Long Duration Of Action Research Articles

Short-term outcomes of mirogabalin in patients with peripheral neuropathic pain: a retrospective study

BackgroundMirogabalin, which is approved for the treatment of peripheral neuropathic pain in Japan, is a ligand for the α2δ subunit of voltage-gated calcium channels. Both pregabalin and mirogabalin act as nonselective ligands at the α2δ-1 and α2δ-2 subunits. Mirogabalin has a unique binding profile and long duration of action. Pregabalin has been reported to produce intolerable adverse effects in some patients. This study investigated outcomes associated with mirogabalin administration in patients with peripheral neuropathic pain who ceased treatment with pregabalin.MethodsWe retrospectively assessed peripheral neuropathic pain using the neuropathic pain screening questionnaire (NeP score) in 187 patients (58 men, 129 women) who were treated with mirogabalin. All patients had switched from pregabalin to mirogabalin due to lack of efficacy or adverse events. Differences in the treatment course (i.e., numeric rating scale (NRS) scores) were compared using one-way analysis of variance with Bonferroni post hoc tests.ResultsThe mean age of the patients was 72.3 years (range, 30–94 years), and the mean duration of disease was 37 months (range, 3–252 months). After treatment with mirogabalin for 1 week, NRS scores significantly decreased compared with baseline and continued to decrease over time. After 8 weeks, NRS scores improved by ≥ 30% from baseline in 113 patients (69.3%). Twenty-four patients (12.8%) stopped mirogabalin treatment due to adverse events. Somnolence (26.7%), dizziness (12.3%), edema (5.9%), and weight gain (0.5%) were noted as adverse events of mirogabalin.ConclusionsThe results of this investigation indicate that mirogabalin is safe and effective for reducing peripheral neuropathic pain.

Ropivacaine vs ropivacaine with morphine after arthroscopic surgery – A study of analgesic efficacy

Multimodal anaesthesia is recommended for treatment of postoperative pain. The rationale behind this is to attain sufficient analgesia due to the synergistic and additive between various analgesics with concomitant reduction in dose of any individual drug required to attain the same effect. Therefore a combination of Ropivacaine with Morphine intra-articular was hypothesized to have better and longer postoperative analgesic effects as compared to Ropivacaine alone.Knee arthroscopies are being performed more and more often as day care surgeries under regional anaesthesia hence there is a need for suitable postoperative analgesia regimen with a long duration of action, good safety profile and which provides the ability for the patient to ambulate.This study was undertaken to compare the effects of intra-articular Ropivacaine with the effects of a combination of intra-articular Ropivacaine and Morphine. 60 patients were divided into two groups of 30 each, one receiving Ropivacaine and the other the combination of Ropivacaine and Morphine.In this study we found that post-operative pain was less in the group receiving the combination of intra-articular Ropivacaine and Morphine. The need for rescue analgesics was also found to be less in the group receiving the combination of intra-articular Ropivacaine and Morphine.

Translocation domain of botulinum neurotoxin A subtype 2 potently induces entry into neuronal cells.

Botulinum neurotoxin (BoNT) is the causative agent of botulism in humans and animals. Only BoNT serotype A subtype 1 (BoNT/A1) is used clinically because of its high potency and long duration of action. BoNT/A1 and BoNT/A subtype 2 (BoNT/A2) have a high degree of amino acid sequence similarity in the light chain (LC) (96%), whereas their N-and C-terminal heavy chain (HN and HC ) differ by 13%. The LC acts as a zinc-dependent endopeptidase, HN as the translocation domain, and HC as the receptor-binding domain. BoNT/A2 and BoNT/A1 had similar potency in the mouse bioassay, but BoNT/A2 entered faster and more efficiently into neuronal cells. To identify the domains responsible for these characteristics, HN of BoNT/A1 and BoNT/A2 was exchanged to construct chimeric BoNT/A121 and BoNT/A212. After expression in Escherichia coli, chimeric and wild-type BoNT/As were purified as single-chain proteins and activated by conversion to disulfide-linked dichains. The toxicities of recombinant wild-type and chimeric BoNT/As were similar, but dropped to 60% compared with the values of native BoNT/As. The relative orders of SNAP-25 cleavage activity in neuronal cells and toxicity differed. BoNT/A121 and recombinant BoNT/A2 have similar SNAP-25 cleavage activity. BoNT/A2 HN is possibly responsible for the higher potency of BoNT/A2 than BoNT/A1.

