Post-licensure comparison of the safety profile of diphtheria/tetanus/whole cell pertussis/haemophilus influenza type b vaccine and a 5-in-1 diphtheria/tetanus/acellular pertussis/haemophilus influenza type b/polio vaccine in the United Kingdom

General practitioner consultation data were used to compare the reactogenicity in infants of a 5-in-1 acellular pertussis vaccine (DTaP₅/Hib/IPV) introduced in the United Kingdom in 2004 to the 4-in-1 whole cell-pertussis vaccine (DTwP/Hib) that it replaced. For each vaccine the incidence in the week following vaccination was compared to other periods to obtain a relative incidence. A lower relative incidence of crying, fever and local reactions was seen with DTaP₅/Hib/IPV than DTwP/Hib. Although there were no other significant differences between vaccines the relative incidence was significantly above one on the day of vaccination for convulsions following DTwP/Hib and for apnoea/collapse following DTaP₅/Hib/IPV.     

Pharmacological evidence for an interaction between constituents (blend effect) of the Japanese-Sino medicine “Keishi-ka-zyutubu-tō” in neuromuscular blockade in diabetic mice

The pharmacological interaction between constituents of Keishi-ka-zyutubu-tō (composed of 7 crude drugs, namely peony, liquorice, jujube, cassia, ginger, Atractylodes lancea, and aconite), a medicine of Japanese-Sino origin, was investigated in in situ sciatic nerve-gastrocnemius muscle preparations using genetically dlabetic KK-CA^y mice. When administered intra-arterially, the drug caused a degree of inhibition of the diabetic neuromuscular junction 280 times greater than normal. The two constituents, peony-liquorice, were only 2.6 times more potent in diabetic muscles. When further combined with peony-liquorice, the potency ratio was increased 4.9 times for cassia, 5.9 times for ginger and 8.7 times for Atractylodes lancea. In combination with the representative compounds contained in the above crude drugs except for jujube, the potency ratio of paeoniflorin (PF) and glycyrrhizin (GLR) was increased 6.6 times for cinnamaldehyde, 6.1 times for [8]-gingerol and 14 times for β-eudesmol in diabetic muscles. Aconite potentiated the blocking effects of peony-liquorice to the same extent in diabetic muscles as in normal muscles. This tendency was also confirmed when mesaconitine was combined with PF-GLR. The single effect of β-eudesmol or [8]-gingerol was 5.2 times or 3.7 times more potent, respectively, on diabetic muscles than on normal muscles. Cinnamaldehyde or mesaconitine demonstrated the same degree of sensitivity in both diabetic and normal muscles. These results indicated that the preferentially more potent neuromuscular blocking effects of Keishi-ka-zyutubu-tō in diabetic muscles were mainly attributable to β-eudesmol, a major component of Atractylodes lancea.     

妥拉苏林辅助治疗婴幼儿肺炎合并心力衰竭的体会

对240例肺炎合并心力衰竭的患儿,按使用毛地黄制剂情况分为三组:单用毒毛旋花子素K组100例,单用妥拉苏林组40例,并用妥拉苏林与毒毛旋花子素K组100例。经对比观察,后者对患儿的心率减慢与肝脏回缩效果最好。     

Semi-mechanistic pharmacokinetic–pharmacodynamic modelling of antibiotic drug combinations

BackgroundDeriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic–pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens.AimsTo outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies.SourcesPubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations.ContentThirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens.ImplicationsSemi-mechanistic PKPD models allow for integration of knowledge on the interaction between antibiotics for various PK and PD profiles, and can account for associated variability within the population as well as parameter uncertainty. Decisions on suitable combination regimens can thereby be facilitated. We find the application of semi-mechanistic PKPD models to be essential for efficient development of antibiotic combination regimens that optimize bacterial killing and/or suppress resistance development.     

医学生就业与创业教育中的“六个结合”

适应高等医学教育发展的新形势,积极探索医学生就业与创业教育的新模式,提高医学人才的培养质量和毕业生的就业率,是一项系统工程.开展医学生就业与创业教育,应当坚持六个方面的结合,注重提高教育的针对性和实效性,帮助医学生树立正确的人生观、价值观和择业观,增强医学生综合素质和就业竞争力.     

Onset of antidepressant effect of olanzapine and olanzapine/fluoxetine combination in bipolar depression

