History of haemophilia

Summary.  Haemophilia, an ancient disease, now has sophisticated methods for diagnosis and treatment. The genetically missing factors can now be supplied by fractionation of human-derived (HD) plasma or with recombinant technology (r). Making therapeutic choices is complicated by past transfusion-transmitted diseases. HD and r products now have similar safety profiles. Several diseases have only HD products for treatment. These products remain important in our treatment armamentarium.     

Calcineurin Inhibitor Withdrawal from Sirolimus-Based Therapy in Kidney Transplantation: A Systematic Review of Randomized Trials

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function, however, it also carries risk of acute rejection. We conducted a systematic review of randomized trials that involved CNI withdrawal from a sirolimus-based immunosuppressive regimen. The search strategy yielded six trials (n = 1047 patients) reported in eight publications. CNI withdrawal from sirolimus-based therapy, was associated with an increased risk of acute rejection (risk difference, 6%; 95% CI 2-10%, p = 0.002) but a higher creatinine clearance (mean difference, 7.49 mL/min; 95% CI 5.08-9.89 mL/min, p < 0.00001) at 1 year compared to continued CNI and sirolimus therapy. Graft loss (relative risk, 0.87; 95% CI 0.46-1.64, p = 0.66) and death (relative risk, 0.88; CI 0.40-1.96, p = 0.76) were similar in both groups at 1 year. Hypertension was significantly reduced in the CNI withdrawal group (relative risk, 0.56; 95% CI 0.40-0.78, p = 0.0006). CNI withdrawal from sirolimus-based therapy is associated with an increased risk of acute rejection in the short term with a significant improvement in renal function and a reduction in hypertension. Longer follow-up is needed to determine if these changes will result in a significant improvement in patient and graft survival.     

Poststroke DNA immunization against neurite growth inhibitors is beneficial to the recovery from local cerebral ischemia in rats

BACKGROUND： Inhibitory signals, i.e. neurite growth inhibitors （NGIs）, presenting on central nervous system （CNS） myelin have been shown to play a crucial role in inhibiting lesioned axonal sprouting and leading to less functional recovery. Vaccines targeting NGIs may provide multifactorial protection against brain insults by overcoming the inhibitory effects of these NGIs and boosting the body＇s immune repair mechanisms. OBJECTIVE： To evaluate the effect of poststroke DNA immunization against NGIs on the rehabilitation for sensorimotor function of rat models of local cerebral ischemia. DESIGN： Completely randomized grouping design, and controlled experiment. SETTING： Brain Injury Research Laboratory, Department of Neurosurgery, National Neuroscience Institute, Singapore. MATERIALS： Sixty adult male Sprague-Dawley rats ranging in age from 45 to 120 days and in weight from 180 to 250 grams were provided by Animal Center of Department of Anatomy, Faculty of Medicine, National University of Singapore. pcDNA3.1（＋）-neurite growth inhibitors （pcDNA-NGIs） a gift was provided by Dr. Xiao from Department of Clinical Research, Singapore General Hospital, Singapore. METHODS： The experiment was carried out at Brain Injury Research Laboratory, Department of Neurosurgery, National Neuroscience Institute, Singapore from August 2003 to April 2005. （1）The involved rats were randomized into 3 groups： pcDNA-NGIs group （group A）, pcDNA3.1 （＋） group （group B） and model group （group C）, with 20 rats in each group. Left focal cerebral ischemia （FCI） was permanently induced through middle cerebral artery occlusion （MCAO） with the assistance of an operating microscope. Successful MCAO was determined by a 20% decrease to baseline in the ipsilateral cerebral blood flow. 100 μg of pcDNA-NGIs eluted in phosphate-buffered saline （PBS） was intramuscularly injected into the tibial muscle once a week after MCAO for 6 weeks in group A. As control, pcDNA3.1 （＋） was also administrated in the same way in group B and nothing was administrated in group C. （2） The modified neurological severity score （mNSS）, a composite of motor, sensory, reflex and balance tests, was used to test the sensorimotor deficit. The mNSS was graded on a scale of 0 - 18, i.e. normal score was 0, maximal deficit score was 18, and 1 point was warded for the inability to perform the tasks or the lack of a tested reflex. （3） The newly generated axons of corticorubral projection were traced by stereotaxic guided injection of 100 g/L biotinylated dextran amine. Rats were sacrificed two weeks after tracing, and cryostat coronal sections of midbrains （30μm） were reacted to BDA according to the manufacturer＇s instruction by the free-floating method. Images were captured on a DM RXA2 LEICA Microscope with a Spot Digital Camera system （Germany）, and the numbers of labeled axons on the denervated side in four standard coronal sections including the red nucleus were manually quantified. MAIN OUTCOME MEASURES： （1） The number of newly generated axons of corticorubral projection. （2）The improvement in sensorimotor deficit. RESULTS： All the involved 60 rats entered the stage of final analysis. （1） The number of newly generated axons of corticorubral projection of rats： Only ipsilateral axons of CRP were noted with little evidence of fibers crossing to the contralateral red nucleus in rats of groups B and C. More BDA-positive fibers crossing the midline and terminating in the contralateral red nucleus in appropriate target areas mirroring the non-differentiated red nucleus were found in rats of group A. Quantitative analysis showed that BDA-labeled axons in the denervated side of rats in group A were more than those in group B （P 〈 0.05）. （2） Improvement in sensorimotor deficit of rats： At 2 weeks after immunization, significant improvement in sensorimotor deficit was found in rats of group A. There were significant differences of improvement in sensorimotor deficit of rats between group A and group B or group C at 12 and 14 weeks after immunization （P 〈 0.05）. CONCLUSION： （1） Poststroke DNA immunization against NGIs leads to increased sensorimotor recovery following FCI and compensatory newly growth of axons from corticorubral projection.     

