Quinolones Research Papers - Academia.edu (original) (raw)

Background: This analysis was designed to assess the efficacy and safety of aripiprazole compared with placebo in subpopulations of patients with acute manic or mixed episodes of bipolar I disorder. Methods: Acutely manic patients experiencing DSM-IV manic/mixed episodes of bipolar I disorder were pooled from two randomized, three-week, flexible-dose, double-blind, placebo-controlled trials (N = 516) and stratified by disease severity (Young Mania Rating Scale, YMRS), episode type, presence or absence of psychotic features, episode frequency, age, gender, and baseline severity of depressive symptoms. Safety and treatment-emergent adverse-event analyses were also performed. Results: Aripiprazole significantly reduced mean YMRS total scores at end point compared with placebo in patients with more severe or less severe illness, with mixed or manic episodes, with or without psychotic features, or with a history of rapid or nonrapid cycling (p b 0.01 for each subpopulation); in men and women (p = 0.001 for both); in patients in the 18-40 and 41-55 year age groups (p ≤ 0.001 for both); and in three subgroups stratified by baseline severity of depressive symptoms using the Montgomery-Åsberg Depression Rating Scale (p b 0.05). The treatment-emergent adverse events reported in ≥ 5% of patients aged 18-40 years receiving aripiprazole were similar to those reported for the overall population. Limitations: This post hoc analysis utilized pooled data from two short-term studies. Conclusion: Efficacy of the second-generation antipsychotic aripiprazole was noted across a broad range of subpopulations often associated with treatment resistance in patients experiencing manic or mixed episodes of bipolar I disorder.

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- Bipolar Disorder, Treatment, Treatment Outcome, Adolescent
- by Aura Rusu
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- Medicinal Chemistry, Pharmaceutical Chemistry, Pharmaceutical Analysis, Quinolones
- by Judith Karp
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- Treatment, Enzyme Inhibitors, Signal Transduction, Quinolones

We examined the cytotoxic potential of nine N-[2-substituted-2-(2-thienyl) ethyl] piperazinyl quinolone derivatives on human oral epithelial mouth carcinoma (KB) and human squamous carcinoma (A431) cell lines. Phototoxic properties of... more

- by Abbas Pardakhty
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- Cytotoxicity, Cell line, Mice, Ultraviolet

Alternating hemiplegia of children is a rare neurological disorder that in its characteristic form has few differential diagnosis. The diagnosis of intractable seizures is difficult to avoid for physicians not aware of the disease. To describe the clinical characteristics of Alternating Hemiplegia of Childhood (AHC), and response to various drugs A Ghanaian child with AHC was followed up for three years at the Neurology Clinic, Korle Bu Teaching Hospital, Accra. Her characteristics including EEG and MRI findings were documented. She was severely unsuccessfully treated as an epileptic. Further clinical re-evaluation provided clues to the diagnosis of alternating hemiplegia of childhood. The child, a female patient, was seen within the first week of life. The initial complaints were abnormal eye movements, and subsequently recurrent hemiplegic episodes, that started at age two and lasted hours to days. Attacks occurred at a frequency of about three per month and lasted from several ho...

- by E. Badoe
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- Magnetic Resonance Imaging, Epilepsy, Electroencephalography, Treatment Outcome

Functional selectivity is the term that describes drugs that cause markedly different signaling through a single receptor (e.g., full agonist at one pathway and antagonist at a second). It has been widely recognized recently that this phenomenon impacts the understanding of mechanism of action of some drugs, and has relevance to drug discovery. One of the clinical areas where this mechanism has particular importance is in the treatment of schizophrenia. Antipsychotic drugs have been grouped according to both pattern of clinical action and mechanism of action. The original antipsychotic drugs such as chlorpromazine and haloperidol have been called typical or first generation. They cause both antipsychotic actions and many side effects (extrapyramidal and endocrine) that are ascribed to their high affinity dopamine D 2 receptor antagonism. Drugs such as clozapine, olanzapine, risperidone and others were then developed that avoided the neurological side effects (atypical or second generation antipsychotics). These compounds are divided mechanistically into those that are high affinity D 2 and 5-HT 2A antagonists, and those that also bind with modest affinity to D 2 , 5-HT 2A , and many other neuroreceptors. There is one approved third generation drug, aripiprazole, whose actions have been ascribed alternately to either D 2 partial agonism or D 2 functional selectivity. Although partial agonism has been the more widely accepted mechanism, the available data are inconsistent with this mechanism. Conversely, the D 2 functional selectivity hypothesis can accommodate all current data for aripiprazole, and also impacts on discovery compounds that are not pure D 2 antagonists.

