Systematic Analysis of Cell Cycle Effects of Common Drugs Leads to the Discovery of a Suppressive Interaction between Gemfibrozil and Fluoxetine

Screening chemical libraries to identify compounds that affect overall cell proliferation is common. However, in most cases, it is not known whether the compounds tested alter the timing of particular cell cycle transitions. Here, we evaluated an FDA-approved drug library to identify pharmaceuticals that alter cell cycle progression in yeast, using DNA content measurements by flow cytometry. This approach revealed strong cell cycle effects of several commonly used pharmaceuticals. We show that the antilipemic gemfibrozil delays initiation of DNA replication, while cells treated with the antidepressant fluoxetine severely delay progression through mitosis. Based on their effects on cell cycle progression, we also examined cell proliferation in the presence of both compounds. We discovered a strong suppressive interaction between gemfibrozil and fluoxetine. Combinations of interest among diverse pharmaceuticals are difficult to identify, due to the daunting number of possible combinations that must be evaluated. The novel interaction between gemfibrozil and fluoxetine suggests that identifying and combining drugs that show cell cycle effects might streamline identification of drug combinations with a pronounced impact on cell proliferation

Characteristics and Programme-Defined Treatment Outcomes among Childhood Tuberculosis (TB) Patients under the National TB Programme in Delhi

Childhood tuberculosis (TB) patients under India's Revised National TB Control Programme (RNTCP) are managed using diagnostic algorithms and directly observed treatment with intermittent thrice-weekly short-course treatment regimens for 6–8 months. The assignment into pre-treatment weight bands leads to drug doses (milligram per kilogram) that are lower than current World Health Organization (WHO) guidelines for some patients.The main aim of our study was to describe the baseline characteristics and treatment outcomes reported under RNTCP for registered childhood (age <15 years) TB patients in Delhi. Additionally, we compared the reported programmatic treatment completion rates between children treated as per WHO recommended anti-TB drug doses with those children treated with anti-TB drug doses below that recommended in WHO guidelines.For this cross-sectional retrospective study, we reviewed programme records of all 1089 TB patients aged <15 years registered for TB treatment from January to June, 2008 in 6 randomly selected districts of Delhi. WHO disease classification and treatment outcome definitions are used by RNTCP, and these were extracted as reported in programme records.Among 1074 patients with records available, 651 (61%) were females, 122 (11%) were <5 years of age, 1000 (93%) were new cases, and 680 (63%) had extra-pulmonary TB (EP-TB)—most commonly peripheral lymph node disease [310 (46%)]. Among 394 pulmonary TB (PTB) cases, 165 (42%) were sputum smear-positive. The overall reported treatment completion rate was 95%. Similar reported treatment completion rates were found in all subgroups assessed, including those patients whose drug dosages were lower than that currently recommended by WHO. Further studies are needed to assess the reasons for the low proportion of under-5 years of age TB case notifications, address challenges in reaching all childhood TB patients by RNTCP, the accuracy of diagnosis, and the clinical validity of reported programme defined treatment completion

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version

Chronic paroxysmal hemicrania and hemicrania continua. Parental indomethacin: the indotest

