Inhibition of Amyloid Peptide Fragment Aβ25–35 Fibrillogenesis and Toxicity by N‐Terminal β‐Amino Acid‐Containing Esapeptides: Is Taurine Moiety Essential for In Vivo Effects?

We report the synthesis and fibrillogenesis inhibiting activity of the new peptide derivatives 1-4, related to the pentapeptide Ac-LPFFD-NH(2) (iAβ5p), proposed by Soto and co-workers and widely recognized as one of the most active β-sheet breaker agents. The Aβ(25-35) fragment of the parent full-length Aβ(1-42) was used as fibrillogenesis model. The activity of peptide derivatives 1-4 was tested in vitro by thioflavin T binding assay, far UV CD spectroscopy, and scanning electron microscopy. Their ability to hinder the toxic effect of Aβ(25-35) in vivo was studied by monitoring the viability of human SH-SY5Y neuroblastoma cells and the prevention of superoxide anion radical release from BV2 microglial cells. The results point to a favourable role in the fibrillogenesis inhibitory activity of the sulphonamide junction for compounds 1 and 2, containing an N,N-dimethyltaurine and a taurine amino-terminal moiety, respectively. Furthermore, compounds 1 and 2 show a significant protective effect on cell viability, rescuing the cells from the toxicity exerted by Aβ(25-35) treatment.     

Medicinal cannabis: is Δ9–tetrahydrocannabinol necessary for all its effects?

Cannabis is under clinical investigation to assess its potential for medicinal use, but the question arises as to whether there is any advantage in using cannabis extracts compared with isolated Delta9-trans-tetrahydrocannabinol (Delta9THC), the major psychoactive component. We have compared the effect of a standardized cannabis extract (SCE) with pure Delta9THC, at matched concentrations of Delta9THC, and also with a Delta9THC-free extract (Delta9THC-free SCE), using two cannabinoid-sensitive models, a mouse model of multiple sclerosis (MS), and an in-vitro rat brain slice model of epilepsy. Whilst SCE inhibited spasticity in the mouse model of MS to a comparable level, it caused a more rapid onset of muscle relaxation, and a reduction in the time to maximum effect compared with Delta9THC alone. The Delta9THC-free extract or cannabidiol (CBD) caused no inhibition of spasticity. However, in the in-vitro epilepsy model, in which sustained epileptiform seizures were induced by the muscarinic receptor agonist oxotremorine-M in immature rat piriform cortical brain slices, SCE was a more potent and again more rapidly-acting anticonvulsant than isolated Delta9THC, but in this model, the Delta9THC-free extract also exhibited anticonvulsant activity. Cannabidiol did not inhibit seizures, nor did it modulate the activity of Delta9THC in this model. Therefore, as far as some actions of cannabis were concerned (e.g. antispasticity), Delta9THC was the active constituent, which might be modified by the presence of other components. However, for other effects (e.g. anticonvulsant properties) Delta9THC, although active, might not be necessary for the observed effect. Above all, these results demonstrated that not all of the therapeutic actions of cannabis herb might be due to the Delta9THC content.     

Is a 9‐month treatment sufficient in tuberculous enterocolitis? A prospective,randomized, single‐centre study

BACKGROUND: Tuberculosis has increased in parallel with the acquired immunodeficiency syndrome epidemic and the use of immunosuppressive therapy, and the growing incidence of extra-pulmonary tuberculosis, especially with intestinal involvement, reflects this trend. However, the duration of anti-tuberculous therapy has not been clarified in intestinal tuberculosis. AIM: To compare the efficacy of different treatment durations in tuberculous enterocolitis in terms of response and recurrence rates. METHODS: Forty patients with tuberculous enterocolitis were randomized prospectively: 22 patients into a 9-month and 18 into a 15-month group. Diagnosis was made either by colonoscopic findings of discrete ulcers and histopathological findings of caseating granuloma and/or acid-fast bacilli, or by clinical improvement after therapeutic trial. Patients were followed up with colonoscopy every other month until complete response or treatment completion, and then every 6 months for 1 year and annually. Complete response was defined as a resolution of symptoms and active tuberculosis by colonoscopy. RESULTS: Complete response was obtained in all patients in both groups. Two patients in the 9-month group and one in the 15-month group underwent operation due to intestinal obstruction and perianal fistula, respectively. No recurrence of active intestinal tuberculosis occurred during the follow-up period in either group. CONCLUSIONS: Tuberculous enterocolitis can be managed by 9-month chemotherapy without disease recurrence. Further investigations are needed in immunocompromised patients.     

