The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac

Methadone is used as a treatment for opiate detoxification in methadone maintenance programs. Intra- and inter-patient variations in methadone bioavailability have been observed after oral methadone treatment and this makes it difficult to predict a dosing regimen. Intestinal absorption and metabolism could explain these variations. The in vitro gut sac model was used to study the intestinal absorption of methadone, and it confirmed that methadone is a substrate for P-glycoprotein. The transport of methadone was increased in presence of P-gp inhibitors verapamil and quinidine. The appearance of a major metabolite of methadone, 2-ethylidene-1, 5-dimethyl-3, 3-diphenyl pyrrolidine (EDDP) in the gut sac contents also demonstrated the existence of intestinal metabolism of methadone.     

The effect of different calcium antagonists and a calcium agonist on the metabolism of propranolol by isolated rat hepatocytes

Summary— The influence of the dihydropyridine calcium entry blockers nicardipine, amlodipine, nifedipine, isradipine and of the dihydropyridine calcium entry promotor BAY K 8644 on the disappearance rate of propranolol by isolated rat hepatocytes was compared to the effect of diltiazem and verapamil, two non-dihydropyridine calcium channel blockers and known inhibitors of hepatic cytochrome P450 mixed function oxidases. All compounds dose-dependently inhibited the disappearance rate of propranolol. Nicardipine and isradipine were more potent in inhibiting the disappearance rate of propranolol than the other dihydropyridines and than diltiazem and verapamil. The inhibitory effect of nicardipine on the disappearance rate of propranolol was not stereoselective and was not influenced by age.     

The application of a new synthetic substrate to the determination of enteropeptidase in rat small intestine and human intestinal biopsies

The application of a new synthetic substrate to the direct determination of enteropeptidase is described. The substrate Gly-(L-Asp)₄-L-Lys-2-naphthylamide contains the amino acid sequence of the activation peptides of trypsinogen linked via an amide bond to the fluorophore 2-naphthylamine. The sequence of amino acids is responsible for the specificity and substrate recognition of the enteropeptidase-catalyzed activation of trypsinogen. Interference in the assay by trypsin is prevented by the addition of soybean trypsin inhibitor to the substrate solution. The fluorimetric determination of the liberated 2-naphthylamine allows the direct observation of the reaction kinetics. For the hydrolysis of the synthetic substrate by purified enteropeptidase the pH optimum was 8.2 and the K_m 0.17 mmol/l. The new substrate was used to determine the distribution of enteropeptidase along the rat small intestine and also to measure enteropeptidase activity in human intestinal biopsies.     

Studies on the absorption and metabolism of folic acid: I. Folate absorption in the dog after exposure of isolated intestinal segments to synthetic pteroylpolyglutamates of various chain lengths

Folic acid absorption was studied in anesthetized dogs by determining the amount and chemical nature of folate in venous blood emerging from isolated intestinal segments containing free folic acid and/or pteroylpolyglutamates of a known chain length. Chromatographically pure test materials placed in the lumen were prepared by unambiguous solid phase synthetic methods. This synthetic procedure not only yields compounds of known structure, it also provides a means by which glutamic acid residues at any given position in the gamma glutamyl chain can be made radioactive. For example, teropterin (pteroyltriglutamate) was synthesized in such a way that (14)C was present only in the middle glutamic acid unit. Suitable placement of label permitted assessment of the extent of peptide cleavage. The action of plasma conjugase was inhibited by copper chloride. Plasma samples were analyzed by Lactobacillus casei and Streptococcus faecalis assay, by column chromatography, and by quantitative measurement of pteridine-bound radioactivity.It was observed that biologically active folate appeared in the mesenteric vein with either pteroylmono-, di-, tri-, penta-, or heptaglutamate in the lumen. Generally speaking the absorption rate appeared to be inversely related to the length of the gamma glutamyl side chain. Roughly twice as much folic acid appeared in the circulation from (3)H-labeled pteroylmonoglutamate as from (14)C-labeled pteroylpentaglutamate when equimolar amounts of each were placed simultaneously in a single intestinal segment. Pteroylmonoglutamate appeared to be the predominant form entering the blood from each of the precursors tested. However, evidence was obtained that pteroyldiglutamate may enter the mesenteric vein soon after placing pteroyldi-, or triglutamate in the lumen, but not with the higher polyglutamates. Comparison of radioactivity and biological activity patterns suggests little conversion, if any, to reduced or methylated forms during the first 30 min of passage through the intestinal mucosa. We conclude that both pteroylmonoglutamates and pteroyldiglutamates may across the intestinal mucosa of the dog, and that reduction and methylation are not essential to the absorption process.     

