Health Risk above the Reference Dose for Multiple Chemicals

Recent work indicates that the regression of toxicity data viewed as categories of pathological staging is useful for exploring the likely health risk at doses above a Reference Dose (RfD), which is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Toxic effects, which may include both quantal and continuous data, are classified into ordered categories of total toxic severity (e.g., none, mild, adverse, severe). These severity categories are regressed on explanatory variables, such as dose or exposure duration, to estimate the probability of observing an adverse or severe effect. In this paper, categorical regression has been expanded to compare the likely risks across multiple chemicals when exposures are above their RfDs. Existing health risk data for diazinon, disulfoton, S-ethyl dipropylthiocarbamate, fenamiphos, and lindane were analyzed. As expected, the estimated risks of adverse effects above the RfD varied among the chemicals. For example, at 10-fold above the RfD these risks were modeled to be 0.002, 0.0001, 0.0007, 0.002, and 0.02, respectively. The results and impacts of this analysis indicate that categorical regression is a useful screening tool to analyze risks above the RfD for specific chemicals and suggest its application in evaluating comparative risks where multiple chemical exposures exist.     

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol A as a Case Study

Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not ‘common enough’ to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where ‘safe’ low doses are predicted from high dose exposures.     

小剂量脾区放射治疗免疫性血小板减少性紫癜16例分析

目的:探讨难治性免疫性血小板减少性紫癜(肿)的新的治疗方法.方法:小剂量脾区放疗,总剂量1 500 cGy.结果:16例患者接受脾区放疗,显效8例,良效4例,进步2例,无效2例,总有效率87.5%.结论:脾区放疗可作为一种对顽固性ITP的新的安全有效的治疗方法.     

小剂量甲氨蝶呤治疗高甲状腺过氧化物酶抗体血症观察

目的：观察小剂量甲氨蝶呤（MTX）对高甲状腺过氧化物酶抗体（TPOAb）血症的疗效及安全性。方法：140例高TPOAb血症桥本甲状腺炎（HT）患者,分为治疗组110例和对照组30例。两组均给予小剂量、短期的抗甲亢和（或）补充左甲状腺素（L-T4）治疗。治疗组在此基础上加服甲氨蝶呤片（每周7.5～10mg）,观察时间3～24个月。比较两组治疗前后TPOAb水平变化、转阴率、甲减患者服用L-T4剂量的变化,及甲功正常者甲状腺功能的变化。结果：治疗后两组TPOAb水平持续明显下降,24个月后,治疗组TPOAb水平明显低于对照组,下降率则明显高于对照组（P〈0.01）;治疗组转阴率为19.1％,明显高于对照组（P〈0.01）。结论：小剂量MTX联合小剂量短期抗甲亢治疗,能显著降低HT患者TPOAb水平,延缓甚至终止TPOAb对甲状腺的破坏进程,优于常规抗甲亢治疗。     

Low Dose Lipid Formulations: Effects on Gastric Emptying and Biliary Secretion

Purpose Food stimulates changes to gastrointestinal secretion and motility patterns, however, the effect of smaller quantities of lipid, such as that contained in a lipid-based drug formulation, has not been detailed. This study aimed to examine the effects of small quantities of lipid on gastric emptying and biliary secretion. Methods The influence of oral administration of three lipid-based formulations and a negative control formulation on gastric emptying and biliary secretion was evaluated in 16 healthy male subjects using gamma scintigraphy, ultrasonography and duodenal aspiration. Results Low quantities (2 g) of long chain lipid stimulated gall bladder contraction and elevated intestinal bile salt, phospholipid and cholesterol levels. Changes in gastric emptying were also evident, although these did not reach statistical significance. Administration of a similar quantity of medium chain lipid, however, had little effect on gastric emptying and gallbladder contraction and did not stimulate appreciable increases in intestinal concentrations of biliary-derived lipids. Conclusions The quantities of long chain lipid that might be administered in a pharmaceutical formulation stimulate gallbladder contraction and elevate intestinal levels of bile salt and phospholipid. This effect is a likely contributor to the ability of lipid based formulations to enhance the absorption of poorly water-soluble drugs.     

