scholarly journals In Silico Simulation of the Systemic Drug Exposure Following the Topical Application of Opioid Analgesics in Patients with Cutaneous Lesions

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 284
Author(s):  
Maksim Khotimchenko ◽  
Victor Antontsev ◽  
Kaushik Chakravarty ◽  
Hypatia Hou ◽  
Jyotika Varshney
Keyword(s):  
Topical Application ◽  
Drug Exposure ◽  
Human Subjects ◽  
Systemic Exposure ◽  
Opioid Analgesics ◽  
Multimodal Analgesia ◽  
Cutaneous Lesions ◽  
Opioid Agonist ◽  
Healthy Human ◽  
In Silico Simulation

The use of opioid analgesics in treating severe pain is frequently associated with putative adverse effects in humans. Topical agents that are shown to have high efficacy with a favorable safety profile in clinical settings are great alternatives for pain management of multimodal analgesia. However, the risk of side effects induced by transdermal absorption and systemic exposure is of great concern as they are challenging to predict. The present study aimed to use “BIOiSIM” an artificial intelligence-integrated biosimulation platform to predict the transdermal disposition of opioid analgesics. The model successfully predicted their exposure following the topical application of central opioid agonist buprenorphine and peripheral agonist oxycodone in healthy human subjects with simulation of intra-skin exposure in subjects with burns and pressure wounds. The predicted plasma levels of analgesics were used to evaluate the safety of the therapeutic pain control in patients with the dermal structural impairments caused by acute (burns) or chronic cutaneous lesions (pressure wounds) with topical opioid analgesics.

Acute peripheral tissue effects of ghrelin on interstitial levels of glucose, glycerol, and lactate: a microdialysis study in healthy human subjects

2013 ◽  
Vol 304 (12) ◽  
pp. E1273-E1280 ◽  
Author(s):  
Esben Thyssen Vestergaard ◽  
Niels Møller ◽  
Jens Otto Lunde Jørgensen
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Human Subjects ◽  
Systemic Exposure ◽  
Metabolic Effects ◽  
Controlled Study ◽  
Healthy Human ◽  
Adipose Tissues ◽  
Ghrelin Receptor ◽  
Basal Period

Ghrelin is a gut-derived peptide and an endogenous ligand for the ghrelin receptor. Intravenous infusion of ghrelin induces insulin resistance and hyperglycemia and increases circulating levels of nonesterified free fatty acids. Our objective was to investigate whether the metabolic effects are mediated directly by ghrelin in skeletal muscle and adipose (peripheral and central) tissues. Ten healthy men (24.9 ± 1.3 yr) received 300 min of supraphysiological ghrelin administration by microdialysis catheters in skeletal muscle and adipose tissues in a randomized, single-blind, and placebo-controlled study. Microdialysis perfusates were analyzed every 30 min for glucose, glycerol, and lactate during both a basal period and a hyperinsulinemic euglycemic clamp. The primary outcome measures were interstitial concentrations of glucose, glycerol, and lactate in skeletal muscle and adipose tissues. Interstitial concentrations of glucose were similar in skeletal muscle, peripheral, and central adipose tissue in the basal period. During hyperinsulinemia, interstitial concentrations of glucose in skeletal muscle decreased in response to ghrelin exposure [2.84 ± 0.25 (ghrelin) vs. 3.06 ± 0.26 mmol/l (placebo), P = 0.04]. Ghrelin exposure did not impact on interstitial concentrations of glycerol and lactate. We conclude that ghrelin administration into skeletal muscle decreases interstitial concentrations of glucose during euglycemic hyperinsulinemia, which is indicative of increased insulin sensitivity without any effects on interstitial glycerol levels in either muscle or adipose tissue. These data contrast with the metabolic effects of ghrelin observed after systemic exposure and suggest the existence of a second messenger that remains to be identified.

scholarly journals Safety and efficacy update: Alvimopan in postoperative ileus

2009 ◽  
Vol 1 ◽  
pp. CMT.S2384 ◽  
Author(s):  
David T. Beattie
Keyword(s):  
Postoperative Ileus ◽  
Bowel Resection ◽  
Human Subjects ◽  
The United States ◽  
Opioid Agonist ◽  
Phase 3 ◽  
Healthy Human ◽  
Primary Metabolite ◽  
Opioid Receptor Antagonists ◽  
Multiple Species