Designer drugs: a medicinal chemistry perspective (II).

During 2012-2018, the clandestine manufacture of new psychoactive substances (NPS) designed to circumvent substance control regulations increased exponentially worldwide, with concomitant increase in fatalities. This review focuses on three compound classes identified as synthetic opioids, synthetic amphetamines, and synthetic cannabinoids and highlights the medicinal chemistry precedents utilized by clandestine laboratories to develop new NPS with increased brain penetration, longer duration of action, and greater potency. Chemical approaches to illicit drug abuse treatment options, particularly for opioid use disorder, are also discussed.

SUN-520 Graves Disease and T3 Thyrotoxicosis: A Case Report

Introduction: Hyperthyroidism is one of the common problems in the world of endocrinology. Identifying the type of thyrotoxicosis is crucial before starting treatment. We present a case of a 37-year-old woman presented with hyperthyroidism and was started on methimazole. Her symptoms persisted and further workup showed T3 thyrotoxicosis. Her symptoms improved after switching her to PTU. She eventually underwent thyroidectomy.Case description: Thirty-seven-year old African American woman presented to her primary care physician(PCP) with symptoms suggestive of hyperthyroidism for three months. Her past medical history is significant for recent delivery one year ago. Her Physical exam is pertinent for hypertension of 160/80 with a heart rate of 120. Her neck is diffusely enlarged with bilateral bruits. Bilateral lid retraction with lid lag was noted along with left lid proptosis. There were no tremors or leg swelling noted. Her Initial workup showed sinus tachycardia in the electrocardiogram. Her TSH level was <0.010 and a free T4 level of 3.48. Ultrasound showed diffuse enlargement of the thyroid gland with no focal nodule. She was started on methimazole 10mg twice daily and metoprolol 25mg twice daily.Three months later, she presented to the emergency room(ER) with tachycardia of 130 and hypertension of 170/85. Work up showed a TSH level of <0.010 and a free T4 level of 3.94. She was compliant with medications. When free T3 levels were checked it turned out to be >30. She was diagnosed with T3 Thyrotoxicosis and was started on propylthiouracil 150mg every 8 hours. Her metoprolol was increased to 50mg every 12 hours. Her symptoms improved and she finally underwent surgery for thyroidectomy.Discussion: Hyperthyroidism is seen in about 1 in 5000 with a strong female predominance. Graves disease, the most common cause of hyperthyroidism is due to excess production of TSH receptor stimulating antibodies. Hyperthyroid patients with graves disease sometimes have a disproportionate increase in serum T3 levels when compared to serum T4. This is thought to be due to increased T3 production or extrathyroidal conversion of T4 to T3. It is very crucial to identify the free hormone levels in a new patient with hyperthyroidism because of the difference in management. Antithyroid drugs are traditionally the first-line treatment option along with beta-blockers prior to definitive therapy like radioactive iodine or thyroidectomy. The main drugs used are methimazole and propylthiouracil(PTU). Methimazole is more commonly used than PTU because of its rapid efficacy, longer duration of action and less adverse effects. For patients with T3 thyrotoxicosis, PTU is preferred as it is known to reduce the peripheral conversion of T4 to T3. Our patient medication was changed from methimazole to PTU, after which she started to notice improvement. She eventually underwent definitive treatment with thyroidectomy.

Effects of acute and repeated treatment with methocinnamox, a mu opioid receptor antagonist, on fentanyl self-administration in rhesus monkeys.

Methocinnamox (MCAM), a mu opioid receptor antagonist with a long duration of action, attenuates heroin self-administration in rhesus monkeys, suggesting it could be an effective treatment for opioid use disorder (OUD). This study examined effects of acute and repeated MCAM administration on self-administration of the high-efficacy mu opioid receptor agonist fentanyl and characterized MCAM pharmacokinetics. Four rhesus monkeys self-administered i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion). MCAM (0.1-0.32 mg/kg) or the opioid receptor antagonist naltrexone (0.001-0.032 mg/kg) was injected prior to test sessions to evaluate acute effects. On a separate occasion, 0.32 mg/kg MCAM was injected every 12 days for 5 total injections to evaluate the effectiveness of repeated treatment. Following acute injection, MCAM and naltrexone decreased fentanyl self-administration on the day of treatment, with attenuation lasting for up to 2 weeks after the larger MCAM dose and <1 day after naltrexone. Repeated MCAM administration decreased fentanyl self-administration for more than 2 months without altering cocaine self-administration. MCAM plasma concentrations peaked 15-45 min after injection, with a half-life ranging from 13.7 to 199.8 min, and decreased markedly 1 day after injection. MCAM selectively reduced opioid self-administration and remained effective with repeated administration. Moreover, MCAM was effective at times when plasma levels were very low, suggesting that pharmacodynamic (i.e., pseudoirreversible binding to mu opioid receptors) and not pharmacokinetic factors play a significant role in its long-lasting effects. Taken together with previous studies, these data indicate that MCAM could be a safe, effective, and long-acting treatment for OUD.