运动改善原发2型糖尿病大鼠血糖和血脂代谢紊乱的实验研究

目的　研究运动对早龄OLETF大鼠血糖和血脂的影响。方法　对 40只原发 2型糖尿病模型 -OLETF大鼠和 15只先天不发生 2型糖尿病的LETO大鼠进行运动干预 ,9周后进行血糖和血脂各项指标检测。结果　OLETF、LETO大鼠基础饲料运动组及OLETF大鼠高脂饲料运动组其血浆胆固醇 (TC)、低密度脂蛋白 (LDL)浓度与它们相应的非运动对照组相比 ,均有极显著降低 (P <0 .0 1) ;OLETF、LETO基础饲料运动组大鼠血浆甘油三酯 (TG)浓度较与它们各组的非运动对照组相比也有明显降低 (P <0 .0 5 ) ;OLETF基础饲料运动组和高脂饲料运动组大鼠与它们各自非运动对照组的空腹血糖水平相比 ,虽有下降的趋势 ,但无显著差异。结论　运动可以显著降低OLETF大鼠血浆胆固醇、甘油三酯及低密度脂蛋白水平。运动能够有效预防OLETF大鼠出现脂质代谢紊乱。     

Rapid high performance liquid chromatography method for erlotinib quantification in vitro: Application to study the effect of resveratrol on metabolism and cellular uptake of erlotinib

Background: Erlotinib is a selective epidermal growth factor receptor inhibitor that is used for the treatment of non-small cell lung cancer and pancreatic cancer. Its metabolism is mainly mediated by cytochrome P450 3A (CYP 3A). Resveratrol, a natural compound found in many plants and supplements, is known to inhibit CYP3A enzyme, therefore, it may act as an inhibitor for the metabolism of erlotinib. Objective: Development of a rapid high performance liquid chromatography with photodiode array detection (HPLC-PDA) method for the quantification of erlotinib in liver microsomes and cancer cells and its application to study resveratrol effect on metabolism and cellular uptake of erlotinib. Methods: HPLC-PDA was used to develop an efficient bioanalytical method with a 2.5-min runtime preceded by a simple protein precipitation step. The method was validated according to the European Medicines Agency guidelines. Erlotinib metabolic stability and resveratrol effect on erlotinib metabolite formation were evaluated in rat liver microsomes. Furthermore, the method was used to measure the intracellular concentrations of erlotinib in cancer colorectal cells and investigating resveratrol effect on the cellular uptake of erlotinib. Results: A rapid HPLC-PDA method was developed and validated for the first time to address potential drug interaction of erlotinib with resveratrol. Resveratrol was a strong inhibitor of erlotinib metabolism in vitro with IC₅₀ = 4.03 μM. Resveratrol, however, had no effect on erlotinib cellular uptake after 1 h incubation in human colorectal cancer cells. Conclusion: The study suggests that resveratrol may produce a potential herb–drug interaction with erlotinib at the metabolism level and should be investigated in patients in the clinic.     

The use of an electronic medical record based automatic calculation tool to quantify risk of unplanned readmission to the intensive care unit: a validation study

Objective

The aim of this study was to refine and validate an automatic risk of unplanned readmission (Stability and Workload Index for Transfer, or SWIFT) calculator in a prospective cohort of consecutive medical intensive care unit (ICU) patients in a teaching hospital with comprehensive electronic medical records (EMRs).

Design

A 2-phase (derivation and validation) prospective cohort study was conducted.

Settings

The study was conducted in an academic medical ICU.

Subjects

A consecutive cohort of adult (age >18 years) patients with research authorization were analyzed.

Intervention

The EMR-based automatic SWIFT calculator was used for this study.

Measurement

Agreement between the manual (“gold standard”) and automatic SWIFT calculation tool was obtained.

Main results

During the derivation phase, we enrolled 191 consecutive medical ICU patients. Scores of SWIFT for these patients calculated manually by the 2 reviewers had strong positive correlation (r = 0.97), and the mean (SD) difference was 0.43 (3.5). The first iteration of the automatic SWIFT calculator in the derivation cohort demonstrated excellent agreement with manual calculation, partial pressure of carbon dioxide in arterial blood (κ = 0.95), partial pressure of oxygen in arterial blood/fraction of inspired oxygen ratio (κ = 0.69), length of ICU stay (κ = 0.91), and Glasgow comma scale (κ = 0.90) and no agreement for source of ICU admission (κ = −0.15). After adjustment in rules, the κ value for hospital admission source improved to 1.0. Automatic calculation demonstrated strong correlation with manual (r = 0.92), and mean (SD) difference was −2.3 (5.9). During validation phase, 100 subjects were enrolled at 5 days. The automatic tool retained excellent correlation with gold-standard calculation for SWIFT (r = 0.92), and the mean (SD) difference was −2.2 (5.5).

