Effects of cysteine on the pharmacokinetics of docetaxel in rats with protein-calorie malnutrition

The objective of this study is to report the effects of cysteine on the pharmacokinetics of intravenous and oral docetaxel in rats with protein-calorie malnutrition (PCM). The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of docetaxel were assessed using control, CC (control with cysteine), PCM and PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of docetaxel were further investigated through in vitro transport studies using rat intestine and Caco-2 cell monolayers. The AUCs (the areas under the plasma concentration-time curve from time zero to time infinity) of intravenous docetaxel in PCM rats were significantly greater than in the control rats because of the significant decrease in the hepatic CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels. The AUC(0-6 h)s of oral docetaxel in PCM rats were significantly smaller than that in the control rats, mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of docetaxel probably via intestinal P-gp inhibition. If the present rat data could be expressed to humans, the alterations in docetaxel absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM state after cysteine supplement.     

Clinical significance of magnesium: a review

With the increased concern surrounding diuretic-induced electrolyte losses, numerous articles have surfaced investigating the detrimental effects of diuretic-induced hypomagnesemia. This article's purpose is to familiarize the reader with hypomagnesemia and hypermagnesemia. Methods of detection, symptoms, etiologies, and potential modes of therapy are discussed. Particular attention is given to the role magnesium plays in the cardiovascular system with additional discussion on lipid alterations and glucose handling. Specific suggestions are given for the inpatient and outpatient treatment of hypomagnesemia.     

Effects of cysteine on the pharmacokinetics of docetaxel in rats with protein–calorie malnutrition

1. The objective of this study is to report the effects of cysteine on the pharmacokinetics of intravenous and oral docetaxel in rats with protein–calorie malnutrition (PCM). The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of docetaxel were assessed using control, CC (control with cysteine), PCM and PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of docetaxel were further investigated through in vitro transport studies using rat intestine and Caco-2 cell monolayers.

2. The AUCs (the areas under the plasma concentration-time curve from time zero to time infinity) of intravenous docetaxel in PCM rats were significantly greater than in the control rats because of the significant decrease in the hepatic CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels. The AUC_{0–6 h}s of oral docetaxel in PCM rats were significantly smaller than that in the control rats, mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of docetaxel probably via intestinal P-gp inhibition.

3. If the present rat data could be expressed to humans, the alterations in docetaxel absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM state after cysteine supplement.

     

Airway relaxant and anti-inflammatory properties of a PDE4 inhibitor with low affinity for the high-affinity rolipram binding site

Inhibitors of phosphodiesterase 4 (PDE4) possess bronchospasmolytic and anti-inflammatory properties, which make them very attractive drugs for the treatment of asthma and COPD. Unfortunately, many PDE4 inhibitors also produce central nervous and gastrointestinal side effects, which have limited their clinical application. PDE4 has two binding sites for the archetypal PDE4 inhibitor rolipram, and it has been suggested that binding to the high-affinity rolipram binding site (HARBS) is responsible for the side effects of PDE4 inhibitors. Recently, we have synthesised the PDE4 inhibitor CC3 which shows low affinity to the HARBS. In the present study we investigated the bronchospasmolytic and anti-inflammatory properties of this novel compound in comparison to rolipram and the PDE3 inhibitor motapizone. The airway-relaxant properties of the PDE inhibitors were analysed in rat precision-cut lung slices (PCLS) in which airways were contracted by methacholine or in passively sensitised PCLS exposed to ovalbumin. The anti-inflammatory properties were investigated by measuring the release of TNF from endotoxin-treated human monocytes.Up to concentrations of 10 microM none of the PDE inhibitors significantly affected bronchoconstriction elicited by 10 microM methacholine. However, if rolipram or CC3 were given in combination with motapizone, methacholine-induced bronchoconstriction was concentration-dependently attenuated. Allergen-induced bronchoconstriction in passively sensitised PCLS was attenuated by CC3 (IC(50) 2.7 microM), rolipram (0.23 microM) and motapizone (8 microM). Combination of equimolar concentrations of motapizone and CC3 (0.34 microM) or rolipram (0.005 microM) showed an additive effect. Endotoxin-induced TNF release from human monocytes was attenuated by all three PDE inhibitors, i.e. CC3 (IC(50) 4.6 microM), rolipram (0.18 microM) and motapizone (5.8 microM). Our findings suggest that PDE4 inhibitors with only low affinity for the HABRS have bronchospasmolytic and anti-inflammatory properties.     

