Enkephalinase Inhibitor Research Articles

Synergistic effect of combining dual enkephalinase inhibitor PL37 and sumatriptan in a preclinical model of migraine.

The aim of this study was to test whether a combination of sumatriptan with dual enkephalinase inhibitor PL37 would result in an additive or a synergistic effect. Combination treatment is frequently used to improve the therapeutic efficacy of drugs. The co-administration of two drugs may result in efficacy at lower doses than those needed for either drug alone, thus minimizing side effects. Here, we tested the effect of the co-administration of two drugs on cutaneous mechanical hypersensitivity (MH), a symptom often affecting cephalic regions in patients with migraine: dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, and sumatriptan, a serotonin 5-HT1B/1D receptor agonist. We investigated the effects of oral administrations of sumatriptan, PL37, or their combination on changes in cutaneous mechanical sensitivity induced by a single intraperitoneal administration of the nitric oxide donor, isosorbide dinitrate (ISDN) in male rats. Mechanical sensitivity was assessed using von Frey filaments applied to the face of animals to determine pain thresholds. Isobolographic analysis was performed to determine the nature of the interaction between sumatriptan and PL37. Sumatriptan as well as PL37 each produced a dose-dependent inhibition of ISDN-induced cephalic MH. Median effective dose (ED50 ) values were 0.3 and 1.1 mg/kg for sumatriptan and PL37, respectively. An isobolographic analysis of the effect of combined doses of sumatriptan and PL37 based on their calculated ED50 values demonstrated a synergistic effect of the combination on cephalic MH, with an interaction index of 0.14 ± 0.04. These results suggest that PL37 acts synergistically with sumatriptan to produce an anti-allodynic effect in a rat model of migraine. Thus, combining PL37 and sumatriptan may be a useful therapeutic strategy in the management of migraine. There have been many advances in migraine treatment, but we still need more options that are effective and have few side effects. Sumatriptan is one available drug for acute treatment of migraine, but it does not work for every patient and is not suitable for some people. We tested a new drug called PL37 (that blocks enkephalinases) together with sumatriptan and the combination minimized side effects and allowed lower doses of the drugs for effective migraine treatment in an animal model.

Influence of STR-324, a Dual Enkephalinase Inhibitor, on Postoperative Pain Scores: A Proof-of-Concept Trial in Patients after Laparoscopic Surgery.

Influence of STR-324, a Dual Enkephalinase Inhibitor, on Postoperative Pain Scores: A Proof-of-Concept Trial in Patients after Laparoscopic Surgery.

Novel Opioids in the Setting of Acute Postoperative Pain: A Narrative Review.

Although traditional opioids such as morphine and oxycodone are commonly used in the management of acute postoperative pain, novel opioids may play a role as alternatives that provide potent pain relief while minimizing adverse effects. In this review, we discuss the mechanisms of action, findings from preclinical studies and clinical trials, and potential advantages of several novel opioids. The more established include oliceridine (biased ligand activity to activate analgesia and downregulate opioid-related adverse events), tapentadol (mu-opioid agonist and norepinephrine reuptake inhibitor), and cebranopadol (mu-opioid agonist with nociceptin opioid peptide activity)-all of which have demonstrated success in the clinical setting when compared to traditional opioids. On the other hand, dinalbuphine sebacate (DNS; semi-synthetic mu partial antagonist and kappa agonist), dual enkephalinase inhibitors (STR-324, PL37, and PL265), and endomorphin-1 analog (CYT-1010) have shown good efficacy in preclinical studies with future plans for clinical trials. Rather than relying solely on mu-opioid receptor agonism to relieve pain and risk opioid-related adverse events (ORAEs), novel opioids make use of alternative mechanisms of action to treat pain while maintaining a safer side-effect profile, such as lower incidence of nausea, vomiting, sedation, and respiratory depression as well as reduced abuse potential.

Efficacy of dual enkephalinase inhibition in a preclinical migraine model is mediated by activation of peripheral delta opioid receptors.

