肝移植术后口腔黏膜炎的防治

目的总结肝移植术后口腔黏膜炎的防治经验。方法回顾性分析6例肝移植术后发生口腔黏膜炎的临床资料。结果 6例患者,Ⅰ~Ⅱ级者4例,Ⅲ~Ⅳ级者2例,Ⅲ~Ⅳ级者中确诊病毒感染1例,多种因素所致的复合性病变1例,全部病例都经治而愈。结论肝移植术后的口腔黏膜炎应根据病情严重程度及病因采取相应的治疗措施。     

多瑞吉治疗鼻咽癌放化疗致口腔黏膜炎疼痛23例

目的观察多瑞吉治疗鼻咽癌放化疗引起口腔黏膜炎所致疼痛的疗效。方法将45例经病理学诊断明确为鼻咽癌并在放疗或化疗过程中出现急性口腔黏膜炎所致中、重度疼痛患者,分为研究组23例和对照组22例,研究组在常规治疗的基础上加用多瑞吉,对照组仅行常规治疗,观察两组患者治疗过程中及治疗结束后的镇痛作用、生活质量评分和不良反应。结果研究组疼痛缓解有效率为82.61%,对照组为31.82%;研究组较对照组生活质量明显改善,差异有统计学意义;研究组不良反应发生率低,且均能耐受。结论多瑞吉用于鼻咽癌放化疗相关性口腔黏膜炎所致中、重度疼痛,镇痛作用强,不良反应轻,能够明显改善患者的生活质量,便于治疗的顺利完成。     

Percutaneous Absorption and Excretion of Xenobiotics after Topical and Intravenous Administration to Pigs

Interspecies comparisons suggest that the weaning pig is a suitablesurrogate for man in percutaneous absorption studies. Despiteknown anatomical and physiological similarities between porcineand human skin, very few investigations of percutaneous absorptionphenomena have been conducted in pigs. This study examined radiolabelexcretion patterns after intravenous (iv) and topical administrationof six ¹⁴C-radioIabeled compounds in weanling Yorkshire sows.Radiolabel recovery from excrement collected over 6 days followingiv doses in physiological saline (200 µg, 10 µCi)showed that malathion (M), parathion (P), caffeine (C), andbenzoic acid (B) were primarily excreted into urine (>80%),while greater fractions of testosterone (T, 72%) and progesterone(R, 35%) were fecally eliminated. Percutaneous absorption wasdetermined from total urine and fecal excretion of radiolabelafter topical application, corrected for incomplete excretionfollowing iv administration. Topical doses in ethanol (200 µg,10 µCi) were applied at a surface concentration of 40µg cm^–2 and penetrated in the following rank order(percentage dose): B (25.7%) > R (16.2%) > C (11.8%) >T (8.8%) > P (6.7%) > M (5.2%). Fecal clearances of radiolabel,expressed as a percentage of total excretion, were greater aftertopical administration for four of the six compounds (B, C,P, and T, p < 0.05). Calculations based on urinary excretionalone underestimated percutaneous absorption determined fromtotal excretion by 5–30%, although the difference betweenthe two estimates was statistically significant only for C (p< 0.05). These results suggest that percutaneous absorptionestimates based on urinary radiolabel excretion alone shouldbe interpreted with caution whenever compounds with unknownpenetration characteristics arc used. Factors known to affecthuman skin absorption, such as applied dose, anatomical region,sex, age, various vehicles and solvents, and differences incutaneous metabolism, should be more closely examined in allanimal species used to model percutaneous absorption phenomenain man.     