Drug absorption in gastrointestinal disease and surgery

It is well recognized that drug absorption from the gastrointestinal tract is influenced by gastric and intestinal motility, surface area available for absorption, and physicochemical properties of the drug. Disease and surgery have been shown to alter these factors. Consequently, drug absorption can be altered as well, and these affect drug therapy. Apparently this effect is variable, but the variability may be due in part to the complexities of performing studies in this area. For example, many patient factors as well as drug characteristics must be considered. In addition, appropriate interpretation of results requires that intravenous data be collected if changes in absorption are based on bioavailability. At this time, the alterations in drug absorption due to gastrointestinal disease and surgery are of unknown or little clinical significance; nevertheless, clinicians should be aware that the possibility of malabsorption exists and anticipate any monitoring of or alterations in therapy that may have to be made.     

Gastrointestinal sparing anti-inflammatory drugs--COX-2 selective inhibitors and NO-releasing NSAIDs

The use of NSAIDs is associated with a wide array of alterations in the gastrointestinal integrity and function. Various approaches have been taken to develop NSAIDs with reduced gastrointestinal toxicity, and few have successfully reduced the incidence of adverse reactions. These include COX-2 selective inhibitors and NO-releasing NSAIDs. Much has been written about the potential of COX-2 inhibitors as antiinflammatory agents that lack the gastrointestinal side effects of traditional NSAIDs. COX-2 expression is most evident at sites of inflammation, while COX-1 accounts for most of the PG synthesis in the normal gastrointestinal tract. However, there are distinct examples of circumstances in which COX-2-derived PGs play a role in the maintenance of the mucosal integrity, and the differentiation of COX-1 and COX-2 is not quite as clear as has been suggested. On the other hand, the rational behind the NO-releasing NSAIDs is that NO released from the derivatives exerts beneficial effects on the gastrointestinal mucosa. The present article overviews the roles of COX and NO in housekeeping functions of the gastrointestinal mucosa in various circumstances and the effects of gastrointestinal sparing NSAIDs, such as COX-2 selective inhibitors and NO-releasing NSAIDs, on the ulcerogenic and healing responses in the gastrointestinal mucosa.     

Effects of seaweed-restructured pork diets enriched or not with cholesterol on rat cholesterolaemia and liver damage

Seaweed enriched-restructured pork (RP) is a potential functional food. However, indications of adverse effects associated with herbal medications, which include among others liver failure, toxic hepatitis, and death have been reported. Cholesterol feeding produces hepatomegalia and fat liver infiltration. The effect of seaweed-RP diet, cholesterol-enriched or not, on plasma cholesterol, liver damage markers, structure, and cytochrome CYP4A-1 were evaluated after 5 wk. Eight rat groups were fed a mix of 85% AIN-93M rodent-diet plus 15% RP. The Cholesterol-control (CC), Cholesterol-Wakame (CW), Cholesterol-Nori (CN) and Cholesterol-Sea Spaghetti (CS) groups respectively consumed similar diets to control (C), Wakame (W), Nori (N), and Sea Spaghetti (S) but as part of hypercholesterolaemic diets. CN and CS significantly blocked the hypercholesterolaemic effect observed in CC group. After 5-wk, N and S diets increased the CYP4A-1 expression. However, seaweed-RPs were unable to reduce the histological liver alterations observed in CC group. Larger and more abundant hepatocellular alterations were found in CS and CN rats suggesting that the hypocholesterolaemic effects of these seaweed-RPs seem to be a two-edged sword as they increased liver damage. Future studies are needed to understand the involved mechanisms.     