The aim of this study was to evaluate whether elevating levels of enkephalin by inhibiting their degradation can attenuate stress-induced migraine-like behaviors in mice. Previous studies in animals have suggested the delta opioid receptor (DOR) as a novel migraine target. The primary endogenous ligands for DOR are enkephalins and their levels can be increased by pharmacological inhibition of enkephalinases; however, it is not clear whether enkephalinase inhibition can be efficacious in preclinical migraine models through activation of DOR or whether other opioid receptors might be involved. Further, it is not clear whether opioid receptors in the central nervous system are necessary for these effects. This study used a model of repetitive restraint stress in mice that induces periorbital hypersensitivity and priming to the nitric oxide donor sodium nitroprusside (SNP; 0.1 mg/kg). Von Frey filaments were used to measure periorbital mechanical thresholds and grimace scores were evaluated by observing mouse facial features. Animals were treated with the dual enkephalinase inhibitor (DENKI) PL37. On day two post-stress, PL37 given to mice via either intravenous injection (10 mg/kg) or oral gavage (20 mg/kg) significantly attenuated stress-induced periorbital hypersensitivity and facial grimace responses. Additionally, both intravenous (10 mg/kg) and oral gavage (20 mg/kg) of PL37 prior to SNP (0.1 mg/kg) administration on day 14 post-stress significantly reduced SNP-induced facial hypersensitivity. Injection of the DOR antagonist naltrindole (0.1 mg/kg) but not the mu-opioid receptor antagonist CTAP (1 mg/kg) prior to PL37 treatment blocked the effects. Finally, pretreatment of mice with the peripherally restricted opioid receptor antagonist naloxone methiodide (5 mg/kg) blocked the effects of PL37. These data demonstrate that inhibiting enkephalinases, and thus protecting enkephalins from degradation, attenuates stress-induced migraine-like behavior via activation of peripheral DOR. Peripheral targeting of endogenous opioid signaling may be an effective therapeutic strategy for migraine.

The history and mystery of sacubitril/valsartan: From clinical trial to the real world.

Heart failure is a serious threat to human health, with morbidity and mortality rates increasing despite the existence of multiple treatment options. Therefore, it is necessary to identify new therapeutic targets for this disease. Sacubitril/valsartan is a supramolecular sodium salt complex of the enkephalinase inhibitor prodrug sacubitril and the angiotensin receptor blocker valsartan. Its combined action increases endogenous natriuretic peptides while inhibiting the renin-angiotensin-aldosterone system and exerting cardioprotective effects. Clinical evidence suggests that sacubitril/valsartan is superior to conventional renin-angiotensin-aldosterone inhibitor therapy for patients with reduced ejection fraction heart failure who can tolerate angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The therapy reduces the risk of heart failure hospitalization, cardiovascular mortality, and all-cause mortality and has a better safety and tolerability record. This review describes the potential pathophysiological mechanisms of cardiomyocyte injury amelioration by sacubitril/valsartan. We explore the protective effects of sacubitril/valsartan and outline the therapeutic value in patients with heart failure by summarizing the results of recent large clinical trials. Furthermore, a preliminary outlook shows that sacubitril/valsartan may be effective at treating other diseases, and provides some exploratory observations that lay the foundation for future studies on this drug.

Future Newborns with Opioid-Induced Neonatal Abstinence Syndrome (NAS) Could Be Assessed with the Genetic Addiction Risk Severity (GARS) Test and Potentially Treated Using Precision Amino-Acid Enkephalinase Inhibition Therapy (KB220) as a Frontline Modality Instead of Potent Opioids.

