The New Acetylcholinesterase Inhibitors PC‐37 and PC‐48 (7‐Methoxytacrine‐Donepezil‐Like Compounds): Characterization of Their Metabolites in Human Liver Microsomes,Pharmacokinetics and In Vivo Formation of the Major Metabolites in Rats

The objective of this study was to elucidate the pharmacokinetics and metabolite formation of newly developed non‐selective AChE/BChE 7‐MEOTA‐donepezil‐like inhibitors for potential therapeutic use in Alzheimer's disease (AD) patients. The chemical structures of metabolites were defined during incubation with human liver microsomes, and subsequently, the metabolization was verified in in vivo study. In vitro metabolic profiling revealed the formation of nine major metabolites in the case of PC‐37 and eight metabolites of PC‐48. Hydroxylation and the enzymatic hydrolysis of bonds close to the piperazine ring appeared to be the principal metabolic pathways in vitro. Of these metabolites, M1–M7 of PC‐37 and M1–M6 of PC‐48 were confirmed under in vivo conditions. Pilot pharmacokinetic experiments in rats were focused on the absorption, distribution and elimination of these compounds. Absorption after i.m. application was relatively fast; the bioavailability expressed as AUC_total was 28179 ± 4691 min.ng/mL for PC‐37 and 23374 ± 4045 min.ng/mL for PC‐48. Both compounds showed ability to target the central nervous system, with brain concentrations exceeding those in plasma. The maximal brain concentrations are approximately two times higher than the plasma concentrations. The relatively high brain concentrations persisted throughout the experiment until 24 hr after application. Elimination via the kidneys (urine) significantly exceeded elimination via the liver (bile). All these characteristics are crucial for new candidates intended for AD treatment. The principle metabolic pathways that were verified in the in vivo study do not show any evidence for formation of extremely toxic metabolites, but this needs to be confirmed by further studies.     

Identifying viable theoretical frameworks with essential parameters for real-time and real world alcohol craving research: a systematic review of craving models

Background: Substance use is known to be episodic, dynamic, complex, and highly influenced by the environment, therefore a situational and momentary focus to alcohol craving research is appropriate. Current advances in mobile and wearable technology provide novel opportunities for craving research. However, the lack of consensus within craving theory impedes the identification and prioritization of parameters to be monitored. The aim of this study is to critically review current craving models in order to determine viable theoretical frameworks of alcohol craving and its essential parameters.

Methods: Eighteen models of craving were reviewed by applying a literature search with a five-step strategy that accounted for the momentary nature of craving and included a snowballing search and a key term extraction algorithm. Based on this review, multiple decision criteria were defined upon which to evaluate the models.

Results: Six models for alcohol craving were supported by sufficient empirical research to be eligible. The inferences drawn on these six models resulted in three decision criteria: the model should (1) incorporate negative affect as a predictor of relapse; (2) explain that dependent drinkers have a higher attentional bias towards alcohol cues than nondependent drinkers; (3) incorporate increased risk of relapse with heightened stress levels.

Conclusions: The affective processing model of negative reinforcement, the cognitive processing model, the incentive sensitization theory of addiction and the theory of neural opponent motivation are classified as viable theoretical frameworks, resulting in negative affect and stress as relevant parameters to include in real-time craving monitoring research.     

Amputation, phantom pain and subjective well-being: a qualitative study

The purpose of this qualitative study was to explore the impact of an amputation and of phantom pain on the subjective well-being of amputees. Sixteen lower-limb amputees were interviewed. A semi-structured interview and two Visual Analogue Scales were used. To interpret the results, a new socio-medical model joining two models, 'The Disablement Process model' and the 'Social Production Function theory', was used. Questions were asked concerning the factors influencing patients' subjective well-being prior to, at the time of and after an amputation. These factors were patients' medical history, their phantom sensations and phantom pain, their daily activities, the social support they received, and the influence of an amputation and phantom pain on long-term behaviour and on their subjective well-being. All factors were found to have an influence on the individual's subjective well-being. All these factors, however, seemed to reinforce each other. Therefore, the greatest influence of factors on subjective well-being occurred when more than one factor was involved. Substituting certain activities by others then becomes less and less effective in inducing a sense of subjective well-being.     

Robotic Resection of Type I Hilar Cholangiocarcinoma with Intrapancreatic Bile Duct Dissection

Background

Type I hilar cholangiocarcinoma is a malignancy of the extrahepatic bile duct for which margin-negative resection with sufficient lymphadenectomy may provide curative treatment. The aim of this video is to highlight the advantages of optical magnification, articulating instruments, and indocyanine green fluorescent cholangiography to demonstrate extrahepatic bile duct resection from the biliary confluence to the intrapancreatic bile duct with comprehensive hilar lymphadenectomy for pathologic staging.

Methods

A 58-year-old male presented with obstructive jaundice and was found to have a biliary stricture arising from the cystic duct and bile duct junction. Endoscopic biopsy of the bile duct confirmed adenocarcinoma. His case was presented at a multidisciplinary tumor conference where consensus was to proceed with upfront robotic en bloc extrahepatic bile duct resection with hilar lymphadenectomy and Roux-en-Y hepaticojejunostomy.

Results

Final pathology demonstrated margin-negative resection of moderately differentiated adenocarcinoma, 1 out of 12 lymph nodes involved with disease, and pathologic stage T2N1M0 (stage IIIC). The patient had no postoperative complications and was discharged home on postoperative day 5. At 6 weeks from his operative date, he was initiated on four cycles of adjuvant gemcitabine/capecitabine, followed by 50 Gray external beam radiation therapy with capecitabine, then four cycles of gemcitabine/capecitabine, completed after 6 months of therapy.

Conclusions

Robotic extrahepatic bile duct resection, hilar lymphadenectomy, and biliary enteric reconstruction is feasible and should be considered for selected cases of bile duct resection.

     

Microcirculatory characteristics of acupuncture points obtained by laser Doppler flowmetry

Acupuncture points (acupoints) form part of the meridian system that constitutes the most fundamental concept in oriental medicine, but their physiological basis has not been clarified. In this study we employed laser Doppler flowmetry (LDF) to extract the microcirculatory characteristics of acupoints and their surrounding tissues, and we interpreted the results from the viewpoint of microcirculatory physiology. Three groups of measurements were performed focusing on the following two important acupoints in oriental medicine in healthy volunteers (n = 13 for group A and n = 9 for groups B and C, respectively): Hoh-Ku (Li4, on the hand) and Ching-Ku (B64, on the foot). The two groups of measurements around Hoh-Ku (Groups A and B) were so designed as to examine the effect of the direction of the nonacupoint away from the acupoint, whereas comparison between the Hoh-Ku and the Ching-Ku measurements was to verify whether the phenomenon was consistent in the upper and the lower extremities. We found that the mean LDF signals were significantly larger at the acupoints than in their surrounding tissues (all p < 0.05), which indicates a larger blood supply into the microvascular beds of acupoints. The results indicate that the physical properties of the vascular structure of acupoints may affect the perfusion resistance, and thereby modulate the microcirculatory perfusion in accordance with tissue needs. This finding facilitates the localization of acupoints, helps in identifying the connection between microcirculatory physiology and responses to acupoint stimulation, and introduces an objective research method for understanding the mechanisms that underlie oriental medicine.