Production,in continuous enzymatic membrane reactor,of an anti-hypertensive hydrolysate from an industrial alfalfa white protein concentrate exhibiting ACE inhibitory and opioid activities

A few hydrolysates of food proteins were reported to exert an antihypertensive effect in vivo due to angiotensin I converting enzyme (ACE) inhibitory peptides or opioid peptides. An industrial alfalfa white protein concentrate (AWPC) hydrolysate, produced on a pilot plant scale, strongly inhibited ACE with an IC50 value of 8.8 μg/ml. Furthermore, the AWPC hydrolysate inhibited the spontaneous contraction of rabbit ileum in a dose-dependent and naloxone-blocked manner, indicating the presence of opioid peptides. The AWPC hydrolysate significantly lowered blood pressure of spontaneously hypertensive rats (SHR) more than 6 h after a single oral administration. The maximum reduction of systolic blood pressure (−29.9 ± 2.0 mmHg) was observed 4 h after an oral administration of 0.5 g/kg hydrolysate dosage. The minimal anti-hypertensive effect was observed for 0.1 g/kg dosage. The AWPC hydrolysate may then be particularly suitable as nutraceutical for functional food useful in the prevention of hypertension.     

Design and synthesis of novel cyclooxygenase-1 inhibitors as analgesics: 5-amino-2-ethoxy-N-(substituted-phenyl)benzamides

We previously found that N‐(4‐aminophenyl)‐4‐trifluoromethylbenzamide (TFAP), a COX‐1 inhibitor, exhibits an analgesic effect without causing gastric damage. Unfortunately, TFAP causes reddish purple coloration of urine, and its analgesic effect is less potent than that of indomethacin. Herein we describe our study focusing on the development of 4‐ and 5‐amino‐2‐alkoxy‐N‐phenylbenzamide scaffolds, designed on the basis of the structures of TFAP and parsalmide, another known COX‐1 inhibitory analgesic agent. 5‐Amino‐2‐ethoxy‐N‐(2‐ or 3‐substituted phenyl)benzamide derivatives exhibited analgesic activity in a murine acetic acid induced writhing test. Among these compounds, 5‐amino‐2‐ethoxy‐N‐(2‐methoxyphenyl)benzamide ( 9 v ) possesses potent COX‐1 inhibitory and analgesic activities, similar to those of indomethacin. In addition, 5‐amino‐2‐ethoxy‐N‐(3‐trifluoromethylphenyl)benzamide ( 9 g ) showed a more potent analgesic effect than indomethacin or 9 v without causing apparent gastric damage or coloration of urine, although its COX‐1 inhibitory activity was weaker than that of indomethacin or 9 v . Thus, 9 g and 9 v appear to be promising candidates for analgesic agents and are attractive lead compounds for further development of COX‐1 inhibitors.     

Determination of non-opioid analgesics in adulterated food and dietary supplements by LC-MS/MS

Commercially available non-opioid analgesics such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) have been used to adulterate some foods and dietary supplements. Considering the rapid growth of the dietary supplement market, it is essential to analyse various analgesics used for adulteration over a time period. Acetaminophen and 16 NSAIDs used to adulterate food and dietary supplements were simultaneously determined by LC-MS/MS. The method was validated by determining the coefficient of determinations, limit of quantification and recovery, and samples were analysed for the determination of analgesics. Consequently, acetaminophen, diclofenac, ibuprofen, indomethacin, naproxen and piroxicam were detected in 53 samples (n = 214). Ibuprofen was the most commonly used adulterant, which was detected in a wide concentration range (1.06–233.40 mg g^–1) and was present in about one-third of the adulterated samples. Various types of samples, in particular pills and capsules (73.6% of the total positive samples), were found to be adulterated with non-opioid analgesics. Samples containing high concentrations of analgesics can have a deleterious effect on human health, and thus the continued monitoring of adulterated food and dietary supplements is essential to maintain a healthy life.     

Unexpected opioid activity profiles of analogues of the novel peptide kappa opioid receptor ligand CJ-15,208

An alanine scan was performed on the novel κ opioid receptor (KOR) peptide ligand CJ‐15,208 to determine which residues contribute to the potent in vivo agonist activity observed for the parent peptide. These cyclic tetrapeptides were synthesized by a combination of solid‐phase peptide synthesis of the linear precursors, followed by cyclization in solution. Like the parent peptide, each of the analogues exhibited agonist activity and KOR antagonist activity in an antinociceptive assay in vivo. Unlike the parent peptide, the agonist activity of the potent analogues was mediated predominantly, if not exclusively, by μ opioid receptors (MOR). Thus analogues 2 and 4 , in which one of the phenylalanine residues was replaced by alanine, exhibited both potent MOR agonist activity and KOR antagonist activity in vivo. These peptides represent novel lead compounds for the development of peptide‐based opioid analgesics.     