In this nonsystematic review and opinion, including articles primarily selected from PubMed, we examine the pharmacological and nonpharmacological treatments of neonatal abstinence syndrome (NAS) in order to craft a reasonable opinion to help forge a paradigm shift in the treatment and prevention of primarily opioid-induced NAS. Newborns of individuals who use illicit and licit substances during pregnancy are at risk for withdrawal, also known as NAS. In the US, the reported prevalence of NAS has increased from 4.0 per 1000 hospital births in 2010 to 7.3 per 1000 hospital births in 2017, which is an 82% increase. The management of NAS is varied and involves a combination of nonpharmacologic and pharmacologic therapy. The preferred first-line pharmacological treatment for NAS is opioid therapy, specifically morphine, and the goal is the short-term improvement in NAS symptomatology. Nonpharmacological therapies are individualized and typically focus on general care measures, the newborn-parent/caregiver relationship, the environment, and feeding. When used appropriately, nonpharmacologic therapies can help newborns with NAS avoid or reduce the amount of pharmacologic therapy required and the length of hospitalization. In addition, genetic polymorphisms of the catechol-o-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genes appear to affect the length of stay and the need for pharmacotherapy in newborns with prenatal opioid exposure. Therefore, based on this extensive literature and additional research, this team of coauthors suggests that, in the future, in addition to the current nonpharmacological therapies, patients with opioid-induced NAS should undergo genetic assessment (i.e., the genetic addiction risk severity (GARS) test), which can subsequently be used to guide DNA-directed precision amino-acid enkephalinase inhibition (KB220) therapy as a frontline modality instead of potent opioids.

The efficacy and safety of Sacubitril/Valsartan on pulmonary hypertension in hemodialysis patients.

Pulmonary hypertension (PH) is a common complication of end-stage renal disease which is associated with adverse outcomes including all-cause mortality and cardiovascular events. Recent studies have demonstrated that Sacubitril/Valsartan (Sac/Val) as an enkephalinase inhibitor and angiotensin II receptor blocker could reduce pulmonary artery systolic pressure (PASP) and improve the prognosis of patients with heart failure. However, whether Sac/Val is effective in hemodialysis (HD) patients with PH is essentially unknown. In this retrospective study, we aimed to evaluate the efficacy and safety of Sac/Val in the treatment of PH in HD patients. A total of 122 HD patients with PH were divided into Sac/Val group (n = 71) and ARBs group (n = 51) based on the treatment regimen. The PASP, other cardiac parameters measured by echocardiography, and cardiac biomarkers including N-terminal fragment of BNP (NT-proBNP) and cardiac troponin I (cTnI) were observed at baseline and 3 months after treatment. There were no significant differences in the baseline characteristics between the two groups. PASP decreased significantly from 45(38, 54) to 28(21, 40) mmHg in Sac/Val group (p < 0.001). PASP reduced from 41(37, 51) to 34(27, 44) mmHg in ARBs group (p < 0.001), and the decrease was more pronounced in the Sac/Val group (p < 0.001). In addition, improvements in the right atrial diameter (RAD), left ventricular diameter (LVD), left ventricular posterior wall thickness (LVPWT), left atrial diameter (LAD), pulmonary artery diameter (PAD), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), and fractional shortening (FS) were found in Sac/Val group (ps < 0.05). After 3 months, LVD, LAD, LVEDV, LVESV, LVEF, SV, and PASP were significantly improved in Sac/Val group compared with ARBs group (ps <0.05). Significant reduction in NT-proBNP [35,000 (15,000, 70,000) pg/ml vs. 7,042 (3,126, 29,060) pg/ml, p < 0.001] and cTnI [0.056(0.031, 0.085) ng/ml vs. 0.036 (0.012, 0.056) ng/ml, p < 0.001) were observed in Sac/Val group. No significant differences were observed in adverse events between the two groups (ps > 0.05). Sac/Val seems to be an efficacious regimen in PH with favorable safety and has huge prospects for treating PH in HD patients.

Research progress on the correlation between sacubitril-valsartan and cognitive function in hypertensive patients

Sacubitril-valsartan can exert antihypertensive effects by blocking the effect of angiotensin Ⅱ and inhibiting the activity of enkephalinase. As a currently common antihypertensive drug, sacubitril-valsartan’s protective effects on target organs have been confirmed in more and more studies. Inhibition of enkephalinase can hinder the degradation and metabolism of beta-amyloid, deposition of which is a characteristic pathological feature of Alzheimer's disease. And hypertension itself is a risk factor for cognitive dysfunction, so long-term medications have the theoretical possibility to result in adverse effects on the cognitions of hypertensive patients. A review of various perspectives towards the effects of sacubitril-valsartan on cognitive function in patients with hypertension will be delivered.