Postoperative ileus (POI) in patients undergoing abdominal surgery is associated with significant morbidity. In 2008, alvimopan (Entereg®) was approved by the Food and Drug Administration (FDA), and is the only available POI therapy in the United States for patients undergoing bowel resection. Data from preclinical studies demonstrate that alvimopan and its primary metabolite, ADL 08-0011, behave as potent μ. opioid receptor antagonists. In animals, alvimopan and ADL 08-0011 attenuate opioid agonist-induced reductions in gastrointestinal (GI) transit. Higher doses of alvimopan are required to inhibit opioid-induced analgesia as a result of its inability to penetrate the central nervous system (CNS). ADL 08-0011 is also peripherally selective, although to a lesser degree than alvimopan. In multiple species, including humans, alvimopan has low oral bioavailability, while ADL 08-0011, following its generation by human gut microflora, is more readily absorbed and achieves higher exposures. Three Phase 2 and five Phase 3 clinical trials have been conducted to investigate the efficacy and tolerability of alvimopan in patients undergoing bowel resection. An additional Phase 3 study was conducted in hysterectomy patients. In the majority of the studies, statistically significant, and clinically meaningful, acceleration of GI recovery has been demonstrated. Consistent with animal data, alvimopan has no effect on opioid agonist-induced analgesia in healthy human subjects and POI patients. Clinical experience to date in POI patients indicates that alvimopan is well tolerated when used according to its approved dosing regimen (12 mg b.i.d. for up to 7 days). In this article, the preclinical and clinical properties of alvimopan are reviewed.

Chiral Pharmacokinetics and Metabolite Profile of Prolonged-release Ketamine Tablets in Healthy Human Subjects

2021 ◽  
Author(s):  
Mahmoud Hasan ◽  
Christiane Modess ◽  
Tarek Roustom ◽  
Anne Dokter ◽  
Markus Grube ◽  
...  
Keyword(s):  
Intravenous Infusion ◽  
Human Subjects ◽  
Systemic Exposure ◽  
Metabolite Profile ◽  
Pharmacokinetic Analysis ◽  
Prolonged Release ◽  
Healthy Human ◽  
Time Curve ◽  
Pharmaceutical Dosage Form ◽  
Tandem Mass Spectrometric

Background The anesthetic ketamine after intravenous dosing is nearly completely metabolized to R- and S-stereoisomers of the active norketamine (analgesic, psychoactive) and 2,6-hydroxynorketamine (potential analgesic, antidepressant) as well as the inactive dehydronorketamine. Oral administration favors the formation of 2,6-hydroxynorketamines via extensive presystemic metabolism. The authors hypothesized that plasma exposure to 2,6-hydroxynorketamines relative to the psychoactive ketamine is greater after prolonged-release ketamine tablets than it is after intravenous ketamine. Methods Pharmacokinetics of ketamine after intravenous infusion (5.0 mg) and single-dose administrations of 10, 20, 40, and 80 mg prolonged-released tablets were evaluated in 15 healthy white human subjects by means of a controlled, ascending-dose study. The stereoisomers of ketamine and metabolites were quantified in serum and urine by validated tandem mass-spectrometric assays and evaluated by noncompartmental pharmacokinetic analysis. Results After 40 mg prolonged-release tablets, the mean ± SD area under the concentrations–time curve ratios for 2,6-hydroxynorketamine/ketamine were 18 ± 11 (S-stereoisomers) and 30 ± 16 (R-stereoisomers) compared to 1.7 ± 0.8 and 3.1 ± 1.4 and after intravenous infusion (both P < 0.001). After 10 and 20 mg tablets, the R-ratios were even greater. The distribution volumes at steady state of S- and R-ketamine were 6.6 ± 2.2 and 5.6 ± 2.1 l/kg, terminal half-lives 5.2 ± 3.4 and 6.1 ± 3.1 h, and metabolic clearances 1,620 ± 380 and 1,530 ± 380 ml/min, respectively. Bioavailability of the 40 mg tablets was 15 ± 8 (S-isomer) and 19 ± 10% (R-isomer) and terminal half-life 11 ± 4 and 10 ± 4 h. About 7% of the dose was renally excreted as S-stereoisomers and 17% as R-stereoisomers. Conclusions Prolonged-release ketamine tablets generate a high systemic exposure to 2,6-hydroxynorketamines and might therefore be an efficient and safer pharmaceutical dosage form for treatment of patients with chronic neuropathic pain compared to intravenous infusion. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Safety, Tolerability, and Pharmacokinetics of a Novel Oral Amphotericin B Formulation (iCo-019) following Single-Dose Administration to Healthy Human Subjects: an Alternative Approach to Parenteral Amphotericin B Administration

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Peter Hnik ◽  
Ellen K. Wasan ◽  
Kishor M. Wasan
Keyword(s):  
Amphotericin B ◽  
Human Subjects ◽  
Systemic Exposure ◽  
Healthy Human ◽  
Dose Administration ◽  
Healthy Humans ◽  
Alternative Approach ◽  
Healthy Human Subjects ◽  
Liver And Kidney ◽  
New Treatment

ABSTRACT This study evaluated the safety, tolerability, and pharmacokinetics of a novel oral amphotericin B (AmB) formulation (iCo-019) following single doses to healthy humans. The data from this study suggest that iCo-019 has a long circulation time and systemic exposure without the associated gastrointestinal, liver, and kidney toxicity associated with AmB. This novel oral AmB formulation can serve as a new treatment strategy to overcome the limitations of the use of parenterally administered AmB products.

