[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.

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.

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.

A randomized controlled trial (volunteer study) of sitafloxacin, enoxacin, levofloxacin and sparfloxacin phototoxicity.

BACKGROUND: Fluoroquinolone antibiotics (FQs) are associated with phototoxic skin reactions following exposure to sunlight. OBJECTIVES: We aimed to compare the phototoxic potential of sitafloxacin, a novel FQ with three others: sparfloxacin, enoxacin, levofloxacin and placebo in Caucasian volunteers. In a second study, two dosage regimens of sitafloxacin were compared with placebo in Oriental subjects. METHODS: Randomized, placebo-controlled, assessor-blinded clinical trial. In 40 healthy Caucasians, sitafloxacin 100 mg twice a day (n = 8), sparfloxacin 200 mg day-1 (n = 8), enoxacin 200 mg three times a day (n = 8), levofloxacin 100 mg three times a day (n = 8) and placebo (n = 8) were given in oral doses for 6 days. In the second study, sitafloxacin 50 mg and 100 mg, both twice daily, were compared with placebo in 17 healthy Oriental subjects. Using an established monochromator technique, baseline threshold erythema levels were established pre-drug and on-drug. The phototoxic index (PI) baseline, minimal erythema dose (MED) divided by on-drug MED for each medication at each wavelength was determined and related to sitafloxacin peak plasma levels. The duration of susceptibility to phototoxicity was assessed by repeat phototesting daily after stopping medication. RESULTS: In the Caucasian study, sitafloxacin 100 mg twice a day produced mild ultraviolet (UV) A-dependent phototoxicity (median PI = 1.45) at 365 +/- 30 nm (half-maximum bandwidth), maximal at 24 h with normalization by 24 h postdrug cessation. The sparfloxacin group experienced severe phototoxicity maximal at 24 h and, unusually for an FQ, extended in the visible region (430 +/- 30 nm), maximal at 400 +/- 30 nm (median PI = 12.35) with abnormal pigmentation at on-drug phototest sites lasting, although fading, for up to 1 year. Enoxacin showed UVA-dependent phototoxicity (335-365 +/- 30 nm) median PI 3.94 (at 365 +/- 30 nm) returning to normal 48 h after stopping the drug. Fading pigmentation at phototoxic sites also lasted up to 1 year. Phototoxicity was not detected in the levofloxacin or placebo groups. In the Oriental study, no clinically relevant phototoxicity was seen with either sitafloxacin or placebo groups. CONCLUSIONS: We conclude that 100 mg twice a day sitafloxacin in Caucasians is associated with a mild degree of cutaneous phototoxicity. Enoxacin 200 mg three times a day and sparfloxacin 200 mg day-1 are much more photoactive. Sparfloxacin phototoxicity is induced by UVA and visible wavelengths. Levofloxacin and placebo failed to show a phototoxic effect. In the Oriental study, sitafloxacin 50 mg twice a day and 100 mg twice a day failed to demonstrate a clinically significant phototoxic effect.

[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.

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.

Can quinolones cause hemorrhagic colitis of late onset? Report of three cases.

PURPOSE: This study was undertaken to demonstrate that quinolones may cause acute colitis resembling penicillin-induced hemorrhagic colitis. METHODS: We reviewed the medical records of patients with acute colitis in our institutes. Twenty-eight patients with acute hemorrhagic colitis in which no pathogenic microorganisms were identified were the subjects of this study. Pseudomembranous colitis caused by Clostridium difficile was excluded. Ulcerative colitis, Crohn's disease, and radiation proctocolitis were also excluded. RESULTS: Among these patients, 25 had a history of recent administration of penicillin derivatives. The remaining three patients had never been given any penicillin derivatives, but had ingested quinolones approximately four weeks before the developing colitis had been identified. Klebsiella oxytoca was also isolated in these three patients. CONCLUSIONS: Quinolones may cause acute hemorrhagic colitis. The time interval from antibiotic ingestion to onset of the condition may be much longer in quinolones than in penicillin derivatives.

Role of nitric oxide in the convulsions following the coadministration of enoxacin with fenbufen in mice.

Effects of nitric oxide (NO) synthase inhibitors on the enoxacin-induced convulsions were examined in mice pretreated with fenbufen. 7-nitroindazole markedly suppressed the incidence of convulsions, whereas L-arginine did not modify the convulsions at all. The suppression of the convulsions by 7-nitroindazole was not reversed by the pretreatment of L-arginine. Brain NO synthase activity was significantly raised at 30 min after enoxacin when combined with fenbufen. The increased NO synthase activity was found to be suppressed by the pretreatment of 7-nitroindazole. These findings suggest that endogenous NO may be involved as a proconvulsant substance in the development of enoxacin-induced convulsions in mice pretreated with fenbufen.