Conclusion

The EMR-based automatic tool accurately calculates SWIFT score and can facilitate ICU discharge decisions without the need for manual data collection.     

The response of the toad intestine to prolonged starvation: a morphological, functional and metabolic study

Abstract. 1. Toads were kept without solid nourishment for four months or more, and the morphological and functional characteristics of their intestines were compared with those of freshly captured animals. 2. The intestinal mucosa is one of the organs that is specifically and preferentially consumed during the process of autophagy. Histological sections reveal that a substantial loss of villous architecture is incurred. The epithelial cells covering the mucosal surface are interspersed with frequent vacuoles, the significance of which is as yet unclear. 3. The absorptive capacity of intestinal slices excised from autophagous toads, determined by their ability to accumulate radioactive phenylalanine, is lower than that of normal animals, but this difference can be ascribed to the distinct tissue composition of the intestinal slices. 4. Intestinal slices of autophagous toads have a lower respiration rate but higher glucose consumption than those of normal animals.     

The use of bed-dials to maintain recumbent positioning for critically ill mechanically ventilated patients (The RECUMBENT study): Multicentre before and after observational study

Background

Observational studies continue to report poor compliance with positioning recommendations for prevention of ventilator-associated pneumonia. Inability to accurately measure backrest elevation may contribute to this poor compliance.

Objective

To determine if provision of an accurate, simple to use angle measurement device with an accompanying education program improved compliance with semirecumbency at 45° over time.

Design

Using a prospective pre- and post-design we implemented angle measurement devices and an associated education intervention in three Australian ICUs. Backrest elevation, contraindications to semirecumbency at 45°, mean arterial pressure (MAP), inotrope use, enteral feeding and weaning status were recorded 3-times daily using a pre-determined randomization schedule for 7 consecutive days prior to implementation and again at 1, 3 and 6 months post-implementation. Illness severity and a clinical pulmonary infection score were recorded for each day of ventilation.

Results

Backrest elevation measurements (n = 1154) were recorded for 141 mechanically ventilated patients. Contraindications to semirecumbency at 45° were noted for 163/1154 (14.1%) measurements the proportion of measurements at 45° rose from baseline by 10.1% (P = 0.03) 1-month following implementation, however this change was not sustained over time. The proportion of measurements 30° increased by 43.8% at 1-month and remained above 70% 6-months after implementation (P < 0.001).For measurements recorded in the absence of a contraindication to semirecumbency, and adjusted for covariates (MAP, inotropic support, sequential organ failure assessment maximum score, clinical pulmonary infection score maximum, and indication for ventilation), decreased backrest elevation was associated with higher severity of illness (0.3° [95% CI 0.1-0.5] for every 1-point increase in APACHE II score). Increased mean backrest elevation was noted for older patients (0.8° [95% CI 0.1-1.5] for each 10-year increment) and measurements recorded during weaning (2.7° [95% CI 1.2-4.1]).

Conclusions

Bedside implementation of an angle measurement device and associated educational intervention did not result in a sustained improvement to compliance with 45° semirecumbency, questioning the clinical feasibility of this nursing intervention. A sustained increased in semirecumbency at 30° or greater was achieved.     

The use of standard calendar software by individuals with acquired brain injury and cognitive complaints: a mixed methods study

Purpose: To explore the actual use of standard calendar software by people with acquired brain injury (ABI) and healthy individuals. Method: Mixed methods design with qualitative and quantitative analyses of the respondents’ use of calendar software. Fifteen individuals with ABI and 15 healthy participants were enrolled. Participants were asked to execute five consecutive tasks using standard calendar software, which resembled everyday use of an electronic calendar. Results: The core processes “task execution” and “information processing” were influenced by internal factors (cognitive and emotional processes and fatigue) as well as environmental factors (software features and distractions). Results obtained by qualitative and quantitative methods showed similar reaction patterns in both groups. However, ABI patients had more cognitive problems and showed stronger emotions during task performance than healthy participants. Healthy participants were more successful and needed less time and mental effort to perform a task. Conclusions: Although ABI patients were able to use standard calendar software, they became upset more easily, needed more effort, became tired sooner and more suddenly. Strategies to support ABI patients in the use of calendar software are suggested from multi-disciplinary perspectives.

Implications for Rehabilitation

• A user-centred approach is necessary when designing dedicated calendar software for acquired brain injury (ABI) patients with cognitive deficits.