Antinociceptive Effect of Intravenous Regional Analgesia in Horses Underwent Selected Short-Time Distal Limb Surgeries

The aim of the present study was to establish appropriate doses for both lidocaine hydrochloride (Hcl) and mepivacaine in intravenous regional analgesia (IVRA) and to assess their intraoperative and postoperative analgesic effects in horses with distal limb surgeries. A total of 55 draft horses were included in the present study. Six clinically healthy horses were selected randomly for establishing the doses of lidocaine Hcl and mepivacaine in IVRA in horse limbs. After selection, 32 horses suffered from various distal limb surgical affections were randomly allocated into three groups: thiopental group (n = 6), animals were operated under general anesthesia using thiopental sodium; IVRA-LID group (n = 12), animals were operated under both general anesthesia and IVRA using lidocaine Hcl; and IVRA-MEP group (n = 14), horses were operated under both general anesthesia and IVRA using mepivacaine. Postoperative pain was measured using both Horse Grimace Pain Scale and multifactorial numerical rating composite pain. The results showed that conjunction of IVRA along with thiopental general anesthesia using either lidocaine or mepivacaine significantly decreased the total required doses of thiopental sodium during the operations and significantly increased the duration of postoperative analgesia to 60 and 150 minutes using lidocaine and mepivacaine, respectively. In conclusion, the uses of local IVRA before distal limb surgery improve the depth of general anesthesia and reduced postoperative pain, despite thiopental anesthesia alone. Mepivacaine is superior to lidocaine in IVRA, with a longer duration of action.

Insights into the Chemical Discovery of Remifentanil.

Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8. Copyright 1991 American Chemical Society. Reprinted with permission.In an effort to discover a potent ultrashort-acting µ-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent µ-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for µ-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent µ agonists in vitro, but depending upon the alkyl ester substitution, the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The [structure-activity relationships] with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

EFFICACY OF ATRACURIUM VERSUS CISATRACURIUM IN PATIENTS UNDERGOING RETROGRADE CHOLANGIOPANCREATOGRAPHY PROCEDURE UNDER GENERAL ANAESTHESIA – A COMPARATIVE STUDY

Objectives: The objectives of the study were to compare the efficacy of injection atracurium 0.5 mg/kg intravenous (IV) versus injection cisatracurium 0.2 mg/kg IV for intubation in patients undergoing endoscopic retrograde cholangiopancreatography procedure (ERCP).&#x0D; Methods: Hundred adult patients of both sexes in the age group of 18–60 years belonging to the American Society of Anesthesiologists I/II category posted for ERCP procedures under general anesthesia were randomly allocated into two groups of 50 each. Group A received injection atracurium besylate 0.5 mg/kg intravenously and Group B received injection cisatracurium besylate 0.2 mg/kg intravenously. Parameters observed were time to the maximum blockade, intubating condition, time required for intubation, duration of action, hemodynamic parameters during intubation, and after 1, 2, 3, 5, and 15 min and any adverse effects.&#x0D; Results: Demographic profile was comparable between the groups. Intubating condition as per Cooper et al. score was excellent in 36 patients in cisatracurium group as compared to 19 patients in atracurium group. The overall intubating condition was found to be better in Group B (p=0.00001). Time to the maximum blockade was significantly high with atracurium as compared to cisatracurium. The mean of intubation time was less with cisatracurium (135±11.1) than that of atracurium (144±9.48) in seconds, which was statistically significant. Duration of neuromuscular blockade was found to be prolonged in Group B as compared to Group A (p=0.000). Hemodynamic parameters during intubation and after 1, 2, 3, 5, and 15 min were comparable between the groups. No adverse effect was seen in both groups.&#x0D; Conclusion: Cisatracurium 0.2 mg/kg provides excellent intubating conditions with rapid onset of action, longer duration of action, and no significant hemodynamic changes as compared with atracurium 0.5 mg/kg for ERCP procedures without any adverse effects.