小剂量米非司酮用于紧急避孕的临床观察

为探讨小剂量米非司酮用于紧急避孕的效果,对200例月经规律,72小时内有无防护性生活或避孕失败的妇女给予米非司酮25mg顿服,观察其避孕有效率为94.7％,月经周期、经期、经量无明显变化者占86.5％。仅有2％有轻微的恶心等副作用。结果表明,单用小剂量米非司酮完全可以用于性生活后72小时内的紧急避孕。     

小剂量阿司匹林口腔崩解片的制备

采用直接压片法制备小剂量阿司匹林口腔崩解片，并优化其处方。所得片剂可在30s内完全崩解。     

高剂量咖啡因应用于极低出生体质量儿的研究进展

咖啡因治疗早产儿呼吸暂停有近40 年的历史,是目前新生儿重症监护室(NICU)最常用的药物之一。常规治疗剂量的咖啡因不仅可显著降低极低出生体质量儿呼吸暂停的发生率,还具有肺保护作用和改善神经发育的作用可以降低多种疾病的发病率,被誉为新生儿界的“银子弹冶。咖啡因的剂量鄄效应关系尚未明确,临床上普遍使用的是世界卫生组织推荐的标准剂量:首剂予以负荷量咖啡因10 mg/kg,24 h后继以2.5 mg/(kg·d)维持。较高剂量的咖啡因的临床治疗效果更为显著,但其安全性及咖啡因的最佳治疗剂量仍具有争议。本研究就高剂量咖啡因在极低出生体质量儿中的临床应用 作一综述。     

Biphasic Dose Response in Low Level Light Therapy

The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response.     

小剂量瑞易宁联合小剂量瑞格列奈治疗首发2型糖尿病的临床观察

目的 :观察在社区开展小剂量瑞易宁联合小剂量瑞格列奈治疗首发2型糖尿病的效果。方法 :3个社区采用多中心、随机、开放、对照试验方法 ,将1999年～2002年体检中首次发现的无症状2型糖尿病患者126例均分为3组 ,每组各42例 ,分别给予 :G组 :瑞易宁5mg,每天早餐前30min口服1次 ;R组 :诺和龙1mg ,早餐时即刻口服1次 ;G R组 :每天早餐前30min口服瑞易宁5mg,另早餐时即刻口服诺和龙1mg,各治疗12wk。观察用药前、后空腹血糖、餐后2h血糖、空腹胰岛素、餐后2h胰岛素和糖化血红蛋白以及血脂、肝肾功能等的变化。结果 :(1)在用药12wk时 ,各组空腹血糖、餐后2h血糖均有显著下降 (P<0 01) ;G组、R组分别与G R组相比餐后2h血糖有显著性差异 (P<0 01) ,而空腹血糖差异不显著 (P>0 05)。(2)在用药前、后空腹胰岛素和餐后2h胰岛素G组变化不显著 (P>0 05) ,而R组和G R组均有显著改变 (P<0 01) ;在12wk时 ,G组与R组、G R组均有显著差异 (P<0 01) ,而R组与G R组差异不显著 (P>0 05)。 (3)各组用药12wk时 ,糖化血红蛋白均较用药前有明显下降 (P<0 01) ,而3组间差异不显著 (P>0 05)。(4)血脂、肝肾功能等均有可比性 ,且各组用药前、后均无显著变化 (P>0 05)。结论 :小剂量瑞易宁联合小剂量瑞格列奈 ,结合心理护理、整体     