• Training ABI patients in the use of assistive technology should focus on the influence of person-related factors such as cognitive and emotional processes and fatigue and environmental factors such as software features and distractions.

• In order to conceive and realize user-centred solutions for AT use in cognitive rehabilitation, a strong multi-disciplinary input is necessary.

     

The impact of COVID-19 pandemic on headache symptoms and drug withdrawal among patients with medication overuse headache: a cross-sectional study

BackgroundCoronavirus disease 2019 (COVID-19) bring about a range of psychological distress and symptom deterioration to headache patients especially to some migraineurs. Compared to migraineurs or normal control, medication overuse headache (MOH) patients are more likely to experience a worse psychological distress and poorer outcome in non-COVID-19 time. However, in COVID-19 pandemic, whether MOH patients would have greater physical and mental symptom deterioration or worse relief of headache symptoms and medications overuse remained unclear. We aim to investigate the impact of COVID-19 on MOH patients to guide for a better management in this study.MethodsWe enrolled MOH patients who were diagnosed and treated at headache clinic of West China Hospital. Information of the pre-pandemic 3 months period and COVID-19 pandemic period was collected. Univariate and multivariate logistic regression were performed to identify independent factors associated with changes in headache symptoms and drug withdrawal.ResultsSeventy-eight MOH patients were enrolled into the study ultimately. In comparison to pre-pandemic period, fewer MOH patients reported decreased headache days, intensity and days with acute medications per month during the pandemic. Available access to regular prophylactic medications was significantly associated with a reduction of at least 50% in headache days and decrease in headache intensity per month with respective odds ratios of 39.19 (95% CI 3.75–409.15, P = 0.002) and 10.13 (95% CI 2.33–44.12, P = 0.002). Following abrupt withdrawal and high educational level were both significant factors in decreasing headache intensity. Male sex was significantly associated with decrease in days with acute medication per month during the pandemic (odds ratios 4.78, 95%CI 1.44–15.87, P = 0.011).ConclusionsOur findings reflect that MOH patients experienced a worse relief of headache symptoms and drug withdrawal during the pandemic. Available access to regular prophylactic medications was the significant independent factor for improvement of headache symptoms. Male sex was significantly associated with decreased days with acute medications per month.     

The use of drama to support reflection and understanding of the residents’ situation in dementia care: a pilot study

Background. One key aspect of person‐centredness is striving to understand both the patients’ experiences and behaviours from their perspective. These aspects are precisely those that staff in dementia care highlight as causing them most difficulty because the people in their care have major problems expressing themselves. There is thus a need to develop a method to help the staff to achieve interpretation through reflection. Aim. The aim of this study was to explore the use of drama as a tool to support reflection among staff working in the residential care of people with dementia. Design. A qualitative evaluation of a programme consisting of three drama sessions with staff working in residential care (n = 10 nurse assistants). Methods. Data comprised observations and tape recordings of the sessions, the researchers’ reflections after each session and a focus‐group interview with the participants. The texts were analysed using qualitative content analysis. Results. The analysis showed that: (i) the exercises stimulate reflection about daily caring practice; (ii) the participants must receive extensive information about the purpose of the sessions; (iii) the research team must secure the defined frames and conditions and have practical knowledge about caring for people with dementia and (iv) the management needs to be stable, committed and supportive. Conclusion. Drama seems to be a valid tool to aid reflection, but several adjustments are needed concerning both the content of the sessions and the methodology. When designing a larger intervention study, it would be preferable to the sessions to be combined with staff support to effect changes in care provision resulting from their increased awareness of the residents’ situation and experience. Implications for practice. Our results showed that drama can be a means to enhance reflection among staff in residential care for people with dementia. Further research is however needed concerning the effects for the staff's situation and nursing care quality.     

The relation of early maladaptive schemas and behavioral inhibition/approach systems to defense styles in abusers of synthetic drug: a cross-sectional study

The aim of the study was to examine the relationship of early maladaptive schemas (EMSs) and behavioral inhibition/approach systems (BIS/BAS) with defense styles in the abusers of synthetic drug admitted at Niyayesh addiction treatment clinic in the city of Shiraz, Iran. In a cross-sectional design, we examined the relationship between EMSs (via Young Maladaptive Schemas Questionnaire —Short Form “YSQ-SF”) and BIS/BAS (via Carver & White BIS/BAS Scale) to defense styles (via Defense Style Questionnaire “DSQ-40”) for 340 abusers of synthetic drug (male = 53.5%, female = 46.5%). To analyze the relationship between the studied variables, zero-order correlation and multivariate regression were used. Also, sex differences in the means of the responses for each of EMSs, BIS/BAS, and defense styles were analyzed using the independent samples t test.