- by Richard Mailman
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- Schizophrenia, Treatment, Drug Discovery, Signal Transduction
- by Joseph Elborn
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- Cystic Fibrosis, Adolescent, Medicine, Child

Akathisia is a subset of the larger antipsychotic side effect profile known as extrapyramidal syndrome (EPS). It is associated with antipsychotic treatment and is characterized as a feeling of inner restlessness that results in a compulsion to move. There are currently no primate models available to assess drug-induced akathisia; the present research was designed to address this shortcoming. We developed a novel rating scale based on both the Barnes Akathisia Rating Scale (BARS) and the Hillside Akathisia Scale (HAS) to measure the objective, observable incidence of antipsychotic-induced akathisia-like behavior in Cebus apella non-human primates (NHPs). To induce akathisia, we administered the atypical antipsychotic aripiprazole (1 mg/kg) or the selective phosphodiesterase 10A (PDE10A) inhibitor MP-10 (1-3 mg/kg). Treatment with both compounds produced significantly greater akathisia scores on the rating scale than vehicle treatment. Characteristic behaviors observed included vocalizations, stereotypies, teeth grinding, restless limb movements, and hyperlocomotion. Adenosine A 2A receptor antagonists have previously been shown to be effective in blocking antipsychotic-induced EPS in primates. The selective A 2A receptor antagonist, SCH 412348 (10-30 mg/kg), effectively reduced or reversed akathisialike behavior induced by both aripiprazole and MP-10. This work represents the first NHP measurement scale of akathisia and demonstrates that NHPs are responsive to akathisia-inducing agents. As such, it provides a useful tool for the preclinical assessment of putative antipsychotics. In addition, these results provide further evidence of the utility of A 2A receptor antagonists for the treatment of antipsychotic-induced movement disorders.

- by John Hunter
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- Animal Behavior, Quinolones, Cebus, Haloperidol
- by Benjamin Rolland
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- Cognitive Science, Borderline Personality Disorder, Neuropsychiatry, Quinolones

Streptococcus pneumoniae is considered the most frequent bacterial cause of community-acquired pneumonia, and is involved in a significant number of cases of acute exacerbations of chronic bronchitis, acute otitis, sinusitis, meningitis and other infectious diseases. Fluoroquinolones have been extensively investigated in recent years in the search for new agents that has been prompted by the emergence of resistance in this microorganism. Furthermore, the study of resistance from a molecular biology standpoint has helped in elucidating almost all the biochemical mechanisms of resistance and the routes of dissemination of genetic information between bacteria. This short review is focused on the mechanism of action of quinolones and on the mechanisms responsible for resistance of S. pneumoniae to them, given their clinical and epidemiological relevance. S. pneumoniae is a case apart because bactericidal activity against this microorganism can be produced through gyrase, topoisomerase I...

- by Teresa Garrigues and +2
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- Streptococcus pneumoniae, Quinolones, Cell Wall, Structure activity Relationship

The indolinonic and quinolinic aromatic nitroxides synthesized by us are a novel class of biological antioxidants, which afford a good degree of protection against free radical-induced oxidation in different lipid and protein systems. To further our understanding of their antioxidant behavior, we thought it essential to have more information on their effects on DNA exposed to free radicals. Here, we report on the results obtained after exposure of plasmid DNA and calf thymus DNA to peroxyl radicals generated by the water-soluble radical initiator, 2,2Ј-azobis(2amidinopropane)dihydrochloride (AAPH), and the protective effects of the aromatic nitroxides and their hydroxylamines, using a simple in vitro assay for DNA damage. In addition, we also tested for the potential of these nitroxides to inhibit hydroxyl radical-mediated DNA damage inflicted by Fenton-type reactions using copper and iron ions. The commercial aliphatic nitroxides 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), and bis(2,2,6,6-tetramethyl-1-oxyl-piperidin-4-yl)sebacate (TINUVIN 770) were included for comparison. The results show that the majority of compounds tested protect: (i) both plasmid DNA and calf thymus DNA against AAPH-mediated oxidative damage in a concentration-dependent fashion (1-0.1 mM), (ii) both Fe(II) and Cu(I) induced DNA oxidative damage. However, all compounds failed to protect DNA against damage inflicted by the presence of the transition metals in combination with H 2 O 2 . The differences in protection between the compounds are discussed in relation to their molecular structure and chemical reactivity.

- by Elisabetta Damiani
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- Free Radicals, Oxidative Stress, DNA damage, Recombinant DNA Technology

The quinolones trap DNA gyrase and DNA topoisomerase IV on DNA as complexes in which the DNA is broken but constrained by protein. Early studies suggested that drug binding occurs largely along helix-4 of the GyrA (gyrase) and ParC (topoisomerase IV) proteins. However, recent X-ray crystallography shows drug intercalating between the -1 and +1 nucleotides of cut DNA, with only one end of the drug extending to helix-4. These two models may reflect distinct structural steps in complex formation. A consequence of drug-enzyme-DNA complex formation is reversible inhibition of DNA replication; cell death arises from subsequent events in which bacterial chromosomes are fragmented through two poorly understood pathways. In one pathway, chromosome fragmentation stimulates excessive accumulation of highly toxic reactive oxygen species that are responsible for cell death. Quinolone resistance arises stepwise through selective amplification of mutants when drug concentrations are above the MIC and below the MPC, as observed with static agar plate assays, dynamic in vitro systems, and experimental infection of rabbits. The gap between MIC and MPC can be narrowed by compound design that should restrict the emergence of resistance. Resistance is likely to become increasingly important, since three types of plasmid-borne resistance have been reported.