The interval between indomethacin administration and clinical response may be clinically relevant in the assessment of chronic paroxysmal hemicrania and hemicrania continua and other unilateral headache disorders with which they can be confounded. Eight patients with chronic paroxysmal hemicrania (6 women and 2 men) and 12 patients with hemicrania continua (8 women and 4 men) were entered into the study. The patients were given 50 mg of indomethacin intramuscularly (i.m.) on day 1 and some of them 100 mg IM on day 2 in an open fashion. The usual attack pattern was reestablished prior to the second test. The mean interval between attacks before the two injections (51 +/- 18 minutes) in chronic paroxysmal hemicrania was significantly shorter than the mean after each of the two indomethacin injections (50 mg = 493 +/- 251 minutes; 100 mg = 668 +/- 211 minutes; P < 0.001; Mann-Whitney test). In every patient, there was a clear refractory period after indomethacin. Since the first "expected" attack after indomethacin administration did not occur, it can, with reasonable certainty, be assumed that the protective phase was initiated already prior to the time of the next "anticipated" attack. The mean attack duration was 22 minutes (last three attacks prior to test). The mean interval between the onset of two consecutive pretest attacks was 73 minutes. Since the interval between attacks was rather stable, one is, therefore, probably allowed to assume that the absolute protective effect of indomethacin on average had begun somewhere between 22 (mean attack duration) and 73 minutes after indomethacin injection. Similarly, in hemicrania continua, the time between 50-mg indomethacin injection and complete pain relief was 73 +/- 66 minutes. The pain-free period after indomethacin injection was around 13 hours (i.e., 13 +/- 8 hours after 50 mg and 13 +/- 10 hours after 100 mg). The use of a test dosage of 50 mg of indomethacin IM ('indotest') gives a clear-cut answer and may be a useful tool in the diagnostic arsenal in every unilateral headache for a proper clinical assessment. A diagnosis of chronic paroxysmal hemicrania or hemicrania continua is a serious matter because it may imply life-long treatment with a potentially noxious drug. It is, therefore, of the utmost importance that an 'indotest' is carried out in a standard fashion. In the future, the rules set forth in the present context should be followed, at least in scientific studies. Pain pressure thresholds at cranial and extracranial levels were not significantly modified after indomethacin injection in any of the headaches

Chronic paroxysmal hemicrania and hemicrania continua: lack of efficacy of sumatriptan.

Attacks of chronic paroxysmal hemicrania are prevented by the continuous administration of indomethacin. Sumatriptan, an agonist of 5-HT1-like receptors, has proven effective in the treatment of cluster headache attacks. There are clear clinical similarities between chronic paroxysmal hemicrania and cluster headache. A natural consequence of these considerations would be to establish whether chronic paroxysmal hemicrania also responds similarly to sumatriptan. Since hemicrania continua is another unilateral headache responsive to indomethacin, it would be meaningful to also include hemicrania continua in such a study. Sumatriptan, 6 mg subcutaneous, was tried in an open fashion in 7 patients (6 women and 1 man) with chronic paroxysmal hemicrania and 7 patients (5 women and 2 men) with hemicrania continua. In chronic paroxysmal hemicrania, the mean interval between the last three attacks prior to sumatriptan treatment (40 +/- 23 minutes) was not statistically different from the mean interval between the three attacks subsequent to sumatriptan treatment of an attack (32 +/- 20 minutes). In none of the patients did the mean duration of the "test attack" decrease as compared to the attacks antedating the test attack (25 +/- 11 minutes and 19 +/- 9 minutes, respectively) (P = 0.027, Wilcoxon). In 2 patients with chronic paroxysmal hemicrania, placebo (saline) administration did not lead to any change in the interval between attacks. There was a mild, but statistically significant reduction in visual analog scale values for headache intensity in hemicrania continua (P = 0.04, Wilcoxon). There was no clear, i.e., clinically meaningful, reduction in visual analog scale values in any particular patient with hemicrania continua. Taken together, these results seem to show that sumatriptan is of no benefit in chronic paroxysmal hemicrania, but may have a partial efficacy in hemicrania continua. However, the latter effect is clinically unimportant. This minor difference in regard to the clinical effect may, nevertheless, be of some interest pathogenetically, indicating minor differences between the two headaches. The lack of sumatriptan effect in chronic paroxysmal hemicrania clearly and markedly strengthens the nonalignment concept in regard to chronic paroxysmal hemicrania and cluster headache

Chronic paroxysmal hemicrania and hemicrania continua: anaesthetic blockades of pericranial nerves