急性胰腺炎伴发胃黏膜病变的临床特征分析

目的分析急性胰腺炎引起的急性胃肠黏膜病变(acute gastrointestinal mucosal lesions,AGML)的临床特征以及对胰腺炎治疗和转归的影响。方法152例急性胰腺炎患者在入院后1~4d内用电子胃镜检查上消化道AGML的发病情况,分析AGML的损伤类型和发病部位。根据有无AGML将患者分成两组,分析AGML和急性胰腺炎多项临床指标的关系。结果152例患者中有87例(57%)发现AGML,男性居多(P<0.01)。年龄、病因、血清淀粉酶以及住院天数和AGML之间无显著关联。重症(坏死型)急性胰腺炎AGML发生率显著高于轻型(水肿型)急性胰腺炎(P<0.05)。急性胰腺炎的不同病因和AGML发生的部位无关。急性胰腺炎导致的AGML以胃部多发的浅表性损伤为主。采用制酸剂治疗后,AGML对患者平均住院天数没有影响。结论AGML是急性胰腺炎临床常见的并发症,在男性患者以及在重型急性胰腺炎中更常见。胃镜检测对早期治疗急性胰腺炎导致的AGML有指导作用。     

Gastrointestinal sparing anti-inflammatory drugs--effects on ulcerogenic and healing responses

The use of nonsteroidal antiinflammatory drugs (NSAIDs) is associated with a wide array of alterations in gastrointestinal integrity and function. Various approaches have been taken to developing NSAIDs with reduced gastrointestinal toxicity, and few have been successfully reduced the incidence of adverse reactions. These include cyclooxygenase-2 (COX-2) selective inhibitors and nitric oxide (NO)-releasing NSAIDs. Especially, much has been written about the potential of COX-2 inhibitors as anti-inflammatory and analgesic agents that lack the gastrointestinal side effects of traditional NSAIDs. COX-2 expression is most evident at sites of inflammation, while COX-1 accounts for the majority of prostaglandin synthesis in the normal gastrointestinal tract. However, there are distinct examples of circumstances in which COX-2-derived prostaglandins play a role in the maintenance of gastrointestinal mucosal integrity, particularly when the mucosa is injured, and the delineation of COX-1 and COX-2 might not be quite as clear as has been suggested. On the other hand, the rational behind the NO-releasing NSAIDs is that the NO released from the derivatives will exert beneficial effects on the gastrointestinal mucosa. This approach has been successfully demonstrated to lessen the incidence of gastrointestinal damage and to promote the healing of gastric ulcers. The present article overviews the roles of COX and NO in housekeeping functions of the gastrointestinal mucosa in various circumstances, and the effects of gastrointestinal sparing NSAIDs, mainly COX-2 selective inhibitors and NO-releasing derivatives of NSAIDs, on the ulcerogenic and healing responses in the gastrointestinal mucosa of experimental animals.     

Excitability of nodose ganglion cells and their role in vago-vagal reflex control of gastrointestinal function

A large body of evidence has demonstrated that vagal afferent neurones show non-uniform properties and that distinct neuronal populations can be identified within the nodose ganglia. Of particular interest is recent work illustrating the significant degree of plasticity displayed by vagal sensory neurones; alterations in vagal afferent neuronal excitability might be important in the development and maintenance of gastrointestinal pathological states. Although it is unclear whether such adaptations are mimicked centrally, recent studies suggest that tonic afferent vagal inputs act as a 'brake' on inputs to the dorsal motor nucleus of the vagus. It would be reasonable to assume, therefore, that plasticity in the excitability of vagal afferent neurones would have dramatic consequences for the regulation and modulation of gastrointestinal vago-vagal reflexes.     