Is the 5‐HT2C Receptor a Therapeutic Target in Cerebral Ischaemia?

This study examines the effect of a 5‐HT_2C agonist (RO 60–0175, (s)‐2‐(chloro‐5‐fluoro‐indol‐1‐yl)‐1‐methylethylamine) and a 5‐HT_2C antagonist (RO 43–0440, benzofuran‐2‐carboxamidine) for neuroprotective activity in a rat model of global cerebral ischaemia. A mini‐osmotic pump implanted subcutaneously delivered 0.25 mg/kg/hr. Seven days after ischaemia the rats were sacrificed and the damage in the CA1 pyramidal cell layer in hippocampus was estimated and the treated groups were compared with vehicle groups. Pretreatment with the 5‐HT_2C agonist RO 60–0175 significantly increased the damage, whereas the 5‐HT_2C antagonist RO 43–0440 had no effect on the cell damage. Measurement of the core temperature in a RO 60–0175‐treated group of rats revealed no effect compared to a vehicle‐treated group. Thus the aggravation of damage in the RO 60–0175‐treated group cannot be explained by temperature effect. Our data do not indicate the 5‐HT_2C receptor as a therapeutic target in cerebral ischaemia.     

Is there a role for adjuvant high-dose interferon-alpha-2b in the management of melanoma?

The knowledge that melanoma is susceptible to attack by the host's immune system has resulted in the testing of a variety of immunotherapies. Interferon-alpha-2b, which has several anti-tumour mechanisms including an antiproliferative effect, an anti-angiogenesis effect, the enhancement of natural-killer cell activity and the upregulation of tumour antigen presentation, has shown tremendous potential. Early trials using low-dose and intermediate-dose regimens demonstrated no benefit to survival. However, the Eastern Cooperative Oncology Group trial EST 1684, showed that a high-dose regimen involving an induction phase of intravenous interferon-alpha-2b 20 MU/m(2) 5 days a week for 4 weeks, followed by a maintenance phase of subcutaneous 10 MU/m(2) 3 days a week for the remainder of a year, led to significant improvements in both disease-free and overall survival compared with observation. On the basis of these results, the US FDA approved high-dose interferon-alpha-2b for the post-surgical adjuvant therapy of high-risk melanoma. Unfortunately, the results of subsequent trials involving high-dose interferon-alpha-2b have not been as clear, and its role in the adjuvant treatment of melanoma remains controversial. Concerns remain regarding the design and interpretation of the clinical trials, the cost and toxicity of treatment, and the appropriate selection of patients who should be treated. This article reviews the existing data and attempt to address the arguments for and against a role for adjuvant high-dose interferon-alpha-2b in the management of melanoma.     

Is nose‐to‐brain transport of drugs in man a reality?

The blood-brain barrier that segregates the brain interstitial fluid from the circulating blood provides an efficient barrier for the diffusion of most, especially polar, drugs from the blood to receptors in the central nervous system (CNS). Hence limitations are evident in the treatment of CNS diseases, such as Parkinson's and Alzheimer's diseases, especially exploiting neuropeptides and similar polar and large molecular weight drugs. In recent years interest has been expressed in the use of the nasal route for delivery of drugs to the brain, exploiting the olfactory pathway. A wealth of studies has reported proof of nose-to-brain delivery of a range of different drugs in animal models, such as the rat. Studies in man have mostly compared the pharmacological effects (e.g. brain functions) of nasally applied drugs with parenterally applied drugs and have shown a distinct indication of direct nose-to-brain transport. Recent studies in volunteers involving cerebrospinal fluid sampling, blood sampling and pharmacokinetic analysis after nasal, and in some instances parenteral administration of different drugs, have in my opinion confirmed the likely existence of a direct pathway from nose to brain.     