Agonist‐Dependent Modulation by the Long‐Acting Mu Opioid Receptor Antagonist, Methocinnamox (MCAM)

Opioid overdose is a leading cause of death in the US. Naloxone (NLX), a mu opioid receptor (MOR) competitive antagonist, is the only treatment currently available for reversing opioid overdose. Unfortunately, NLX’s effects are limited by a short duration of action and ease of surmountability by opioid agonists. Methocinnamox (MCAM) is a novel MOR antagonist that has a long duration of action in vivo and holds promise as a better treatment for overdose and perhaps opioid use disorder. In this study, we compared the antagonist properties of MCAM to that of NLX and beta‐funaltrexamine (β‐FNA; an irreversible MOR antagonist). In HEK cells that express human MOR, DAMGO inhibited forskolin‐stimulated cAMP levels in a concentration dependent manner with an EC50 of 10 nM and a maximal inhibition of 40%. Pretreatment (15 min or 2 hrs) with NLX (100 nM, 10 x Ki) shifted the DAMGO concentration response curve (CRC) to the right, 100‐fold, in a fully surmountable manner that was independent of pretreatment time and fully reversed following NLX washout. Pretreatment with β‐FNA (10 nM) reduced the DAMGO maximal response in a time‐dependent, non‐surmountable and irreversible manner with no effect on the potency of DAMGO. By contrast to both β‐FNA and NLX, pretreatment with MCAM (10 nM) reduced the maximal response in a time‐dependent, non‐surmountable, non‐washable, and irreversible manner and shifted the DAMGO CRC to the right 1000‐fold. We hypothesized that this rightward shift in the DAMGO CRC may be due to allosteric properties of MCAM at MOR. A hallmark of allosterism is ligand dependence, so we next tested effects of MCAM, β‐FNA and NLX on a different mu opioid agonist, fentanyl. As expected, pretreatment with β‐FNA reduced the maximal response to fentanyl in a non‐surmountable manner without affecting potency, whereas NLX pretreatment shifted the CRC of fentanyl to the right (decreased the potency) in a manner that was fully surmountable and independent of pretreatment time. By contrast, pretreatment with MCAM reduced the maximal response to fentanyl in a non‐surmountable manner and shifted the CRC to the left (increased potency). Altogether, these data suggest that MCAM may be an irreversible orthosteric antagonist and an allosteric modulator at MOR.Support or Funding InformationSupported by NIH/NIDA RO1 grant DA048214

Compulsion zone theory of the self‐administration paradigm explains different drug durations of extinction responding with different cocaine analogues.

The compulsion zone theory of cocaine self‐administration states that lever‐pressing behavior is a drug‐induced behavior that is induced only when drug concentrations are between the priming and satiety thresholds. This explains responding after the termination of access to cocaine (the extinction phase of each session). Therefore, self‐administered drugs with longer durations of action would be expected to induce protracted extinction responding.To test this hypothesis, extinction responding was measured in rats after self‐administering 3 indirect dopamine agonists: cocaine (n = 11 rats) or the cocaine‐mimetic drugs, RTI‐55 (n = 7 rats), and bupropion (n = 7 rats). These drugs are known to have different half‐lives, with a rank order of RTI‐55, bupropion, and cocaine from longest to shortest. Across these drugs, we observed the number of lever‐presses correlated with the rank order, there were, on average, 20 presses for cocaine, 35 bupropion presses 53 RTI‐55 lever presses after the termination of access to each drug, respectively. However, lever‐pressing behavior would extinguish on an average of 18 minutes with cocaine, and 27 minutes with bupropion, while responding induced by RTI‐55 persisted for several hours, extinguishing within an average of 288 minutes. These durations were significantly different from one another (p &lt; 0.01, t‐test) and correlated with the established rank order of the half‐life of each drug.Additionally, we tested apomorphine (n=12 rats) a direct dopamine receptor agonist that is reliably self‐administered and has a short half‐life. Apomorphine‐induced responding extinguished in an average of 7 minutes. Apomorphine showed comparable lever presses to cocaine with an average of 23 per extinction. This indicates the extinction lever‐pressing is a method of measurement not limited to dopamine reuptake inhibitors but can be observed in direct‐acting agonists.These data provide further evidence that the lever‐pressing behavior after the termination of drug access is a drug‐induced response drug‐induced. The different durations of extinction responding, and numbers of extinction presses are not consistent with the idea that extinction occurs because animals learn that the drug is no longer available. Importantly, the compulsion zone theory applies to both self‐administered dopamine reuptake inhibitors other than cocaine, as well as direct‐acting dopamine receptor agonists. Thus, drugs with a longer half‐life take longer to transit the compulsion zone and induce lever‐pressing behavior for a correspondingly longer time. Further study into extinction responding may yield more information on the pharmacokinetic characteristics of self‐administered drugs.Support or Funding InformationSupported by NIDA grant U01DA039550Percent of active extinction sessions over time, with the cut‐off criteria data. Active sessions were grouped into 10‐minute bins. We see a rightward shift in extinction sessions of drugs with longer t1/2.Figure 1Durations of normalized sessions with the criteria applied. These durations were significantly different relative to the half‐life of each drug after the criteria are applied.*indicates significance (p &lt; 0.01, t‐test)Figure 2