Cellular immune mechanisms in the pathogenesis of Crohn's disease

Crohn's disease is a chronic relapsing inflammatory disease of the intestine of unknown cause. It has been suggested that the disease may result from an abnormality of the immunological functions of the gut. Recent advances in the study of the gastrointestinal immune system show that T cells in the intestinal mucosa are more activated, contain a higher proportion of T4 cells having the phenotypic and functional characteristics of helper-inducer cells, have greater capacity for IL-2 production, and have altered responsiveness to antigen stimulation. In the intestinal mucosa in Crohn's disease the predominance of T cells with helper-inducer function is maintained, and there is no evidence of augmented suppressor activity. Although natural killer cells are infrequent in the intestinal mucosa in Crohn's disease, lymphokine activated killer cell precursors and cytolytic T cell precursors are present and it is possible that these cells also play an important role in the disease. The failure to identify specific infections or environmental etiologies in Crohn's disease is consistent with the hypothesis that the disease is due to an inappropriate immunological hyper-responsiveness to ubiquitous components of the alimentary tract.     

鸡Ⅱ型胶原双盲随机对照治疗类风湿关节炎的研究

目的观察口服鸡Ⅱ型(CCⅡ)胶原胶囊治疗我国活动性类风湿关节炎(RA)患者的疗效和安全性。方法采用随机、双盲双模拟、平行对照临床研究。共入选病例60例,口服鸡Ⅱ型胶原胶囊90μg/d,或甲氨蝶呤(MTX)10mg/周,疗程24周。其中5例患者被剔除,最后纳入统计共55例,MTX组29例,CⅡ组26例。结果口服CCⅡ能明显改善RA患者的休息痛、晨僵、压痛关节指数、肿胀关节指数、患者评价、日常生活能力、血沉和C反应蛋白(P<0.05),但对压痛关节指数、肿胀关节指数、关节功能、日常生活能力、血沉的改善不及MTX(P<0.05)。按国内抗风湿药疗效评价标准,两组在治疗12周时疗效差异无统计学意义,治疗18、24周时CⅡ疗效不及MTX(P<0.05)。ACR20%在12、18和24周时MTX组疗效较CⅡ组好(P<0.05);ACR50%在18周时MTX组疗效较CⅡ组好(P<0.05),但12和24周时两组差异无统计学意义。CⅡ组无因不良反应停药者,对肝、肾功能、血常规未见影响,胃肠道等不适反应明显低于MTX组(P<0.05),MTX组有1例患者因服药后转氨酶升高3倍以上而停药。结论口服CCⅡ治疗RA具有一定的疗效且不良反应较少,但总体疗效不及MTX。     

Efficacy and safety of prucalopride in adults and children with chronic constipation

Introduction: Chronic constipation (CC) is a debilitating condition with high prevalence rates both in children and adults. Despite the broad range of medical and pharmaceutical treatments, the bowel function does not restore in a fair amount of patients. Prucalopride is a first-in-class selective, high affinity serotonin 5-hydroxytryptamine type 4 (5-HT4) receptor agonist promoting gastro-intestinal prokinetic activity and has been evaluated for the treatment of CC.

Areas covered: A PubMed search (1965 – 2014) using the following terms alone or in combination: prucalopride, 5-HT4, R093877, safety, toxicity, pharmacokinetics, pharmacodynamics, transit, cardiac, human ether-a-go-go related gene (hERG), arrhythmia, potassium current, elderly, children.

Expert opinion: Prucalopride, a highly selective 5-HT4 receptor agonist, stimulates gastrointestinal motility and has been proven to be effective in the treatment of CC in adults by increasing stool frequency, reducing constipation-related symptoms and improving quality of life (QoL). The safety and tolerability have been proven to be excellent. More research would be preferable on the effect of prucalopride on men, children and in other gastrointestinal motility disorders.     