There are conflicting reports of an association between Chlamydia pneumoniae (C. pneumoniae) infection and coronary artery disease (CAD); randomized trials of antibiotics for the secondary prevention of CAD are currently underway. Physicians may be tempted to believe that their choice of antibiotic class in treating any infection may alter the risk of CAD. Our objective was to determine if the use of antibiotics with antichlamydial activity in the general population reduces the risk of myocardial infarction. A healthcare claims database with 354,258 patients with continuous health and pharmacy coverage for at least 2 years between January 1, 1991 and December 31, 1997 was used for the analyses. Hazard ratios were derived from proportional hazards models with time-dependent covariates, relating antibiotic prescription to first claim related to incident first myocardial infarction during the observation pe-riod, adjusting for previous CAD, age, sex, diabetes, hypertension, hyperlipidemia, and chronic obstructive pulmonary disease. There were a total of 1,684,091 person-years of observation and 16,139 incident myocardial infarctions. The adjusted hazard ratios were 1.10 (95% confidence intervals [CI] 1.04 to 1.16) for macrolides, 1.20 (95% CI 1.13 to 1.26) for quinolones, 1.10 (95% CI 0.96 to 1.21) for cephalosporins, 1.00 (95% CI 0.96 to 1.06) for tetracyclines, 1.01 (95% CI 0.96 to 1.06) for penicillins, and 1.13 (95% CI 0.98 to 1.30) for trimetroprim-sulfamethoxazole. The hazard ratios for individual antibiotics with activity against C. pneumoniae within each group were similar. Use of antibiotics with activity against C. pneumoniae does not reduce the risk of myocardial infarction in the general population. ᮊ2002

- by Ariel Pablos-méndez
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- Chlamydia pneumoniae, United States, Cephalosporins, Risk factors

Waste water a b s t r a c t

- by Ivone Vaz-Moreira
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- Water, Water Purification, Multidisciplinary, Antibiotic Resistance
- by Jordi Vila
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- DNA, Quinolones, Dna Gyrase, Molecular Conformation

A simple, sensitive and specific agar diffusion bioassay for the antibacterial enrofloxacin was developed. Using a strain of Staphylococcus aureus ATCC 6538P as the test organism, enrofloxacin at concentrations ranging from 3.2 to 12.8 g ml −1 could be measured in injection. A prospective validation of the method showed that method was linear (r = 0.99998), precise (R.S.D. = 0.27) and accurate (it measured the added quantities). The method shows results that confirm its precision, not differing significantly the other method described in the literature. We conclude that microbiological assay is satisfactory for quantitation of in vitro antibacterial activity of enrofloxacin.

- by Celso Bittencourt
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- Pharmaceutics, Staphylococcus aureus, Quinolones, Anti-Bacterial Agents

The validation of a microbiological assay, applying cylinder plate method for determination of the activity of lomefloxacin in coated tablets is described. Using a strain of Bacillus subtilis ATCC 9372 as the test organism, lomefloxacin was measured in concentrations ranging from 2.0 to 8.0 microg/mL. The method validation showed that it is linear (r = 0.9999), precise (relative standard deviation = 1.15%), and accurate (it measured the added quantities). The excipients did not interfere in the determination. It was concluded that the microbiological assay is satisfactory for quantitation of lomeflox tablets.

- by Herida Regina Nunes Salgado
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- Analytical Chemistry, Pharmaceutical Chemistry, Diffusion, Quinolones
- by Salvatore Gentile
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- Schizophrenia, Safety, Pregnancy, Quinolones

The simultaneous prescription of two or more antipsychotic drugs in combination is a common treatment strategy for those patients who have demonstrated a suboptimal response to clozapine; nevertheless, evidence suggesting potential advantages of combination treatment with clozapine plus one antipsychotic in terms of efficacy and tolerability are still sparse. The present 24-week double-blind, randomized, placebo-controlled trial of adjunctive aripiprazole to clozapine therapy in schizophrenia was aimed to explore the efficacy of aripiprazole add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of patients with treatment-resistant schizophrenia receiving clozapine. After clinical and neurocognitive assessments patients were randomly allocated to receive, in a double-blind design, either up to 15 mg/day of aripiprazole or a placebo. A final sample of thirty-one patients completed the study. The results obtained indicate that aripiprazole added to stable clozapine treatment showed a beneficial effect on the positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenia patients. Regarding executive cognitive functions, aripiprazole augmentation of clozapine had no significant effects. The findings provide evidence that aripiprazole augmentation of clozapine treatment is well-tolerated and may be of benefit for patients who are partially responsive to clozapine monotherapy; further doubleblind, placebo-controlled trials in a larger number of patients are required to evaluate the therapeutic potential of aripiprazole augmentation of clozapine.