Hybrid Nanostructured Films for Topical Administration of Simvastatin as Coadjuvant Treatment of Melanoma

This work aims at (1) assessing the potential of repurposing simvastatin (SV) to support the most common therapies against melanoma and (2) developing an innovative topical adhesive film, composed by chitosan-coated nanostructured lipid carriers (Ch-NLC) used as drug vehicle. A factorial design approach was employed as the basis for the formulation development. Optimized Ch-NLC displayed a particle size of 108 ± 1 nm, a polydispersity index of 0.226, a zeta potential of 17.0 ± 0.6 mV, as well as an entrapment efficiency of 99.86 ± 0.08%, and SV loading of 14.99 ± 0.01%. The performance of SV-Ch-NLC films was assessed in terms of release, permeation, and adhesion, as critical quality attributes. Cutaneous tolerability and in vitro cytotoxicity studies were performed to warrant film safety and drug effectiveness, respectively. The topical films provided a sustained release kinetic profile of SV and were classified as nonirritant systems. The encapsulation of SV increased cytotoxicity in melanoma cells. The key role of squalene as nanostructuring agent of the lipid nanoparticle matrix and as permeation enhancer was highlighted, suggesting its key action for potentiating skin permeation and uptake into melanoma cells. Topical SV-Ch-NLC films are thus able to provide an in situ extended drug delivery and useful as coadjuvant treatment of melanoma skin lesions.     

Oral Administration of Polaprezinc Attenuates Fluorouracil‐induced Intestinal Mucositis in a Mouse Model

5‐Fluorouracil (5‐FU) has broadly been applied to treat colorectal cancer as one of the most effective chemotherapeutic agents. However, it frequently causes intestinal mucosal injury and related side effects, such as abdominal pain and diarrhoea, which limit the use of 5‐FU in a clinic setting. Polaprezinc has gradually become known as a mucosal protective agent for the management of gastric ulcer. This study aimed to investigate the prophylactic efficacy of Polaprezinc administered orally against intestinal mucositis induced by 5‐FU in mice on the condition that the antitumour effect could not be compromised. We induced intestinal mucositis in SPF‐grade ICR mice with 5‐FU, and evaluated intestinal damage in the absence or presence of Polaprezinc. We examined the score of diarrhoea and the loss of weight after the 5‐FU treatment and assessed the integrity of villus and the proliferation of small intestine crypt cells by haematoxylin and eosin staining and PCNA immunohistochemical detection. The antitumour effect of 5‐FU on colorectal cancer was assessed with or without Polaprezinc in a xenograft model. The result showed that Polaprezinc significantly reduced the elevated diarrhoea score and the body‐weight loss caused by 5‐FU abolished histological abnormality and crypt cell hypoproliferation in a dose‐dependent manner, without affecting 5‐FU efficacy on colon xenograft tumour in mice. We conclude that Polaprezinc could inhibit 5‐FU‐induced diarrhoea and alleviate the weight loss during 5‐FU chemotherapy, as a possible candidate for treatment and prevention of intestinal mucositis, through protecting intestinal mucosa and improving the quality of life after chemotherapy.     

诺模图法预测口服给药的吸收速率常数

目的：用已知的达峰时间(tpeak)和消除速率常数(ke)建立诺模法，估算口服给药的吸收速率常数(ka)。方法：根据口服给药的血药浓度—时间曲线曲线方程和tpeak,ka和ke的函数关系，进行数学推导建立诺模图。应用诺模图分析46个药物的ka与数学解析法计算的ka，比较评价诺模图的准确度。用高效液相色谱荧光法检测18位健康志愿者羧甲司坦的血药浓度，将羧甲司坦实测血药浓度与由ka结合其他药代动力学参数的估计血药浓度比较，评估诺模图执行误差。结果：诺模图估算的ka值与解析法计算的ka值接近；MDPE和MDAPE执行误差分别为1．32％，18．15％。结论：本文设计的诺模图准确可靠，执行误差符合临床药代动力学要求。可为制定合理的个体化给药方案提供一个方便快捷的方法。     

