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European Journal of Pharmaceutical... Jun 2024Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical...
Cutaneous Pharmacokinetics-Based Bioequivalence: A Clinical Dermal Open Flow Microperfusion Verification Study Using Lidocaine and Prilocaine Combination Topical Products.
BACKGROUND
Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical generic products. A clinical dermal open flow microperfusion (dOFM) study has previously demonstrated the BE of topical drug products containing a hydrophilic drug. However, the utility of dOFM to evaluate the topical BE of drug products containing moderately lipophilic drugs, more representative of most topical drugs, has not yet been established.
OBJECTIVE
To evaluate the ability of a clinical dOFM study to assess BE of topical products containing two moderately lipophilic drugs that have only minor differences in chemical and physical properties.
METHODS
The study included 20 healthy subjects. Four application sites on each thigh were treated with fixed dose lidocaine/prilocaine combination products, and dermal drug concentrations were monitored with two dOFM probes per application site for 12 hours. A reference cream was compared to itself and to an approved generic cream (both serving as positive controls for BE), and to a gel (negative control). BE was established based on AUC and C using the scaled-average-BE approach. Systemic exposure of both drugs was assessed throughout the study.
RESULTS
BE was successfully demonstrated for the positive controls, and not for the negative control, for both drugs. The systemic exposure of both drugs was negligible.
CONCLUSIONS
dOFM accurately demonstrated BE between bioequivalent topical creams, sensitively discriminated between different formulations and differentiated the cutaneous PK of both study drugs, even though they differ only slightly in chemical and physical properties. These results support the utility of dOFM as a cutaneous PK BE approach for topical lipophilic drugs, including lidocaine and prilocaine.
PubMed: 38857708
DOI: 10.1016/j.ejps.2024.106827 -
Cureus Apr 2024Introduction The skin, along with its subcutaneous tissue, constitutes one of the major organ systems of the human body. Dermatosurgery is the branch dealing with skin...
Introduction The skin, along with its subcutaneous tissue, constitutes one of the major organ systems of the human body. Dermatosurgery is the branch dealing with skin conditions that operate at the level of skin, without disturbing the of the human organ system. Materials and methods A cross-sectional study was undertaken, which included 100 patients comprised of 50 patients in each group. For group A, the topical anesthetic agent used was a eutectic mixture of topical 2.5% lignocaine and 2.5% prilocaine cream (EMLA); for group B, infiltration anesthesia with 2% lignocaine injection. Patients satisfying the inclusion and exclusion criteria were recruited for the study. All the participants were requested to rate the pain at the time of drug administration, during the dermatosurgical procedure, and post-procedurally with a visual analogue scale (VAS) separately. Results In this study, 50% of the participants were of the age group of 21-40 years. Males constituted 57.8% whereas females constituted 42.2%. The common procedures performed in the study were electrocautery at 37%, intralesional platelet-rich plasma (PRP) at 16%, and intralesional steroid at 7%. In group A, the VAS score during drug administration was 0. In the group B, 70% had a VAS score of 4-6, and 30% had a VAS score of 1-3 pre-procedurally. The mean VAS score during procedure was 3.06 for group A and 1.03 for group B. Conclusion The study inferred that topical anesthesia is a better choice in superficial dermatosurgical procedures for providing adequate anesthesia and improved compliance when compared to infiltrative anesthesia.
PubMed: 38738090
DOI: 10.7759/cureus.57966 -
Medicine May 2024After the success of the enhanced recovery after surgery protocol, perioperative care has been further optimized in accelerated enhanced recovery pathways (ERPs), where... (Comparative Study)
Comparative Study
Hyperbaric bupivacaine versus prilocaine for spinal anesthesia combined with total intravenous anesthesia during oncological colon surgery in a 23-hour stay enhanced recovery protocol: A non-randomized study.
