Therapeutic Control Chart As A Tool To Aid Drug Monitoring. A Comparison Between The Acenocoumarol And Digoxin Laboratory Control.
INTROCASO G, RAGGI M, CAVALLERO A
Laboratory Medicine Service, Cardiological Center ´´Monzino´´, Milan, Italy
Background: Retrospective data of patients under oral anticoagulant (OA) and digoxin therapy were used to estimate a reference change using a statistical method. The cumulative probability allow us to obtain it for two consecutive measurements with p ≤ 0.05 preparing a therapeutic control chart (TCC). The present study was conducted to evaluate the statistical and clinical differences between the acenocoumarol and digoxin TCCs.
Methods: We compared two populations of patients under acenocoumarol anticoagulant (group 1) and digoxin (group 2) evaluated in our laboratory. It was calculated for each group a mean (X) and control limits: X+/-1σ and X+/-2σ (mean+/-standard deviation). For group 1 (N=323), forty-five patients without major (OA) therapy complications, with more international normalized ratio (INR) determinations in the therapeutic range (INR= 2-3) and with a normal distribution of INR values according to the Kurtosis and asymmetric coefficient, were selected. For group 2 (N=282), eighty-nine patients were considered with digossin results with normal distribution comprised from 0.8 to 2 ng/mL and borderline values.
Results: For acenocoumarol study (group 1) we found that the cumulative probability at X+/-1σ INR= 1.8 and at INR= 3 was p= 0.15 and p= 0.17, respectively. The (group 1) TCC has suggested that for results close to the therapeutic control limits, we needed at least two consecutive INR results to detect a significant over or under-anticoagulation (i.e. p 0.17x0.17= 0.02). For digoxin study (group 2), we observed that at therapeutic limit 0.8 ng/mL correspond a p= 0.27 instead at control limit equal to 2 ng/mL the probability became p= 0.04. This means that, at level of upper therapeutic limit is necessary only one measurement of digossin testing to define a risk of over administration.
Conclusions: 1) The therapeutic control chart with different cumulative probability could added analytical and clinical data to drug monitoring. The differences between the acenocoumarol and digoxin TCC could be explained through the different pharmacokinetic mechanisms. 2) The acenocoumarol TCC, requiring two control tests at level of therapeutic limits, has demonstrated the more complexity of anticoagulant therapy versus the digoxin therapy.
|
Reduction Of Surgical Site Infections During Paediatric Cardiac Surgery
IODICE F, KELLEHER A, SHEARER H
Royal Brompton Hospital, London, UK
Background: Surgical site infections (SSIs) are a substantial cause of morbidity, mortality, and of increased costs among hospitalized patients. Patients who develop SSIs are up to 60% more likely to spend time in the intensive care unit, 5 times more likely to be readmitted to the hospital and two times more likely to die than are patients without SSIs. (1) The objective of antimicrobial prophylaxis is to reach serum and tissue drug levels that exceed, throughout surgery, the MICs for the organisms most likely encountered. Timing of antibiotic administration is essential in achieving this goal. In order to achieve low SSIs rates the antimicrobial should be administered as near to the incision time as possible and within 60 minutes of incision. (2) The primary aim of our study was to identify our current antibiotic timing administration in pediatric cardiac surgical patients and determine subsequent interventions in order to improve our current practice.
Materials and Methods: We collected data for 27 children age range (10 days-16 years, mean 18 months), undergoing cardiac procedures. The following data was collected: shower/bath on day prior to surgery, completion time of intubation of line insertion and foley catheter positioning, time of incision, types and timing of antibiotic administration and type of surgical preparation.
Results:
Conclusions: The data collection on antibiotic timing is part of a project to reduce SSIs. Other interventions include preoperative washing on the ward, and improved wound surveillance. Currently the mean timing of our antibiotic administration falls within the desired range of 60 minutes from incision time, however we have noticed and extreme variations among different operators.
