Perspective of CADD and AIDD in medicinal chemistry / 药学学报

Artificial intelligence-aided drug discovery (AIDD) is a new version of computer-aided drug discovery (CADD). AIDD is featured in significantly promoting the performance of conventional CADD. AI markedly enhances the learning ability of CADD. In the 1960s, CADD was established from conventional QSAR approaches, which mainly used regression approaches to derive substructure-activity relationship for compounds with a common scaffold, and guide drug molecular design, figure out the binding features of drugs, and identify potential drug targets. Since the 1990s, structural biology has provided three-dimensional structures of drug targets, enabling drug discovery based on target structure (SBDD), fragment-based drug discovery (FBDD), and structure-based virtual screening (SBVS) with CADD approaches. In the past 30 years, many first in class (FIC) and best in class (BIC) drugs were discovered with CADD. Now, AIDD will further revolutionize CADD by reducing human interventions and mining big chemical and biological data. It is expected that AIDD will significantly enhance the abilities of CADD, virtual screening and drug target identification. This article tries to provide perspectives of CADD and AIDD in medicinal chemistry with case studies.

Efficacy and safety of rifaximin in the prevention of spontaneous bacterial peritonitis: A Meta-analysis / 临床肝胆病杂志

ObjectiveTo evaluate the efficacy and safety of rifaximin in the prevention of spontaneous bacterial peritonitis (SBP). MethodsCNKI, Wanfang Data, CBM, PubMed, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) and cohort studies on rifaximin in the prevention of SBP published up to July 5, 2020. The articles were screened according to the inclusion and exclusion criteria, and data extraction and quality assessment were performed. RevMan 5.3 software was used to conduct the meta-analysis. Results A total of 13 studies (with 2207 patients in total) were included, among which there were 6 RCTs and 7 cohort studies. The results of the meta-analysis showed that compared with the non-prevention group, the rifaximin group had significantly lower incidence rate of SBP (odds ratio ［OR］=0.36, 95% confidence interval ［CI］: 0.14-0.96, P=0.04) and mortality rate (OR=0.59, 95% CI: 037-0.95, P=0.03); compared with the norfloxacin group, the rifaximin group had significantly lower incidence rate of SBP (OR=039, 95% CI: 025-0.62, P＜0.001), mortality rate (OR=0.55, 95% CI: 0.34-0.92, P=0.02), and adverse reactions (OR=0.36, 95% CI: 0.22-059, P＜0.001). The subgroup analysis based on the type of prevention showed that there was no significant difference in primary prevention between the two groups (OR=0.56, 95% CI: 0.23-1.35, P=0.20), and in secondary prevention, the rifaximin group had a significantly lower incidence rate of SBP (OR=0.18, 95% CI: 0.08-0.43, P＜0.001). In addition, it was also found that rifaximin significantly reduced the incidence rate of hepatorenal syndrome (OR=0.34, 95% CI: 0.15-0.77, P=0.01) and hepatic encephalopathy (OR=0.55, 95% CI: 0.32-0.95, P=0.03). ConclusionRifaximin is safe and effective for the primary and secondary prevention of SBP. Rifaximin is superior to norfloxacin in secondary prevention, which still needs to be confirmed by high-quality multicenter RCTs.

New Derivatives of (E)-3-(5-((substitutedphenylamino)methyl)-1,3,4-thiadiazol-2-yl)-2-styryl quinazolin-4(3H)-one: Searching for New Antifungal and Antibacterial Agents