- by Gianluca Pandolfo
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- Psychiatry, Psychopharmacology, Schizophrenia, Drug interactions

Five hundred fecal samples from 462 patients (68.4% ambulatory) (February-April, 2007) from Madrid (Spain) were screened for extended-spectrum β-lactamase (ESBL) producers using ceftazidime and cefotaxime (1 mg/L) MacConkey (MAC) agar plates and a chromogenic media (chromID ESBL; bioMérieux, Marcy-l'Etoile, France). bla ESBL , qnr, aac(6′)Ib-cr, and 16S rRNA methylase genes were assessed. A prevalence of 8.2% of ESBL fecal carriers was observed (8.9% hospitalized, 7.9% nonhospitalized patients), higher than that previously observed (1991, 0.6%; 2003, 7.0%). Sensitivity, specificity, and positive and negative predicted values were 100%, 94.8%, 63%, and 100% for chromID ESBL and 87.8%, 89.8%, 43.4%, and 98.9% for MAC, respectively. ESBL distribution was as follows: CTX-M-9group, 40% (mainly CTX-M-14); CTX-M-1-group, 26.6% (mainly CTX-M-15); SHV-type, 29% (mainly SHV-12); and TEM-type, 4.4%. These enzymes were found in pulsed-field gel electrophoresis nonclonally related Escherichia coli and Klebsiella pneumoniae isolates. Transferable quinolone resistance was confirmed in CTX-M-9 (qnrS1), CTX-M-15 [aac(6′)Ib-cr, qnrS1], and SHV-12 (qnrB7, qnrS1) producers but not 16S rRNA methylase genes. The chromID ESBL medium was reliable to screen ESBL fecal carriers with a general decrease in the laboratory workload. Time-to-time monitoring of ESBL fecal carriers is useful to ascertain current trend of ESBL epidemiology.

- by Teresa Coque
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- Microbiology, Epidemiology, Medical Microbiology, Community

The development of an RP-HPLC method for the separation of aripiprazole and its nine impurities was performed with the use of partial least squares regression, response surface plot methodology, and chromatographic response function. The HPLC retention times and computed molecular parameters of the aripiprazole and its nine impurities were further used for the quantitative structure-retention relationship (QSRR) study. The QSRR model, R 2 : 0.899, Q 2 : 0.832, root mean square error of estimation: 4.761, root mean square error of prediction: 6.614, was developed. Very good agreement between the predicted and observed retention times (t R ) for three additional aripiprazole impurities (TC1-TC3) indicated the high prediction potential of the QSRR model for t R evaluation of other aripiprazole impurities and metabolites. The developed HPLC method is the first reported method for the efficient separation of aripiprazole and its nine impurities, which could be used for the analysis of an additional three aripiprazole impurities (TC1-TC3).

- by Katarina Nikolic
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- Analytical Chemistry, Chemometrics, Prediction, Experimental Design

Drug-induced acneiform eruptions are inflammatory follicular reactions that resemble acne vulgaris both in morphology and distribution, which manifest clinically as papulopustules and occasionally as comedones. We report a case of a patient who developed acneiform eruptions while being treated with aripiprazole which resolved after discontinuation of aripiprazole and application of topical retinoic acid. The acneiform eruption could be explained on the basis of Type III allergic mechanism in an already sensitized individual.

- by Vinod Sinha
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- Young Adult, Acne Vulgaris, Quinolones, Clinical Sciences

Background: This project aimed to provide an organized, sequential, and evidence-supported approach to the pharmacotherapy of posttraumatic stress disorder (PTSD), following the format of previous efforts of the Psychopharmacology Algorithm Project at the Harvard South Shore Program. Method: A comprehensive literature review was conducted to determine the best pharmacological choices for PTSD patients and to update the last published version (1999) of the algorithm. We focused on optimal pharmacological interventions to address the prominent symptoms of PTSD, with additional attention to the impact that common comorbidities have on treatment choices. Results: We found that SSRIs and SNRIs are not as effective as previously thought, and that awareness of their long-term side effects has increased. New evidence suggests that addressing fragmented sleep and nightmares can improve symptoms (in addition to insomnia) that are frequently seen with PTSD (e.g., hyperarousal, reexperiencing). Prazosin and trazodone are emphasized at this initial step; if significant PTSD symptoms remain, an antidepressant may be tried. For PTSD-related psychosis, an antipsychotic may be added. In resistant cases, two or three antidepressants may be used in sequence. Following that, or with partial improvement and residual symptomatology, augmentation may be tried; the best options are antipsychotics, clonidine, topiramate, and lamotrigine. Conclusion: This heuristic may be helpful in producing faster symptom resolution, fewer side effects, and increased compliance. (HARV REV PSYCHIATRY 2011;19:240-258.)