-
Dimick JB. Pronovost PJ, Cowan JA, et al. Variation in postoperative complication rates after high risk surgery in the US. Surgery 2003; 134 : 534-40
-
Bratzler DW, Houck P. Antimicrobial Prophylaxis for Surgery: An Advisory Statement from the National Surgical Infection Prevention Project Clinical Infectious Diseases 2004; 38:1706-15
|
Insulin Resistance: Between Myth And Reality
IONESCU-TÎRGOVIŞTE C
National Institute of Diabetes, Nutrition and Metabolic Diseases “Prof. NC Paulescu”, Bucharest, Romania.
Background: Almost invariably, during the last two decades it was stated that type 2 diabetes appears as a consequence of increased peripheral insulin resistance (considered to be the primordial factor), associated with a beta cell defect (considered to be secondary both chronologically and as pathogenic importance). There are perhaps few diabetes cases that evolve with a normal beta cell mass. Leaving behind the actual definition/classification of diabetes, we state that the diabetic syndrome is unitary by the decrease of the beta cell mass, considered to be a sine qua non condition for the decompensation of blood glucose regulation. The decrease of the beta cell mass is explained wither by an increased apoptosis or by a decreased regeneration or by an association of both mechanisms. Even if the studies of islets obtained from different diabetes animal models indicated an important capacity of regeneration, however, in human diabetes during adult life this regeneration seems to be quasi-inexistent and thus incapable to compensate an increased apoptosis. The cause of increased apoptosis in diabetes could be related to the secretory beta cell dysfunction expressed by the increase of proinsulin and pro-amylin incompletely processed in the endoplasmic reticulum of these cells. Both increased proinsulin and the amiloid transformation of amylin could trigger the pro-apoptotic beta cell mechanisms. The decrease of the beta cell mass is usually slow and blood glucose decompensation appears only when >50% of the initial beta cell mass is destroyed. Increased proinsulin can interfere with beta cell regeneration while the amiloidogenic transformation of amylin can lead to increased beta cell apoptosis mediated by the endoplasmic reticulum. Genetic studies based on the classical candidate gene methods as well as the modern studies based on the Genome Wide Scan (GWS) techniques, managed to identify a dozen genes involved in T2DM pathogenesis, almost all being somehow related to beta cell function. The assiduous investigation of peripheral insulin resistance genes had a predictably failure since an abstract concept based on mathematical equations (as is insulin-resistance) cannot be localized in the real human genome. Since the increasing prevalence of diabetes mellitus has to be explained by the intervention of some environmental factors (increase of caloric intake, especially of animal lipids and decrease of physical exercise, both capable to influence the transcription of some genes), the genetic factor (rather epigenetic) involved refers to the genetically determined limits of the complex mechanisms that ensure the energetic homeostasis of the human body. The constant surplus of fuels from the human energetic system rises problems of adaptation that were not encoded in the original genome. Inclusion of insulin resistance in this disorder seems to be improper.
Conclusions: Peripheral insulin-resistance exists and can be well illustrated by the absence of insulin receptors in the rare forms of extreme insulin-resistance with a well defined genetic basis. The absence of a related mechanism in type 2 diabetes explains the rhetoric question of Flores J.C. form a recent review (Diabetologia 51:1100-1110, 2008): “Where are the insulin resistance genes?”
|
New Features Of Antidepressant Drugs - Modification Of Histamine Kinetics
IRMAN-FLORJANC T, RAJTAR S
Deptartment of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Background: Antidepressant drugs (AD) exert their effects by affecting different targets. Detailed insight into the mode of action of AD could lead not only to better understanding their pharmacological effects but also to improve or expand current utilization of these drugs in clinical practice. Our studies were focused on the effects of AD, mainly amitriptyline, on histamine kinetics in experimental animals. Methods: Different types of in vitro and in vivo studies were performed, using cat, rat and guinea pig. Animals were pre-treated with amitriptyline or other AD, given intraperitoneally. In order to investigate effects on histamine kinetics animals received histamine liberator (compound 48/80) or i.v. injection of histamine and we followed plasma and/or blood histamine concentrations. In addition, the ability of amitriptyline to interfere in histamine metabolism was studied by following effects on the two main histamine degrading enzymes, diamino oxidase (DAO) and histamine-N-methyltransferase (HNMT) measured in rat and guinea pig tissues.