Objective: The objective of the paper was to evaluate the antifungal and antibacterial potential of new derivatives of ((E)-3-(5-((substitutedphenylamino)methyl)-1,3,4-thiadiazol-2-yl)-2-styryl quinazolin-4(3H)-one. Materials and Methods: Various syntheses of (E)-3-(5-(substitutedaminomethyl)-1,3,4-thiadiazol-2-yl)-2-styrylquinazolin-4(3H)-one derivatives have been synthesized by reacting 2-substituted benzoxazin-4-one with (E)-2-(4-Substituedstyryl)-4H-benzo[d] [1,3]oxazin-4-one. All synthesized compounds have been characterized by the infrared, 1HNMR, and mass spectral analysis. Proposed compounds have been evaluated for antifungal and antibacterial activity. The antimicrobial activity of synthesized compounds (QNM-1 to QNM-15) has been carried through the serial dilution method. For bacterial screening, bacterial species were taken includes Staphylococcus aureus (MTCC-96), Bacillus subtilis (MTCC-441), Pseudomonas aeruginosa (MTCC-424), and Escherichia coli (MTCC-40). Norfloxacin (1-Ethyl-6-fluoro-1,4,dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid) was used as the standard drug for antibacterial study. For antifungal screening, the following fungal species were used includes Aspergillus niger (MTCC-281), Candida albicans (MTCC-227), and Fusarium oxysporum (MTCC-284). Clotrimazole was selected as a standard drug for antifungal study. Results and Discussion: QNM-1, QNM-2, QNM-3, QNM-5, QNM-7, QNM-9, QNM-12, QNM-14, and QNM-15 were the most active compounds [Table 1] in the synthesized series which were active against both Gram-positive and Gram-negative organisms by the antibacterial screening. In the case of antibacterial activity, the presence of electronegative group (Cl, Br, F, and NO2) at both R may enhance the activity when they are p-substituted, but the compounds QNM-6 (R1=-C6H5Br (o); Ar=-C6H5), QNM-10 (R1 = -C6H5F (o); Ar= -C6H5F), QNM-11 (R1 =-C6H5NO2 (p); Ar=-C6H5F), and QNM-4 (R1 =-C6H5F (m); Ar=-C6H5) with given substitution may result in diminishing the activity. In case of antifungal activity, compounds QNM-1, QNM-5, QNM-7, QNM-9, QNM-11, QNM-12, QNM-14, and QNM-15 were the most active compounds in the synthesized series which were active against both Gram-positive and Gram-negative organisms. In that series, compounds QNM-14, QNM-11, QNM-5, and QNM-7 have shown the highest activity. Compounds QNM-3, QNM-6, QNM-10, and QNM-13 have the least active. This result has also concluded that o-substituted compounds, i.e., -C6H5Cl(o), -C6H5Cl (m), -C6H5Br(o), -C6H5F (o), -C6H5F (p) at R1 position my resulted in diminishing or lower the activity

Survey Electrocoagulation Process in Removal of Norfloxacin Antibiotic from Aqueous Solutions

Pharmaceutical compounds have been recognized as a hazardous class of organic pollutants due to their long term effects towards the aquatic environment. The present work studies the efficiency of electrogalation (EC) process in removal Norfloxacin (NFX) from aqueous solutions by aluminum electrodes. This study experimentally was run in a batch electrochemical reactor (1.5 L glass beaker)and six electrodes which installed in parallel. In each of test, 1 L of wastewater added tothetest reactor, then effect of four parameters including the voltage 10-60 V (current density: 1,2,3 and 4 mA/cm2), reaction time (5-60 min) initial concentration of NFXand the pH of wastewater (pH=3-9) on process performance were investigated. Results of this study showed that the efficiency of the system could be promoted by increasing the contact time, initial pH of the solution, and the applied voltage. However, the efficiency of EC process has decreased, when higher level of NFX ions was presented in the aqueous phase.The optimal conditions for Norfloxacin removal were: pH 7, initial NFX concentration 25 mg/L, voltage 60 V and reaction time 45 min and the highest removal rate was under these conditions 98.4%. The results of this study indicate that EC process could be applied for the removal of NFX from aqueous solution with a high efficiency

Assessing The Rationale Of Fdc Containing Ofloxacin And Azoles: Dissolution, Permeation And Antimicrobial Studies

Objective: To study fixed-dose combinations (FDC) of antibacterial and antiprotozoal products (ofloxacin and azoles), prescribed for the treatment of diarrhea. Methods: Rationality of these FDC products was verified by assessing parameters such as drug content and release by assay and dissolution tests, respectively mentioned in the Indian Pharmacopoeia (IP). Amount of drug solubilized and permeated as per the Biopharmaceutics Classification System (BCS) was determined. Ex vivo permeation study was performed on the gut of goat using the everted gut sac technique. Antimicrobial efficacy in terms of minimum inhibitory concentration (MIC) was assessed using agar well diffusion method against Shigella boydii, the causative agent for diarrhea. Comparative studies were performed on an individual as well as combination doses of antibacterial and antiprotozoal products for the synergistic effects to assess the rationale of these FDC. Results: The BCS solubility of ciprofloxacin (CPX), norfloxacin (NFX) and tinidazole (TNZ) was high in acidic medium (pH 1-5) and decreased at pH above 5. The assay studies showed that the individual drug contents of FDC were within the IP limits. In vitro dissolution results for both, individual drugs and their combination illustrated 99 % drug release within 30 min in 0.01N HCl. Ex vivo permeation of TNZ was higher than CPX and NFX in individual drugs. No significant change in the permeation rate was observed for individual drugs and their FDC. CPX and NFX exhibited more antimicrobial activity in terms of inhibitory zones than their FDC with antiprotozoal TNZ, above 2.5 µg/ml MIC. The pharmaceutical, biopharmaceutical and antimicrobial evaluation study showed the similarity of FDC with the individual drugs. Conclusion: The study showed no significant data to justify the therapeutic advantage of FDC over individual drugs.