Is miR‐34a a Well‐equipped Swordsman to Conquer Temple of Molecular Oncology?

Overwhelmingly increasing advancements in miRNA biology have opened new avenues for pharmaceutical companies to initiate studies on designing effective, safe, and therapeutically active candidates using miRNA mimetics and miRNA inhibitors. In accordance with this approach, development of miravirsen and SPC3649, an LNA‐based (locked nucleic acid) antisense molecule against miR‐122, to treat hepatitis C has sparked interest in identifying most efficient microRNAs for journey from bench‐top toward pharmaceutical industry and breakthroughs in delivery technology will pave the way to ‘final frontier’. MRX34, a liposome‐formulated mimic of miR‐34 for treatment of metastatic cancer with liver involvement and unresectable primary liver cancer, has also entered in clinical trial. There is a successive increase in the research work related to miR‐34 biology and miRNA regulation of modulators of intracellular signaling cascades. We partition this review into how miR‐34a is regulated by different proteins and how Wnt‐ and TGF‐induced intracellular signaling cascades are modulated by miR‐34a. In this review, we bring to limelight how miR‐34a regulates its target genes to induce apoptosis and inhibit cell proliferation as evidenced by in vitro and in vivo analysis. We also discuss miR‐34 regulation of PDGFR and c‐MET and recent advancements in nanotechnologically delivered miR‐34a. Spotlight is also set on modulation of chemotherapeutic sensitivity by miR‐34a in cancer cells using reconstruction studies. Clinical trial of miR‐34 is indicative of its tremendous potential, and continuous cutting research will prove to be effective in efficiently translating laboratory findings into clinically effective therapeutics.     

A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

A retrospective study was conducted to assess our 10‐year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (C_min) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of C_min was set between 2 and 7 mg/L (underexposure, C_min < 2 mg/L; overexposure, C_min > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid C_min. One thousand and forty‐nine patients had 2484 linezolid C_min assessed during treatment with conventional doses. Median (IQR) linezolid C_min was 5.08 mg/L (2.78–8.52 mg/L). Linezolid C_min was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCL_C‐G estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124–1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCL_C‐G estimates >100 mL/min. (OR 3.046; 95% CI 2.234–4.152, p < 0.001). Linezolid C_min was not correlated linearly with CrCL_C‐G (R² = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid C_min variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.     

Is there a role for day‐to‐day home blood pressure variability in guiding management of hypertension?

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Methylamphetamine synthesis: Does an alteration in synthesis conditions affect the δ13C, δ15N and δ2H stable isotope ratio values of the product?

Conventional chemical profiling of methylamphetamine has long been employed by national forensic laboratories to determine the synthetic route and where possible the precursor chemicals used in its manufacture. This laboratory has been studying the use of stable isotope ratio mass spectrometry (IRMS) analysis as a complementary technique to conventional chemical profiling of fully synthetic illicit drugs such as methylamphetamine. As part of these investigations the stable carbon (δ(13) C), nitrogen (δ(15) N), and hydrogen (δ(2) H) isotope values in the precursor chemicals of ephedrine and pseudoephedrine and the resulting methylamphetamine end-products have been measured to determine the synthetic origins of methylamphetamine. In this study, results are presented for δ(13) C, δ(15) N, and δ(2) H values in methylamphetamine synthesized from ephedrine and pseudoephedrine by two synthetic routes with varying experimental parameters. It was demonstrated that varying parameters, such as stoichiometry, reaction temperature, reaction time, and reaction pressure, had no effect on the δ(13) C, δ(15) N, and δ(2) H isotope values of the final methylamphetamine product, within measurement uncertainty. Therefore the value of the IRMS technique in identifying the synthetic origin of precursors, such as ephedrine and pseudoephedrine, is not compromised by the potential variation in synthetic method that is expected from one batch to the next, especially in clandestine laboratories where manufacture can occur without stringent quality control of reactions.     

Preclinical pharmacology of mGlu2/3 receptor agonists: novel agents for schizophrenia?