Results: AD interfere with histamine system through different mechanisms. Tricyclic AD inhibit histamine release and change plasma histamine kinetics after its secretion induced by histamine liberator in the rat. Amitriptyline and other types of AD also significantly lower the increase of plasma histamine levels induced by the injection of histamine and they change the pharmacokinetic profile of the amine in feline and rat plasma and blood. Amitriptyline decreases the rate of DAO release into plasma after the heparin activation in guinea pig. It also increases DAO and HNMT mRNA expression as well as the activity of both enzymes in guinea pig tissues while in the rat it does not affect DAO activity. In vitro studies indicate that amitriptyline change the activity of both histamine degrading enzymes in a concentration- and animal species- dependent manner.
Conclusion: Inhibition of histamine release and increased capacity of histamine degrading enzymes in tissues renders lower concentrations of histamine in the tissues which could inhibit development of allergic/inflammatory response. Rational taking advantage of the growing knowledge on pharmacological effects of amitriptyline and other antidepressants could enrich their use in clinical practice.
|
Synthesis and Evaluation of Highly Potent Antimicrobial Chromanyl-1,2,4-dithiazoles
ISHAR MPS1, RAJ T,1 BHATIA RKA, KUMAR R2
1Bio-Organic and Photochemistry Laboratory, Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar-143 005, Punjab, India. 2Department of Microbiology, Guru Nanak Dev University, Amritsar-143 005, Punjab, India
Background
A large number of hetrocycles of natural and synthetic origin exhibit valuable antimicrobial activity and include drugs such as fluconazole, ketoconazole etc. Recently, dithiazoles, have attracted considerable interest due their high fungitoxicity and of other related 1,2-dithia-heterocycles. On the other hand, a number of chromone derivatives also display antimicrobial activity. Therefore, it was decided to synthesize chromanyl-1,2,4-dithiazoles possessing both chromone and dithiazole moieties, and evaluate their anti-microbial activities.
Results:
Substituted 3-formylchromen-4-one (1a-f) were reacted with two equivalents of thio-benzamide (2) in dry xylene for 3 hours leading to 3-(5-phenyl-3H-[1,2,4]dithiazol-3-yl)chromen-4-one (3a-f) in high yields.
These chromanyl-1,2,4-dithiazoles (3a-f) were evaluated in vitro for antifungal and antibacterial activities. Antibacterial activities (percentage growth inhibition, MIC) were determined on Gve and Gve bacterial starins i.e., E.Coli, Pseudomonas aeruginosa, Shigella flexneri and Staphylococcus using ciprofloxacin and chloramphenicol as positive controls. Compounds 3a,d,e,f show very good antibacterial activity. Similarly, the antifungal activities (MICs) were determined using turbidimetry method on Aspergillus niger, Geotrichum candidum, Candida albicans and Candida tropicalis employing fluconazole as positive control. Some of the compounds display very high antifungal activity (3f, MIC= 5 M & 3b,d MIC= 28 M); fluconazole showed MIC= 9 M under similar conditions.
Conclusions
Compounds 3a,d,e,f shows vary good antibacterial activity and compounds 3f,b,d have high antifungal activity. In general, compound bearing F/Cl substitutents on chromone ring displayed high antifungal activity. These useful ‘leads’ can be evaluated for toxicity and developed further
|
Discovery Of A Novel Anti-MRSA Agent, TAK-599 (Ceftaroline Fosamil):
An N-Phosphono Water-Soluble Prodrug For Intravenous Injection
ISHIKAWA T, HASHIGUCHI S, AND IIZAWA Y
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd.
Background: Our research program was started with the aim of discovering clinically effective agents for methicillin-resistant Staphylococcus aureus (MRSA) infection.