Bioequivalence of norfloxacin tablets in Chinese Healthy volunteers under Fasting and Fed Condition / 中国临床药理学与治疗学

AIM: To compare the bioavailability of norfloxacin tablets produced by Zhejiang Pharmaceutical Co., Ltd with the original product BACCIDAL, and to evaluate bioequivalence of two formulations, a randomized, open, two-cycle, self-crossing trial in healthy Chinese population was designed. METHODS: Under fasting and fed conditions, healthy volunteers were given a single dose of norfloxacin test or reference tablets for 100 mg. Liquid chromatography-mass spectrometry (LC-MS/MS) method were used to determine drug concentration in the plasma taken at different time points before and after dosing. Pharmacokinetic parameters and the bioequivalence of the two formulations were calculated by WinNonlin 7.0 software. RESULTS: A total of 28 healthy volunteers were enrolled and completed the fasting test. The pharmacokinetic parameters for test and reference preparations in fasting state were as follows: C

Influence Of Binding Solution Concentration, Drying Duration And Drying Temperature On Physiochemical Performance Of Norfloxacin Granules And Tablets

Objective: To investigate the possible individual and joined influences that binding solution concentration, drying temperature and drying duration might have on the physiochemical attributes of granules and tablets using norfloxacin as a model drug. Methods: According to implemented 23 central composite designs, each of the investigated variables were examined at 5 different levels through different 16 formulation runs. For each formulation, obtained granules were qualified for their bulk density, tap density, Hausner ratio, percent of fine and drug content properties whereas the respective tablets were evaluated for their weight variation, drug content, friability, hardness, disintegration, and drug dissolution attributes. Results: Indicated that concentration of binder solution, as compared to drying temperature and drying duration, measured more profound influences on granules' tap density, Hausner ratio, % fine and drug content either through its individual linear and quadratic effects or through its joint effect with drying durations (p<0.05 at 95% CI for all influences). Whilst tablets' friability appeared to be noticeably influenced by the three investigated variables (P ranged 0.001-0.017 at 95% CI), tablets' hardness and disintegration were found to be considerably affected only by binder solution concentration (p = 0.001 and 0.082 at 95% CI, respectively). Moreover, none of the investigated variables has measured a significant influence on tablets' drug content or drug dissolution properties. Conclusion: The study concluded that quadratic and joint influences of variables on attributes of granule and tablet formulations shouldn't be overlooked and better to be considered in the screening design.

Quantification of norfloxacin in human plasma by LC-MS/MS and validation of the analytical method / 药学学报

A LC-MS/MS method for quantification of norfloxacin in human plasma had been developed. This method was applied to the pharmacokinetics study of norfloxacin in the human. The plasma sample was precipitated by methanol and ciprofloxacin was used as the internal standard (IS). Chromatographic separation was performed on a Symmetry® C18 column(100 mm×4.6 mm, 5 μm). Mobile phase contains 0.3% formic acid and 5% methanol in deionized water at a flow rate of 0.45 mL·min-1. Norfloxacin and ciprofloxacin (IS) were ionized with an ESI source and operated in positive ion mode. The detected ions were m/z 320.3→302.1 (norfloxacin), m/z 332.3→314.1 (ciprofloxacin). This LC-MS/MS method yielded a linearity over the range of 10-1 000 ng·mL-1 with the lower limit of quantitation (LLOQ) of 10 ng·mL-1. The intra and inter-assay precisions (RSD%) were within the range of 2.64%-7.23% and the accuracy (RE%) was less than ±5.00%. The pharmacokinetic parameters tmax, Cmax, AUC0-t, and t1/2 were 1.28±0.364 h, 627±171 ng·mL-1, 2 938±850 h·ng·mL-1, and 6.01±1.36 h, respectively. This LC-MS /MS method was proven simple, sensitive, rapid and suitable for pharmacokinetics study of norfloxacin in the human and Approved by the Medical Ethics Committee of Liuzhou Workers' Hospital.