Effect of dapagliflozin on the prognosis of patients with acute myocardial infarction undergoing percutaneous coronary intervention

Background and aimsThe effect of dapagliflozin (DAPA) on the prognosis of patients with acute myocardial infarction (AMI) is unclear. The present study was conducted to evaluate the association between DAPA administration and adverse events in patients with AMI undergoing percutaneous coronary intervention (PCI).MethodsThis single-center retrospective analysis study included a total of 786 patients with AMI from January 2019 to August 2021 who were or were not administered DAPA at discharge. The primary endpoint was the composite of major adverse cardiovascular events (MACE), including overall deaths, heart failure, nonfatal MI, nonfatal stroke, and unplanned repeat revascularization (URR). Differences in the triglyceride glucose (TyG) index and the atherogenic index of plasma (AIP) both during hospitalization and 12 months after discharge (if achievable) were also compared.ResultsDuring a median follow-up of 23 months, 130 patients had MACE (118 in the DAPA-free group and 12 in the DAPA group). Kaplan–Meier survival analyses revealed that the cumulative incidence of MACE (log-rank test, p = 0.009), heart failure (p = 0.003), nonfatal MI (p = 0.005), and URR (p = 0.031) was higher in the DAPA-free group. In addition, the multivariate Cox analysis showed that DAPA was significantly associated with the reduced risk of MACE (hazard ratio = 0.170, 95% confidence interval = 0.078–0.373, p < 0.001). Considering each specific adverse event, the DAPA-free group was associated with heart failure, nonfatal MI, and URR in multivariate Cox regression analyses. Stratification analyses suggested that DAPA has a strong protective effect in patients with AMI of advanced age with concomitant diabetes or those who are not on angiotensin receptor enkephalinase inhibitors. Furthermore, the TyG index and AIP of the patients 12 months after DAPA administration at discharge were significantly lower than those during hospitalization.ConclusionsDAPA is an independent protective factor against MACE and may provide incremental prognostic information in patients with AMI undergoing PCI.

Central administration of human opiorphin alleviates dextran sodium sulfate-induced colitis in mice through activation of the endogenous opioid system.

The opioid system plays a crucial role in maintaining gastrointestinal homeostasis. Endogenous opioid peptide enkephalins have anti-inflammatory effect and participate in the treatment of inflammatory bowel diseases (IBDs). Here, we investigated the effect of natural enkephalinase inhibitor human opiorphin (HO) on dextran sodium sulfate (DSS)-induced colitis in mice. Our results showed that central administration of HO attenuated DSS-induced colitis, as indicated by the reduction of disease activity index (DAI) scores, macroscopic scores, histological scores, and the myeloperoxidase (MPO) activity. Moreover, HO alleviated DSS-induced inflammation by decreasing inflammatory cytokines TNF-α, IL-6, and IL-1β, and increasing anti-inflammatory cytokine IL-10 in both serum and colon tissues in DSS-treated mice. The potential anti-inflammatory effect of HO at a dose of 40 μg/kg was observed as evidenced by a decrease in nuclear factor κB (NF-κB) p65, toll-like receptor-4 (TLR-4), iNOS, and COX-2. HO also improved intestinal barrier function by enhancing the expression of tight junction proteins. Furthermore, HO treatment significantly inhibited activities of neutral endopeptidase (NEP) and aminopeptidase N (APN), elevated serum enkephalins concentrations, and increased expressions of mu and delta opioid receptors. In addition, pretreatment with opioid receptor antagonist naloxone hydrochloride (NH) compromised the protective effect of HO and aggravated colitis symptoms, as indicated by inhibited anti-inflammatory effects, disrupted intestinal barrier function, and decreased opioid receptor activity. In conclusion, these data indicate that HO protects against DSS-induced colitis by inhibiting TLR4/NF-κB pathway activation and improving intestinal barrier function through activation of the endogenous opioid system. Therefore, targeting the opioid system with peptidase inhibitors intervention would be a novel strategy in the therapy of IBD.