- by Laura Bajor and +1
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- Cognitive Science, Algorithms, Psychopharmacology, Schizophrenia

Lycanthropy is an unusual belief or delusion that one has been transformed into an animal, or behaviors or feelings suggestive of such a belief. We report a case of lycanthropic delusions of becoming a snake in a 47-year-old woman who suffered from a major depressive disorder with psychotic features. We also present a literature review of articles published on the subject in English or French since 1975 identified via a MedLine search using the terms "lycanthropy" or "werewolf." Many case reports have described lycanthropy as a delusional disorder occurring acutely in patients who think they suffer from a demonic possession as a punishment for their acts. In these cases, symptoms are generally rapidly reversible. Lycanthropy seems to be a nonspecific manifestation of many psychiatric diseases, most commonly major depressive disorder with psychotic features. It is largely influenced by the cultural environment of the patient so that the animal species frequently represents the patient's delusional representation of evil. Lycanthropy could be considered a culturebound syndrome that occurs in association with Axis I, DSM-IV psychiatric pathology. (Journal of Psychiatric Practice 2012;18:51-54)

- by Rami Khalil and +1
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- Mythology, Lebanon, Culture, Treatment Outcome

Background: During the past decade, there has been some progress in the pharmacotherapy of schizophrenia and schizoaffective disorder. Current evidence supports the use of various second-generation, or atypical, antipsychotic medications, although few of these agents have been associated with long-term efficacy and tolerability. Aripiprazole is an atypical antipsychotic that has been found to improve positive and negative symptoms of schizophrenia with a favorable adverse-effect profile.

- by S.V. Tourjman
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- Schizophrenia, Clinical Trial, Treatment, Treatment Outcome

Tardive dyskinesia (TD), the principal adverse effect of long-term conventional antipsychotic treatment, can be debilitating and, in many cases, persistent. We sought to explore the incidence and management of TD in the era of atypical antipsychotics because it remains an important iatrogenic adverse effect. We conducted a review of TD incidence and management literature from January 1, 1965, to January 31, 2004, using the terms tardive dyskinesia, management, therapy, neuroleptics, antipsychotics, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Additional articles were obtained by searching the bibliographies of relevant references. We considered articles that contributed to the current understanding of both the incidence of TD with atypical antipsychotics and management strategies for TD. The incidence of TD is significantly lower with atypical, compared with typical, antipsychotics, but cases of de novo TD have been identified. Evidence suggests tha...

- by Lawrence Annable and +1
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- Schizophrenia, Canadian Psychiatry, Serotonin, Dopamine
- by Christoph Hiemke
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- Schizophrenia, Lactation, Pregnancy, Case Report

Successful treatment of penile Bowen's disease with 5% imiquimod cream Sir: We report the fourth case of successful treatment of penile Bowen's disease (squamous cell carcinoma in situ) with imiquimod cream. A 29year-old man presented... more

- by Alberto Calvo
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- Heterosexuality, Medical Microbiology, Quinolones, Clinical Sciences
- by L. Molinos
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- Anaerobic Bacteria, Pneumonia, Aminoglycosides, Cephalosporins
- by Christoph Hiemke and +1
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- Schizophrenia, Quinolones, Clinical Sciences, Aged

Cannabinoid receptor 2 (CB2) plays an important role in human physiology and the pathophysiology of different diseases, including neuroinflammation, neurodegeneration, and cancer. Several classes of CB2 receptor ligands, including 2-oxoquinoline derivatives, have been previously reported. We report the synthesis and results of in vitro receptor binding of a focused library of new fluorinated 2-oxoquinoline CB2 ligands. Twelve compounds, 13-16 18, 19, 21-24, 27, and 28 were synthesized in good yields in multiple steps. Human U87 glioma cells expressing either hCB1 (control) or hCB2 were generated via lentiviral transduction. In vitro competitive binding assay was performed using [ 3 H]CP-55,940 in U87hCB1 and U87hCB2 cells. Inhibition constant , 27, and 28 for CB2 were >10000, 2.8, 5.0, 2.4, 22, 0.8, 1.4, >10000, 486, 58, 620, and 2400 nM, respectively, and those for CB1 were >10000 nM. Preliminary in vitro results suggest that six of these compounds may be useful for therapy of neuropathic pain, neuroinflammatory diseases and immune disorders. In addition, compound 19, with its subnanomolar Ki value, could be radiolabeled with 18 F and explored for PET imaging of CB2 expression.