Effect of trimethoprim-sulfamethoxazole vs. norfloxacin on fecal E. coli resistance pattern and efficacy in patients receiving prophylaxis for spontaneous bacterial peritonitis

Background: Spontaneous Bacterial Peritonitis (SBP) is an infection of ascitic fluid. It is highly mortal and recurrent condition, so prophylaxis with Norfloxacin (NOR) or Trimethoprim-sulfamethoxazole (TMP-SMX) seems to play an important role in the prevention of further episodes of SBP. Aims of the study were to assess the effect of TMP-SMX/NOR on the sensitivity pattern of fecal E. coli after long term prophylaxis in Spontaneous Bacterial Peritonitis (SBP) and to compare the efficacy of TMP-SMX and NOR in prophylaxis of SBP.Methods: An interventional, prospective, open label, single center study conducted in Maulana Azad medical college, New Delhi, India. 52 patients of SBP or with high risk of SBP were screened and finally 39 patients were recruited. Stool sensitivity testing of fecal E. coli was done and they were divided into TMP-SMX group(n=18) and NOR group(n=21) according to sensitivity. After 45±3 days (7 weeks) their stool sample was re-examined for change sensitivity pattern of E. coli. Efficacy variables like any episode of SBP, fever (FEV) resolution of ascites (ASC), bacteremia (BACT), extraperitoneal infection (EPI), liver transplantation (LT) or death (D) were noted throughout the period of 24 weeks.Results: Resistance developed in 60% vs. 48% in TMP-SMX vs. NOR group(p=0.46) after 45 days of prophylaxis. By the end of 24 weeks, Incidence of SBP (29%vs. 25%, p>0.99), episodes of FEV(P=0.60), EPI(p>0.99), ASC(p>0.99) and death (14% vs. 16%, p>0.99) were almost similar in both the groups (TMP-SMX vs. NOR) respectively.Conclusions: Both TMP-SMX and NOR showed same degree of resistance and found equi-efficacious when administered as long-term prophylactic therapy in SBP. TMP-SMX can be a suitable as well as cost effective alternative to NOR for the prophylaxis of SBP.

Prevalencia de infección de la vía urinaria y perfil microbiológico en mujeres que finalizaron el embarazo en una clínica privada de Lima, Perú / Prevalence of urinary tract infection and microbiological profile in women who end their pregnancy in a private clinic in Lima, Peru

Resumen Objetivo: Describir la prevalencia de infección de la vía urinaria en mujeres que finalizaron el embarazo en una clínica privada (nivel II-2) de Lima, Perú, además de conocer el perfil microbiológico e identificar la resistencia a los antibióticos. Materiales y métodos: Estudio retrospectivo, observacional y transversal efectuado en pacientes que finalizaron el embarazo en la Clínica Jesús del Norte del distrito de Independencia de Lima, Perú, entre enero de 2016 y diciembre del 2017. Criterio de inclusión: pacientes con al menos seis citas médicas de control prenatal en la clínica. Se obtuvo el resultado de los urocultivos y el de resistencia a los antibióticos. Se buscaron medidas de tendencia central como promedios, desviación estándar y frecuencias. Resultados: Se registraron 1455 pacientes que cumplieron con el criterio de inclusión; de éstas 108 (7.4%) tuvieron infección de la vía urinaria con urocultivo positivo. El microorganismo aislado con más frecuencia fue Escherichia coli en 70 (63.6%) casos, con resistencia a ampicilina (60.8%), ciprofloxacina (34.7%) y norfloxacina (34.7%), y sensibilidad a amikacina, nitrofurantoína y cefuroxima. En 13 (11.8%) pacientes también se identificó Escherichia coli y enterobacterias productoras de betalactamasas de espectro extendido resistentes a cefalosporinas. Conclusión: La prevalencia de infección de la vía urinaria estuvo dentro del valor de referencia expresado en los reportes internacionales (7.4%). Los microorganismos aislados con mayor frecuencia fueron E. coli y E. coli productora de betalactamasas de espectro extendido.