Nicotinamide Adenine Dinucleotide (NAD+) and Enkephalinase Inhibition (IV1114589NAD) Infusions Significantly Attenuate Psychiatric Burden Sequalae in Substance Use Disorder (SUD) in Fifty Cases.

There is a shortage of clinical studies examining the efficacy of Nicotinamide Adenine Dinucleotide and Enkephalinase infusions (IV1114589NAD) in treating Substance Use Disorder (SUD). This study aims to provide evidence that IV1114589NAD infusions significantly attenuate substance craving behavior. The study cohort consisted of addicted poly-drug, mixed gender, multi-ethnic individuals resistant to standard treatment. The investigation utilized Likert-Scales to assess behavioral outcomes. Using Wilcoxon signed-rank tests and sign tests, our team detected significant results by comparing baseline to post outcome scores after IV1114589NAD injections: craving scores (P=1.063E-9); anxiety (P=5.487E-7); and depression (P=1.763E-4). A significant reduction in cravings, anxiety, and depression followed a dose-dependent linear trend. Linear trend analyses showed a significant relationship between NAD infusions and decreasing scores for cravings (P=0.015), anxiety (P=0.003), and depression (P=8.74E-5). A urine analysis was conducted on a subset of 40 patients midway through the study to assess relapse; 100% of the urine samples analyzed failed to detect illicit substance use. The opioid crisis in America has claimed close to 800,000 lives since 2004; daily deaths are estimated to stand at 127, and in 2021, over 107,000 deaths were due to overdose. There is an urgency to find safe, side-effect-free solutions. Current interventions, such as Naltrexone implants, are invasive and may interfere with dopamine homeostasis leading to an anti-reward phenomenon. Larger randomized double-blinded placebo-controlled studies are needed to elucidate further the significance of the results presented in this study. The current pilot study provides useful preliminary data regarding the effectiveness of IV1114589NAD infusions in SUD treatment. This pilot study provides significant evidence that NAD infusions are beneficial in the treatment of SUD. This investigation serves as a rationale to extend these findings onto future research investigating the use of NAD/NADH as a stand-alone treatment, especially in patients showing high genetic risk as measured in the Genetic Addiction Risk Severity (GARS) test. Utilizing GARS will help provide a real personalized therapeutic approach to treat Reward Deficiency Syndrome (RDS).

The Efficacy and Safety of Enkephalinase Inhibitor Racecadotril in Treatment of Acute Diarrhea in Children: A Randomized Clinical Trial

Background: Acute diarrhea in children with an annual prevalence of about 2 billion episodes accounts for 1.9 million deaths in developing countries. According to the World Health Organization (WHO), only 35% of children with diarrhea receive proper treatment for dehydration; hence, the detection of appropriate interventions enables us to prevent mortality and decrease the morbidity rate. Methods: This prospective randomized clinical trial was conducted from September 2018 to May 2019 in the Pediatric Gastroenterology Ward at the Mofid Children's Hospital, where 95 children were hospitalized with non-exudative acute gastroenteritis and moderate to severe dehydration. Among these patients, 53 children were administered intravenous (IV) fluid therapy and oral rehydration solution (ORS), and 42 children received IV rehydration and ORS plus Racecadotril (ORS+R). Daily bowel movements and their consistency were recorded at admission, 24 hours, and 48 hours after hospitalization. All data were analyzed by SPSS software version 25. Results: There was no statistically meaningful difference between the intervention and control groups in terms of age, gender, and weight. According to the statistical analysis, the dehydration severity was same in both groups, and no difference was revealed between the two groups regarding fever and vomiting. All laboratory findings were similar in both groups at the time of admission. Although the average duration of diarrhea was shorter in the racecadotril group than in the control group, there was no statistically significant difference between the two groups. The results indicated a rapid decline in the number of bowel movements by the first and second days after beginning of the treatment in both groups; however, no statistically meaningful difference was noticed. The present results indicated no significant difference between the two groups regarding the recovery rate in the first 24 hours of treatment. Moreover, although the recovery rate of children treated for 48 hours was faster in the racecadotril+ORS group than in the oral rehydration group, no significant difference was revealed. Conclusions: There was no meaningful relationship between the administration of racecadotril with the duration of diarrhea, the frequency of diarrhea, and the recovery rate in the first and second days after treatment. However, in 24 and 48 hours after treatment, there were a decrease in the number of watery stools and an increase in solid stools; hence, further studies with larger sample sizes and more accurate measurements determining factors affecting acute diarrhea and differentiating different types of diarrhea are recommended to further illustrate the role of racecadotril on the treatment of diarrhea in children.

