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Clinical Drug Investigation Jul 2023PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female individuals.
METHODS
Two phase I, randomized, double-blind, placebo-controlled trials were conducted in men (Trial 1) and women (Trial 2). The participants were randomized 3:1 to receive PSD502 (7.5 mg of lidocaine and 2.5 mg of prilocaine per spray) or a placebo. For male individuals, a single dose (three sprays) once daily was applied to the glans penis for 21 days except for nine sprays (three doses) on days 7 and 14, 4 h apart for each dose. For female individuals, two sprays were applied to the vagina and one to the cervix once daily for 7 days. The primary endpoint was safety. Pharmacokinetics analysis was also performed.
RESULTS
Twenty-four male and 24 female individuals were recruited. Treatment-emergent adverse events occurred in 38.9% (7/18) of male individuals and 66.7% (12/18) of female individuals in the PSD502 group, respectively. Both trials reported 50.0% (3/6) treatment-emergent adverse events for the placebo. No grade ≥ 3 treatment-emergent adverse events, serious adverse events, or treatment-emergent adverse events leading to early withdrawal or discontinuation occurred. After consecutive applications, lidocaine and prilocaine cleared rapidly in both trials. Plasma concentrations exhibited high inter-individual variability. The maximum plasma concentrations of active ingredients were far below the anticipated minimum toxic concentrations. The area under the plasma concentration-time curve of metabolites were ≤ 20% of the parent drugs. No clinically significant accumulations were observed in the two trials.
CONCLUSIONS
PSD502 was well tolerated and showed low plasma concentrations in healthy Chinese male and female individuals.
Topics: Female; Humans; Male; Double-Blind Method; East Asian People; Healthy Volunteers; Lidocaine; Lidocaine, Prilocaine Drug Combination; Prilocaine; Premature Ejaculation; Administration, Topical; Penis; Vagina; Cervix Uteri
PubMed: 37380910
DOI: 10.1007/s40261-023-01277-4 -
Expert Opinion on Pharmacotherapy Jun 2022Premature ejaculation (PE) is a sexual dysfunction of unknown etiology affecting a substantial number of males and deteriorating sexual health and quality of life of the...
INTRODUCTION
Premature ejaculation (PE) is a sexual dysfunction of unknown etiology affecting a substantial number of males and deteriorating sexual health and quality of life of the patient and his partner. Treatment still remains challenging; however, pharmacotherapy is considered the mainstay of therapy with behavioral and psychosexual interventions being particularly important as adjudicate procedures, within the context of a holistic approach.
AREAS COVERED
The authors review the literature on the available medications for PE, both officially registered and non-registered. Currently, only dapoxetine and an anesthetic spray containing lidocaine and prilocaine (Fortacin™) are officially approved, with the rest being used off-label. Herein, updated data regarding the efficacy and safety of the pharmaceutical agents are presented.
EXPERT OPINION
On-demand dapoxetine is reportedly efficacious and safe in treating lifelong PE and is the first medication to be approved for this purpose. Fortacin has also shown considerable efficacy and may be reliably used on-demand. Phosphodiesterase type 5 inhibitors (PDE5Is) have been found to be effective in the treatment of PE and are therefore recommended either as monotherapy or combined with other therapies (i.e. dapoxetine). Adverse events of any therapy should be taken under consideration. Physicians should encourage patients to discuss their needs and expectations and grade any improvement of their condition with treatment.
Topics: Benzylamines; Ejaculation; Humans; Male; Phosphodiesterase 5 Inhibitors; Premature Ejaculation; Quality of Life; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 35108136
DOI: 10.1080/14656566.2022.2035361 -
Gels (Basel, Switzerland) Jan 2023This study aimed to formulate semisolid niosomal encapsulated lidocaine and prilocaine using the patented palm oil base Hamin-C for further characterization and in vivo...