Medical and Psychiatric Effects of Long-Term Dependence on High Dose of tramadol

Background: Tramadol dependence has been studied recently after large-scale exposure. Although tramadol dependence has increased rapidly in Egypt since 2004, no studies have evaluated the effect of high dose long-term tramadol dependence. Objectives: To address the chronic sequel of tramadol dependence over at least 5 years duration with a large dose (more than 675 mg/day, three tablets or more, each tablet of 225 mg). The study was aimed to check the physical and psychiatric status during tramadol dependence and 3 months after complete treatment. Methods: The present study was applied on 79 patients with single tramadol-dependence dose of 675 mg or more for 5 years or more. We examined the physical and psychological impact of tramadol abuse before and after 3 months of stoppage of the drug. Results: The blood chemistry was nearly within normal parameters, although slight nonsignificant rise in liver enzymes was reported in some cases. Patients during tramadol dependence period were angry, hostile, and aggressive. On the other hand, after treatment the main problem observed was the significant increase in comorbid anxiety, depressive, and obsessive-compulsive symptoms, but no increase was found in psychotic symptoms. Tramadol-dependence dose was more important than duration of use in psychiatric illness. Conclusions: Tramadol dependence on high dose could be physically safe to some limit, but psychiatrically it has many side effects.     

大剂量益母草对大鼠肝、肾的亚急性毒性作用

目的：考察大剂量益母草对大鼠肝、肾的亚急性毒性影响。方法：取益母草煎液,以60g·kg^-1·d^-1剂量灌胃给予大鼠,每日1次,连续给药15d,停药后继续观察15d。实验第15天、第30天时取大鼠血和肝、肾组织标本,分剐检测相关肝、肾功能指标,并观察肝、肾形态组织学变化。结果：给药15d后,大鼠血清谷氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）水平,N-乙酰氨基葡萄糖苷酶（NAG）活性,及尿素氮（BUN）、肌酐（Cr）和尿蛋白（Upro）水平均明显升高,与空白对照组相比差异有统计学意义,肝、肾组织可见轻度病理改变。停药15d后,给药组大鼠尿蛋白水平未见降低,其余各项指标水平均降低,肝、肾组织病理改变减轻。结论：大剂量益母草对大鼠肝、肾有毒性作用,其毒性影响在短期内不完全可逆。     

Studies on Low Dose Sub–acute Administration of Soman,Sarin and Tabun in the Rat

Abstract: The effects of low–dose administration of the organophosphate cholinesterase inhibitors, soman, sarin and tabun, on growth rates over 85 days were studied in rats. Acetylcholinesterase (AChE) activity was determined in the striatum and the remainder of the brain 24 hrs following the last exposure to these agents. Further, the cumulative mortality of daily administration of several doses of soman, sarin and tabun for 25 days was studied. The animals treated with 25 μg/kg of soman or sarin for 85 days demonstrated reduced growth rates which returned to control levels after 30 days. The animals which received 50 μg/kg of sarin also grew at reduced rates which returned to control levels after 35 days, while the tabun–treated (100 μg/kg) animals required 38 days to return to control growth rates. The striatal AChE activity of the soman–treated group was reduced to 36% of control while the AChE activities of the high–dose sarin–treated group were reduced to 66% of control. The striatal AChE activity of the tabun–treated group was only 13% of control. It is suggested that growth rates may be used to monitor the development of tolerance to lowdose administration of organophosphate cholinesterase inhibitors     

Pharmacokinetics in Low Dose Extrapolation Using Animal Cancer Data

Pharmacokinetics in Low Dose Extrapolation Using Animal CancerData. WHITTEMORE, A. S., GROSSER, S. C, AND SILVERS, A. (1986).Fundam. Appl. Toxicol. 7, 183-190. Data on rodents exposed tocarcinogens indicate that their tumor probabilities are proportionalto effective concentrations of parent compound or metabolitesat the target tissues. This proportionality suggests that observednonlinear dose-response curves reflect dose-dependent kineticsbetween applied dose rate and effective concentrations. Thereforelow dose extrapolation procedures that include pharmacokineticdata could improve extrapolation accuracy. To test such procedures,we simulated bioassay and pharmacokinetic "data." Then, ignoringthe mechanisms generating the data, we used four extrapolationprocedures to estimate tumor probability at a low applied doserate. Two of the procedures use a pharmacokinetic model andsimulated pharmacokinetic data, and two do not. The pharmacokineticmodel used for extrapolation was only an approximation to theone used to generate the pharmacokinetic data. The proceduresthat include pharmacokinetics often performed better and neverdid much worse than those that ignore them, regardless of therelations used to generate the data, the amount of experimentalerror in the pharmacokinetic data, and the appropriateness ofthe pharmacokinetic and extrapolation models used. Moreoverthey performed substantially better when effective concentrationand tumor probability were concave-up functions of applied doserate.     