After the success of the enhanced recovery after surgery protocol, perioperative care has been further optimized in accelerated enhanced recovery pathways (ERPs), where optimal pain management is crucial. Spinal anesthesia was introduced as adjunct to general anesthesia to reduce postoperative pain and facilitate mobility. This study aimed to determine which spinal anesthetic agent provides best pain relief in accelerated ERP for colon carcinoma. This single center study was a secondary analysis conducted among patients included in the aCcelerated 23-Hour erAS care for colon surgEry study who underwent elective laparoscopic colon surgery. The first 30 patients included received total intravenous anesthesia combined with spinal anesthesia with prilocaine, the 30 patients subsequently included received spinal anesthesia with hyperbaric bupivacaine. Primary endpoint of this study was the total amount of morphine milligram equivalents (MMEs) administered during hospital stay. Secondary outcomes were amounts of MMEs administered in the recovery room and surgical ward, pain score using the numeric rating scale, complication rates and length of hospital stay. Compared to prilocaine, the total amount of MMEs administered was significantly lower in the bupivacaine group (n = 60, 16.3 vs 6.3, P = .049). Also, the amount of MMEs administered and median pain scores were significantly lower after intrathecal bupivacaine in the recovery room (MMEs 11.0 vs 0.0, P = .012 and numeric rating scale 2.0 vs 1.5, P = .004). On the surgical ward, median MMEs administered, and pain scores were comparable. Postoperative outcomes were similar in both groups. Spinal anesthesia with hyperbaric bupivacaine was associated with less opioid use and better pain reduction immediately after surgery compared to prilocaine within an accelerated ERP for elective, oncological colon surgery.
Topics: Humans; Anesthesia, Spinal; Bupivacaine; Male; Female; Anesthetics, Local; Colonic Neoplasms; Middle Aged; Aged; Enhanced Recovery After Surgery; Prilocaine; Pain, Postoperative; Length of Stay; Anesthesia, Intravenous; Pain Measurement
PubMed: 38728520
DOI: 10.1097/MD.0000000000037957 -
Physical Chemistry Chemical Physics :... May 2024It is generally accepted that water, as an effective plasticizer, decreases the glass transition temperatures (s) of amorphous drugs, potentially resulting in physical...
It is generally accepted that water, as an effective plasticizer, decreases the glass transition temperatures (s) of amorphous drugs, potentially resulting in physical instabilities. However, recent studies suggest that water can also increase the s of the amorphous forms of the drugs prilocaine (PRL) and lidocaine (LID), thus acting as an anti-plasticizer. To further understand the nature of the anti-plasticizing effect of water, interactions with different solvents and the resulting structural features of PRL and LID were investigated by Fourier transform infrared spectroscopy (FTIR) and quantum chemical simulations. Heavy water (deuterium oxides) was chosen as a solvent, as the deuterium and hydrogen atoms are electronically identical. It was found that substituting hydrogen with deuterium showed a minimal impact on the anti-plasticization of water on PRL. Ethanol and ethylene glycol were chosen as solvents to compare the hydrogen bonding patterns occurring between the hydroxyl groups of the solvents and PRL and LID. Comparison of the various s showed a weaker anti-plasticizing potential of these two solvents on PRL and LID. The frequency shifts of the amide CO groups of PRL and LID due to the interactions with water, heavy water, ethanol, and ethylene glycol as observed in the FTIR spectra showed a correlation with the binding energies calculated by quantum chemical simulations. Overall, this study showed that the combination of weak hydrogen bonding and strong electrostatic contributions in hydrated PRL and LID could play an important role in inducing the anti-plasticizing effect of water on those drugs.
PubMed: 38712380
DOI: 10.1039/d4cp00995a -
Genes Mar 2024Autoimmunity is defined as the inability to regulate immunological activities in the body, especially in response to external triggers, leading to the attack of the...
Autoimmunity is defined as the inability to regulate immunological activities in the body, especially in response to external triggers, leading to the attack of the tissues and organs of the host. Outcomes include the onset of autoimmune diseases whose effects are primarily due to dysregulated immune responses. In past years, there have been cases that show an increased susceptibility to other autoimmune disorders in patients who are already experiencing the same type of disease. Research in this field has started analyzing the potential molecular and cellular causes of this interconnectedness, bearing in mind the possibility of advancing drugs and therapies for the treatment of autoimmunity. With that, this study aimed to determine the correlation of four autoimmune diseases, which are type 1 diabetes (T1D), psoriasis (PSR), systemic sclerosis (SSc), and systemic lupus erythematosus (SLE), by identifying highly preserved co-expressed genes among datasets using WGCNA. Functional annotation was then employed to characterize these sets of genes based on their systemic relationship as a whole to elucidate the biological processes, cellular components, and molecular functions of the pathways they are involved in. Lastly, drug repurposing analysis was performed to screen candidate drugs for repositioning that could regulate the abnormal expression of genes among the diseases. A total of thirteen modules were obtained from the analysis, the majority of which were associated with transcriptional, post-transcriptional, and post-translational modification processes. Also, the evaluation based on KEGG suggested the possible role of T differentiation in the simultaneous onset of the four diseases. Furthermore, clomiphene was the top drug candidate for regulating overexpressed hub genes; meanwhile, prilocaine was the top drug for regulating under-expressed hub genes. This study was geared towards utilizing transcriptomics approaches for the assessment of microarray data, which is different from the use of traditional genomic analyses. Such a research design for investigating correlations among autoimmune diseases may be the first of its kind.
