The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory ...stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response.
In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics.
Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%.
In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol.
Statins and muscle pain Pergolizzi, Joseph V.; Coluzzi, Flaminia; Colucci, Robert D. ...
Expert review of clinical pharmacology,
03/2020, Letnik:
13, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Introduction: Statins remain among the most frequently prescribed drugs and constitute a cornerstone in the prevention of cardiovascular disease. However, muscle symptoms are often reported from ...patients on statins. Muscle symptoms are frequently reported as adverse events associated with statin therapy.
Areas covered: In the present narrative review, statin-associated muscle pain is discussed. It elucidates potential mechanisms and possible targets for management.
Expert opinion: In general, the evidence in support of muscle pain caused by statins is in some cases equivocal and not particularly strong. Reported symptoms are difficult to quantify. Rarely is it possible to establish a causal link between statins and muscle pain. In randomized controlled trials, statins are well tolerated, and muscle-pain related side-effects is similar to placebo. There are also nocebo effects of statins. Exchange of statin may be beneficial although all statins have been associated with muscle pain. In some patients reduction of dose is worth trying, especially in primary prevention Although the benefits of statins outweigh potential risks in the vast majority of cases, careful clinical judgment may be necessary in certain cases to manage potential side effects on an individual basis.
Opioid analgesics remain the cornerstone of effective management for moderate-to-severe pain. In the face of persistent lack of access to opioids by patients with legitimate pain problems, the rate ...of prescription opioid abuse in the United States has escalated over the past 15 years. Abuse-deterrent opioid products can play a central role in optimizing the risk-benefit ratio of opioid analgesics--if these products can be developed cost-effectively without compromising efficacy or creating new safety issues for the target treatment population. The development of scientific methods for assessing prescription opioid abuse potential remains a critical and challenging step in determining whether a claim of abuse deterrence for a new opioid product is indeed valid and will thus be accepted by the medical, regulatory, and reimbursement communities. To explore this and other potential impediments to the development of prescription opioid abuse-deterrent formulations, a panel of experts on opioid abuse and diversion from academia, industry, and governmental agencies participated in a Tufts Health Care Institute-supported symposium held on October 27 and 28, 2005, in Boston, MA. This manuscript captures the main consensus opinions of those experts, and also information gleaned from a review of the relevant published literature, to identify major impediments to the development of opioid abuse-deterrent formulations and offer strategies that may accelerate their commercialization.
Background ENA-001 (formerly known as GAL-021) is a novel, first-in-class respiratory stimulant. Pharmacokinetic and pharmacodynamic properties, plus safety and tolerability, were assessed in a ...randomized, single-center study of healthy volunteers. Methodology This four-period study was designed to test continuous two-hour intravenous infusion regimens of ENA-001 at doses of 0.96, 1.44, and 1.92 mg/kg/hour versus placebo. Each participant received four infusions with a seven-day minimum washout between them: one infusion each of the three doses of ENA-001 and one placebo. Pharmacokinetic and pharmacodynamic parameters were assessed and adverse events were recorded. Results A total of 17 participants completed the study. ENA-001 was generally safe and well tolerated over the dose range studied (0.96 to 1.92 mg/kg/hour). ENA-001 was able to drive hyperventilation in a dose-dependent manner in healthy participants. Increases in ventilation due to ENA-001 were not associated with like-magnitude blood pressure response. ENA-001-stimulated decreases in ETCO
were associated with small, statistically significant, increases in SpO
levels. Hyperventilation occurred in two participants at the highest dose level, leading to study discontinuation. The terminal half-life of ENA-001 was 6.33 hours. Conclusions The respiratory stimulant ENA-001 demonstrated well-behaved pharmacokinetics following the two-hour infusion. Mean peak plasma concentrations and the mean total systemic exposure values were approximately dose-proportional in the dose range studied.
Opioids remain the standard of care for treating moderate to severe pain resulting from surgery or injury in cases of acute pain, and are recommended for patients who have not responded to nonopioid ...analgesics. Effective management of pain has an impact on clinical course and often depends on achieving an acceptable balance between opioid efficacy, safety, and tolerability. Common opioid-related adverse events such as nausea and vomiting are associated with an overall lower achievement of effective pain management and patient satisfaction. However, in practice, clinicians employ various strategies to maximize efficacy, minimize these adverse effects, and ensure the careful, judicious, and evidence-based use of opioids for patients who require them. Typical strategies for management and minimization of these types of adverse events include dose reduction, dose titration, opioid rotation, prescription for an antiemetic, and recommending the patient take opioids with food. Overall, the most straightforward approach that clinicians tend to employ that does not require additional visits or adjustment of prescriptions, is to recommend patients take opioids with food. However, given the current climate with opioids, it is critical and imperative that decisions for use of opioids be grounded in a solid and thorough evidence-base. In fact, several opioids are recommended to be taken explicitly with or without food because of interactions with abuse-deterrent technologies that can cause increased adverse events or inadequate analgesia. Therefore, we sought to review, synthesize, and summarize the literature for randomized, controlled trials and other studies to support the hypothesis that taking opioids with food reduces opioid-related events such as nausea and vomiting. Based on the current evidence we surveyed, the recommendation to take opioids with food does not appear to consistently and unequivocally reduce nausea and vomiting and, in many cases, increases the frequency of these adverse events in the studies we examined.
Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed ...to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.
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