低剂量吉西他滨联合奈达铂治疗晚期鼻咽癌的疗效观察

目的:探讨低剂量持续静脉滴注吉西他滨联合奈达铂对晚期鼻咽癌患者的疗效、不良反应和耐受性。方法:对36例晚期鼻咽癌患者使用低剂量吉西他滨联合奈达铂方案化疗:吉他西滨250 mg.m-2静脉滴注6 h,d1,8;奈达铂80 mg.m-2静脉滴注,d1,每21 d为1个疗程,连续使用2个疗程后评价;并与30例同期采用顺铂+氟尿嘧啶(PF)方案化疗的晚期鼻咽癌患者进行比较。结果:低剂量吉西他滨联合奈达铂方案组的有效率(CR+PR)为72.2%,明显高于PF组的43.3%,经统计学处理,2组差异有统计学意义(P<0.05);不良反应主要为骨髓抑制(特别是对血小板的抑制),胃肠道反应较轻。结论:低剂量持续静脉滴注吉西他滨联合奈达铂是治疗晚期鼻咽癌的可行方案之一。     

A Tier Approach for Evaluating the Respiratory Allergenicity of Low Molecular Weight Chemicals

A Tier Approach for Evaluating the Respiratory Allergenicityof Low Molecular Weight Chemicals. SARLO, K., AND CLARK, E.D. (1992). Fundam. Appl. Toxicol. 18, 107–114. A multi-level approach for evaluating low molecular weight chemicalsas respiratory sensitizers is proposed. The approach involvesfour levels of testing that utilize both in vitro and in vivomethods. Tier 1 evaluates structure-activity information todetermine if the chemical can covalently modify carrier molecules.It also includes a literature search to determine if the compoundbelongs to a family of chemicals that has been reported to inducehypersensitivity. Tier 2 tests the chemical's potential to haptenatecarrier molecules (i.e., protein) under in vitro conditions.Positive results in Tiers 1 and 2 lead to testing in a guineapig injection model to assess chemical immunogenicity (Tier3). A positive result at this level leads to testing in a guineapig inhalation model to address questions about relevant routesof chemical exposure and allergenicity (Tier 4). Tier 4 resultsare used in determining safe chemical exposure levels. We haveevaluated three chemicals using this scheme: phthalic anhydride,reactive black b dye, and toluene diisocyanate. All three havereactive groups and haptenate protein in vitro. They inducea humoral immune response when injected into guinea pigs atequimolar concentrations, and they sensitize animals via inhalationexposure. The severity of the response (antibody titer and respiratoryreactivity) can be used to rank-order the chemicals in termsof allergenic "potency." Our data indicate that this approachcan detect chemical allergens and can be used to characterizethem as moderate or strong respiratory sensitizers.     

Predicting Fraction Dose Absorbed in Humans Using a Macroscopic Mass Balance Approach

A theoretical approach for estimating fraction dose absorbed in humans has been developed based on a macroscopic mass balance that incorporates membrane permeability and solubility considerations. The macroscopic mass balance approach (MMBA) is a flow model approach that utilizes fundamental mass transfer theory for estimating the extent of absorption for passively as well as nonpassively absorbed drugs. The mass balance on a tube with steady input and a wall flux of J _w = P _w C _b results in the following expression for fraction dose absorbed, F: F = 2 An ₀ ¹ C*_b dz* where the absorption number, An = L/R · P _w/v _z >;, L and R are the intestinal length and radius, P _w is the unbiased drug wall permeability, v _z is the axial fluid velocity, C*_b = C _b/C_o and is the dimension-less bulk or lumen drug concentration, C _b and C _o are the bulk and initial drug concentrations, respectively, and z* is the fractional intestinal length and is equal to z/L. Three theoretical cases are considered: (I) C _o S, C _m S, (II) C _o > S, C _m S, and (III) C _o > S, C _m > S, where S is the drug solubility and C _m is the outlet drug concentration. Solving the general steady-state mass balance result for fraction dose absorbed using the mixing tank (MT) and complete radial mixing (CRM) models results in the expressions for the fraction dose absorbed in humans. Two previously published empirical correlations for estimating fraction dose absorbed in humans are discussed and shown to follow as special cases of this theoretical approach. The MMBA is also applied to amoxicillin, a commonly prescribed orally absorbed -lactam antibiotic for several doses. The parameters used in the correlation were determined from in situ or in vitro experiments along with a calculated system scaling parameter. The fraction dose absorbed calculated using the MMBA is compared to human amoxicillin pharmacokinetic results from the literature with initial doses approximated to be both above and below its solubility. The results of the MMBA correlation are discussed with respect to the nonpassive absorption mechanism and solubility limitation of amoxicillin. The MMBA is shown to be a fundamental, theoretically based model for estimating fraction dose absorbed in humans from in situ and in vitro parameters from which previously published empirical correlations follow as special cases.     