- by Andrei Volgin
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- Organic Chemistry, Multiple sclerosis, Glioma, Neuropathic pain

Five phase-pure modifications of the antipsychotic drug aripiprazole were prepared and characterized by thermal analysis, vibrational spectroscopy and X-ray diffractometry. All modifications can be produced from solvents, form I additionally by heating of form X8 to $1208C (solid-solid transformation) and form III by crystallization from the melt. Thermodynamic relationships between the polymorphs were evaluated on the basis of thermochemical data and visualized in a semi-schematic energy/temperature diagram. At least six of the ten polymorphic pairs are enantiotropically and two monotropically related. Form X8 is the thermodynamically stable modification at 208C, form II is stable in a window from about 62-778C, and form I above 808C (high-temperature form). Forms III and IV are triclinic (P1), I and X8 are monoclinic ( P2 1 ) and form II orthorhombic (Pna2 1 ). Each polymorph exhibits a distinct molecular conformation, and there are two fundamental N-HÁ Á ÁO hydrogen bond synthons (catemers and dimers). Hirshfeld surface analysis was employed to display differences in intermolecular short contacts. A high kinetic stability was observed for three metastable polymorphs which can be categorized as suitable candidates for the development of solid dosage forms. ß b Calculated according to Eq. (2) (k ¼ 0.003). c Calculated: difference between D fus H of the individual polymorph and D fus H I . d Freshly crystallized form. e After storage for about 12 months. f Most intensive band.

- by Ulrich Griesser
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- Thermodynamics, Polymorphism, Kinetics, Crystallization

Since quinine was first isolated, animals, plants and microorganisms producing a wide variety of quinolone compounds have been discovered, several of which possess medicinally interesting properties ranging from antiallergenic and anticancer to antimicrobial activities. Over the years, these have served in the development of many synthetic drugs, including the successful fluoroquinolone antibiotics. Pseudomonas aeruginosa and related bacteria produce a number of 2alkyl-4(1H)-quinolones, some of which exhibit antimicrobial activity. However, quinolones such as the Pseudomonas quinolone signal and 2-heptyl-4-hydroxyquinoline act as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. Here, we review selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa. In particular, we review their nomenclature and biochemistry, their multiple properties as membrane-interacting compounds, inhibitors of the cytochrome bc 1 complex and iron chelators, as well as the regulation of their biosynthesis and their integration into the intricate quorum-sensing regulatory networks governing virulence and secondary metabolite gene expression.

- by Stephan Heeb
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- Microbiology, Medical Microbiology, Quinolones, Pseudomonas aeruginosa

We used the multilocus sequence typing (MLST) method to study the genetic diversity of Campylobacter coli isolated from chickens in Senegal, and to check the presence of genetic exchange with Campylobacter jejuni. In addition, we assessed the resistance of the isolates to ciprofloxacin and nalidixic acid, and their gyrA sequences. MLST revealed a low level of diversity and the absence of lineages among C. coli isolates. In addition, an exchange of alleles with C. jejuni was found. Twenty percent of the ciprofloxacin-resistant isolates lacked mutations within the quinolone resistance-determining region (QRDR) of GyrA. There was no link between quinolone resistance and sequence type (ST).

- by Eric Cardinale
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- Genetics, Microbiology, Medical Microbiology, Senegal

Marbofloxacin is a fluoroquinolone antibiotic expected to be effective in the treatment of infections involving Gramnegative and some Gram-positive bacteria in horses. In order to design a rational dosage regimen for the substance in horses, the pharmacokinetic properties of marbofloxacin were investigated in 6 horses after i.v., subcutaneous and oral administration of a single dose of 2 mg/kg bwt and the minimal inhibitory concentrations (MIC) assessed for bacteria isolated from equine infectious pathologies. The clearance of marbofloxacin was mean ± s.d. 0.25 ± 0.05 l/kg/h and the terminal half-life 7.56 ± 1.99 h. The marbofloxacin absolute bioavailabilities after subcutaneous and oral administration were 98 ± 11% and 62 ± 8%, respectively. The MIC required to inhibit 90% of isolates (MIC 90 ) was 0.027 µg/ml for enterobacteriaceae and 0.21 µg/ml for Staphylococcus aureus.

- by A. Bousquet-melou
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- Treatment Outcome, Biological Sciences, Bacteria, Horses
- by Dhinii Mardhiyani
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- Quinolones

Aripiprazole (Abilify ® ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia. Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G-protein coupled receptors (GPCRs) [especially dopamine (D 2 ) and 5-HT 1A ] and antagonistic action at others (especially 5-HT 2A ). Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia. In short-term studies rapid onset of action (within one week) has been demonstrated. Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder. At recommended doses, aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder. There is only limited information available on the use of aripiprazole in children and adolescents, and pilot data suggest that a revised dosing strategy, based on weight, is indicated in this population. In the long-term studies, the use of aripiprazole was associated with continued efficacy, good compliance and increased time-to-relapse.