Methods&Results: Considering the excellent safety and bactericidal properties of cephalosporin derivatives compared with those of the other classes of antibiotics, such as vancomycin (VCM), we examined chemical modifications of cefozopran. Considerable SAR studies led us to find potent anti-MRSA compound T-918251. Although T-91825 showed insufficient water-solubility (2.3 mg/mL) for parenteral administration, our efforts were rewarded with the discovery of a crystalline form of the N-phosphono prodrug, TAK-599, as an acetic acid solvate1. TAK-599 has not only a practical level of water solubility (>100 mg/mL, pH=7), but also good chemical stability in the crystalline state and in solution. In pharmacokinetic studies, TAK-599 was converted rapidly into the active form T-91825 in blood when administered intravenously to rats and monkeys. Considering both the pharmacokinetics of TAK-599 and the potent anti-MRSA activity of T-91825, TAK-599 exhibited excellent in vivo anti-MRSA efficacy, superior to that of VCM.
Conclusions: TAK-599 (ceftaroline fosamil) is a promising candidate for MRSA infection. Currently, clinical trials of ceftaroline fosamil are underway, in cooperation with Forest Laboratories, Inc.
Ref 1) Tomoyasu Ishikawa, et al. Bioorg. Med. Chem. 2003, 11, 2427.
|
Dehydroepiandrosterone (DHEA) Reduced Adiposity And Insulin Resistance
ISHIZUKA T, KAJITA K, IKEDA T, MORI I, FUJIOKA K, UNO Y, MORITA H
Department of General Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
Background: We have been shown that DHEA administration decreased insulin resistance in Otsuka Long Evans Fatty (OLETF) rats, hereditary obese type 2 diabetic animals derived from Long Evans Tokushima (LETO) rats. Considering that androgen receptor (AR) deficient mice represent obesity, AR acts to prevent fat accumulation in whole body. We have further examined the effect of DHEA on telomere length and preadipocyte distribution in adipose tissue. Moreover, we assessed the role of AR in DHEA-induced growth suppression in preadipocyte.
Methods: Two mg genomic DNA isolated from adipose tissue was digested with restriction enzyme, Hinf 1/Rsal, and then Southern analysis was performed to measure telomere length. Moreover, 3T3-L1 preadipocytes were treated with DHEA and testosterone (TEST) for 24 hr, and then cell proliferation was assayed with BrdU uptake. We also assessed the effect of flutamide, AR inhibitor, and fulvestrant, estrogen receptor (ER) inhibitor, on DHEA-induced reduction of cell growth utilizing siRNA.
Results: Treatment with 0.4% DHEA for 52 wk reduced body weight and fat weight, but not food consumption, in LETO and OLETF rats. Decreased telomere length was observed in genomic DNA isolated from adipose tissue in control OLETF, which was prevented with DHEA administration. These results indicated that accelerated cell division associated with obese adipose tissue resulted in rapid telomere shorting. These results suggested that DHEA-induced growth suppression in preadipocyte may lead to attenuate subsequent differentiation, which resulted in increased preadipocyte cell number. Actually, incubation with DHEA and TEST decreased BrdU uptake to the similar extent in 3T3-L1 preadipocyte. Pretreatment with flutamide, but not fulvestrant abolished this effect. AR siRNA also inhibited DHEA-induced decreases in BrdU uptake. Moreover, we found that no difference was observed between DHEA and TEST on cell growth. Our results of inhibitor and siRNA study revealed that this effect was mediated via AR.
Conclusions: These results suggested that DHEA-induced suppression of preadipocyte proliferation, might lead to anti-obesity, anti-senescence effects and improvement of insulin resistance.
|
Nature’s Magic: Antiteratogenic Potential Of Blue-Green Algae Spirulina
JAHANGIR SM1, ISLAM AFM S2
1 Chittagong Medical College, Chittagong, Bangladesh; 2 Comilla Medical College, Comilla, Bangladesh
Background: The rationale for search of a low cost, affordable antiteratogenic medicinal agent lies in the difficulties we face in the identification of human teratogen and the limitations of data derived from preclinical animal studies about teratogenic potential of a medicinal agent. Spirulina being a rich source of folic acid is a focus of interest in this respect as antiteratogenic effect of folic acid seems well established. Thus the objective of the study was to explore preventive role of Spirulina in hydrocortisone-induced cleft plate.
