Synthesis and antibacterial activity of N-[5-chlorobenzylthio-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives

A series ofN-[5-(chlorobenzylthio)-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives (4a-1) have been synthesized by reaction of piperazinyl quinolones with 5-chloro-2-(chloroben-zylthio)-1,3,4-thiadiazoles. Their structures were confirmed by elemental analysis, IR and NMR spectra. The antibacterial activities of4a-1 against a variety of Gram-positive and Gram-negative bacteria were determined. Several compounds showed a good antibacterial activity against Gram-positive bacteria among which, compound 4e with a 2-chlorobenzylthio moiety in ciprofloxacin derivative, exhibited high activities againstStaphylococcus aureus andStaphylococcus epidermidis (MIC=0.06 μg/mL). The structure-activity relationship (SAR) study revealed that the position of chlorine atom on benzyl moiety would dramatically affect the antibacterial activities of the synthesized compounds.     

Incorporating in vitro information on drug metabolism into clinical trial simulations to assess the effect of CYP2D6 polymorphism on pharmacokinetics and pharmacodynamics: dextromethorphan as a model application

In vitro-in vivo extrapolation of clearance, embedded in a clinical trial simulation, was used to investigate differences in the pharmacokinetics and pharmacodynamics of dextromethorphan between CYP2D6 poor and extensive metabolizer phenotypes. Information on the genetic variation of CYP2D6, as well as the in vitro metabolism and pharmacodynamics of dextromethorphan and its active metabolite dextrorphan, was integrated to assess the power of studies to detect differences between phenotypes. Whereas 6 subjects of each phenotype were adequate to achieve 80% power in showing pharmacokinetic differences, the power required to detect a difference in antitussive response was less than 80% with 500 subjects in each study arm. Combining in vitro-in vivo extrapolation with a clinical trial simulation is useful in assessing different elements of study design and could be used a priori to avoid inconclusive pharmacogenetic studies.     

Involvement of hypothalamic pituitary adrenal axis on the analgesic cross-tolerance between morphine and nifedipine

Bidirectional cross-tolerance develops between opioids and Ca(2+) channel blockers relating to their antinociceptive effects; however, the role of hypothalamic pituitary adrenal (HPA) axis on this action has not been elucidated yet. We examined the analgesic cross-tolerance between morphine and nifedipine, a dihydropyridine calcium channel blocker, in intact and adrenalectomized (ADX) rats and also evaluated modification of HPA activity during this phenomenon. The tail-flick test was used to assess the nociceptive threshold. The plasma level of corticosterone, as a marker of HPA function, was measured by radioimmunoassay. Our results showed that, in sham operated rats which were chronically treated with morphine, nifedipine failed to affect nociceptive threshold but it could induce significant antinociceptive effect in ADX morphine treated animals. This effect was reversed by corticosterone replacement. Furthermore, morphine could not induce analgesic effect either in sham operated or in ADX animals that received chronic nifedipine. Chronic morphine inhibited the effect of nifedipine on corticosterone secretion but nifedipine treatment had no effect on morphine-induced corticosterone secretion. Based on these results, we can conclude that HPA axis is involved in the induction of cross-tolerance between morphine and nifedipine due to chronic morphine and not nifedipine treatment.     

Substance abuse in Iranian high school students

Adolescent substance abuse potentially holds a number of negative implications for the health and well-being of the individual, including increased risk for injury and death from interpersonal violence, motor vehicle accidents, and drowning, increased probability of engaging in high risk sexual behaviors; and increased risk for suicidal ideation and behaviors. The aim of this paper is to estimate prevalence of substance abuse among the sample of 10th grade male students in Tabriz City, and to evaluate the associated factors. Of all 10th grade male students in Tabriz, Iran, 1785(13.7%) were randomly sampled. Mean age of the subjects was 16.3+/-0.87 years. A self-administered questionnaire was used to collect demographic data, substance abuse, smoking status and friends smoking. The influence of different factors on substance abuse was evaluated with a logistic regression model. Among 1785 students 226 (12.7%, 95% CI: 11.2-14.3) had ever used alcohol and 36 (2.0%, 95% CI: 1.5-2.8) had used drugs. The results indicate that older age (OR=1.55), having general risk taking behavior (OR=1.70), higher smoking stage (OR=3.70), having self-injury (OR=1.22), higher socioeconomic class (OR=1.62), and ever use of illicit drugs (OR=5.72) were factors associated with student's ever use of alcohol. This study has shown low prevalence of substance abuse and determined some of its risk factors among students. More studies about adolescent population are necessary to approve the observed results of this study and thus allow for a certain generalization of the observations.     