紫外线治疗仪治疗14例造血干细胞移植病人口腔粘膜炎的疗效观察

目的观察紫外线治疗仪治疗造血干细胞移植病人口腔粘膜炎的疗效。方法治疗组应用紫外线治疗仪局部照射口腔溃疡处6—10秒,从6秒开始,每日1次,逐日递增,持续7天。对照组采取口腔溃疡面只涂生长因子,不进行口腔照射。结果’两种方法均能使溃疡面减小,以至痊愈。对照组口腔溃疡平均愈合时间为15天。治疗组平均愈合时间为9天,可有效减轻局部疼痛,缩短病程。t检验有统计学差异,P〈0．05。结论紫外线治疗仪局部照射能加快溃疡面愈合,缩短病程,有效缓解病人的痛苦,提高治疗效果。     

Biopharmaceutics: Enhanced Absorption of Calcium after Oral Administration of Maltitol in the Rat Intestine

The enhancing effects of maltitol (α-D-glucopyranosyl-1,4-sorbitol) on absorption of calcium by the rat intestine have been studied by use of [⁴⁵Ca]CaCl₂ in-vivo. After intragastric administration of [⁴⁵Ca]CaCl₂ solution with maltitol, plasma ⁴⁵Ca concentration remained at the maximum level for more than 80 min, whereas for animals given [⁴⁵Ca]CaCl₂ solution without maltitol, plasma ⁴⁵Ca concentration declined sharply after the peak. Determination of ⁴⁵Ca radioactivity remaining in the various segments of the gastrointestinal tract revealed that administration of maltitol elicited slower gastric emptying and slower intestinal transit, resulting in extensive ⁴⁵Ca distribution along the small intestine throughout the experimental period. The luminal contents of the small intestine were significantly higher in rats given maltitol than in the control group. These results suggest that the enhancing action of maltitol on intestinal calcium absorption could be attributed to reduced gastrointestinal calcium transit and increased luminal fluid content, presumably because of the osmotic activity of maltitol; this would not only accelerate the dissolution of calcium into the increased luminal contents, but also enable a larger area of the small intestine to absorb calcium for a longer period of time.     

Effect of Iron on the Absorption and Distribution of Clodronate after Oral Administration in Rats

The effect of iron on the absorption and distribution of disodium clodronate in rats after oral administration was studied. Disodium clodronate (300 mg/25 μCi/kg) was given both alone and with an equivalent amount of ferrous sulphate. The radioactivity in plasma and various tissue was measured. Concentration of clodronate in plasma was also determined with the GC-mass-selective detection method and the values compared with those measured with the isotope method. After administration, clodronate was rapidly cleared from plasma. Most of the dose was taken up by bone and only small amounts were found in non-calcified tissues. Concurrent ingestion of iron caused a marked decrease in the absorption of clodronate.     

Avoidance of First-Pass Metabolism of Propranolol after Rectal Administration as a Function of the Absorption Site

Pharmaceutical Research -     

鼻咽癌患者放疗致口腔黏膜炎的护理

目的探讨鼻咽癌患者放疗致口腔黏膜炎的护理方法。方法选取我院2008--2011年收治的50名鼻咽癌患者,观察患者化疗后进行口腔、饮食和心理等护理后的临床效果。结果50例患者通过积极的治疗和护理,无0级表现患者;I级表现15例,占30．O％;lI级表现32例,占64．0％;Ⅲ级表现3例,占6．0％;无Ⅳ级表现患者;总体有效率为94．0％（47／50）。结论对于鼻咽癌放射治疗所致口腔黏膜炎的患者,应在常规治疗的情况下给予积极的护理干预,可以有效的提高临床疗效。减轻患者的痛苦。     