This study aimed to formulate semisolid niosomal encapsulated lidocaine and prilocaine using the patented palm oil base Hamin-C for further characterization and in vivo pain assessment. Seven formulations were initially studied with various chemical compositions. A thin-layer film hydration method was used to produce niosome using a mixture of surfactant (Span 40 or Span 60) and cholesterol (CHOL) at a 1:1 ratio, with/without a charge-inducing agent (diacetyl phosphate) (DCP) and with/without labrasol. Niosome F1 formulation had been identified as the highest %EE achieved, at 53.74 and 55.63% for prilocaine and lidocaine, respectively. Furthermore, NIO-HAMIN F1 emulgel indicated the best formulation with higher permeability of prilocaine and lidocaine compared to the rest of the formulations. The reformulation of optimization of NIO-HAMIN F1 emulgel using a cold process to NIO-HAMIN F1-C emulgel to improve the viscosity resulted in higher diffusion of prilocaine and lidocaine by 5.71 and 33.38%, respectively. In vivo pain perception studies by verbal rating score (VRS) and visual analogue score (VAS) on healthy subjects show a comparable local anesthetic effect between NIO-HAMIN F1-C emulgel and EMLA cream.
PubMed: 36826266
DOI: 10.3390/gels9020096 -
International Journal of Toxicology Aug 2022DNA damage is an established initiating event in the mutagenicity and carcinogenicity of genotoxic chemicals. Accordingly, assessment of this endpoint is critical for...
DNA damage is an established initiating event in the mutagenicity and carcinogenicity of genotoxic chemicals. Accordingly, assessment of this endpoint is critical for chemicals which are being developed for use in humans. To assess the ability of the Chicken Egg Genotoxicity Assay (CEGA) to detect genotoxic pharmaceuticals, a set of 23 compounds with different pharmacological and reported genotoxic effects was tested for the potential to produce nuclear DNA adducts and strand breaks in the embryo-fetal livers using the P-nucleotide postlabeling (NPL) and comet assays, respectively. Due to high toxicity, two aneugens, colchicine and vinblastine, and an autophagy inhibitor, hydroxychloroquine, could not be evaluated. Out of the 20 remaining pharmaceuticals, 10 including estrogen modulators, diethylstilbestrol and tamoxifen, antineoplastics cyclophosphamide, etoposide, and mitomycin C, antifungal griseofulvin, local anesthetics lidocaine and prilocaine, and antihistamines diphenhydramine and doxylamine, yielded clear positive outcomes in at least one of the assays. The antihypertensive vasodilator hydralazine and antineoplastics streptozotocin and teniposide, produced only DNA strand breaks, which were not dose-dependent, and thus, the results with these 3 pharmaceuticals were considered equivocal. No DNA damage was detected for 7 compounds, including the purine antagonist 6-thioguanine, antipyretic analgesics acetaminophen and phenacetin, antibiotic ciprofloxacin, antilipidemic clofibrate, anti-inflammatory ibuprofen, and sedative phenobarbital. However, low solubility of these compounds limited dosages tested in CEGA. Overall, results in CEGA were largely in concordance with the outcomes in other systems in vitro and in vivo, indicating that CEGA provides reliable detection of DNA damaging activity of genotoxic compounds. Further evaluations with a broader set of compounds would support this conclusion.
Topics: Animals; Chickens; Comet Assay; DNA Adducts; DNA Damage; Humans; Mutagenicity Tests; Mutagens; Pharmaceutical Preparations
PubMed: 35658642
DOI: 10.1177/10915818221093583 -
The Cochrane Database of Systematic... Sep 2023Lumbar puncture (LP) is a common invasive procedure, most frequently performed to diagnose infection. Physicians perform LP in newborn infants with the help of an... (Review)
Review
BACKGROUND
Lumbar puncture (LP) is a common invasive procedure, most frequently performed to diagnose infection. Physicians perform LP in newborn infants with the help of an assistant using a strict aseptic technique; it is important to monitor the infant during all the steps of the procedure. Without adequate analgesia, LP can cause considerable pain and discomfort. As newborns have increased sensitivity to pain, it is crucial to adequately manage the procedural pain of LP in this population.
OBJECTIVES
To assess the benefits and harms, including pain, discomfort, and success rate, of any pharmacological intervention during lumbar puncture in newborn infants, compared to placebo, no intervention, non-pharmacological interventions, or other pharmacological interventions.