Topics: Humans; Signal Transduction; Autoimmune Diseases; Diabetes Mellitus, Type 1; Oligonucleotide Array Sequence Analysis; Gene Regulatory Networks; Immune System; Scleroderma, Systemic; Lupus Erythematosus, Systemic; Psoriasis; Gene Expression Profiling
PubMed: 38674328
DOI: 10.3390/genes15040393 -
Hemodialysis International.... Apr 2024In hemodialysis patients, pain associated with needle insertion into an arteriovenous fistula is a physical and psychological problem. The aim of this study was to...
INTRODUCTION
In hemodialysis patients, pain associated with needle insertion into an arteriovenous fistula is a physical and psychological problem. The aim of this study was to assess the effectiveness of pre-puncture application of an ice pack, EMLA cream, or lidocaine spray to reduce pain associated with access puncture.
METHODS
This was a multicenter study done in nine hemodialysis centers in Iraq. The study utilized a randomized, parallel-group design, in which patients being dialyzed using an arteriovenous access were allocated into one of four groups. Access puncture was preceded by nothing (control group), by use of ice pack cooling at the puncture site, by application of EMLA cream, or by application of lidocaine spray. Pain after access puncture was assessed during a single treatment for each patient. Pain was quantified using a Visual Analogue Scale.
FINDINGS
A total of 1548 patients agreed to participate, and 1041 patients were included in the data analysis. Use of an ice pack, EMLA cream, or lidocaine spray each was associated with a lower pain score on access puncture compared with no pretreatment. The mean Visual Analogue Scores in the four groups were: 69.7 ± 15.7 in the controls, 39.8 ± 13.2 in the ice pack group, 45 ± 18.4 in the EMLA group, and 52.9 ± 15.2 in lidocaine group. Ranking of the pain severity scores suggested that ice pack use was associated with the least pain, followed by use of EMLA cream and use of lidocaine spray (severity score ranking, from lowest to highest, being 1.62, 2.18, and 2.63, respectively).
DISCUSSION
Application of an ice pack prior to vascular access puncture is a fast and inexpensive technique to limit pain associated with this procedure.
PubMed: 38605472
DOI: 10.1111/hdi.13152 -
Cureus Mar 2024Intrauterine devices (IUDs) are considered a reliable contraceptive option for women, but they can come with side effects. There is a disconnect in standard guidelines... (Review)
Review
Intrauterine devices (IUDs) are considered a reliable contraceptive option for women, but they can come with side effects. There is a disconnect in standard guidelines for IUD insertion within and without the U.S. The objective of this review was to address a gap in the literature regarding official procedures for pain management during IUD implantation. This scoping review was initiated using keywords to extract relevant articles from multiple databases: U.S. National Library of Medicine National Institutes of Health (PubMed), MEDLINE (Ovid), and Excerpta Medica dataBASE (EMBASE, Ovid). Initially, 457 articles were identified and after a rigorous screening and selection process, 37 articles were chosen to be further assessed to ascertain if they met the study's inclusion criteria. Those 37 articles were further evaluated fully to check for relevancy. From that process, 19 articles were chosen for the review, and all passed quality assessment evaluations using the JB Appraisal Tools. To best address the research question, the data from the 19 articles were divided into three categories: 1) circumstantial factors, 2) non-pharmacological methods, and 3) pharmacological methods. Circumstantially, women with previous vaginal deliveries experienced the lowest pain during the procedure, and nulligravid (never pregnant) women experienced the most pain. Lower pain scores were reported by lactating women compared to non-lactating. Black women experienced the most anticipated pain compared to other races. Regarding non-pharmacological methods, different insertion techniques, tools, and the use of a cold compress were found to not affect the level of pain during IUD insertion. Lastly, it was shown that pharmacological methods such as lidocaine gel, lidocaine paracervical block, and lidocaine combined with either diclofenac or prilocaine decreased pain scores at different time stamps of the procedure. Also, oral ketorolac and a vaginal combination of misoprostol and dinoprostone helped reduce pain. Findings from this scoping review revealed a lack of uniformity across practices when performing IUD insertions, possibly due to differences in procedures across circumstantial factors, non-pharmacological methods, and pharmacological methods. More research is needed to investigate the intricacies of pain with IUD insertion. Moving forward, especially following a potential increase in the use of IUDs after the reversal of Roe v. Wade, establishing this gap may lead to a more refined standardized protocol to mitigate pain with IUD insertions.