Methocinnamox Produces Sustained Antagonism of the Antinociceptive Effects of Morphine and Persistent Decreases in [3H]DAMGO Binding to μ Opioid Receptors in Rat Cortex

The opioid crisis continues in the US despite the availability of pharmacotherapies that are effective in some patients. A novel μ opioid receptor antagonist, methocinnamox (MCAM), has a long duration of action in blocking the effects of opioids, which could provide a substantial advantage over currently available medications, particularly for overdose. MCAM has been shown to attenuate the behavioral effects of μ, but not k, opioid receptor agonists, and this antagonism, which can last for several weeks, is thought to be due to pseudoirreversible binding of MCAM to μ opioid receptors. In the current study, a warm water tail withdrawal procedure was used to examine sustained antagonism by MCAM in one group of 8 rats. This study showed that 10 mg/kg MCAM attenuated the antinociceptive effects of morphine (1.78–17.8 mg/kg) 5 and 13 days after MCAM administration with antagonism beginning to wane 21 days after MCAM. In separate groups of 8 rats, that same dose of MCAM decreased [3H]DAMGO binding to μ opioid receptors in rat cortical homogenates measured 1, 5 and 21 days after MCAM injection, indicating that MCAM occupied μ opioid receptors at all time points tested. For example, maximal binding (Bmax) was 28.51 ± 3.33 and 30.96 ± 1.73 fmol/mg protein 5 and 21 days, respectively, after vehicle administration, and 16.03 ± 4.15 and 12.50 ± 1.27 fmol/mg protein 5 and 21 days, respectively, after administration of 10 mg/kg MCAM. Binding affinity (KD) was not markedly changed after MCAM administration. Thus, MCAM produces a sustained decrease in [3H]DAMGO binding to μ opioid receptors in rat cortex that parallels antagonism of the antinociceptive effects of μ opioid receptor agonists. This finding supports the notion that MCAM blocks the behavioral effects of μ opioid receptor agonists by binding pseudoirreversibly to these receptors. The unique binding profile of MCAM to μ opioid receptors could increase the usefulness of MCAM as a treatment for opioid abuse and overdose.Support or Funding InformationSupported by NIH (R01DA005018 and R01048417) and the Welch Foundation (AQ‐0039).

Effects of Acute and Repeated Methocinnamox Treatment on Fentanyl Self‐administration in Rhesus Monkeys