Abstract Objective: To describe the prevalence of urinary tract infections (UTI) and their microbiological profile in pregnant women attended in a private clinic of level II-2 of Lima, Peru. Materials and methods: An analytical cross-sectional observational study was conducted, in women they had their delivery in a private clinic during January 2016 to December 2017. Inclusion criteria were those who had at least 06 prenatal care. Results of urocultures and their respective antibiotic resistance were obtained. In the statistical analysis, central tendency measures such as averages, standard deviation and frequencies were found. Results: 1455 met the selection criteria. We found 108 patients (7.4%) with UTI with a positive urine culture. The 70 cases (63.6%) were Escherichia coli resistant to antibiotics such as: ampicillin (57.6%), ciprofloxacin (30.7%) and norfloxacin (30.7%), and sensitive to: amikacin, nitrofurantoin and cefuroxime. However, was is found that 13 (11.8%) had Escherichia coli BLEE resistant to cephalosporins. Conclusion: The prevalence of urinary infection was within what was expected in relation to international reports. The most commonly isolated uropathogen was Escherichia coli, followed by Escherichia coli BLEE.

Preparation and in vitro Release of Norfloxacin Thermosensitive in Situ Gel for Vaginal Use / 中国药师

Objective:To prepare norfloxacin thermosensitive in situ gel and investigate its in vitro drug release behavior. Meth-ods:Poloxamer 407 and poloxamer 188 were used as the matrix of norfloxacin thermosensitive in situ gel,and the gel was prepared by a cold dissolving method. The formula was optimized by a central composite design-response surface method. In vitro drug release be-havior of norfloxacin thermosensitive in situ gel was studied as well. Results:Within a certain concentration range, the gelation tem-perature decreased gradually with the amount increase of poloxamer 407, and that increased gradually with the amount increase of poloxamer 188. The optimal formula was as follows:the concentration of poloxamer 407 was 20.6%(w/v),and that of poloxamer 188 was 5.7%(w/v),which obtained suitable gelling temperature. The release of norfloxacin from the thermosensitive in situ gel reached up to (87.5% ± 5.4% 7 in 6 h. Conclusion: Norfloxacin thermosensitive in situ gel has excellent temperature sensitivity, and can slow down the drug release,which shows potential use for vaginal drug delivery system.

A simple and sensitive method for determination of Norfloxacin in pharmaceutical preparations / Um método simples e sensível para determinação da norfloxacina em preparações farmacêuticas

In this approach, a new voltammetric method for determination of norfloxacin was proposed with high sensitivity and wider detection linear range. The used voltammetric sensor was fabricated simply by coating a layer of graphene oxide (GO) and Nafion composited film on glassy carbon electrode. The advantage of proposed method was sensitive electrochemical response for norfloxacin, which was attributed to the excellent electrical conductivity of GO and the accumulating function of Nafion under optimum experimental conditions, the present method revealed a good linear response for determination of norfloxacin in the range of 1×10^-8mol/L-7×10^-6 mol/L with a detection limit of 5×10^-9 mol/L. The proposed method was successfully applied in the determination of norfloxacin in capsules with satisfactory results...

Propos-se, por essa abordagem, novo método voltamétrico, com alta sensibilidade e faixa linear de detecção mais ampla, para a determinação de norfloxacino. O sensor voltamétrico utilizado foi fabricado simplismente por cobertura de camada de óxido de grafeno (GO) e filme de Nafion em eletrodo de cabrono vítreo. A vantagem do método proposto foi a resposta eletroquímica sensível para o norfloxacino, atribuída à condutividade elétrica excelente do GO e à função acumulada do Nafion. Sob condições experimentais ótimas, o presente método revelou boa resposta linear para a determinação do norfloxacino na faixa de limite de detecção de 1×10^-8mol/L-7×10^-6 mol/L. O método proposto foi aplicado com sucesso na determinação de norfloxacino em cápsulas, com resultados satisfatórios...

Development and validation of a rapid turbidimetric assay to determine the potency of norfloxacin in tablets

Norfloxacin is one of the first commercially available (and most widely used) fluoroquinolone antibiotics. This paper reports the development and validation of a simple, sensitive, accurate and reproducible turbidimetric assay method to quantify norfloxacin in tablets formulations in only 4 hours. The bioassay is based on the inhibitory effect of norfloxacin upon the strain ofStaphylococcus epidermidis ATCC 12228 IAL 2150 used as test microorganism. The assay was performed 3x3 parallel lines like, three tubes for each concentration of reference substance and three tubes for each sample concentration. The results were treated statistically by analysis of variance and were found to be linear (r2 = 0.9999) in the selected range of 25-100 μg mL-1; precise (intra-assay: relative standard deviation (RSD) = 1.33%; inter-assay: RSD = 0.21%), accurate (100.74%) and robust with RSD lower than 4.5%. The student's t-test showed no statistically significant difference between the proposed turbidimetric method and an HPLC method previously validated. However the turbidimetric assay can be used as a valuable alternative methodology for the routine quality control of this medicine, complementary to other physical-chemical methods.