Medium-term results with the Press Fit Condylar (PFC) Sigma knee prosthesis the Wrightington experience

The PFC Sigma total knee was introduced in 1997, incorporating a number of design changes. We report the mid-term results of a consecutive series of PFC Sigma knee arthroplasties performed between November 1997 and December 1998. Out of a total of 156 patients (166 knees), 5 patients (5 knees) were lost to follow-up and 6 patients (6 knees) died of unrelated causes. This left 145 patients (155 knees), 90 female and 55 male, with a mean age of 70 years (range, 53-88) and an average follow-up of 90 months (range, 84-96). Posterior cruciate retaining components were used in 136 knees (88%) and posterior-stabilized in 19 (12%). The patella was resurfaced in 74 (48%) knees. Follow-up was at 3, 6 and 12 months, then yearly. Preoperative American Knee Society and Oxford scores were compared with follow-up scores. The Knee Society radiological score was used for radiographic assessment. One knee (0.6%) was revised due to aseptic loosening. One knee (0.6%) had superficial wound infection, which settled with oral antibiotics. Two knees became deeply infected. Of these, one resolved following early debridement, the other developed chronic infection. Using revision for any reason as the end-point our cumulative success rate was 99.4%. The mean preoperative Knee score improved from 45 (30-65) to 84 (45-92), Functional score from 38 (25-55) to 73 (50-95) and Oxford score from 43 (33-52) to 17 (14-29). Radiographic review showed radiolucent lines in 54 (35%) tibial and 17 (11%) femoral components. The Radiological Knee Society score was less than 4 in all except one tibia where the score was 7. Our study shows excellent clinical results with the PFC Sigma total knee replacement after almost eight years follow-up.     

Breast cancer in kurdish women of northern Iraq: incidence, clinical stage, and case control analysis of parity and family risk

Background  

Breast cancer in the Middle-East occurs in relatively young women and frequently presents as advanced disease. A protective effect of multiparity is not apparent, and high familial risk is reported in some countries. This study investigates breast cancer rates and clinical stage related to age in the Kurdish region of Iraq and evaluates risk associated with parity and family history. Findings are compared with nearby countries and the West.     

Redesigned immunization card and center-based education to reduce childhood immunization dropouts in urban Pakistan: a randomized controlled trial

In Pakistan during 2000-2004, about 11-13% of children who received the first dose of diphtheria-pertussis-tetanus (DPT1) failed to complete its third dose (DPT3). We assessed the effect of a redesigned immunization card and center-based education to mothers on DPT3 completion. We enrolled 1500 mother-child units at DPT1, randomized them to three intervention and one standard care groups, and recorded their DPT3 visits during a 90-day follow-up. In multivariable analysis, a significant increase of 31% (adjusted RR=1.31, 95% CI=1.18-1.46) in DPT3 completion was estimated in the group that received both redesigned card and center-based education compared with the standard care group.     

Novel, rapid assay for measuring entry of diverse enveloped viruses, including HIV and rabies

Entry is the first and essential step in virus replication and is a target for therapeutic intervention. However, current knowledge on entry mechanism for the majority of viruses is poor, partly due to lack of a simple, sensitive and accurate entry assay that can be applied to diverse viruses. To overcome this obstacle, a novel contents-mixing-based virus entry assay is described that can be broadly applied to many enveloped viruses. By fusing firefly luciferase to the HIV Nef protein, luciferase was directly packaged into HIV particles pseudotyped with envelope proteins of diverse viruses including HIV, rabies and others. Upon cell entry, the luciferase-fusion protein was released into the cell cytoplasm, reacted with its substrates and was detected by light emission. The assay was validated by demonstrating its versatility in measuring virus entry. Entry was detected much more rapidly (in real-time) with higher sensitivity (a multiplicity of infection <0.1 gives a robust signal) and lower background (signal/noise ration >1000) than other comparable assays. In addition to its utility in studying virus entry mechanisms, the assay will aid in screening potential entry/fusion inhibitors and in diagnosis of virus infections.