- by Paul Perry
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- Quinolones, Atypical Antipsychotics, Neurosciences

Introduction and hypothesis We report our experience with surgical excision for treatment of Skene's gland abscess/ infection after conservative measures have failed. Methods A retrospective review of patients that underwent surgical excision of Skene's gland abscess/infection by a single surgeon from 06/1995 to 09/2008 was performed. Patients were separated into groups based on indication for procedure. Recurrence rate and success rate were calculated. Results The final study group included 34 patients. After initial excision, 88.2% (30/34) of patients had resolution of symptoms. Recurrence of signs and symptoms that prompted further treatment occurred in 30% (9/30). In those that recurred, 88.8% (8/9) of patients had resolution of symptoms after further therapy. Overall success rate in complete resolution of symptoms after all treatment was 85.3%. Only patients to fail were in the urethral pain and recurrent UTI groups. Conclusion Surgical excision is a safe and effective therapy for the treatment of Skene's gland abscess/infection after conservative measures have failed.

- by Nirit Rosenblum
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- Lactobacillus, Urogynecology, Young Adult, Urinary Tract Infections

Background: The evidence for choices between antipsychotics for children and adolescents with schizophrenia and other psychotic disorders is limited. The main objective of the Tolerability and Efficacy of Antipsychotics (TEA) trial is to compare the benefits and harms of quetiapine versus aripiprazole in children and adolescents with psychosis in order to inform rational, effective and safe treatment selections. Methods/Design: The TEA trial is a Danish investigator-initiated, independently funded, multi-centre, randomised, blinded clinical trial. Based on sample size estimation, 112 patients aged 12-17 years with psychosis, antipsychotic-naïve or treated for a limited period are, 1:1 randomised to a 12-week, double-blind intervention with quetiapine versus aripiprazole. Effects on psychopathology, cognition, health-related quality of life, and adverse events are assessed 2, 4, and 12 weeks after randomisation. The primary outcome is change in the positive symptom score of the Positive and Negative Syndrome Scale. The recruitment period is 2010-2014.

- by Christian Gluud
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- Schizophrenia, Quality of life, Adolescent, Child

Prolactin elevations occur in people treated with antipsychotic medications and are often much higher in women than in men. Hyperprolactinemia is known to cause amenorrhea, oligomenorrhea, galactorrhea and gynecomastia in females and is also associated with sexual dysfunction and bone loss. These side effects increase risk of antipsychotic nonadherence and suicide and pose significant problems in the long term management of women with schizophrenia. In this manuscript, we review the literature on prolactin; its physiology, plasma levels, side effects and strategies for treatment. We also present the rationale and protocol for an ongoing clinical trial to treat symptomatic hyperprolactinemia in premenopausal women with schizophrenia. More attention and focus are needed to address these significant side effects and help the field better personalize the treatment of women with schizophrenia.

- by Stephanie Feldman
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- Research Design, Schizophrenia, Quinolones, Clinical Sciences

Haplophytin-A (10-methoxy-2,2-dimethyl-2,6-dihydro-pyrano[3,2-c]quinolin-5-one), a novel quinoline alkaloid, was isolated from the Haplophyllum acutifolium. In this study, we investigated the effect of haplophytin-A on the apoptotic activity and the molecular mechanism of action in human promyelocytic leukemia HL-60 cells. Treatment with haplophytin-A (50 M) induced classical features of apoptosis, such as, DNA fragmentation, DNA ladder formation, and the externalization of annexin-Vtargeted phosphatidylserine residues in HL-60 cells. In addition, haplophytin-A triggered the activations of caspase-8, -9, and -3, and the cleavage of poly (ADP-ribose) polymerase (PARP) in HL-60 cells. In addition, haplophytin-A caused the loss of mitochondrial membrane potential ( « m ) and the release of cytochrome c and Smac/DIABLO to the cytosol, and modulated the expression levels of Bcl-2 family proteins. We further demonstrated that knockdown of caspase-8 using its siRNA inhibited the mitochondrial translocation of tBid, the activations of caspase-9 and caspase-3, and subsequent DNA fragmentation by haplophytin-A. Furthermore, haplophytin-A-induced the formation of death-inducing signaling complex (DISC) and then activated caspase-8 in HL-60 cells. During haplophytin-A-induced apoptosis, caspase-8-stimulated tBid provide a link between the death receptor-mediated extrinsic pathway and the mitochondria-mediated intrinsic pathway. Taken together, these results suggest that the novel compound haplophytin-A play therapeutical role for leukemia via the potent apoptotic activity through the extrinsic pathway, involving the intrinsic pathway.

- by Kyung-tae Lee
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- Apoptosis, Molecular Mechanics, Cytochrome C, Quinolones

Objective: There has been much interest in the use of atypical antipsychotics in anorexia nervosa (AN). However, newer, more weight-neutral medications have not been studied in AN, and there are no reports of the use of antipsychotics in bulimia nervosa (BN). Method: We report on the treatment of eight patients (five with AN and three with BN) with aripiprazole for time periods of four months to more than three years. Results: All individuals had reduced distress around eating, fewer obsessional thoughts about food, weight and body image, significant lessening of eating-disordered behaviors, and gradual weight restoration where appropriate. Depression, generalized anxiety, and cognitive flexibility improved as well. Discussion: In summary, these findings support the need to perform controlled trials of aripiprazole in AN and BN. V V C 2010 by Wiley Periodicals, Inc.