O norfloxacino foi a primeira fluorquinolona (e mais utilizada) disponível no mercado. Este trabalho divulga um novo desenvolvimento e validação de um método turbidimétrico simples, sensível, preciso e reprodutível para a quantificação de norfloxacino em comprimidos em apenas 4 horas. O bioensaio é baseado no efeito inibitório de norfloxacino sobre a cepa Staphylococcus epidermidis ATCC 12228 IAL 2150, utilizada como micro-organismo teste. O bioensaio foi efetuado através do delineamento de linhas paralelas 3x3, em que três tubos foram utilizados para a solução padrão e três tubos para as concentrações da amostra. Os resultados foram tratados estatisticamente pela análise de variância, apresentando coeficiente de correlação linear der2 = 0,9999, na faixa de 20 a 100 μg mL-1; precisão (intra-ensaio: desvio padrão relativo (RSD) 1,33%; inter-ensaio: RSD=0,21%), exatidão (100,74%) e robustez com RSD menor que 4,5%. O teste-tmostrou não haver diferença estatisticamente significativa entre o método turbidimétrico proposto e um método por HPLC previamente validado. No entanto, o ensaio turbidimétrico pode ser utilizado como método alternativo para o controle de qualidade de rotina para este antimicrobiano, como um complemento de outros métodos físico-químicos.

Determination of Related Substances in Norfloxacin Glutamate and Sodium Chloride Injections / 中国药师

Objective:To detect the related substances in norfloxacin glutamate and sodium chloride injections on the basis of nor-floxacin related substances analysis method described in Chinese Pharmacopoeia 2010 edition to establish a more scientific and feasible method. Methods:HPLC was performed under the following conditions:a Diamonsil C18(2)(250 mm ×4.6 mm,5μm) column, mo-bile phase A of 0. 025 mol·L-1 phosphoric acid-acetonitrile(87∶13), phase B of acetonitrile, with gradient elution at a flow rate of 1. 0 ml·min-1 , the detection wavelength of 278nm and 262nm, the injection volume of 20 μl, and the column temperature of 25℃. Results:Under the HPLC conditions, the samples had good stability and separation. An excellent linear relationship was achieved within the range of 0. 032-3. 179μg·ml-1(r=1. 000 0),the detection limit of impurity A was 0. 159 ng,and the average recovery was 98. 3% with RSD of 0. 64%(n=9). Conclusion:Compared with the existing methods, the gradient elution method is accurate, sen-sitive, specific and reproducible, and can be used in the determination of related substances in norfloxacin glutamate and sodium chlo-ride injections.

Simultaneous determination of seven antimicrobial agents in adulterated herbal medicines for relieving cough and asthma by HPLC-DAD / 中国药学杂志

OBJECTIVE: To establish a method for simultaneous determination of seven antimicrobial agents (sulfadiazine, pipe-midic acid, trimethoprim, sulfamethazine, ofloxacin, norfloxacin and sulfamethoxazole) in adulterated Chinese patent medicines for relieving cough and asthma. METHODS: The analysis was performed on a Venusil MP C18 column (4.6 mm × 250 mm, 5 μm) with a gradient elution (0-10 min, 10% A; 10-40min, 10% A → 40% A) of acetonitrile-methanol(1:1) (A)-0.3% ammonium formate solution containing 0.1% formic acid (B) with a flow rate of 1 mL · min-1. The detection wavelength was 280 nm, reference wavelength was 360 nm, and the scanning range was from 190 to 400 nm. The column temperature was 30°C. RESULTS: Sulfadiazine, pipemidic acid, trimethoprim, sulfamethazine, ofloxacin, norfloxacin and sulfamethoxazole had good linearities in the range of 1.4-18.0 μg · mL-1(r=1.0000), 1.4-17.6 μg · mL-1 (r=0.9997), 2.4-30.0 μg · mL-1 (r=0.9998), 1.5-19.2 μg · mL-1 (r=1.0000), 2.6-32.8 μg · mL-1 (r=0.9996), 2.0-24.4 μg · mL-1 (r=1.0000) and 1.4-17.6 μg · mL-1 (r=1.0000), respectively. The recoveries of high, median, and low concentrations control samples were 94.5%-100.6%, 90.3%-98.3%, 93.5%-98.0%, 95.1%-101.7%, 92.8%-103.1%, 93.2%-100.9% and 95.5%-106.3%, respectively. The test result of three batches of negative samples was negative, and the test result of three batches of analog positive samples was positive. Trimethoprim and sulfamethoxazole were found in three batches of counterfeit drugs. CONCLUSION: The method can be used for examining seven antimicrobial agents in adulterated Chinese patent medicines.