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.

In vitro phototoxic activities of new quinolone antibacterial agents: lipid peroxidative potentials.

To determine the fundamental photochemical properties of new quinolones that can induce photosensitivity, the in vitro phototoxicity of these drugs (enoxacin, norfloxacin, ofloxacin, ciprofloxacin, and lomefloxacin) was examined with respect to photosensitizing ability to peroxidize unsaturated lipid squalene in ethanol solution. Lomefloxacin and ciprofloxacin showed the highest efficiency in sensitization of peroxidation of the lipid. Moderate repression of peroxidation occurred by addition of sodium azide (a quencher of singlet molecular oxygen), suggesting that the nonsinglet oxygen mechanism is operative in addition to the singlet oxygen mechanism.

Preparation of microcapsules masking the bitter taste of enoxacin by using one continuous process technique of agglomeration and microencapsulation.

In order to mask the bitter taste of drugs, a novel microencapsulation process combined with the wet spherical agglomeration (WSA) technique was developed by using a modified phase separation method. The spherical agglomerates of enoxacin (ENX) with various additives including disintegrants were successfully produced in the system of acetone-n-hexane-ammonia water or acetone-n-hexane-distilled water by the WSA, using flocculation phenomena of particles in liquid. Resultant agglomerates could be microencapsulated continuously with Eudragit RS utilizing the phase separation method in the same system as agglomeration under stirring. 'Explosible' microcapsules which were free from the bitter taste could be produced in formulating finer particle size of ENX and 50 per cent of Primojel in core agglomerates, using distilled water as a bridging liquid, and treating with 20 per cent polymer coating level. These microcapsules were bioequivalent to the commercial ENX 100 mg tablets in beagle dogs. One continuous process technique of agglomeration and microencapsulation was useful for the design of ENX powders which masked the bitter taste and controlled the drug release rate.

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.

Oral enoxacin for infection prevention in adults with acute nonlymphocytic leukemia. The Enoxacin Prophylaxis Study Group.

A randomized, double-blind, placebo-controlled trial was conducted in eight hematologic units to determine the efficacy and safety of oral enoxacin for infection prevention in adult patients with acute nonlymphocytic leukemia. One hundred nineteen patients undergoing remission induction or consolidation chemotherapy were enrolled; 62 of them received enoxacin (400 mg orally every 12 h). Patients received antifungal prophylaxis with oral mycostatin (1,000,000 U four times daily) or clotrimazole (1 troche five times daily). Analysis was performed on an intent-to-treat basis. There was no significant difference between groups in race, age, or type and stage of leukemia, but there were more males in the placebo group (P = 0.073 [Fisher's exact test]). Fewer enoxacin patients had gram-negative bacteremia (1 versus 14 [P < 0.001]), gram-negative infection at any site (2 versus 19 [P < 0.001]), or bacterial and/or fungal infection (17 versus 26 [P = 0.056]). There was no significant difference in the number of patients with gram-positive infection at any site (12 versus 16), gram-positive bacteremia (9 versus 10), deep fungal infection (6 versus 2), death (2 versus 3), other antimicrobial therapy required (48 versus 48), therapy with amphotericin B (15 versus 7 [P = 0.105]), any adverse event (45 versus 36), or any study drug-associated adverse events (13 versus 6). Logistic regression confirmed (odds ratios and 95% confidence intervals are given in parentheses) that enoxacin reduced the risk of gram-negative infection (0.07; 0.01 to 0.30), especially gram-negative bacillary bacteremia (0.05; 0.01 to 0.37), without altering the risk of gram-positive bacterial (0.63; 0.26 to 1.5), deep fungal (2.57; 0.47 to 13.9), or Clostridium difficile (1.16; 0.3 to 4.56) infection. The median time to the onset of fever of more than or equal 102.8 F (39.3 degree C) was 32 days for the enoxacin group versus 15 days for patients receiving placebo (P=0.0007 [Wilcoxon test]). In patients with acute nonlymphocytic leukemia, oral enoxacin prevents gram-negative infections, delays the onset of fever, does not alter the incidence of gram-positive or proven deep fungal infections, and is well tolerated.