口炎清颗粒对头颈部恶性肿瘤患者放疗后放射性口腔黏膜炎的防治作用

目的:探讨口炎清颗粒对头颈部恶性肿瘤患者放疗后放射性口腔黏膜炎的防治作用。方法:122例行放疗的头颈部恶性肿瘤患者随机分为口炎清组(61例)和氯己定组(61例)。在放疗的基础上,口炎清组患者于放疗前2~3 d给予口炎清颗粒20 g,溶于50 m L温开水含服,每日2次;氯己定组患者于放疗前2~3 d给予复方氯己定含漱液10~20 m L,含漱,每日2次。两组疗程均为7周。观察两组患者口腔黏膜炎反应发生情况,视觉模拟(VAS)评分及不良反应发生情况。结果:放疗第3周后口炎清组患者2~3级及放疗第4~7周后2~4级口腔黏膜炎发生率均显著低于氯己定组同期,差异均有统计学意义(P<0.01)。放疗第2~7周后,口炎清组患者VAS评分均显著低于氯己定组,差异均有统计学意义(P<0.01)。两组患者不良反应发生率比较,差异无统计学意义(P>0.05)。结论:口炎清颗粒可降低头颈部恶性肿瘤患者放疗后放射性口腔黏膜炎的反应严重程度,减轻患者疼痛,改善患者生存质量,且安全性与氯己定相当。     

Adequacy of Rifampin Absorption after Jejunostomy Tube Administration

It is not always possible to administer antituberculosis pharmacotherapy orally for reasons that may be a direct consequence of tuberculosis itself. To our knowledge, no published literature is available regarding antituberculosis drug absorption via feeding tube. We present the case of a patient with tuberculosis meningitis who required medication administration via percutaneous endoscopic jejunostomy (PEJ) tube. Blood samples were collected during the continuation phase of antituberculosis therapy, immediately before dose administration, and then at 1, 2, 4, and 6 hours after dose administration for quantification of serum rifampin concentrations. Assaying these concentrations by high‐pressure liquid chromatography demonstrated a peak serum rifampin level (C_max) of 18 μg/ml and total rifampin exposure (area under the curve from 0–6 hours [AUC_0–6]) of 50.1 μg/ml. These are high compared with rifampin C_max and AUC_0–6 values reported in patients after oral rifampin administration; C_max tends to range between 4.0–10.5 μg/ml and AUC_0–6 7.0–52.9 μg/ml after oral administration of 600 mg at steady state. Based on our patient's results, therefore, rifampin administered by PEJ tube appears to be well absorbed, with preservation of adequate C_max and AUC values. It is worth noting that this was in the context of drug administration in the fasted state. In the absence of any published evidence of adequate absorption via jejunal feeding tube in the nonfasted state, it would seem prudent to ensure that patients are fasted when rifampin is administered via PEJ tube, just as patients are when oral rifampin is administered. This report represents the first documented evidence, to our knowledge, of adequate rifampin absorption when administered via PEJ tube and provides important reassurance for health care providers, patients, and families facing similar clinical scenarios.     

Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem

Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlus™ Oral Cavity Compartmental Absorption and Transit (OCCAT™) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo® sublingual tablets (zolpidem tartrate). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., C_max, T_max, and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (F_{a_IO}). The OCCAT™ model captured the observed pharmacokinetics for Intermezzo® sublingual tablets (R² > 0.9). The predicted deviations (%) for C_max, AUC_0–inf, AUC_0–20 min, and T_max were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated ~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the F_{a_IO} was not only associated with drug diffusivity and unbound fraction in epithelium tissue (f_ut) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logD_pH = 7.4). The novel physiologically based IO absorption OCCAT™ model showed satisfactory performance and will be helpful to guide development of future intraoral formulations.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9727-7) contains supplementary material, which is available to authorized users.KEY WORDS: diffusivity, intraoral delivery, oral cavity compartmental absorption and transit (OCCAT™) model, unbound fraction in epithelium tissue, zolpidem     