Differential effects of topiramate in patients with traumatic brain injury and obesity—a case series

Rationale Topiramate is an antiepileptic drug known to have effects on weight. In order to use this as a tool to treat eating disorders, it is useful to examine whether these effects can be predicted in certain patients.Objectives To report the effects of topiramate, initiated for the treatment of epilepsy, on top of ongoing treatment, on eating patterns and weight of 17 patients with traumatic brain injury (TBI) with post-traumatic epilepsy and weight gain of various etiologies.Methods Patients were followed up according to their usual treatment plan. Topiramate was added on top of current and stable treatment. Dose was titrated based on the patients neurological status. Patients were asked to report side effects. No other changes were made.Results Of the 17 patients included, one patient dropped out. Six patients with binge eating disorder (BED) demonstrated the most pronounced effects, with marked attenuation of binges and normalizing body mass index. Less noticeable were the effects in patients with mood disorders. Topiramate was ineffective in patients whose overweight was a side effect of their medication. Side effects were rated as mild and included somnolence, paresthesias, mild cognitive disturbances and some gastrointestinal disturbances.Conclusions In this report of the actual effects of topiramate in a clinical setting on weight and eating habits of 17 patients with TBI and obesity of various etiologies, topiramate seemed to be a safe intervention. Topiramate appeared to be differentially effective, with particular effects on primary pathological eating patterns.     

Resistance to Nondepolarizing Neuromuscular Blocking Agents

Several case reports of resistance to short-term administration of nondepolarizing neuromuscular blocking agents (NNMBAs) have been reported in research and surgical settings. Recently, several reports documented resistance to NNMBAs during therapy for prolonged paralysis in critically ill patients. Adverse outcomes associated with NNMBA resistance may include inadequate ventilatory management or suppression of patient movement, and an increased risk of dose-dependent cardiovascular adverse effects. Pharmacoeconomic issues must be considered in that the cost of NNMBA therapy in a resistant patient may be significant. Although the specific etiologies of resistance are not clear, several pharmacodynamic and pharmacokinetic alterations may occur as a consequence of disease state or concomitant drug therapy. Pharmacodynamic changes include altered acetylcholine receptor physiology or sensitivity, inhibition of serum cholinesterase activity, and interaction with plasma constituents. Alterations in distribution volume, protein binding, and clearance may also contribute to resistance in several disease states.     

Role of ion channels in mechanisms controlling gastrointestinal pain pathways

Hypersensitivity or sensitization of nociceptive primary afferents in the gastrointestinal tract has been proposed as a mechanism for organic and functional gastrointestinal pain. This hypersensitivity can be the result of alterations, either induced by a sensitizing agent or without a peripheral cause, in the functional properties of ion channels located in primary afferents. The tetrodotoxin-resistent sodium channel, known as Na(v)1.8, is present in nociceptive primary afferents, including those from the gut, and it has been implicated as being the main candidate for the enhanced activity that characterizes nociceptor sensitization. Other voltage-gated channels, such as calcium and potassium channels, can also contribute to the sensitization of primary afferents observed in gastrointestinal pain states.     

Effect of exercise training on antioxidant system in brain regions of rat

The purpose of this investigation was to determine whether any alterations in antioxidant enzyme activities and levels of glutathione (GSH) in brain regions occurred following exercise training. Sprague-Dawley rats were given exercise training on a treadmill for 7.5 weeks and sacrificed 18 h after the last exercise along with the sedentary control rats. Different brain regions—cerebral cortex (CC), brainstem (BS), corpus striatum (CS), and hippocampus (H)—were isolated; GSH, oxidized glutathione (GSSG), Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities were determined. The exercise training increased SOD activity significantly (130% of sedentary control) in BS and in CS. SOD activity in H was the lowest of all four brain regions. Different brain regions showed GSH-Px activity in decreasing order for CS < BS < CC < H. GSH levels were 43% less in BS than CC and CS. The ratio of GSH/ GSSG significantly increased from 6.8 to 8.3 in CC, and from 9.4 to 13.5 in BS as a result of exercise training. Different brain regions contained different activities of antioxidant enzymes, as well as GSH and GSSG levels, which were preferentially altered as a result of exercise training to cope with oxidative stress.     