Efflux-mediated resistance identified among norfloxacin resistant clinical strains of group B Streptococcus from South Korea / 한국역학회지

OBJECTIVES: Group B Streptococcus (GBS), a common bowel commensal, is a major cause of neonatal sepsis and an emerging cause of infection in immune-compromised adult populations. Fluoroquinolones are used to treat GBS infections in those allergic to beta-lactams, but GBS are increasingly resistant to fluoroquinolones. Fluoroquinolone resistance has been previously attributed to quinolone resistance determining regions (QRDRs) mutations. We demonstrate that some of fluoroquinolone resistance is due to efflux-mediated resistance. METHODS: We tested 20 GBS strains resistant only to norfloxacin with no mutations in the QRDRs, for the efflux phenotype using norfloxacin and ethidium bromide as substrates in the presence of the efflux inhibitor reserpine. Also tested were 68 GBS strains resistant only to norfloxacin not screened for QRDRs, and 58 GBS strains resistant to ciprofloxacin, levofloxacin or moxifloxacin. Isolates were randomly selected from 221 pregnant women (35-37 weeks of gestation) asymptomatically carrying GBS, and 838 patients with GBS infection identified in South Korea between 2006 and 2008. The VITEK II automatic system (Biomerieux, Durham, NC, USA) was used to determine fluoroquinolone resistance. RESULTS: The reserpine associated efflux phenotype was found in more than half of GBS strains resistant only to norfloxacin with no QRDR mutations, and half where QRDR mutations were unknown. No evidence of the efflux phenotype was detected in GBS strains that were resistant to moxifloxacin or levofloxacin or both. The reserpine sensitive efflux phenotype resulted in moderate increases in norfloxacin minimum inhibitory concentration (average=3.6 fold, range=>1-16 fold). CONCLUSIONS: A substantial portion of GBS strains resistant to norfloxacin have an efflux phenotype.

Urinary Tract Infections Associated with Escherichia Coli: A 2005 to 2009 Clinical Assessment of Trends in Fluoroquinolones Activities in Maiduguri-City, Nigeria.

Urinary Tract Infections caused by Escherichia coli were investigated for infectivity patterns, trends in sensitivity to fluoroquinolones, multi-fluoroquinolone resistant pattern and the fluoroquinolones’ inter-activities relation. 1590 patients (785/805 male/female) with clinical symptoms suggestive of UTI and confirmed with microbiological assay of the mid-stream of early morning urine specimens were surveyed. Isolated pathogens were cultured and sensitivity tests were performed. UTI cases increased by 17.7% between 2005 and 2009 with Escherichia coli accounting for 41% and showing an increase from 5.7% in 2005 to 28.0% in 2009 and a significant correlation (P<0.05). E. coli-UTIs were higher in females (56.6%) than males (43.4%). Pathogen’s susceptibility to agents varied but the activities of ciprofloxacin, ofloxacin, pefloxacin and nalidixic acid against E. coli recorded significant yearly decrease (P<0.05). The overall susceptibilities of E. coli were 71%, 58%, 48%, 34% and 15% for ofloxacin, ciprofloxacin, pefloxacin, norfloxacin and nalidixic acid respectively. About 35% of ciprofloxacin-resistant E. coli indicated sensitivity to ofloxacin whereas only 20% was the converse. Multifluoroquinolones- resistant cases (282, 43.6%) were observed in E. coli which increased from 30.2% in 2006 to 57.5% in 2009. The study observed a rapid and progressive loss of activities of quinolones, increasing multifluoroquinolone- resistant, high resistance rates and poor inter-activities relations between the fluoroquinolones against E. coli in the region.