芬太尼透皮贴剂治疗急性放射性黏膜炎所致疼痛的疗效观察

目的：观察芬太尼透皮贴剂治疗头颈部恶性肿瘤患者放疗中急性放射性口腔黏膜炎所致中、重度疼痛的控制作用,生活质量改善程度及治疗不良反应。方法：102例经病理确诊为头颈部恶性肿瘤,在放疗过程中出现急性放射性口腔黏膜炙所致中、重度疼痛患者,随机分为治疗组（芬太尼透皮贴剂＋常规治疗）52例和对照组（常规治疗）50倒。观察两组患者放疗中及结束后镇痛作用、生活质量评分和不良反应。结果：疼痛缓解有效率治疗组为90％,而对照组为32％,两组差异有统计学意义;生活质量明显改善治疗组优于对照组,差异有统计学意义;不良反应主要为便秘、恶心呕吐、皮肤瘙痒及嗜睡,发生率低,均能耐受,用药结束后未见药物依赖。结论：芬太尼透皮贴剂在控制急性放射性口腔黏膜炎所致中、重度疼痛的作用强,不良反应少,能够明显改善患者的生活质量,便于放疗顺利完成,从而有利于提高放疗疗效,具有较高的临床实用价值。     

Polyethylene Glycol as a Solvent for Diazepam: Bioavailability and Clinical Effects after Intramuscular Administration,Comparison of Oral,Intramuscular and Rectal Administration,and Precipitation from Intravenous Solutions

Abstract The bioavailability of diazepam (10 mg) was compared in a doubleblind cross–over manner in two studies on 15 healthy subjects. Serum diazepam levels were measured and the occurrence of pain at the injection site as well as fatigue was noted 20, 40, 60, 90 and 180 min. after the administration of 0.15 mg/kg of diazepam to seven subjects. Three intramuscular preparations were used: valium® (Roche), diapam® (Orion) and 301–K 2/74 (Orion). The last–mentioned preparation contained only half the propylene glycol contained in the other preparations, and polyethylene glycol (Macrogol) was the main solvent. The other eight subjects were similarly tested after the administration of diazepam orally, intramuscularly and rectally. In addition the precipitation of diazepam from intravenous solutions was investigated with diazepam in both solvents. Bioavailability and fatigue were similar after each treatment. 301–K 2/74 and its solvent placebo caused significantly less pain in the thigh than valium® or diapam®. The results suggest that an intramuscular injection of diazepam, deep into vastus lateralis muscle, and rectal and oral administration result in comparable bioavailability and clinical effects. A reduction in the amount of propylene glycol solvent used was associated with less pain at the injection site. When diapam® was injected into an infusion tube at a rate of 5 mg/min., the rate of infusion of 5 % glucose or 0.9 % saline had to be as fast as 20 ml/min. in order to prevent visible precipitation, whereas no precipitation was observed when 301–K 2/74 was injected at the 5 mg/min. rate into infusions moving at 5 ml/min. Further clinical studies with intramuscular and intravenous 301–K 2/74 are warranted.     

Adverse Effect Profile of Topical Ocular Administration of Fingolimod for Treatment of Dry Eye Disease

Fingolimod is a promising prodrug in attenuating multiple sclerosis and prolonging survival of organ allograft, with many other protective effects. Its mechanism of action is related to the internalization of sphingosine 1‐phosphate receptors (S1PRs). Our previous study indicated that fingolimod eyedrops was efficacious in inhibiting ocular inflammation in a dry eye disease (DED) model of non‐obese diabetic (NOD) mice. In the current study, we evaluated potential adverse effects of fingolimod eyedrops. Inbred 10‐week‐old BALB/c mice were randomly divided into four groups, fingolimod‐treated groups at three different concentrations (0.01%, 0.1% and 0.5%) and a negative control group without intervention. Our results showed that in the 0.5% fingolimod group, adverse effects such as photophobia, catacleisis and corneal oedema were observed after 1 week of treatment. 1 month later, corneal opacity, oedema and neovascularization persisted till the mice were killed 2 months later. In contrast, there was no significant abnormality in the negative control group, and 0.01% and 0.1% fingolimod‐treated groups. During a 2‐month treatment period, we did not detect fingolimod, nor significant change in blood cells in peripheral blood, nor pathological changes in retina and systemic organs. Combined with our previous study and the current results, we recommend that an optimal range of safe and effective concentration of fingolimod as eyedrops is between 0.005% and 0.1%.     