Opioid abuse remains a serious public health challenge despite the availability of effective medications. Recent studies showed that the pseudoirreversible mu opioid receptor antagonist methocinnamox (MCAM) attenuates the reinforcing and respiratory‐depressant effects of heroin in rhesus monkeys, suggesting it could be an effective treatment for opioid abuse and overdose. The current study extends this work by evaluating MCAM for its capacity to attenuate the reinforcing effects of the potent, high‐efficacy opioid fentanyl. Because successful treatment of opioid use disorder requires long‐term and, usually, repeated treatment, the current study also evaluated effects of repeated MCAM administration.Four rhesus monkeys responded for i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion) under a fixed‐ratio 30 schedule. Once responding was stable, naltrexone (0.0032, 0.01, or 0.032 mg/kg) or MCAM (0.1 or 0.32 mg/kg) was administered s.c. prior to a session. On a separate occasion, 0.32 mg/kg of MCAM was injected every 12 days for a total of 5 administrations over 49 days. Cocaine was substituted for fentanyl every fourth session to examine the selectivity of effects of MCAM.When given acutely, both doses of MCAM decreased responding for fentanyl on the day of treatment, with the larger dose (0.32 mg/kg) decreasing the number of infusions from an average of 24 under baseline to 7. Responding remained significantly lower than baseline for 2 and 14 days following administration of 0.1 and 0.32 mg/kg of MCAM, respectively. Naltrexone also decreased fentanyl self‐administration, with the largest dose (0.032 mg/kg) decreasing the number of infusions from 26 under baseline to 3 after treatment; however, responding returned to baseline the next day. When given every 12 days, MCAM decreased responding for fentanyl for more than 70 days; the time for responding to recover after 5 injections of MCAM was not different from the time to recovery after 1 injection. MCAM did not alter responding for cocaine in either experiment.MCAM decreased self‐administration of the potent, high‐efficacy opioid fentanyl but not cocaine. Effects of a single injection of MCAM lasted much longer (&gt; 2 weeks) than those of naltrexone (&lt; 24 hr), and MCAM remained effective for over 2 months with repeated treatment. These results confirm and extend previous studies, demonstrating that MCAM produces longlasting and selective suppression of opioid self‐administration and that MCAM remains effective following repeated administration. Moreover, recovery of responding following discontinuation of repeated MCAM treatment indicates that the opioid system was not disrupted. The long duration of action of MCAM is likely due, at least in part, to pseudoirreversible binding to mu opioid receptors, suggesting it would insurmountably block the abuse‐related effects of opioids. Taken together, these data indicate that MCAM could be a safe, effective, and long‐acting treatment for opioid use disorder and overdose.Support or Funding InformationThis work was supported, in part, by the National Institutes of Health [R01DA005018, R01DA048417, and R01DA007315] and the Welch Foundation [AQ‐0039].

Methocinnamox (MCAM) Reverses and Provides Extended Protection from Fentanyl‐Induced Respiratory Depression in Awake Unrestrained Rats

Opioid use disorder affects over 2 million Americans with an increasing number of deaths due to overdose from the synthetic opioid fentanyl and its analogs. Opioid toxicity is due, in large part, to the suppression of respiratory function. The FDA‐approved opioid receptor antagonist naloxone (e.g. Narcan®) is used currently to reverse opioid‐induced respiratory depression; however, its short duration of action limits its clinical utility. Many abused opioids have a duration of action longer than naloxone and reemergence of respiratory depression is common after rescue with naloxone. Methocinnamox (MCAM) is a selective, pseudoirreversible mu opioid receptor antagonist with a long duration of action that may reverse and provide long‐term protection from the respiratory‐depressant effects of fentanyl. Previous research has shown that MCAM reverses and prevents the respiratory‐depressant effects of heroin in nonhuman primates. However, the effects of MCAM on opioid agonist‐induced respiratory depression has not been examined in other species. Moreover, its effectiveness in antagonizing the respiratory depressant effects of intravenous (i.v.) opioids, including fentanyl, has not been examined. This study compared the ability of naloxone and MCAM to reverse and protect from fentanyl‐induced respiratory depression in rats. On different occasions, male Sprague‐Dawley rats (N = 8) received 0.01, 0.032, 0.056, 0.1, or 0.178 mg/kg fentanyl i.v. and ventilatory parameters were recorded using a whole‐body plethysmograph. Fentanyl decreased respiration in a dose‐ and time‐dependent manner. Compared with respiration under control conditions, these doses of fentanyl decreased minute volume by 20–65% with 0.178 mg/kg of fentanyl producing the largest and longest decrease in minute volume. Within 1 minute after i.v. administration, naloxone (10 mg/kg) and MCAM (10 mg/kg) reversed fully the respiratory depressant effects (minute volume) of 0.178 mg/kg fentanyl. The day after antagonist administration, MCAM, but not naloxone, attenuated fully the respiratory depressant effects of 0.178 mg/kg fentanyl. This study extends to another species (rats), another route of administration (i.v.), and another mu opioid receptor agonist (fentanyl) the ability of MCAM to reverse and provide extended protection from the respiratory depressant effects of opioids. Prolonged antagonism by MCAM may provide a useful treatment option for the current opioid crisis, including toxicity from fentanyl and related highly potent analogs.Support or Funding InformationSupported by NIH (R01DA005018 and R01DA048417) and the Welch Foundation (AQ‐0039).

Benzalkonium Chloride in Albuterol Solutions: Time for a Change?