甘露醇联合小剂量地塞米松治疗早期重症手足口病的效果观察

目的观察甘露醇联合小剂量地塞米松治疗早期重症手足口病临床效果。方法选取330例早期重症手足口病患儿为观察组,及类似的早期重症手足口病患儿330例为对照组。对照组给予利巴韦林、喜炎平加入0.9%氯化钠注射液静脉滴注,及常规和对症支持治疗。观察组在对照组的治疗基础上给予甘露醇联合小剂量地塞米松治疗。观察比较两组患儿发展为危重症的例数、发热和肢体抖动或惊跳消失时间、脑膜刺激征消失时间。结果观察组患儿发展为危重症的例数明显少于对照组(P<0.01);观察组发热消退时间、惊跳或肢体抖动消失时间、脑膜刺激征消失时间均明显少于对照组(P<0.01)。结论甘露醇联合小剂量地塞米松治疗早期重症手足口病,能有效防止患者进展为危重症,保护脑功能。     

西咪替丁对低剂量率照射比格犬肝细胞凋亡的影响及其机制研究

目的:研究西咪替丁对低剂量率照射比格犬肝细胞凋亡的影响及其机制。方法:将健康雄性比格犬随机分为正常对照组、模型对照组、阳性药物组(香菇多糖,21.33 mg/kg)和西咪替丁低、中、高剂量组(5.33、10.67、21.33 mg/kg),每组4只。除正常对照组外,其余各组比格犬均予~(60)Co-γ射线(剂量率:0.040 8 mGy/min)累积照射23 d,各给药组于每日照射前口服相应药物1次。停止照射24 h后,采用TUNEL法检测各组比格犬肝细胞凋亡情况,并计算凋亡细胞百分比;采用免疫组化法检测其肝组织中凋亡相关蛋白[Bax、Bcl-2、胱天蛋白酶3(Caspase-3)、p53]的表达水平。结果:与正常对照组比较,模型对照组比格犬肝组织中凋亡细胞以及Bax、Caspase-3、p53阳性细胞均明显增加,凋亡细胞百分比以及Bax、Caspase-3、p53蛋白表达水平均显著升高;Bcl-2阳性细胞明显减少,其蛋白表达水平均显著降低(P<0.05或P<0.01)。与模型对照组比较,各给药组比格犬肝组织中上述阳性细胞均有不同程度的变化,其中各给药组凋亡细胞百分比和p53蛋白表达水平,阳性药物组和西咪替丁低、高剂量组Bax蛋白表达水平以及西咪替丁各剂量组Caspase-3蛋白表达水平均显著降低;西咪替丁各剂量组Bcl-2蛋白表达水平均显著升高;且西咪替丁中、高剂量组凋亡细胞百分比以及西咪替丁各剂量组Caspase-3蛋白表达水平均显著低于阳性对照组,西咪替丁低剂量组p53蛋白表达水平显著高于阳性药物组(P<0.05或P<0.01)。结论:西咪替丁可抑制低剂量率照射所致的比格犬肝细胞凋亡,对其具有一定的辐射保护作用。这种作用可能与上调Bcl-2蛋白的表达,下调Bax、Caspase-3、p53蛋白的表达有关。