immediately developed a convulsive fit, severe disturbance of consciousness and apnea. We then administered at once, a single dose of diazepam intravenously for convulsion treatment, kept her airway open and controlled her ventilation. Convulsion disappeared in a minute and her condition improved gradually. We suspect that convulsive seizure may have been induced by the drug interaction between single oral dose of enoxacine before the operation and single intravenous dose of flurbiprofen axetil after the operation. We also suspect that the serum concentration of enoxacine was kept high because of metabolic disturbance and renal dysfunction resulting from her old age and dehydration. This case suggests that medication before the emergency operation must be considered in anesthetic management because of the possible side effect such as convulsion induced by the drug interaction between neuquinolones and anti-inflammatory drugs.

Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.

Roflumilast is an oral phosphodiesterase 4 (PDE4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). It is metabolized by CYP1A2 and CYP3A4 to its primary metabolite, roflumilast N-oxide, through which >90% total PDE4 inhibitory activity (tPDE4i) is mediated. Fluoroquinolones, of which enoxacin is the most potent CYP1A2 inhibitor, are used to treat COPD exacerbations. This phase I, open, nonrandomized, fixed-sequence, 2-period study evaluated the effects of steady-state enoxacin on the single-dose pharmacokinetics of roflumilast and roflumilast N-oxide. Twenty healthy participants received roflumilast, 500 µg once daily, on days 1 and 12, and enoxacin, 400 mg twice daily, on days 7 to 18. Pharmacokinetic profiles were obtained for days 1 to 6 and 12 to 19. The safety and tolerability of all treatments were also assessed. In 19 evaluable participants, coadministration led to 56% higher mean systemic exposure, 20% higher mean peak concentrations, and 36% lower mean apparent oral clearance compared with roflumilast alone. For roflumilast N-oxide, 23% higher mean systemic exposure and 14% lower mean peak concentrations were seen after coadministration. Roflumilast was well tolerated both alone and in combination with enoxacin. A weak interaction was shown between roflumilast and enoxacin, as mean tPDE4i increased by 25%, but is unlikely to have clinical relevance.

Evaluation of Pharmasolve corneal permeability enhancement and its irritation on rabbit eyes.

The aim of this study was to explore the use of Pharmasolve as a new kind of permeability enhancer in ophthalmic drug delivery systems. The ocular irritation of different concentrations of Pharmasolve on rabbit eyes was evaluated in detail. Four drugs ranging from hydrophilic to lipophilic, namely ribavirin, puerarin, enoxacin, and ibuprofen, were used as model compounds to investigate the effects of different concentrations of Pharmasolve on the corneal permeability. The mechanism of ocular permeation enhancement of drugs by Pharmasolve was also discussed. The results showed that Pharmasolve presented no irritation when the concentration used was lower than 10%. Pharmasolve could enhance the ocular permeability of the four test drugs; the maximum enhancement in P(app) was 4.04, 2.76, and 2.67-fold for ribavirin, enoxacin, and puerarin, respectively; 2.5% (v/v) Pharmasovle increased the P(app) by about 1.47-fold for ibuprofen; which suggested that it would have a great potential to be used as a safe and effective penetration enhancer in ocular drug delivery systems in the future.

Quantitative comparison of the convulsive activity of combinations of twelve fluoroquinolones with five nonsteroidal antiinflammatory agents.

Concomitant administration of certain fluoroquinolone antimicrobials and nonsteroidal antiinflammatory agents (NSAIDs) induces serious convulsion in humans. There are differences in convulsive activity among fluoroquinolones and in the potentiation of fluoroquinolone-induced convulsion among NSAIDs, but a comprehensive, quantitative comparison has not been carried out. This study evaluates the inhibitory effects of twelve fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pazufloxacin, prulifloxacin, sparfloxacin, and tosufloxacin) alone or in the presence of an NSAID (4-biphenylacetic acid, diclofenac sodium, loxoprofen, lornoxicam or zaltoprofen) on the GABA(A) receptor binding of [(3)H]muscimol in an in vitro study using mice synaptic plasma membrane. The rank order of inhibitory effects of the fluoroquinolones was prulifloxacin asymptotically equal to norfloxacin > ciprofloxacin > or = enoxacin > gatifloxacin > or = ofloxacin asymptotically equal to tosufloxacin asymptotically equal to lomefloxacin > levofloxacin > or = sparfloxacin > or = pazufloxacin asymptotically equal to fleroxacin. 4-Biphenylacetic acid most potently enhanced the inhibitory effects of the fluoroquinolones, while zaltoprofen, loxoprofen, lornoxicam and diclofenac had essentially no effect. The clinical risk of convulsion for each combination was estimated using a pharmacodynamic model based on receptor occupancy using the in vitro data set obtained and pharmacokinetic parameters in humans collected from the literature. The combinations of 4-biphenylacetic acid with prulifloxacin and enoxacin were concluded to be the most hazardous.