* Abbreviations: BAC — : benzalkonium chloride NaCl — : sodium chloride UD — : unit dose Benzalkonium chloride (BAC), a quaternary ammonium compound, is a common antimicrobial agent used in many everyday household products. It kills on contact most bacteria, fungi, and some viruses, with a relatively long duration of action. It has surfactant qualities and can penetrate bilipid membrane layers, allowing for deeper penetration of medicines delivered dermally. In high concentrations (>7.5%), BAC can be caustic and, if ingested, can cause severe gastrointestinal injury, respiratory depression, and neurologic toxicity.1 Even at lower concentrations, BAC can be a skin, eye, and oral mucosa irritant. However, when used as a preservative in medicinals, BAC is so dilute that such effects are usually not an issue. Children’s airways have a limited repertoire of physiologic mechanisms (eg, edema, inflammation, and bronchoconstriction) to deal with exogenous chemicals, resulting in coughing, wheezing, and difficulty breathing. Introducing any chemical into a child’s airways should entail careful scrutiny, weighing both risks and benefits. For many years, BAC has been employed as a preservative in some inhalant albuterol solutions used in the management of wheezing in asthma despite previous reports of its ability to precipitate bronchospasm.2–5 In this month’s issue of Pediatrics , Pertzborn et al6 further investigate the risk … Address correspondence to Alan D. Woolf, MD, MPH, Pediatric Environmental Health Center, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: alan.woolf{at}childrens.harvard.edu

Comparison of Periarticular Infiltration and Combination Delivery of Local Anesthetics for Reducing Pain and Opioid Consumption after Total Knee Arthroplasty.

Surgical-site delivery of local anesthetics decreases pain and opioid consumption after total knee arthroplasty (TKA). The optimal route of administration is unknown. We compared local anesthetic delivery using periarticular soft-tissue infiltration to delivery using a combination of preimplantation immersion and intra-articular injection (combination treatment). The records of patients who underwent unilateral, cemented, primary TKA with spinal anesthesia and adductor canal blocks at a single Veterans Affairs Medical Center were retrospectively reviewed. Three subgroups were compared, including controls who did not receive additional local anesthetics, patients who received periarticular infiltration, and patients who received combination treatment. Mean daily pain scores and mean 24-hour opioid consumption on postoperative days (PODs) 0 and 1 were calculated, and analysis of variance was used to assess for significant differences. Factors that were associated with lower pain scores and opioid consumption were then identified using multivariate stepwise regression. There were 26 controls, 25 periarticular infiltration patients, and 39 combination patients. The periarticular infiltration cohort had significantly lower mean pain scores and opioid consumption than controls on POD 0, but not on POD 1. The combination cohort had significantly lower mean pain scores and opioid consumption than controls on PODs 0 and 1. There were no significant differences between the infiltration and combination groups on either day. Multivariate regression analysis showed that infiltration was associated with significantly decreased opioid consumption on both days and decreased pain on POD 0. Combination treatment was associated with significantly decreased pain and opioid consumption on both days. Both local anesthetic periarticular infiltration and combination treatment are associated with decreased pain and opioid consumption after TKA. The stronger effects of the combination treatment compared with periarticular infiltration on POD 1 suggests that combination delivery may have a longer duration of action.

Telmisartan in the hypertension treatment: from pharmacological characteristics to clinical benefits

The current study describes pharmacological features and benefits of using the angiotensin II receptor blocker telmisartan in actual clinical practice. This bifunctional agent has a number of unique pharmacokinetic features: the longest duration of action, high lipophilicity and maximum efficiency in PPARy activation. The results of numerous studies confirmed the high efficacy of telmisartan and the ability to control blood pressure during the day and the early-morning hours compared to other antihypertensive drugs. The main pleutrophic effects of telmisartan have been proven at most stages of the cardiovascular and renal continuum, the main of which are a decrease in insulin resistance, an adiponectin levels increase, an improvement of endothelial function, angioprotective and renoprotective effects, and the regression of left ventricular hypertrophy. The ability of telmisartan to improve prognosis of patients with high cardiovascular risk and to reduce mortality and the number of cardiovascular complications has been proven. Based on the data of large-scale studies, the possibilities of using telmisartan (80 mg/day) were considered, including in combination with hydrochlorothiazide, as the most effective dual fixed-dose combination and one of the main modern antihypertensive strategies.