Correlational analyses revealed that all five EMSs were correlated with both neurotic and immature defense styles, and negatively with mature defense style. Also, BIS and all BAS subscales were related to both neurotic and immature and negatively to mature defense style. Finally, there were significant sex differences in BIS, BAS subscales, EMSs, and defense styles. We concluded that EMSs, excessive BIS and BAS subscales, and maladaptive defense styles (e.g., neurotic and immature styles) are important factors in understanding the causes of drug abuse in the abusers of synthetic drug.     

Enhancing cancer trial management: An intervention study of the impact of providing information, trial results and support to patients in phase I and II anti-cancer drug trials at trial conclusion

This paper presents qualitative findings from a three year study which set out to develop and test a nurse-led strategy for improving the management of the conclusion of patients’ participation in early cancer clinical trials. Most previous research has concentrated on recruitment, obtaining informed consent, and ensuring participation in trials. This study focused on the management of trial conclusion, a neglected area. The strategy (trial exit interviews, written information and telephone follow-up) was evaluated through a randomised controlled trial that assessed its impact on, and effectiveness in improving, the trial conclusion experience. Outcome measures were patient perceptions of trial participation and conclusion, patients’ knowledge and understanding, psychological distress, satisfaction with the intervention and adjustment to no longer being in a trial. Data were collected through questionnaires, standardised psychosocial and patient-satisfaction measures, and in-depth interviews.The findings reported in this paper relate to the data collected through in-depth interviews. The interview data showed that patients in the intervention group expressed fewer fears of abandonment at the conclusion of the trial, they appreciated being given feedback about the trial in which they had participated, expressed satisfaction with the exit interview, and derived a feeling of support from the follow-up telephone call. These findings support and illuminate other quantitative findings that we have reported elsewhere (Cox et al., 2005) and demonstrate that low cost, simple interventions can be effectively incorporated into practice.     

Effectiveness of Acceptance and Commitment Therapy (ACT) on aggression of patients with psychosis due to methamphetamine use: A pilot study

Background and purpose: The aim of the current study was to evaluate the effectiveness of Acceptance and Commitment Therapy (ACT) on aggression and general health of patients with a diagnosis of psychosis due to methamphetamine use.

Materials and Methods: This pilot study is an experimental controlled study with repeat measurements. Thirty patients were randomly assigned to study and control groups. The study group, received six weekly sessions of ACT, in addition to the usual treatment, while the control group received only the usual treatment. Both groups were tested using the General Health Questionnaire (GHQ-28) and Buss Perry Aggression Questionnaire (BPAQ) at three cross sections of time.

Results: General health was improved significantly in study group comparing with control group (P < 0.0001). There were significant differences between the three time points of therapy (p = 0.0001; F(2,56) = 41/456). Additionally, there were significant differences between the means of the three time points of therapy in aggressiveness variable (p = 0.0001; F(2,56) = 190/845).

Findings: ACT improved general health and decreased aggressiveness in the study group compared to the control group and may be a good therapy for methamphetamine dependents who suffer from psychosis.     

The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB1 receptor antagonism--or inverse agonism--as potential obesity treatment and other therapeutic use

There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders. Towards this end, antagonists of cannabinoid receptors have been designed through rational drug discovery efforts. Devoid of the abuse concerns that confound and impede the use of cannabinoid receptor agonists for legitimate medical purposes, investigation of the use of cannabinoid receptor antagonists as possible pharmacotherapeutic agents is currently being actively investigated. The compound furthest along this pathway is rimonabant, a selective CB(1) (cannabinoid receptor subtype 1) antagonist, or inverse agonist, approved in the European Union and under regulatory review in the United States for the treatment of obesity. This article summarizes the basic science of the endocannabinoid system and the therapeutic potential of cannabinoid receptor antagonists, with emphasis on the treatment of obesity.     

The use of ultrasound to facilitate spinal anesthesia in a patient with previous lumbar laminectomy and fusion: A case report

We describe a case of ultrasound (US)‐facilitated spinal anesthesia in a patient with a prior lumbar laminectomy and spinal fusion who presented for total knee arthroplasty. Traditional, landmark‐guided spinal anesthesia had previously failed. Although pre‐procedural US identified a soft‐tissue window at L3/4, a 25G pencilpoint needle encountered resistance. Reassured from US imaging that this was not bone, we used a 22G cutting tip needle successfully. We believe spinal anesthesia would not have been possible in this patient without US, adding to the evidence that US‐facilitated neuraxial anesthesia is useful, particularly in technically difficult, if not ‘impossible,’ cases. © 2009 Wiley Periodicals, Inc. J Clin Ultrasound, 2009