Agonists for mGlu2/3 receptors decrease the evoked release of glutamate at certain (ie. forebrain / limbic) glutamatergic synapses, indicating that the functional role of mGlu2 and/or mGlu3 receptors is to suppress glutamate excitations. This offers a mechanism for dampening glutamate excitation under pathological states resulting from excessive glutamate release. Based, in part, on the psychotomimetic actions of phencyclidine (PCP)- like drugs, excessive or pathological glutamate release has been implicated in a number of clinical conditions including psychosis. With this in mind, the pharmacology of multiple mGlu2/3 receptor agonists have been investigated in PCP treated rats. Agonists for mGlu2/3 receptors such as LY354740 and LY379268 have been shown to block certain behavioral responses to PCP in rats. The effects of mGlu2/3 agonists on PCP-induced behaviors are blocked by a low doses of a selective mGlu2/3 receptor antagonist, indicating that these actions are mediated via mGlu2/3 receptors. In addition, mGlu2/3 agonists potently suppress glutamate release in rat prefrontal cortex, as reflected by excitatory post-synaptic potentials (EPSPs) induced by serotonin (5-HT) acting on 5HT(2A) receptors. These actions of LY354740 and LY379268 are also blocked by a selective mGlu2/3 antagonist. Atypical antipsychotic drugs such as clozapine also suppress 5-HT-induced EPSPs in this brain region, thus suggesting a common pathway for the actions of atypical antipsychotic drugs and mGlu2/3 receptor agonists. As glutamatergic dysfunction has been implicated in psychotic states and possibly in the etiology of schizophrenia, clinical studies with mGlu2/3 agonists may be warranted to further explore the validity of the glutamatergic hypothesis of schizophrenia.     

Cannabinoid findings in children hair – what do they really tell us? An assessment in the light of three different analytical methods with focus on interpretation of Δ9‐tetrahydrocannabinolic acid A concentrations

Hair analysis for drugs and drugs of abuse is increasingly applied in child protection cases. To determine the potential risk to a child living in a household where drugs are consumed, not only can the hair of the parents be analyzed but also the hair of the child. In the case of hair analysis for cannabinoids, the differentiation between external contamination and systemic uptake is particularly difficult, since the drug is quite often handled extensively prior to consumption (e.g. when preparing a joint) and smoke causes a further risk for an external contamination. Δ9‐tetrahydrocannabinolic acid A (THCA‐A), the non‐psychoactive biogenetic precursor of Δ9‐tetrahydrocannabinol (THC), is a suitable marker for external contamination since it is not incorporated into the hair matrix through the bloodstream in relevant amounts. In the presented study, hair samples from 41 children, 4 teenagers, and 34 drug‐consuming parents were analyzed for THCA‐A, THC and cannabinol (CBN) applying methanolic extraction and a fully validated liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method (Method 1). For comparison, a part of the samples was also analyzed applying alkaline hydrolysis followed by liquid/liquid extraction and gas chromatography‐mass spectrometry (GC‐M)S (Method 2), or by headspace‐solid phase microextraction‐gas chromatography‐mass spectrometry (HS‐SPME‐GC‐MS) (Method 3). Furthermore, 458 seized marihuana samples and 180 seized hashish samples were analyzed for the same cannabinoids by gas‐chromatography‐flame ionization detector (GC‐FID). In all but one of the hair samples, the concentration of THCA‐A was higher than the concentration of THC and in 14 cases no THC could be detected despite the presence of THCA‐A, suggesting that in almost all cases a significant external contamination had occurred. Within‐family comparison showed a higher THCA‐A/THC ratio in hair of children than of their consuming caregivers. Mean and median of this ratio of all hair samples (6.7 and 4.2) were between those of marihuana (11.0 and 8.3) and hashish (2.8 and 2.1) with a large variation in all samples. Comparison of the Methods 1 to 3 showed clearly that the choice of the analytical procedure has a strong influence on the quantitative results, mainly because of decarboxylation of THCA‐A during hair hydrolysis by NaOH and other analytical steps, which lead to artifactually elevated THC concentrations. In conclusion, these findings suggest that the major part of the cannabinoids detected in the hair samples from children arose from an external contamination through ‘passive’ transfer by e.g. contaminated hands or surfaces and not from inhalation or deposition of side stream smoke. Copyright © 2014 John Wiley & Sons, Ltd.