Comparitive Study Between Ultrasound Guided Rectus Sheath Block versus Local Wound Infiltration for Post-Operative Analgesia in Patients Undergoing Midline Exploratory Surgeries

Abstract Background Poorly controlled acute pain after abdominal surgery is related to somatic pain signals derived from the abdominal wall and is associated with a variety of unwanted post-operative consequences, including patient suffering, distress. respiratory complications, delirium, myocardial ischemia, prolonged hospital stay, an increased likelihood of chronic pain, increased consumption of analgesics, delayed bowel function and increase the requirement for rescue analgesics. Appropriate pain treatment protocols to reduce postoperative morbidity, improve the results of the surgery and decrease hospital costs. Objective To assess the postoperative analgesic efficacy of Rectus Sheath Block (RSB) compared local wound infiltration after midline incision regarding the pain relief, effect on hemodynamics, requirement of first supplemental doses of analgesia and total number of doses received. Patients and Methods All patients were informed with the procedure US guided RSB block and were trained to use the visual analogue scale (VAS). The study was conducted on 50 randomly chosen patients aged 20 to 60 years, American Society of Anesthesiologists (ASA) class I or II scheduled for elective midline exploratory surgery. In Ain Shams University Hospitals after approval of the medical ethical committee. They were allocated in two groups of 25 patients each: RSB block Group: received general anaesthesia and 20 ml of 0.25% bupivacaine on each side under ultrasound guidance. Local wound infiltration: received general anaesthesia and with 0.25% bupivacaine 20 ml at surgical site. Results The results of the study revealed that there is Patients receiving RSB block had significantly lower pain scores at rest for 12 h and on mobilization for 6 h after operation and decrease total need of analgesic in first 24 h post-operative compared with patients who received wound infiltration of local aneasthetic. Conclusion U/S-guided rectus sheath block is as effective analgesic technique as local infiltration of the surgical wound, with longer duration of action and pethidine -sparing effect during the postoperative period after midline exploratory surgeries.

Monolithic and core-shell particles stationary phase morphologies in protein analysis; peptide mapping of erythropoietin hormone and determination of carbetocin

Chromatographic application of two recent HPLC stationary phases for protein analysis was demonstrated. These two stationary phases are namely monolithic rods and core-shell particles. Monolithic rods have higher permeability and larger porous structure allowing faster elution, while smaller core-shell particles have narrower particle size distribution and better packing allowing larger number of resolved peptides. Peptide mapping of erythropoietin hormone, which is used in the treatment of symptomatic anaemia associated with chronic renal failure in adult and pediatric patients, was carried out on monolithic column and core-shell particles. Comparison between the effectiveness of separation on both columns was established and the new morphologies proved their capability of replacing the totally porous particles with higher resolution power at shorter analysis time. Carbetocin is an oxytocin analogue with a longer duration of action that stimulates uterine contraction and milk ejection in mammals. Monolithic column was also applied for quantitative HPLC analysis of carbetocin using ethanol as cheap and greener alternative organic modifier without compromise to a full impurity profiling. The proposed method was validated concerning with accuracy, precision, robustness, sensitivity, limits of detection and quantitation and proved to be green and stability indicating.

Infective endocarditis - can we treat it more effectively?

Infective endocarditis (IE), despite the diagnostic and therapeutic advances, still remains a serious disease associated with high mortality and serious complications. The present guidelines of the European Cardiology Society of 2015 recommend administration of the antibiotics indicated in empirical therapy for multiple weeks and in targeted treatment often for 6–8 weeks. This is associated with a risk of adverse effects of antibiotic therapy in the form of nephro- and/or hepatotoxicity and an increased risk of infections with Clostridioides difficile, while long-term hospitalisation is associated with high non-drug costs. The recommendations developed by the Austrian Society for Infectious Diseases and Tropical Medicine list dalbavancin among the new antibiotics that may find application in the treatment of IE of staphylococcal aetiology. This antibiotic is a lipoglycopeptide antibiotic alternative to vancomycin in the treatment of Staphylococcus aureus MRSA infections, especially in a situation where the minimum inhibitory concentration for vancomycin is high but below the breakpoint. Dalbavancin has very good pharmacokinetic and pharmacodynamic properties, with a long duration of action of up to 14 days after administration of a single dose (1500 mg in a 30-minute infusion). This antibiotic is characterised by high clinical efficacy with good treatment tolerance and safety profile, without causing toxic effects in internal organs in comparison with vancomycin. In view of its safety, clinical efficacy and convenient dosing, dalbavancin may prove a useful therapeutic option in the treatment of IE.