Cholinergic therapy in dementia

After reviewing the evidence for cholinergic pathology in Alzheimer's disease and related disorders, this paper reviews strategies for treating dementia using cholinomimetic drugs. Special attention is paid to cholinesterase inhibitors, particularly tacrine, the drug recently approved by the FDA. New studies suggesting that muscarinic and nicotinic cholinergic receptor active drugs may be more effective will be reviewed. Brief mention will be made of strategies to slow the progression of Alzheimer's disease.     

预防肝硬化上消化道出血的临床研究

目的　探讨普萘洛尔和低剂量兰索拉唑长期维持治疗对预防肝硬化门脉高压消化道出血的疗效。方法　1 1 9例肝硬化门脉高压患者随机分为 3组 :Ⅰ组 :给予口服普萘洛尔加上护肝治疗。Ⅱ组 :联合给予低剂量兰索拉唑和普萘洛尔。Ⅲ组 :仅给予护肝治疗。兰索拉唑维持服药 6个月 ,普萘洛尔及一般对症治疗维持 1年。观察治疗前后各组患者所伴发溃疡、门脉高压性胃病 (PHG)、急性胃黏膜病变 (AGML)情况 (发生率 ) ,各组消化道出血的复发率、门静脉直径 (PVD)、脾静脉直径 (SVD)的变化。结果　经 1年观察 ,结果显示 ,普萘洛尔组、联合治疗组、对照组出血的复发率分别为 1 5 0 %、2 2 %、48 5 % ,组Ⅰ、组Ⅱ复发率显著低于组Ⅲ ,同时 ,组Ⅰ与组Ⅱ间的差异有显著性意义。治疗可见组Ⅰ、组Ⅱ患者所伴发的溃疡、PHG、AGML明显改善 ,PVD、SVD缩小。结论　普萘洛尔组联合抑制酸维持治疗 ,可预防引起消化道出血多种病因 ,较单用普萘洛尔的疗效好     

Cholinergic balance in dementia with Lewy bodies: reversible worsening of Parkinsonism at rivastigmine dosage modulation

We describe a patient with probable dementia with Lewy bodies (DLB) whose Parkinsonism worsened after administration of rivastigmine within the therapeutic dose range. Some extrapyramidal signs (EPS) then reversed to pre-treatment level after rivastigmine dose reduction. We draw attention to the need of EPS monitoring during titration of cholinesterase inhibitors in patients with DLB. This is the first report to our knowledge of iatrogenic worsening of Parkinsonism which was successfully managed by dose reduction.