Dual enkephalinase inhibitor PL37 as a potential novel treatment of migraine: evidence from a rat model.

The dual enkephalinase inhibitor PL37, a small molecule that protects enkephalins from rapid degradation, has demonstrated analgesic properties in animal pain models and in early human clinical trials. This study tested the antimigraine potential of PL37 on cutaneous mechanical hypersensitivity affecting cephalic regions in migraineurs. Using behavioural testing and c-Fos immunoreactivity in male rats, we investigated the effects of single (oral or intravenous) and repeated oral administration of PL37 on changes in cutaneous mechanical sensitivity and sensitization of the trigeminocervical complex induced by repeated administration of the nitric oxide donor, isosorbide dinitrate. In naïve rats, single or repeated administration of PL37 or vehicle had no effect on cephalic mechanical sensitivity. However, single oral PL37 treatment effectively inhibited isosorbide dinitrate-induced acute cephalic mechanical hypersensitivity. Single intravenous but not oral PL37 administration inhibited chronic cephalic mechanical hypersensitivity. Daily oral administration of PL37 prevented cephalic mechanical hypersensitivity and decreased touch-induced c-Fos expression in trigeminocervical complex following repeated isosorbide dinitrate administration. These data reveal the therapeutic potential of the dual enkephalinase inhibitor PL37 as an acute and prophylactic treatment for migraine. Protecting enkephalins from their degrading enzymes therefore appears to be an innovative approach to treat migraine.

Therapeutic effects and safety of early use of sacubitril/valsartan after acute myocardial infarction: a systematic review and meta-analysis.

infarction (AMI) can be reduced by the use of sacubitril/valsartan. However, the therapeutic effects of sacubitril/valsartan in clinical settings are inconsistent. In this paper, the related research on the application of sacubitril/valsartan in AMI was comprehensively searched, in order to explore the clinical efficacy and safety of early application of sacubitril/valsartan after AMI. English databases, including American National Library of Medicine, Medline, and Embase, and Chinese databases, including Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure (CNKI), Wanfang, and VIP, were searched using a combination of the following search terms: AMI, acute ST-segment elevation myocardial infarction (STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI), sacubitril/valsartan sodium tablets, and angiotensin receptor enkephalinase inhibitors. The experimental group was given Sacubitril/Valsartan sodium tablets, while the control group was given angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB). Cochrane Handbook 5.0 risk assessment table were used for quality assessment and bias risk assessment. A total of 5 articles were included in the meta-analysis. The total incidence of adverse cardiovascular events in the sacubitril/valsartan group was significantly lower than that in the control group {relative risk (RR) =0.61 [95% confidence interval (CI): 0.46, 0.82], significance testing Z=3.36, and P=0.0008}. The difference between the rehospitalization rate of the sacubitril/valsartan group and control group was statistically significant [RR =0.67 (95% CI: 0.47, 0.95), significance testing Z=2.23, and P=0.03]. The difference in low blood pressure between the sacubitril/valsartan group and the control group was statistically significant [RR =1.28 (95% CI: 1.18, 1.40), significance testing Z=5.58, and P<0.00001]. The difference in left ventricular ejection fraction (LVEF) between the sacubitril/valsartan group and control group was statistically significant [mean difference (MD) =3.09 (95% CI: 1.69, 4.49), significance testing Z=4.33, and P<0.0001]. Sacubitril/valsartan was found to inhibit ventricular remodeling after AMI, improve cardiac function, and reduce the incidence of adverse cardiovascular events after myocardial infarction, the rehospitalization rate, and the mortality rate.