Current Phase II clinical data for ridaforolimus in cancer

Introduction: Chronic constipation (CC) is a common gastrointestinal (GI) motility disorder that significantly impairs the quality of life in affected subjects. As almost half of the patients suffering from CC are not satisfied with currently available medicines, there is a need to develop new molecules with better effectiveness and tolerability.

Areas covered: The authors include all experimental and clinical trials (up to Phase II) about new investigational drugs for the treatment of CC. The article identifies nine new agents: mitemcinal, TD-8954, YKP10811, itopride, RM-131, KWA-0711, elobixibat, velusetrag, and naronapride. All nine agents have shown prokinetic effects in different stages of the development. The mechanisms of new developing drugs include: the activation of 5-hydroxytryptamine type-4 (5-HT₄), ghrelin and motilin receptors, antagonizing dopamine type-2 (D₂) receptors, inhibition of ileal bile acid reabsorption and acetylcholine esterase, as well as water absorption from the GI tract.

Expert opinion: At this current point in time, new generations of 5-HT₄ receptor agonists (velusetrag, noranopride and YKP10811) are hoped to progress, further in the future, due to better efficiency and safety. However, it is not possible to make a concise conclusion at this current time due to a lack of evidence. Further clinical trials with a longer duration and a larger sample size are warranted.     

Validation of Protocols for Assessing Early Pregnancy Failure in the Rat: Clomiphene Citrate

Validation of Protocols for Assessing Early Pregnancy Failurein the Rat: Clomiphene Citrate. CUMMINGS, A. M., PERREAULT,S. D., AND HARRIS, S. T. (1991). Fundam. Appl. Toxicol. 16,506–516. A battery of protocols for the assessment ofmaternally mediated toxicity during early pregnancy in the ratis being evaluated for its utility in detecting and denningmechanisms of early pregnancy failure. In this report, clomiphenecitrate (CC), an estrogen agonist/antagonist, was used as amodel compound in this evaluation process. The protocols involvedosing rats with CC during, and evaluation of multiple endpointsfollowing, (a) the first 8 days of pregnancy; (b) early pseudopregnancy,accompanied by decidual induction; and (c) the pre- and postimplantationintervals of early pregnancy. In addition, the effect of CCon embryo transport rate was assessed. Eight days of dosingwith CC during early pregnancy produced a dose-dependent reductionin the number of implantation sites seen on Day 9, concomitantwith alterations in maternal hormonal parameters. No effecton the decidual cell response was found, indicating that themechanism of fertility reduction was not mediated via compromiseduterine decidualization. The preimplantation period was highlyvulnerable to the toxic effects of CC while no postimplantationresorptions were seen. When embryo transport rate was measured,a statistically significant embryo transport rate accelerationwas detected, but this was insufficient to account for all ofthe observed preimplantation loss. The data suggest an effectof CC on embryo viability, on the embryo's ability to implant,or on the reproductive tract resulting in compromised embryosurvival as the potential mechanism(s) mediating CC-inducedearly pregnancy failure. The battery of protocols was thus successfulin identifying CC as a reproductive toxicant and in elucidatingthe causes of the observed early pregnancy failure.     

Life style, environmental and genetic susceptibility to cervical cancer

We have studied cervical cancer (CC) patients from Venezuela and the US to elucidate the contribution of certain acquired and genetic susceptibility factors to the development of the disease. For acquired susceptibility factors, infection with high risk human papilloma virus (HPV), having multiple sex partners and having early sexual activities are significant risk factors for CC in Venezuela. The latter two are not significant risk factors for the US population. Infection with high risk HPV is a more significant risk factor for the US than the Venezuela populations. On the other hand, cigarette smoking is significantly associated with CC in the US but not the Venezuela populations. From genetic susceptibility factors, polymorphisms in the CYP2E1 and mEH genes are not associated with CC but the GSTM1 null genotype is for the US population. Our study indicates that the same susceptibility factors can have very different roles in the development of the same disease such as CC in different countries. The information is useful for the development of effective but different disease prevention programs for different countries in the control of CC.