Effects of PEG-electrolyte (colyte) lavage on serum acetaminophen concentrations

The purpose of this study was to evaluate whole gut lavage with polyethylene glycol electrolyte solution (Colyte), as a potentially adjunctive measure in lowering serum acetaminophen levels. The effect of bowel lavage was evaluated on serial serum acetaminophen concentrations after 2-g and 4-g doses in 7 and 12 male patients, respectively. Mean peak level of serum acetaminophen after 2 g (60 min after intake) was not significantly lowered by bowel lavage. After 4 g, peak acetaminophen serum levels were significantly lower after bowel lavage (65.4% of controls,P<0.001). Urinary concentrations of the mercapturic acid conjugate of the toxic metabolite were also significantly reduced by lavage (55% after 2 g and 45% after 4 g,P<0.01). Activated charcoal given orally after administration of 4 g of acetaminophen had no significant effect on peak serum levels and had no additive effect on lavage. These studies suggest that rapic, complete bowel lavage with a polyethylene glycol electrolyte solution may be beneficial as an adjunct to the treatment of the acetaminophen intoxication.The project was supported by VA research grant 0030.2.This work was presented in part at the annual meeting of the American Gastroenterology Association in New Orleans, May 1991.     

两种非甾体类抗炎药对清醒状态血管源性头痛模型大鼠颅内Fos表达的影响

目的：通过电刺激大鼠上矢状窦硬脑膜建立血管源性头痛清醒动物模型,观察模型动物Fos阳性神经元在三叉神经节及三叉神经脊束核尾侧亚核的分布情况,以及非甾体类抗炎药对乙酰氨基酚及布洛芬对清醒大鼠颅内三叉神经节及三叉神经脊束核尾侧亚核Fos阳性细胞的变化。方法：30只雄性SD大鼠随机分为对照组（生理盐水组）、对乙酰氨基酚组、布洛芬组,每组给药后50分钟分别给予频率为20Hz、电流为3-5mA和脉宽为0.25ms的电刺激,刺激后给予大鼠灌注固定取脑,在颅内取三叉神经节及三叉神经脊束核尾侧亚核制作石蜡切片,利用Image J软件对阳性细胞进行计数统计。结果：电刺激后盐水组与非甾体类药物组在双侧三叉神经节、三叉神经脊束核尾侧亚核Fos蛋白表达的差异具有显著统计学意义,对乙酰氨基酚组与布洛芬组在双侧三叉神经节、三叉神经脊束核尾侧亚核Fos蛋白表达未见统计学差异。结论：给予非甾体类抗炎前后在双侧三叉神经节、三叉神经脊束核尾侧亚核的Fos表达的改变提示三叉神经节、三叉神经脊束核尾侧亚核参与了疼痛的传递和表达以及药物对疼痛控制的药理过程。     

Efficacy and Speed of Onset of Pain Relief of Fast-Dissolving Paracetamol on Postsurgical Dental Pain: Two Randomized,Single-Dose,Double-Blind,Placebo-Controlled Clinical Studies

Background

Paracetamol (APAP), also known as acetaminophen, is the most commonly used over-the-counter analgesic for the treatment of mild-to-moderate pain. However, the speed of onset of pain relief is limited mainly to the standard, immediate-release formulation. Efficacy and speed of onset of pain relief are critical in acute pain situations such as postsurgical dental pain, because reducing pain can improve clinical outcome and reduce the risk of transition from acute pain to more chronic pain. Efficacy and rapid onset also reduce the risk of excessive dosing with the analgesic.

Objective

We sought to investigate the dose–response efficacy and speed of onset of pain relief of a fast-dissolving APAP formulation compared with lower doses of APAP and placebo in dental patients after impacted third molar extraction.

Methods

Two single-center, single-dose, randomized, placebo-controlled, double-blind, double-dummy, parallel-group studies (Study I and Study II) were conducted to evaluate the efficacy and speed of onset of pain relief of different doses of a fast-dissolving APAP tablet (FD-APAP), standard APAP, and placebo in patients with postsurgical dental pain following third molar extraction. In Study I, a single dose of FD-APAP 1000 mg, FD-APAP 500 mg, or placebo was given to 300 patients; in Study II, a single dose of FD-APAP 1000 mg, standard APAP 650 mg, or placebo was given to 401 pateints. All 701 patients from both studies were included in the analysis and safety assessment.

Results

FD-APAP 1000 mg demonstrated significantly greater effect compared with FD-APAP 500 mg, APAP 650 mg, and placebo for all efficacy measurements, including sum of pain relief and pain intensity difference, total pain relief, sum of pain intensity difference, pain intensity difference, and pain relief score during 6 hours after the dose. Onset of confirmed first perceptible relief in subjects treated with FD-APAP 1000 mg was 15 minutes, which was 32% and 25% significantly shorter than onset of pain relief of FD-APAP 500 mg (22 minutes) and standard APAP 650 mg (20 minutes), respectively. FD-APAP 500 mg and APAP 650 mg demonstrated efficacy over placebo for most of the measurements; however, their effects were significantly lower and lasted for a shorter period of time than for FD-APAP 1000 mg. All study treatments were well tolerated.