Enoxacin photosensitivity.

A 71-year-old Korean farmer had pruritic erythematous patches on sun-exposed areas after enoxacin treatment for prostatitis. Suggestive features of photoallergy, such as moderate blurring of the margin and possible ectopic flare phenomenon, were reproduced by oral provocation test with enoxacin. Because all quinolones have structural similarities, and photosensitivity was observed in nalidixic acid and enoxacin, it would be advisable to warn all patients taking quinolones about photosensitivity.

Enoxacin relieves symptoms of recurrent urinary infections more rapidly than cefuroxime axetil.

In patients with a history of recurrent infections, treatment with enoxacin (200 mg/12 h for 3 days) relieved symptoms of acute urinary infection significantly more rapidly than treatment with cefuroxime axetil (125 mg/12 h for 7 days). Other parameters, including clinical and bacteriological cure rates and patients' overall opinion of their treatment, did not differ significantly between the treatments.

[The effectiveness of enoxacin for the treatment of complicated urinary tract infection]. / Studio sull'efficacia dell'enoxacina nel trattamento delle infezioni delle vie urinarie complicate.

In this study we evaluated the efficacy of enoxacin in treating complicated urinary tract infections (UTI). We isolated 21 bacterial strains from 20 enrolled patients and all the strains showed "in vitro" susceptibility to enoxacin. The most represented bacterial strain was E. coli (47.7%). After 48 hs and after 30 days from the end of the treatment, we observed clinical and bacteriological recovery in 65% and 55% of the patients, respectively. However, 6 out of the 20 patients (30%) interrupted the treatment due to mild-severe side effects. In conclusion, enoxacin showed a good antibacterial activity, but it could be necessary to lower daily dosage and to extend the treating period to prevent side effects.

Single-dose enoxacin compared with 3-day treatment for urinary tract infection.

Oral treatment of simple urinary tract infections generally involves 5 to 7 days of antibiotic therapy. This study with enoxacin, a new antibacterial agent of the quinolone-azaquinolone class, investigated the efficacy of a single dose compared with 3 days of treatment. A total of 154 outpatients with symptoms of simple cystitis were treated in an open randomized study with enoxacin, either one 600-mg dose or 200 mg twice a day for 3 days. A urine sample was collected for culture before treatment, 7 to 10 days after treatment, and 4 to 6 weeks after treatment. Seventy-three patients had positive bacterial cultures from the pretreatment urine sample; the predominant pathogen was Escherichia coli, along with a number of other gram-negative organisms and Staphylococcus spp. Of these patients, 33 received a single dose of enoxacin and 40 were treated for 3 days. Follow-up examination at 7 to 10 days showed negative urine cultures in 76% of patients from the single-dose group and 89% from the multiple-dose group, a difference that was not statistically significant (P = 0.665, Fisher's exact test). A number of patients were lost to follow-up at 4 to 6 weeks. However, of those who did attend, only three patients were shown to have relapsed or become reinfected (two in the multiple-dose group and one in the single-dose group). Enoxacin was well tolerated in both groups of patients; the few adverse events were mostly mild.

Enoxacin-induced photosensitivity: study of two cases.

Enoxacin is a second-generation quinolone derivative recently introduced in Spain. Its activity comes through the inhibition of bacterial DNA-gyrase and it has a good antibacterial capacity against a broad spectrum of gram-positive and gram-negative bacteria. It is presumed to be less toxic than the rest of the quinolones and its use is increasing, specially to treat infections of the urogenital tract. Cases of photosensitivity to enoxacin have been very rarely reported. We describe 2 patients with photosensitivity reactions due to this drug.