SEARCH METHODS
We searched CENTRAL, PubMed, Embase, and three trial registries in December 2022. We also screened the reference lists of included studies and related systematic reviews for studies not identified by the database searches.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) and quasi-RCTs comparing drugs used for pain management, sedation, or both, during LP. We considered the following drugs suitable for inclusion. • Topical anesthetics (e.g. eutectic mixture of local anesthetics [EMLA], lidocaine) • Opioids (e.g. morphine, fentanyl) • Alpha-2 agonists (e.g. clonidine, dexmedetomidine) • N-Methyl-D-aspartate (NMDA) receptor antagonists (e.g. ketamine) • Other analgesics (e.g. paracetamol) • Sedatives (e.g. benzodiazepines such as midazolam) DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We used the fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) or standardized mean difference (SMD) for continuous data, with their 95% confidence intervals (CIs). Our main outcomes were successful LP on first attempt, total number of LP attempts, episodes of bradycardia, pain assessed with validated scales, episodes of desaturation, number of episodes of apnea, and number of infants with one or more episodes of apnea. We used the GRADE approach to evaluate the certainty of the evidence.
MAIN RESULTS
We included three studies (two RCTs and one quasi-RCT) that enrolled 206 newborns. One study included only term infants. All studies assessed topical treatment versus placebo or no intervention. The topical anesthetics were lidocaine 4%, lidocaine 1%, and EMLA. We identified no completed studies on opioids, non-steroidal anti-inflammatory drugs, alpha-2 agonists, NMDA receptor antagonists, other analgesics, sedatives, or head-to-head comparisons (drug A versus drug B). Based on very low-certainty evidence from one quasi-RCT of 100 LPs in 76 infants, we are unsure if topical anesthetics (lidocaine), compared to no anesthesia, has an effect on the following outcomes. • Successful LP on first attempt (first-attempts success in 48% of LPs in the lidocaine group and 42% of LPs in the control group) • Number of attempts per LP (mean 1.9 attempts, [standard error of the mean 0.2] in the lidocaine group, and mean 2.1 attempts [standard error of the mean 2.1] in the control group) • Episodes of bradycardia (0% of LPs in the lidocaine group and 4% of LPs in the control group) • Episodes of desaturation (0% of LPs in the lidocaine group and 8% of LPs in the control group) • Occurrence of apnea (RR 3.24, 95% CI 0.14 to 77.79; risk difference [RD] 0.02, 95% CI -0.03 to 0.08). Topical anesthetics compared to placebo may reduce pain assessed with the Neonatal Facial Coding System (NFCS) score (SMD -1.00 standard deviation (SD), 95% CI -1.47 to -0.53; I² = 98%; 2 RCTs, 112 infants; low-certainty evidence). No studies in this comparison reported total number of episodes of apnea. We identified three ongoing studies, which will assess the effects of EMLA, lidocaine, and fentanyl. Three studies are awaiting classification.
AUTHORS' CONCLUSIONS
The evidence is very uncertain about the effect of topical anesthetics (lidocaine) compared to no anesthesia on successful lumbar puncture on first attempt, the number of attempts per lumbar puncture, episodes of bradycardia, episodes of desaturation, and occurrence of apnea. Compared to placebo, topical anesthetics (lidocaine or EMLA) may reduce pain assessed with the NFCS score. One ongoing study will assess the effects of systemic treatment.
Topics: Humans; Infant, Newborn; Analgesics; Anesthetics, Local; Apnea; Bradycardia; Fentanyl; Hypnotics and Sedatives; Lidocaine; Lidocaine, Prilocaine Drug Combination; Pain; Spinal Puncture
PubMed: 37767875
DOI: 10.1002/14651858.CD015594.pub2 -
Sustained delivery of prilocaine and lidocaine using depot microemulsion system: and animal studies.Drug Development and Industrial Pharmacy Feb 2020Topical drug delivery for local anesthetics has been an interesting area of research for formulators considering the resistance and barrier properties of skin and high...
Topical drug delivery for local anesthetics has been an interesting area of research for formulators considering the resistance and barrier properties of skin and high clearance rate of drugs like prilocaine and lidocaine (duration of action < 2.5 h). In this study, efforts have been made to sustain the release of prilocaine and lidocaine by using depot microemulsion system. Drug loaded microemulsions were formulated using Capmul MCM, Pluronic F127, polyethylene glycol 200 (PEG 200) and water from pseudo-ternary diagrams. The S at 1:4 ratio showed larger microemulsion area in comparison to 1:2 ratio. The studies indicate sustained release of prilocaine and lidocaine from the microemulsion up to 8 h, in comparison to 4 h with ointments. Skin irritation study on rabbits confirmed the safety of drug loaded microemulsions for local drug delivery. The improved data is reflected in the studies, were radiant heat tail-flick test and sciatic nerve model showed prolong duration of action for both prilocaine and lidocaine microemulsions in comparison to ointment. The and efficacy of prilocaine and lidocaine was non-significant. The improved efficacy was due to high penetration of microemulsion and depot effect due to local precipitation (destabilization of microemulsion) of drug in the skin layer. The sustained local anesthetic effect is highly desirable for the treatment of skin irritation due to skin burns and pre- and post-operative pain.