Electron microscopic localization of enkephalin-like immunoreactivity in the human adrenal medulla

Enkephalin-like immunoreactivity in human adrenomedullary cells was studied at the light and electron microscopic levels. Enkephalin immunostaining was associated with chromaffin granules and, in a few cells, with the rough endoplasmic reticulum as well. The relative number of stained granules varied from cell to cell, and a correlation with a particular granular population was not noted. Both large and small granules were labelled. It is concluded that in the human the ability to store enkephalin immunoreactive peptides is a general property of chromaffin granules and, furthermore, is not correlated with specific granular subpopulations or the particular type of catecholamine stored within the cell.     

Management of pain in end‐stage renal disease patients: Short review

Pain management in end stage renal disease (ESRD) patients is a complex and challenging task to accomplish, and effective pain and symptom control improves quality of life. Pain is prevalent in more than 50% of hemodialysis patients and up to 75% of these patients are treated ineffectively due to its poor recognition by providers. A good history for PQRST factors and intensity assessment using visual analog scale are the initial steps in the management of pain followed by involvement of palliative care, patient and family counseling, discussion of treatment options, and correction of reversible causes. First line should be conservative management such as exercise, massage, heat/cold therapy, acupuncture, meditation, distraction, music therapy, and cognitive behavioral therapy. Analgesics are introduced according to WHO guidelines (by the mouth, by the clock, by the ladder, for the individual, and attention to detail) using three‐step analgesic ladder model. Neuropathic pain can be controlled by gabapentin and pregabalin. Substitution/addition of opioid analgesics are indicated if pain control is not optimal. Commonly used opioids in ESRD patients are tramadol, oxycodone, hydromorphone, fentanyl, methadone, and buprenorphine. Methadone, fentanyl, and buprenorphine are the ideal analgesics in ESRD. However, complex pain syndrome requires multidrug analgesic regimen comprising opioids, non‐opioids, and adjuvant medication, which should be individualized to the patient to achieve adequate pain control.     

The association between opioid analgesics and unsafe driving actions preceding fatal crashes

Currently, most epidemiological research into the impact of opioid analgesics on road safety has focused on the association between opioid use and traffic crash occurrence. Yet, the role of opioid analgesics on crash responsibility is still not properly understood. Therefore, we examined the impact of opioid analgesics on drivers (all had a confirmed BAC = 0) involved in fatal crashes (1993-2006) using a case-control design based on data from the Fatality Analysis Reporting System. Cases had one or more crash-related unsafe driving actions (UDA) recorded; controls had none. We calculated adjusted odds ratios (ORs) of any UDA by medication exposure after controlling for age, sex, other medications, and driving record. Compared to drivers who tested negative for opioid analgesics, female drivers who tested positive demonstrated increased odds of performing an UDA from ages 25 (OR: 1.35; 95% CI: 1.05; 1.74) to 55 (OR: 1.30; 95% CI: 1.07; 1.58). For male drivers this was true from ages 25 (OR: 1.66; 95% CI: 1.32; 2.09) to 65 (OR: 1.39; 95% CI: 1.17; 1.67). The detection of opioid analgesics was not associated with greater risk of an UDA for older drivers. Research is necessary to examine why these age differences exist, and if possible, to ensure that opioid analgesics do not contribute to crashes.     

Novel Biodegradable 3D-Printed Analgesics-Eluting-Nanofibers Incorporated Nuss Bars for Therapy of Pectus Excavatum

A novel hybrid biodegradable Nuss bar model was developed to surgically correct the pectus excavatum and reduce the associated pain during treatment. The scheme consisted of a three-dimensional (3D) printed biodegradable polylactide (PLA) Nuss bar as the surgical implant and electrospun polylactide–polyglycolide (PLGA) nanofibers loaded with lidocaine and ketorolac as the analgesic agents. The degradation rate and mechanical properties of the PLA Nuss bars were characterized after submersion in a buffered mixture for different time periods. In addition, the in vivo biocompatibility of the integrated PLA Nuss bars/analgesic-loaded PLGA nanofibers was assessed using a rabbit chest wall model. The outcomes of this work suggest that integration of PLA Nuss bar and PLGA/analgesic nanofibers could successfully enhance the results of pectus excavatum treatment in the animal model. The histological analysis also demonstrated good biocompatibility of the PLA Nuss bars with animal tissues. Eventually, the 3D printed biodegradable Nuss bars may have a potential role in pectus excavatum treatment in humans.