Efficacy and safety of Fosfomycin trometamol in elderly diabetic patients with acute urological tract infections / 中华泌尿外科杂志

Objective To evaluate the efficacy and safety of Fosfomycin trometamol(FMT)versus Norfloxacin(FPA)in elderly diabetic patients with acute urological tract infections.Methods From Jan.2012 to Mar.2013,eighty-six patients with uncomplicated and complicated urinary tract infection were randomized into FMT group(n =43)and FPA group(n =43).Patients in both groups were balanced with regard to baseline urinary tract symptoms,fever,leukocytosis,positive urinary culture and disease type(P＞0.05).Patients received FMT 3 g daily and Norfloxacin 0.4 g twice daily for a week.Extended treatment was given to 35 patients not cured within a week.Total treatment course should not exceed two weeks.Patient's symptoms,signs,complete blood count,urinalysis,urine culture,pharmacological sensitivity tests,renal and liver function tests were performed.Results After one week of FMT treatment,28(65.1％)cases were cured and 10 cases were improved(1 was with abnormal urinalysis,9 had positive urine culture).In total,in 38(88.4％)patients treatment was as effective;In FPA group,23(53.5％)were cured and 7 cases were improved(7 had positive urine culture).In total,there were 30(69.8％)patients classified as effective.Difference was statistically significant(P＜0.05 =.After 2 weeks of FMT treatment,38(88.4％)cases were cured and 2 patients were improved(1 was with abnormal urinalysis,1 had positive urine culture).In total,40(93.0％)patients were classified as effective.In FPA group,25(58.1％)cases were cured and in 8 patients were improved(8 had positive urine culture).In total,there were 33(76.7％)patients classified as effective;Difference was statistically significant(P＜0.05 =.Bacterial clearance rate in FMT and FPA group was 88.9％ and 72.7％,respectively.Difference was statistically significant(P＜0.05 =.The adverse reaction rates were 9.3％ and 14.0％,respectively.Difference was not statistically significant(P＞0.05).Conclusions FMT is an effective and safe antibiotic in the treatment of urinary tract infections in elderly diabetic patients.

Formulation and evaluation of Norfloxacin gastro retentive drug delivery systems using natural polymers.

Gastric retentive floating drug delivery system (GFDDS) is enabled the prolonged continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improves the bioavailability of medications with narrow absorption window. The design of the delivery system is based on the controlled release formulation with floating and swelling features in order to prolong the gastric retention time of the drug delivery systems. In the present study norfloxacin as candidate, guar gum, sodium CMC, HPMC15 KM is studied along with other excipients like PVP K30 (binder), sodium bicarbonate microcrystalline cellulose were used in different concentrations to get the desired controlled release profile over a period of 12 hrs. All the formulations were evaluated for buoyancy lag time, duration of buoyancy, dimensional stability, drug content and in vitro drug release profile. Based on the in vitro studies carried out for the optimized formulation by dissolution the performance of the developed formulation promises to be efficient in controlling the drug release rate with the guar gum , a natural polymer.

Comparative in vitro antibacterial activities study of some mucoadhesive polymeric suspensions containing fluoroquinolones.

To study in vitro antibacterial activities of mucoadhesive suspensions containing Norfloxacin, Ciprofloxacin and Ofloxacin, three different formulations of each drug were prepared by using three polymers, such as Hydroxypropyl methylcellulose (HPMC), Carbapol934 (C934) and Carbapol940 (C940), along with some common ingredients (bases). For the antibacterial activities study of the samples, agar well diffusion method was performed taking Staphylococcus aureus (ATCC 25923), Bacillus subtilis and Escherichia coli (ATCC 25922). Considering the overall antibacterial activities, it could be mentioned that HPMC containing formulations were superior to others in most of the cases. Amongst C934 and C940 containing suspensions, the former was more potent than the later. Antibacterial activities of most of the formulations were either more effective or similar to those of corresponding drugs in water against the strains used in the study. Only few formulations were inferior to the corresponding drugs in water. Ciprofloxacin in citrate buffer was not better than Ciprofloxacin containing suspensions. Samples like both marketed suspensions and discs of different drugs were inferior to all the formulations and corresponding drugs in water/Ciprofloxacin in citrate buffer. The negative controls of the study, i.e., the different bases, distilled water and citrate buffer did not show any antibacterial activity.