Topics: Administration, Cutaneous; Anesthetics, Local; Animals; Chemistry, Pharmaceutical; Delayed-Action Preparations; Diglycerides; Drug Delivery Systems; Emulsions; Goats; Lidocaine; Monoglycerides; Poloxamer; Polyethylene Glycols; Prilocaine; Rabbits; Rats; Rats, Wistar; Skin; Skin Absorption
PubMed: 32000536
DOI: 10.1080/03639045.2020.1716377 -
European Journal of Pediatrics Jan 2021Male circumcision (MC) is one of the most common surgical procedures performed on neonates. In the last decades, there have been consistent advances in the understanding... (Review)
Review
Male circumcision (MC) is one of the most common surgical procedures performed on neonates. In the last decades, there have been consistent advances in the understanding of pain mechanisms in newborns, and analgesia has become a fundamental part of neonatal care. MC is still often performed with inappropriate analgesic methods, and there is still great variability among the various centers about surgical and anesthethic techniques to do it. The purpose of this review is to summarize the findings in the literature about pain management and analgesia during newborn MC. We performed a systematic review of neonatal MC studies published in the last 20 years. The most effective technique appeared to be the combination of pharmacological and non-pharmacological methods of analgesia.Conclusion: Combining local anesthesia with non-pharmacological analgesic strategies appears to be effective preventing procedural pain during MC. However, a standardized protocol for analgesia during MC is yet to be determined. Sensorial saturation appeared to help when used in conjunction with the local anesthesia techniques. What is Known: • Male circumcision is a painful procedure and it is frequently performed with inappropriate analgesic methods. • A gold standard practice in analgesia during male circumcision is still lacking and there is a great variability in the modus operandi between centers. What is New: • The combination of RB + EMLA + sucrose appears to be an analgesic strategy superior to other approaches. • We advocate for the integration of sensorial saturation during male circumcision in order to improve the efficacy of current analgesic practices.
Topics: Anesthetics, Local; Circumcision, Male; Humans; Infant, Newborn; Lidocaine; Lidocaine, Prilocaine Drug Combination; Male; Pain; Prilocaine
PubMed: 32748017
DOI: 10.1007/s00431-020-03758-6 -
Regional Anesthesia and Pain Medicine Sep 2020Ambulatory anorectal surgery requires an anesthetic of short duration but profound depth. Saddle block anesthesia (SBA) can provide dense sacral anesthesia with minimal... (Review)
Review
BACKGROUND
Ambulatory anorectal surgery requires an anesthetic of short duration but profound depth. Saddle block anesthesia (SBA) can provide dense sacral anesthesia with minimal motor blockade, but the ideal local anesthetic agent remains undefined. This systematic review aims to identify the optimal SBA regimen for ambulatory anorectal surgery.
METHODS
We sought randomized trials examining SBA for ambulatory anorectal surgery and stratified patients into four subgroups according to local anesthetic type and dose: (1) longer acting, higher dose; (2) longer acting, lower dose; (3) shorter acting, higher dose; and (4) shorter acting, lower dose. Longer acting agents included bupivacaine and levobupivacaine; shorter acting agents included chloroprocaine, mepivacaine, and prilocaine. Lower dose was defined as ≤5 mg and ≤20 mg for longer and shorter acting local anesthetics, respectively. The primary outcome was time to discharge; secondary outcomes included times to sensory and motor block regression, urine voiding, and ambulation, as well as block success.
RESULTS
A total of 11 trials (1063 patients) were included. Overall study quality and reporting consistency was poor. Doses ranged from 1.5-7.5 mg to 3-30 mg of longer and shorter acting local anesthetics, respectively. Hyperbaric local anesthetics were used in eight trials (953 patients, 86%). The median time to discharge appeared similar across all subgroups with an overall time of 182 (IQR 102) min. The use of long-acting, lower dose regimens was associated with a faster median time to motor block regression. Block success approached 99% among all trials.