Minimizing Carry-Over Effects After Treatment Failure and Maximizing Therapeutic Outcome

2014 ◽  
Vol 222 (3) ◽  
pp. 171-178 ◽  
Author(s):  
Mareile Hofmann ◽  
Nathalie Wrobel ◽  
Simon Kessner ◽  
Ulrike Bingel
Keyword(s):  
Treatment Failure ◽  
Human Subjects ◽  
Subsequent Treatment ◽  
Clinical Samples ◽  
Administration Route ◽  
Healthy Human ◽  
Negative Experiences ◽  
Analgesic Treatment ◽  
Balanced Design ◽  
Carry Over

According to experimental and clinical evidence, the experiences of previous treatments are carried over to different therapeutic approaches and impair the outcome of subsequent treatments. In this behavioral pilot study we used a change in administration route to investigate whether the effect of prior treatment experience on a subsequent treatment depends on the similarity of both treatments. We experimentally induced positive or negative experiences with a topical analgesic treatment in two groups of healthy human subjects. Subsequently, we compared responses to a second, unrelated and systemic analgesic treatment between both the positive and negative group. We found that there was no difference in the analgesic response to the second treatment between the two groups. Our data indicate that a change in administration route might reduce the influence of treatment history and therefore be a way to reduce negative carry-over effects after treatment failure. Future studies will have to validate these findings in a fully balanced design including larger, clinical samples.

Detection of Soluble Fibrin Monomer Complexes in Blood by Means of Protamine Sulphate Test

1968 ◽  
Vol 20 (01/02) ◽  
pp. 044-049 ◽  
Author(s):  
B Lipiński ◽  
K Worowski
Keyword(s):  
Human Subjects ◽  
Coronary Thrombosis ◽  
Mean Value ◽  
Healthy Human ◽  
Protamine Sulphate ◽  
Soluble Fibrin ◽  
Fibrin Monomer ◽  
Dog Plasma ◽  
The Mean ◽  
Precipitable Protein

SummaryIn the present paper described is a simple test for detecting soluble fibrin monomer complexes (SFMC) in blood. The test consists in mixing 1% protamine sulphate with diluted oxalated plasma or serum and reading the optical density at 6190 Å. In experiments with dog plasma, enriched with soluble fibrin complexes, it was shown that OD read in PS test is proportional to the amount of fibrin recovered from the precipitate. It was found that SFMC level in plasma increases in rabbits infused intravenously with thrombin and decreases after injection of plasmin with streptokinase. In both cases PS precipitable protein in serum is elevated indicating enhanced fibrinolysis. In healthy human subjects the mean value of OD readings in plasma and sera were found to be 0.30 and 0.11, while in patients with coronary thrombosis they are 0.64 and 0.05 respectively. The origin of SFMC in circulation under physiological and pathological conditions is discussed.

Chronic stress decreases circulating endocannabinoid 2-arachidonoylglycerol in healthy human subjects

2015 ◽  
Author(s):  
Buqing Yi ◽  
Igor Nichiporuk ◽  
Matthias Feuerecker ◽  
Gustav Schelling ◽  
Alexander Chouker
Keyword(s):  
Chronic Stress ◽  
Human Subjects ◽  
Healthy Human ◽  
Healthy Human Subjects

Transmodulation of Dopaminergic Signaling to Mitigate Hypodopminergia and Pharmaceutical Opioid-induced Hyperalgesia

2020 ◽  
Vol 9 (3) ◽  
pp. 164-184
Author(s):  
Raymond Brewer ◽  
Kenneth Blum ◽  
Abdalla Bowirrat ◽  
Edward J. Modestino ◽  
David Baron ◽  
...  
Keyword(s):  
Opioid Analgesic ◽  
Opioid Analgesics ◽  
Well Being ◽  
Deficiency Syndrome ◽  
Pain Tolerance ◽  
Opioid Agonist ◽  
Opioid Agonist Therapy ◽  
Analgesic Agents ◽  
Opioid Induced Hyperalgesia ◽  
Intensive Investigation

Neuroscientists and psychiatrists working in the areas of “pain and addiction” are asked in this perspective article to reconsider the current use of dopaminergic blockade (like chronic opioid agonist therapy), and instead to consider induction of dopamine homeostasis by putative pro-dopamine regulation. Pro-dopamine regulation could help pharmaceutical opioid analgesic agents to mitigate hypodopaminergia-induced hyperalgesia by inducing transmodulation of dopaminergic signaling. An optimistic view is that early predisposition to diagnosis based on genetic testing, (pharmacogenetic/pharmacogenomic monitoring), combined with appropriate urine drug screening, and treatment with pro-dopamine regulators, could conceivably reduce stress, craving, relapse, enhance well-being and attenuate unwanted hyperalgesia. These concepts require intensive investigation. However, based on the rationale provided herein, there is a good chance that combining opioid analgesics with genetically directed pro-dopamine-regulation using KB220 (supported by 43 clinical studies). This prodopamine regulator may become a front-line technology with the potential to overcome, in part, the current heightened rates of chronic opioid-induced hyperalgesia and concomitant Reward Deficiency Syndrome (RDS) behaviors. Current research does support the hypothesis that low or hypodopaminergic function in the brain may predispose individuals to low pain tolerance or hyperalgesia.

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