Theoretical Considerations on Two Equations for Estimating the Extent of Absorption After Oral Administration of Drugs

Purpose. The amount of drug absorbed into portal blood after oral dosing (D_p.o,g) has been estimated using Ficks principle (Q-method), i.e., D_p.o,g = Q_h · (AUC_p.o,g – AUC_p.o,c), where Q_h is the portal blood flow rate, and AUC_p.o,g and AUC_p.o,c are the areas under the concentration-time curves of portal vein and systemic blood after oral dosing, respectively. However, this method may underestimate D_p.o,g, when the drug is subject to systemic intestinal elimination. An alternate equation (CL-method; D_p.o,g = CL_S · AUC_p.o,g) is described using a simple pharmacokinetic model, to estimate D_p.o,g in the presence of systemic intestinal elimination, where CL_S is systemic clearance. Methods. The model is composed of central, intestine and liver compartments, assuming that drug is eliminated by intestinal and/or hepatic pathways only. A comparison of both methods for estimating D_p.o,g was made using computer-simulation or experimental data of phenacetin from the literature. Results. The simulation study demonstrated that the Q-method underestimated D_p.o,g in the presence of significant intrinsic intestinal clearance, compared to the CL-method,. The similar results were observed using the experimental data of phenacetin. Conclusions. The CL-method can provide a better estimate of D_p.o,g, while the Q-method may underestimate D_p.o,g, when there is significant systemic intestinal elimination of drugs after oral administration. In addition, useful information for understanding the relationship between the extent of absorption and the first-pass effect by intestine and/or liver after oral dosing of drugs can be obtained from the present approach.     

Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Dissolution Behavior of Glibenclamide

Purpose. The dissolution behavior of two commercially availableglibenclamide formulations was tested in various media. The aim of thestudy was to investigate whether the use of biorelevant dissolutionmedia (BDM) would be advantageous over the use of standard mediafor predicting the in vivo performance of the two formulations.Methods. The dissolution tests were performed using USP 23 apparatus2. Conventional buffers and USP media were compared with two BDMcontaining different amounts of lecithin and sodium taurocholate.Results. The dissolution of two drug powders was highly dependenton wetting, particle size, pH, and the composition of the mediumused. In addition, the dissolution behavior of the two glibenclamideformulations showed differences in all media tested. The dissolutionresults of the two formulations were compared with those from anin vivo bioequivalence study undertaken by the central quality controllaboratory of the German pharmacists (ZL). The bioequivalencecriterion set by the ZL requires more than 80;pc drug release within 10minutes. Results in FaSSIF, one of the BDMs, met the ZL criterionand this medium was also able to discriminate between the twoformulations. This was not the case for the other media tested.Conclusions. The study indicates that BDM are better able to discriminatebetween glibenclamide formulations than standard dissolutionmedia.     

Polar Molecular Surface as a Dominating Determinant for Oral Absorption and Brain Penetration of Drugs

Purpose. To study oral absorption and brain penetration as a function of polar molecular surface area. Methods. Measured brain penetration data of 45 drug molecules were investigated. The dynamic polar surface areas were calculated and correlated with the brain penetration data. Also the static polar surface areas of 776 orally administered CNS drugs that have reached at least Phase II efficacy studies were calculated. The same was done for a series of 1590 orally administered non-CNS drugs that have reached at least Phase II efficacy studies. Results. A linear relationship between brain penetration and dynamic polar surface area (Ų) was found (n = 45, R = 0.917, F_1,43 = 229). Brain penetration decreases with increasing polar surface area. A clear difference between the distribution of the polar surface area of the 776 CNS and 1590 non-CNS drugs was found. It was deduced that orally active drugs that are transported passively by the transcellular route should not exceed a polar surface area of about 120 Ų. They can be tailored to brain penetration by decreasing the polar surface to <60–70 Ų. This conclusion is supported by the inverse linear relationship between experimental brain penetration data and the dynamic polar surface area of 45 drug molecules. Conclusions. The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route. This property should be considered in the early phase of drug screening.