---

Sommario Si descrive il caso di un paziente affetto da Demenza a corpi di Lewy (Dementia with Lewy Bodies, DLB) probabile, in cui si è assistito ad un peggioramento del parkinsonismo dopo somministrazione di rivastigmina a dosi terapeutiche. Alcuni segni extrapiramidali sono regrediti al livello pre-trattamento con una riduzione posologica di rivastigmina. Si sottolinea la necessità di un monitoraggio dei segni extrapiramidali durante la titolazione della terapia con inibitori dell’acetilcolinesterasi cerebrale in pazienti con DLB. Questo è il primo caso descritto, a nostra conoscenza, di un peggioramento iatrogeno di parkinsonismo efficacemente gestito con una riduzione posologica della terapia con rivastigmina.

     

Synthesis of a new hydroxyethylene dipeptide isostere Phe ψ[CH2CH(OH)]Phe as HIV-1 protease inhibitor

A new type of pseudodipeptide isostere exampled by Phe ψ[CH2CH(OH)]Phe was synthesized from phenylalanine. The H]V protease inhibitory activity (IC50) of Noa-His-Pheψ[CH2CH(OH)]Phe-Ile-Amp was 0. 8 pmol·L-1.     

Pharmacology of KB‐R7943: A Na+–Ca2+ exchange inhibitor

The Na⁺–Ca²⁺ exchange (NCX) system plays a pivotal role in regulating intracellular Ca²⁺ concentration in cardiomyocytes, neuronal cells, kidney and a variety of other cells. It performs a particularly important function in regulating cardiac contractility and electrical activity. One of the leading NCX inhibitors is KB‐R9743 (KBR) that appears to exhibit selectivity for Ca²⁺‐influx‐mode NCX activity (reverse mode of NCX). In this article we reviewed pharmacology of KBR and provide a brief summary of studies with other NCX inhibitors, such as SEA0400 (SEA) and SN‐6 (SN). Potential clinical usefulness of KBR and other NCX inhibitors is still controversial but the reviewed findings may be helpful in designing more selective and clinically useful NCX inhibitors for the treatment of cardiac, neuronal and kidney diseases.     

Activation of guinea pig eosinophil respiratory burst by leukotriene B4: role of protein kinase C

Leukotriene B4 (LTB4) and the protein kinase C activator, 4-beta-phorbol dibutyrate (PDBu), both induced a pronounced and concentration-dependent stimulation of hydrogen peroxide (H2O2) generation by purified guinea pig peritoneal eosinophils in the concentration range 1 nM-1 microM. The LTB4 response was inhibited competitively by the specific LTB4 receptor antagonist, U-75302, with a KB of 25 nM, while the concentration-response curves for both stimuli were shifted rightwards (3.8-fold and 2.8-fold for LTB4 and PDBu, respectively) by the competitive protein kinase C inhibitor, 1-O-hexadecyl-2-O-methylglycerol at a concentration of 300 microM. LTB4 appears, therefore, to induce respiratory burst in eosinophils via a receptor-mediated mechanism involving protein kinase C.     

Acute toxicity of two pyrethroids,permethrin, and cypermethrin in neonatal and adult rats

The present study aims specifically at obtaining a comparison of the acute toxicity of cypermethrin (CY), a type I pyrethroid, and permethrin (PERM), a type II pyrethroid, administered orally as a single dose to neonatal and adult rats, and at assessing the importance of pyrethroid biotransformation in CY and PERM toxicity through use of drug metabolism inhibitors. Our experiments show that CY is more toxic than PERM to adult and neonatal rats. The sensitivity of neonatal rats both to CY and to PERM toxicity is higher, the younger the animals. CY is much more toxic than PERM in the neonatal rat, compared with the adult. In rats aged 8, 16, and 21 days, pretreatment with piperonil butoxide (PB), a monooxygenase inhibitor, or with tri-o-tolyl phosphate (TOTP), an esterase inhibitor, does not produce significant variations in the lethal effects of CY and PERM. Instead, in the adult rats, a significant increase in CY (X²=5.97;p<0.05) and PERM (X²=4.37;p<0.05) mortality occurred in rats pretreated with esterase inhibitors, whereas no increase in CY and PERM toxicity was found in adult animals pretreated with monooxygenase inhibitor. It was concluded that the higher level of sensitivity of the neonate rat to pyrethroid toxicity is probably due to incomplete development of the enzymes which catalyze the metabolism of pyrethroids in the liver of young animals. It is suggested that ester hydrolysis is an important pyrethroids detoxification reaction in the adult rat.