Methods: This study included 40 pregnant mice (10 mice per treatment, weighing 28 ± 3 g, mean ± SD). Incidence of cleft palate was compared in offsprings of mice treated as follows:
A) normal saline, B) hydrocortisone 166 mg/kg b.w., C) hydrocortisone followed by normal saline, D) hydrocortisone followed by spirulina suspension 150 mg/kg b.w. All doses were given in a volume of 1ml orally once daily through 11th to 14th day of gestation.
Results: Incidence of cleft palate in offsprings of mice treated simultaneously with hydrocortisone and spirulina was found to be significantly less compared to that in offsprings of mice treated otherwise (i.e. hydrocortisone and hydrocortisone+ normal saline). Selected parameter estimates are shown in the table (***a: p < .0001 vs. A; ***b : p<.0001 vs. B and C):
Conclusions: Spirulina, when administered through 11th to 14th day of gestation, prevented hydrocortisone-induced cleft palate in offsprings of mice.
|
Title: Caffeine Sets The Brain’s Excitability By Priming The Activation Of The Endogenous Cannabinoid System
ISOKAWA M
The University of Texas at Brownsville, Department of Biological Sciences, Brownsville, Texas 78520, U.S.A.
Caffeine is the world’s most popular psychoactive drug and stimulant. Caffeine affects vigilance, attention, mood and arousal, and may facilitate attentiveness and some forms of learning. Caffeine’s stimulant properties have been explained mainly due to its ability to interact with the adenosine receptor and induce a release of excitatory neurotransmitters, glutamate and dopamine.
Interestingly, caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens, the mesolimbic brain region that is directly involved in the primary reward effects of psychoactive drugs. This suggests that caffeine may share neurochemical properties with other prototypical drugs of abuse and psychostimulants, even if caffeine does not seem to cause obvious addictive symptomes reported in all prototypical drugs of abuse such as tolerance, craving, and relapse.
Neurobiological mechanisms that cause reward feelings and pleasure involve the endogenous cannabinoid (eCB) system in the brain. Most importantly, eCB participates in the common mechanisms underlying relapse to drug re-exposure by acting on the synaptic plasticity responsible for limbic emotional memory and learning. At cellular and molecular levels, eCB binds to the same receptor as marijuana and hashish bind to, which is the type 1 cannabinoid receptor (CB1R), and disinhibits mesolimbic reward neurons by blocking their GABAergic inhibitory neurotransmission. Disinhibited reward neurons cause a pleasure and reward feeling by releasing massive doses of dopamine.
Findings from my laboratory suggest that caffeine blocks GABAergic neurotransmission by regulating the brain’s endogenous cannabinoid system; more specifically, by facilitating the synthesis and release of eCB through cytosolic calcium regulatory mechanisms. This effect seems independent of previously reported caffeine’s ability to interfere with GABAergic transmission by competitively binding to multiple regulatory sites of the GABAA receptor, or by disrupting chloride transporters and shifting chloride equilibrium potential to reduce its conductance.
In my presentation, I will focuse on the caffeine’s potential ability to interact with the brain’s endogenous cannabinoid system; specifically on: 1) cellular and molecular mechanisms for the physiological interaction between these two psychoactive compounds (caffeine and eCB), and 2) how they may contribute to normal reward learning as well as maladaptive learning in drug addiction by modulating the release of GABA. This project is dedicated to new discoveries on the roles of caffeine in the synaptic function and plasticity of central neurons in health and diseases including substance abuse, maladaptive learning, and addiction; all of which are topics of great interest to a wide range of neuropharmacologists and clinical practitioners.
|
Hypothesis On The Physiological Significance Of The Expression Of The Drug Transporters Mdr1 And Abcg2 During Normal Tissue Regeneration And After Cancer Therapy
|
Dostları ilə paylaş: |