Greater occipital nerve (GON), supraorbital nerve (SON), and minor occipital nerve (MON) blockades-in this sequence-were carried out on the symptomatic side in patients with chronic paroxysmal hemicrania (CPH) (no = 6) and hemicrania continua (HC) (no = 7). Prior to the blockade, indomethacin was discontinued for a sufficiently long time (24 h) to allow a constant flow of attacks/constant pain. The local anaesthetic agent used was lidocaine. The blockades were invariably negative in CPH. In HC, the GON and MON blockades generally had no positive influence. The pattern as regards SON blockades was slightly different, in that the pre-test average VAS-value of 7.3 decreased to 4.6 (p < 0.05, Student's t-test, and p = 0.065 Wilcoxon) and-on an individual basis-decreased in 4 out of 7 patients. GON/MON blockades will help distinguish CPH/HC from cervicogenic headache. SON blockade will have to be carried out in a good-sized series of HC patients in order to establish more concrete evidence of the putative effect in HC. SON blockades may eventually also aid in the distinction between HC and supraorbital nerve neuralgia (where the blockade effect generally seems to be complete)

Measuring burden in caregivers of people with multiple sclerosis: psychometric properties of the CSI questionnaire

Jose M Garc&iacute;a-Dom&iacute;nguez,1 Mar&iacute;a L Mart&iacute;nez-Gin&eacute;s,1 Olga Carmona,2 Ana B Caminero,3 Daniel Prefasi,4 Jorge Maurino,4 Javier Ballesteros5 On behalf of the W-IMPACT Clinical Investigators 1Department of Neurology, Hospital Universitario Gregorio Mara&ntilde;&oacute;n, Madrid, Spain; 2Department of Neurology, Hospital de Figueres, Figueres, Spain; 3Department of Neurology, Hospital Nuestra Se&ntilde;ora de Sonsoles, Complejo Asistencial de &Aacute;vila, &Aacute;vila, Spain; 4Medical Department, Roche Farma, Madrid, Spain; 5Department of Neurosciences and CIBERSAM, Universidad del Pa&iacute;s Vasco, Leioa, Spain Background: Understanding caregiver strain may be crucial to determine which interventions are most needed to mitigate the negative impact of caring for people with multiple sclerosis (MS). The Caregiver Strain Index (CSI) is a brief self-assessment tool for measuring the caregivers&rsquo; perceived level of burden. Limited information is available on the psychometric performance of the CSI in MS.Objective: The objective of this study was to assess the factor structure and construct validity of the CSI in MS.Methods: A multicenter, cross-sectional study in adults with relapsing-remitting and primary-progressive MS (McDonald 2010 criteria) was conducted. A non-parametric item response theory (IRT) procedure, Mokken analysis, was conducted to assess the dimensional structure of the CSI. A parametric IRT model for dichotomous responses, Rasch model, was conducted to assess item characteristics. Discriminative validity was assessed comparing the distribution of its overall score between people with mild and moderate-severe disability according to the Expanded Disability Status Scale.Results: A total of 72 MS caregivers were studied. The prevalence of a high level of strain was 23.6% (n=17). Internal reliability was high (Cronbach&rsquo;s alpha =0.91). According to Mokken analysis, CSI represented a unidimensional construct of caregiver burden although two of the total 13 items (#1 and #13) could not be assigned to any factor by an automatic item selection procedure. Without these items, the scalability moved from a weak (Hi =0.37) to a medium scale (Hi =0.44). However, the item characteristic curve of the Rasch model showed a range of appropriate difficulty and the item and person parameters showed good fit (Andersen likelihood ratio test =18.40, df =11; P-value =0.07; all item values for the infit). The CSI score showed a good discriminative validity between the levels of disability of the care recipient.Conclusion: The CSI questionnaire shows appropriate psychometric characteristics being a useful instrument to assess different aspects of burden in MS caregivers in clinical practice. Keywords: caregivers, multiple sclerosis, psychometrics, caregiver burden, strai