CONCLUSIONS
There is presently insufficient qualitative and quantitative evidence to identify an optimal SBA regimen for ambulatory anorectal surgery. Nonetheless, we found that doses as low as 1.5 and 3 mg of longer and shorter acting hyperbaric local anesthetics, respectively, can achieve effective and reliable SBA with timely hospital discharge. Despite similar discharge times, longer acting, lower dose local anesthetics may produce faster motor block regression following SBA for ambulatory anorectal surgery.
Topics: Ambulatory Surgical Procedures; Anesthesia, Local; Anesthesia, Spinal; Anesthetics, Local; Bupivacaine; Humans; Mepivacaine
PubMed: 32699103
DOI: 10.1136/rapm-2020-101603 -
Atherosclerosis Nov 2023To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of...
BACKGROUND AND AIMS
To understand pathophysiological mechanisms underlying migraine as a cardiovascular risk factor, we studied neuropeptide action and endothelial function as measures of peripheral microvascular function in middle-aged women with or without migraine.
METHODS
We included women with the endocrine disorder polycystic ovary syndrome (PCOS), a population with supposed elevated cardiovascular risk, with and without comorbid migraine. In 26 women without and 23 women with migraine in the interictal phase (mean age 50.8 ± 2.9 years) local thermal hyperemia (LTH) of the skin of the volar forearm was measured cross-sectionally under control conditions, after inhibition of neuropeptide release by 5% lidocaine/prilocaine (EMLA) cream application, and after inhibition of nitric oxide formation by iontophoresis of NG-monomethyl-l-arginine (L-NMMA). Hereafter, changes in the natural logarithm of the reactive hyperemia index (lnRHI) and augmentation index (AI) during reperfusion after occlusion-derived ischemia were measured.
RESULTS
While mean values under control conditions and L-NMMA conditions were similar, migraine patients had a significantly higher mean area of the curve (AUC) of the total LTH response after EMLA application than those without (86.7 ± 26.5% versus 67.9 ± 24.2%; p = 0.014). This was also reflected by a higher median AUC of the plateau phase under similar conditions in women with migraine compared to those without (83.2% (IQR[73.2-109.5]) versus 73.2% (IQR[54.3-92.0]); p = 0.039). Mean changes in lnRHI and AI scores were similar in both groups.
CONCLUSIONS
In PCOS patients with migraine, neuropeptide action was lower compared with those without migraine. While larger studies are warranted, these findings provide a potential mechanism supporting previous findings that migraine may be independent from traditional risk factors, including atherosclerosis.
Topics: Middle Aged; Humans; Female; omega-N-Methylarginine; Polycystic Ovary Syndrome; Vasodilation; Risk Factors; Migraine Disorders
PubMed: 37400308
DOI: 10.1016/j.atherosclerosis.2023.06.078 -
Turk Gogus Kalp Damar Cerrahisi Dergisi Apr 2021In this study, we present our experiences with local injections of triamcinolone and prilocaine in patients diagnosed with Tietze syndrome.
BACKGROUND
In this study, we present our experiences with local injections of triamcinolone and prilocaine in patients diagnosed with Tietze syndrome.
METHODS
Between January 2016 and January 2019, a total of 28 patients (12 males, 16 females; median age: 33 years; range, 21 to 51 years) who were diagnosed with TS in our clinic were retrospectively analyzed. Triamcinolone hexacetonide and prilocaine hydrochloride were injected into painful joints. At first week, pain sensation of the patients was recorded using the Pain Rating Scale developed by the British Pain Society. Pain was also assessed at one, two, and three weeks after injections qualitatively and based on physical examination.
RESULTS
At one week, the pain severity before the local injection treatment was above average the pain-related discomfort rates, and the response was quite favorable after the treatment (p=0.005 and p=0.001, respectively). A statistically significant rating was observed for treatment response and success (p=0.003). Totally 75% of the patients experienced more than 70% reduction in pain level after the injection.
CONCLUSION
Our treatment approach involving injection of a mixture of steroid and a local anesthetic provides a rapid relief from pain, irrespective of age, sex, or employment status in patients diagnosed with Tietze syndrome.
PubMed: 34104518
DOI: 10.5606/tgkdc.dergisi.2021.21120