The inhibition of enkephalin catabolism by dual enkephalinase inhibitor: A novel possible therapeutic approach for opioid use disorders.

Despite the increasing impact of opioid use disorders on society, there is a disturbing lack of effective medications for their clinical management. An interesting innovative strategy to treat these disorders consists in the protection of endogenous opioid peptides to activate opioid receptors, avoiding the classical opioid-like side effects. Dual enkephalinase inhibitors (DENKIs) physiologically activate the endogenous opioid system by inhibiting the enzymes responsible for the breakdown of enkephalins, protecting endogenous enkephalins and increasing their half-lives and physiological actions. The activation of opioid receptors by the increased enkephalin levels, and their well-demonstrated safety, suggests that DENKIs could represent a novel analgesic therapy and a possible effective treatment for acute opioid withdrawal, as well as a promising alternative to opioid substitution therapy minimizing side effects. This new pharmacological class of compounds could bring effective and safe medications avoiding the major limitations of exogenous opioids, representing a novel approach to overcome the problem of opioid use disorders. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

First-in-human trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324, a dual enkephalinase inhibitor for pain management.

AimDual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR‐324 belongs to the DENKI pharmacological class. This first‐in‐human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR‐324 in healthy male participants.MethodsThis was a randomised, double‐blind, placebo‐controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004‐11.475 mg h−1 of STR‐324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two‐group, partial crossover design with four treatment periods separated by 1 month wash‐out, and in part 2, 48 participants divided into three groups received either the active drug (1.25‐11.25 mg h−1) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated.ResultsNo clinically relevant changes in safety parameters were observed. All treatment‐emergent adverse events were mild and transient. The pharmacokinetics of STR‐324 could not be determined due to most concentrations being below quantifiable limits. STR‐324 metabolite concentrations were measurable, showing dose proportionality of C max and AUCinf with an estimated t 1/2 of 0.2‐0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose‐dependent.ConclusionSTR‐324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h−1. Although pharmacokinetic characterisation of STR‐324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed.Trial registry: EudraCT (2014‐002402‐21) and toetsingonline.nl (63085).

Endorphinergic Enhancement Attenuation of Post-traumatic Stress Disorder (PTSD) via Activation of Neuro-immunological Function in the Face of a Viral Pandemic.

Polymorphic gene variants, particularly the genetic determinants of low dopamine function (hypodopaminergia), are known to associate with Substance Use Disorder (SUD) and a predisposition to PTSD. Addiction research and molecular genetic applied technologies supported by the National Institutes of Health (NIH) have revealed the complex functions of brain reward circuitry and its crucial role in addiction and PTSD symptomatology. It is noteworthy that Israeli researchers compared mice with a normal immune system with mice lacking adaptive immunity and found that the incidence of PTSD increased several-fold. It is well established that raising endorphinergic function increases immune response significantly. Along these lines, Blum's work has shown that D-Phenylalanine (DPA), an enkephalinase inhibitor, increases brain endorphins in animal models and reduces stress in humans. Enkephalinase inhibition with DPA treats Post Traumatic Stress Disorder (PTSD) by restoring endorphin function. The Genetic Addiction Risk Severity (GARS) can characterize relevant phenotypes, genetic risk for stress vulnerability vs. resilience. GARS could be used to pre-test military enlistees for adaptive immunity or as part of PTSD management with customized neuronutrient supplementation upon return from deployment. Based on GARS values, with particular emphasis on enhancing immunological function, pro-dopamine regulation may restore dopamine homeostasis. Recognition of the immune system as a "sixth sense" and assisting adaptive immunity with Precision Behavioral Management (PBM), accompanied by other supportive interventions and therapies, may shift the paradigm in treating stress disorders.