Conclusions

FD-APAP 1000 mg tablets demonstrated efficacy over placebo. Also, FD-APAP 1000 mg had significantly superior effect, faster onset, and longer duration of pain relief compared with FD-APAP 500 mg and APAP 650 mg tablets. ClinicalTrials.gov identifiers: NCT01082081 and NCT01075243.     

对乙酰氨基酚口腔崩解片的研制

目的 以对乙酰氨基酚（扑热息痛）为模型药物制备新型口服速释剂型口腔崩解片。方法 以崩解时间为指标,采用正交试验筛选片剂的处方组成,并优化制备工艺。结果 以MCC／L-HPC 50：15作为崩解剂,部分制粒压片工艺制得的扑热息痛口腔崩解片,体外平均崩解时间为35s,置于口腔40s内可崩解,无砂砾感,片剂体外溶出度1min可达95％。结论 扑热息痛口腔崩解片于口腔内可迅速崩解,制备工艺简单可行,有效地改善了药物粉末的流动性,适宜于大生产。     

Protective Effects of Polydatin from Grapes and Reynoutria japonica Houtt. on Damaged Macrophages Treated with Acetaminophen

The unregulated use of acetaminophen (APAP), an antipyretic and analgesic drug, harms hepatocytes and kidney cells, leading to liver failure and acute kidney injury. Herein, we investigate whether APAP damages macrophages in the immune system by observing its effects on macrophage proliferation and apoptosis. Using proteomics, we analyzed the effects of APAP on macrophage protein expression profiles and evaluated whether polydatin, the active ingredient in grapes and wine, can repair the damaged cells. The results showed that APAP alters the morphology and physiological processes of macrophages, inhibits macrophage proliferation, and promotes apoptosis. We observed 528 differentially expressed proteins when 500 µg/mL APAP was administered to the cells. These proteins are involved in biological processes including cell division, apoptosis, and acute phase response. Overall, our findings demonstrate that APAP harms the immune system by damaging macrophages and that polydatin can repair this damage.     

扑热息痛栓的生物利用度测定实验

本文报道以半合成脂肪酸酯为基质,聚乙烯吡咯烷酮(PVP)作为吸收促进剂的扑热息痛检剂和不含PVP的同种栓剂及市售栓剂的体外释放率及家兔体内吸收率的实验观察.结果表明,含PVP的栓剂比不含PVP的栓剂和市售栓剂的体外释放速度及体内吸收率都快.     

Refining the level for anticipated hepatotoxicity in acetaminophen poisoning

Treatment of an acetaminophen overdose with N-acetyl cysteine usually is based on the position of the 4-h acetaminophen (APAP) level on the Rumack-Matthew nomogram; however, there is disagreement on the level at which clinically relevant hepatotoxicity occurs. A retrospective review of all acute adult formulation APAP exposures reported to our poison center between 1986 and 1993 was performed and cases corresponding to the “possible risk or toxicity” range on the nomogram were identified. Our current poison center protocol for APAP poisoning does not recommend treatment with N-acetylcysteine (NAC) in low-risk patients if the 4-h serum APAP level or the extrapolated equivalent falls within the possible toxicity range on the nomogram. Seventeen cases met the inclusion criteria for the study and received no NAC; six additional patients met inclusion criteria but received one or two doses of NAC before therapy was discontinued. No patients in either group demonstrated clinical evidence of hepatotoxicity. This pilot study suggests that patients with no risk factors and APAP levels in the “possible risk” range may not require NAC therapy.     

Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children

Aims Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1–2  h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.
Methods Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40  mg  kg⁻¹ were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70  kg person using an allometric power model.
Results Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.2  l  h⁻¹ (CV 47%), volume of distribution 67.1  l (CV 58%) and absorption rate constant 0.77  h⁻¹ (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72  h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).
Conclusions Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1–2  h before anticipated pain or fever in children.     

Pharmacokinetic Monitoring in Subcutaneous Tissue Using in Vivo Capillary Ultrafiltration Probes

Capillary ultrafiltration probes were utilized for in vivo sampling of therapeutic drugs in awake rats. Capillary ultrafiltration probes implanted into subcutaneous tissue were able to follow the disposition of acetaminophen and theophylline. Ultrafiltration probes provided samples at a rate of 2–3 µL/min. Ultrafiltrates were analyzed by liquid chromatography with either UV or electrochemical detection. Simultaneous ultrafiltration and microdialysis probes and multiple ultrafiltration probes were used in individual animals to validate the technique. The pharmacokinetics of two well-established drugs, acetaminophen and theophylline, were monitored in awake, freely moving rats to demonstrate the viability of the technique. The half-life for acetaminophen was determined to be 20.9 ± 1.0 min (n = 6) for a 2 mg/kg dosing. The half-life of elimination for theophylline was determined to be 3.0 ± 0.1 hr (n = 4) for a 4 mg/kg dose. The capillary ultrafiltration probes exhibited a constant flow rate of 2.4 ± 0.1 µL/min and removed 50 nL/min/mm of fluid from the extracellular space. Capillary ultrafiltration sampling is shown to be an excellent tool for in vivo monitoring of drug disposition and a suitable method for determining pharmacokinetic parameters in awake animals.