- by Vikas Duvvuri
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- Clinical Psychology, Psychiatry, Eating Disorders, Treatment Outcome
- by Albert Padwa
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- Quinolones, CHEMICAL SCIENCES, Cyclization, Alkylation

Fluoroquinolones are an important class of widespectrum antibacterial agents. The first quinolone described was nalidixic acid, which showed a narrow spectrum of activity. The evolution of quinolones to more potent molecules was based on changes at positions 1, 6, 7 and 8 of the chemical structure of nalidixic acid. Quinolones inhibit DNA gyrase and topoisomerase IV activities, two enzymes essential for bacteria viability. The acquisition of quinolone resistance is frequently related to (i) chromosomal mutations such as those in the genes encoding the A and B subunits of the protein targets (gyrA, gyrB, parC and parE), or mutations causing reduced drug accumulation, either by a decreased uptake or by an increased efflux, and (ii) quinolone resistance genes associated with plasmids have been also described, i.e. the qnr gene that encodes a pentapeptide, which blocks the action of quinolones on the DNA gyrase and topoisomerase IV; the aac(6Ј)-Ib-cr gene that encodes an acetylase that modifies the amino group of the piperazin ring of the fluoroquinolones and efflux pump encoded by the qepA gene that decreases intracellular drug levels. These plasmid-mediated mechanisms of resistance confer low levels of resistance but provide a favourable background in which selection of additional chromosomally encoded quinolone resistance mechanisms can occur.

- by Jordi Vila
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- Microbiology, Veterinary Medicine, Enzyme Inhibitors, Microbial biotechnology
- by Rossetos Gournellis
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- Quinolones, Clinical Sciences, Psychotic Disorders, Thiazoles

Objective The objective of this study was to evaluate the possible relationship between the administration of parenteral enrofloxacin and the onset of acute retinal degeneration in cats. The animals studied included 17 cats that received systemic enrofloxacin and developed retinal degeneration soon thereafter. Procedures In this retrospective clinical study, cats that received parenteral enrofloxacin and developed acute blindness were identified. Parameters recorded included breed, age, sex, enrofloxacin dosage (daily dose and number of days administered), medical condition for which the antibiotic had been prescribed, ophthalmic signs, examination results, and the visual outcome. Fundus photographs were obtained in seven cats, and electroretinography was performed in five cats. Histopathology was performed on two eyes from one cat (case 1) that received enrofloxacin 5 months previously and developed retinal degeneration. Results All cats were the domestic shorthair breed; seven were females (one neutered) and ten were males (seven castrated). Ages ranged from 3 to 16 years old (mean ± SD; 8.8 ± 4.6 years). The medical disorders for which enrofloxacin was administered ranged from lymphoma and pancreatitis to otitis and dermatitis, and eight cats had urinary diseases. The daily and total dosage of enrofloxacin and number of days of administration were also highly variable. Presenting clinical signs were most often mydriasis and acute blindness. All cats had diffuse retinal degeneration as evidenced by increased tapetal reflectivity and retinal vascular attenuation. Absence of recordable electroretinographic responses suggested diffuse and extensive outer retinal disease. Vision returned in a few cats, but the retinal degeneration persisted or even progressed. Histopathology of two eyes revealed primarily outer retinal degeneration, with diffuse loss of the outer nuclear and photoreceptor layers, and hypertrophy and proliferation of the retinal pigment epithelium. Conclusion Parenteral enrofloxacin is potentially retinotoxic in some cats, and may result in acute and diffuse retinal degeneration. Blindness often results, but some cats may regain vision. Practitioners should adhere closely to the manufacturer's current enrofloxacin dosage recommendation (5 mg/kg q 24 h), and continue clinical observations for this drug toxicity in cats.

- by Stacy Andrew
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- Blindness, Veterinary, Cats, Retinal Degeneration

C o p y r i g h t © 2 0 1 1 I n f o r m a U K L i m i t e d N o t f o r S a l e o r C o m m e r c i a l D i s t r i b u t i o n U n a u t h o r i z e d u s e p r o h i b i t e d . A u t h o r i s e d u s e r s c a n d o w n l o a d ,... more

C o p y r i g h t © 2 0 1 1 I n f o r m a U K L i m i t e d N o t f o r S a l e o r C o m m e r c i a l D i s t r i b u t i o n U n a u t h o r i z e d u s e p r o h i b i t e d . A u t h o r i s e d u s e r s c a n d o w n l o a d , Abstract Background: Aripiprazole is an atypical antipsychotic with a pharmacological and clinical profile distinct from other atypical antipsychotics.

- by Mocrane Abbar
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- Economics, Bipolar Disorder, Quinolones