Role of Racecadotril in Children with Acute Diarrhea

Background: Diarrhea is a leading cause of illness and death among children in developing countries. Racecadotril (acetorphan), an enkephalinase inhibitor with antisecretory and anti-diarrheal actions, is an effective and safe treatment for acute diarrhea in adults and children.&#x0D; Objectives: The objective of this study is to evaluate the efficacy and tolerability of racecadotril as a treatment of acute diarrhea in children.&#x0D; Methods: This double-blind, randomized controlled clinical trial was conducted in Dr. MR Khan Children Hospital &amp; Institute of Child Health over 1 year (June 2017- May 2018). The study was approved by the ethical committee of the institute. The efficacy and tolerability of racecadotril (1.5 mg/kg) administered orally 3 times daily) as adjuvant therapy to oral rehydration or intravenous fluid were compared with those of placebo in 40 children aged 3 months to 60 months of children who had acute diarrhea.&#x0D; Results: During the first 72 hours of treatment, patients receiving racecadotril had a significantly lower stool output (grams per hour) than those receiving placebo. The mean (±SE) 72-hours stool output was 54.75± 12.92 g per kilogram in the racecadotril group and 152.50±37.64 g per kilogram in the placebo group (p&lt;0.001). The number of purging is significantly reduced in the racecadotril group than the placebo group (11.95±2.41 Vs 14.85±1.95, p= 0.000) on third day of admission. The duration of hospital stay is significantly lower in the racecadotril group than the placebo group (73.30±23.44 vs. 177.30±25.8. p= 0.000) group. Racecadotril was well tolerated; only 3 patients taking racecadotril had adverse effects like vomiting and 2 patients had hypokalaemia and 3 patients in the placebo group developed vomiting and 1patient developed hypokalaemia which all are mild and transient.&#x0D; Conclusion: In young children with acute watery diarrhea, racecadotril is an effective and safe treatment along with rehydration therapy.&#x0D; DS (Child) H J 2020; 36(1) : 8-13

Dual Enkephalinase Inhibitors and Their Role in Chronic Pain Management.

Dual enkephalinase inhibitors (DENKIs) are pain medications that indirectly activate opioid receptors and can be used as an alternative to traditional opioids. Understanding the physiology of enkephalins and their inhibitors and the pharmacology of these drugs will allow for proper clinical application for chronic pain patients in the future. DENKIs can be used as an alternative mode of analgesia for patients suffering from chronic pain by preventing the degradation of endogenous opioid ligands. By inhibiting the two major enkephalin-degrading enzymes (neprilysin and aminopeptidase N), DENKIs can provide analgesia with less adverse effects than nonendogenous opioids. The purpose of this paper is to review the current literature investigating DENKIs and explore their contribution to chronic pain management.

A Novel Precision Approach to Overcome the "Addiction Pandemic" by Incorporating Genetic Addiction Risk Severity (GARS) and Dopamine Homeostasis Restoration.

This article describes a unique therapeutic precision intervention, a formulation of enkephalinase inhibitors, enkephalin, and dopamine-releasing neuronutrients, to induce dopamine homeostasis for detoxification and treatment of individuals genetically predisposed to developing reward deficiency syndrome (RDS). The formulations are based on the results of the addiction risk severity (GARS) test. Based on both neurogenetic and epigenetic evidence, the test evaluates the presence of reward genes and risk alleles. Existing evidence demonstrates that the novel genetic risk testing system can successfully stratify the potential for developing opioid use disorder (OUD) related risks or before initiating opioid analgesic therapy and RDS risk for people in recovery. In the case of opioid use disorders, long-term maintenance agonist treatments like methadone and buprenorphine may create RDS, or RDS may have been in existence, but not recognized. The test will also assess the potential for benefit from medication-assisted treatment with dopamine augmentation. RDS methodology holds a strong promise for reducing the burden of addictive disorders for individuals, their families, and society as a whole by guiding the restoration of dopamine homeostasisthrough anti-reward allostatic neuroadaptations. WC 175.