OBJECTIVES: The current analysis investigated the onset of antidepressant effect of olanzapine/fluoxetine combination. METHODS: Data for these post hoc analyses were obtained from a clinical trial comparing olanzapine, placebo, and olanzapine/fluoxetine combination in bipolar depression (BD). Subjects were 833 patients with a DSM-IV diagnosis of bipolar I disorder, depressed. The Montgomery-Asberg Depression Rating Scale measured depressive symptoms. Multiple analytic methods were applied, including traditional (mean differences) analysis, pattern analysis, survival analysis of sustained response, mixed-effects regression, and area-under-the-curve analysis. RESULTS: Traditional analysis showed significantly greater improvement in depression scores at week 1 for olanzapine/fluoxetine combination versus placebo (-9.55 versus -5.08, p < 0.001) and for olanzapine versus placebo (-8.31 versus -5.08, p < 0.001). Pattern analysis revealed olanzapine/fluoxetine combination had a significantly greater percentage of early persistent responders than placebo or olanzapine (32.4% versus 12.7%, p < 0.001; and 18.3%, p < 0.05, respectively). Survival analysis showed a significantly shorter time to sustained response for the combination versus placebo (p < 0.001), for olanzapine versus placebo (p = 0.04), and for the combination versus olanzapine (p = 0.03). Mixed-effects regression analysis revealed a significant therapy-by-time interaction (p < 0.001). Early area-under-the-curve analysis revealed a significantly greater percentage of improvement for the combination versus placebo (26.7% versus 13.9%, p < 0.001) and for olanzapine versus placebo (22.0% versus 13.9%, p < 0.001). CONCLUSIONS: Based on consistent results from related methods of measuring onset, olanzapine/fluoxetine combination demonstrated rapid onset of antidepressant effect (within 7 days) compared to placebo that was sustained over 8 weeks of treatment in a sample of BD patients. Using multiple statistical techniques may help profile a drug's onset of effect.     

Spatio-temporal delivery of both intra- and extracellular toll-like receptor agonists for enhancing antigen-specific immune responses

For cancer immunotherapy, triggering toll-like receptors (TLRs) in dendritic cells (DCs) can potentiate antigen-based immune responses. Nevertheless, to generate robust and long-lived immune responses, a well-designed nanovaccine should consider different locations of TLRs on DCs and co-deliver both antigens and TLR agonist combinations to synergistically induce optimal antitumor immunity. Herein, we fabricated lipid-polymer hybrid nanoparticles (LPNPs) to spatio-temporally deliver model antigen ovalbumin (OVA) on the surface of the lipid layer, TLR4 agonist monophosphoryl lipid A (MPLA) within the lipid layer, and TLR7 agonist imiquimod (IMQ) in the polymer core to synergistically activate DCs by both extra- and intra-cellular TLRs for enhancing adaptive immune responses. LPNPs-based nanovaccines exhibited a narrow size distribution at the mean diameter of 133.23 nm and zeta potential of ?2.36 mV, showed a high OVA loading (around 70.83 μg/mg) and IMQ encapsulation efficiency (88.04%). Our data revealed that LPNPs-based nanovaccines showed great biocompatibility to immune cells and an excellent ability to enhance antigen internalization, thereby promoting DCs maturation and cytokines production. Compared to Free OVA, OVA-LPNPs promoted antigen uptake, lysosome escape, depot effect and migration to secondary lymphatic organs. In vivo immunization showed that IMQ-MPLA-OVA-LPNPs with dual agonists induced more powerful cellular and humoral immune responses. Moreover, prophylactic vaccination by IMQ-MPLA-OVA-LPNPs effectively suppressed tumor growth and increased survival efficacy. Hence, the nanovaccines we fabricated can effectively co-deliver antigens and different TLR agonists and realize coordinated stimulation of DCs in a spatio-temporal manner for enhanced immune responses, which provides a promising strategy for cancer immunotherapy.     

Safety Pharmacology Society: 9th Annual Meeting

The keynote presentation of the Safety Pharmacology (SP) Society 9th Annual Meeting addressed the urgency, for pharmaceutical organizations, to implement strategies for effectively communicating drug risks to all concerned stakeholders and, in particular, the general public. The application of chronobiology to SP investigational protocols can improve the search of drug-induced adverse effects. The Distinguished Service Award Lecture reviewed a life-long journey through trials and tribulations in the quest of the ever-distant scientific truth. The revision process of Directive 86/609/EC for improving animal welfare should be conducted with the purpose of maintaining a fair balance among animal protection, human health and research imperatives in order to prevent the migration of pharmaceutical activities outside Europe. Additional topics of interest were the behavioral, metabolic and cardiovascular problems experienced by small animals housed at the standard laboratory temperature. A technology for the automated collection of blood and urine samples in rats implanted with telemetry sensors was presented. Non-clinical, clinical, regulatory and legal aspects of abuse liability were expertly reviewed. The ‘degradability’ of pharmaceuticals into environment-friendly chemicals should be an actively searched and optimized feature of future pharmaceuticals in order to prevent drug pollution of ecosystems. Transgenic and diseased animal models should be selected whenever they can facilitate the determination of drug-induced adverse effects. SP strategies to investigate the safety of drug combination products were exemplified and analyzed in depth. The future of SP was proposed to lie not in the performance of regulatory studies of pharmacodynamic nature but in developing and early applying an array of screening assays for clearing clinical candidates against known drug-induced organ function injuries. In conclusion, the 2009 SP Society annual meeting offered a wealth of thought-provoking material to attendees for improving SP investigation strategies.     

升麻解毒药对在方剂中的作用

文章就升麻的解毒功效及其药对组合在方剂配伍中的作用,结合本草文献、实验研究和临床经验进行了论述。总结出升麻的解毒作用主要有解时疫疠毒、解疮疡斑疹肿毒、解虫毒和解药毒4个方面。并分别阐述了升麻配玄参、配生地黄、配大青、配黄连、配石膏、配虎杖、配鳖甲、配金银花和连翘、配甘草、配牛蒡子、配马蔺子、配射干、配牛蒡子和桔梗、配葛根、配黄芩、配黄柏、配芍药的意义。