PubMed: 38586685
DOI: 10.7759/cureus.55785 -
Dermatology and Therapy Apr 2024Systemic toxicity of eutectic mixture of local anesthetics (EMLA) cream is rare and is most commonly observed in children, for example, upon extensive application, and...
INTRODUCTION
Systemic toxicity of eutectic mixture of local anesthetics (EMLA) cream is rare and is most commonly observed in children, for example, upon extensive application, and rarely occurs in adults with certain dispositions.
CASE REPORT
We report the case of a 71-year-old man who developed methemoglobinemia and systemic intoxication upon topical application of EMLA cream for leg ulcer and stasis dermatitis prior to surgical debridement. Approximately 45 min after application, the patient was found to be in a somnolent state, was unable to articulate, and showed peripheral cyanosis. The blood concentration of methemoglobin (MetHb) was 15.1%, and therefore, a diagnosis of systemic toxicity of EMLA due to methemoglobinemia was established. After removal of the cream, oxygen was applied, and further observation revealed that the patient's condition rapidly improved without any residue. In the following, we also discuss literature related to systemic EMLA intoxication.
CONCLUSION
EMLA cream may cause severe systemic toxicity even in adults under certain conditions, for example, when applied on damaged skin or in extensive amounts.
PubMed: 38568445
DOI: 10.1007/s13555-024-01139-7 -
Journal of Clinical Medicine Mar 2024: The injection of local anesthetics is the procedure that still causes the most fear and anxiety in a dental session; to minimize this problem, we can use topical...
: The injection of local anesthetics is the procedure that still causes the most fear and anxiety in a dental session; to minimize this problem, we can use topical anesthesia. The aim of this study is to analyze the tolerability and the clinical efficacy in the control of pain, during the subsequent injection of the local anesthetic, of an experimental anesthetic patch with a new formulation, which was previously tested in gel formula. : A total of 150 children, aged 4 to 9 years, were included in the study. Each patient was treated using three different pre-anesthesia methods (placebo gel, experimental gel, and experimental patch), according to a split-mouth procedure, within a week of each other. The injection pain was analyzed using the WBFPRS and FLACC scales. Patients' caregivers' satisfaction was recorded at the end of the procedures. The data were analyzed using one-way ANOVA-RM, Wilcoxon-Mann-Whitney, Mann-Whitney U, and χ tests. : In this study, significantly higher pain ratings were observed with the topical placebo gel and lower pain ratings were observed with the experimental patch. : The use of the patch proved to be very effective in reducing pain both subjectively and objectively, in the absence of both local and systemic side effects, validating its use in the oral mucosa.
PubMed: 38541784
DOI: 10.3390/jcm13061558 -
Regional Anesthesia and Pain Medicine Mar 2024Injecting mixtures of local anesthetics with or without adjuvants is a common practise in regional and particularly obstetric anesthesia to decrease block onset time...
INTRODUCTION
Injecting mixtures of local anesthetics with or without adjuvants is a common practise in regional and particularly obstetric anesthesia to decrease block onset time and/or augment epidural analgesia for cesarean section. While evidence on the efficacy of this practise is equivocal, little is known about its safety in terms of the pharmacologic compatibility of local anesthetics.
METHODS
We assessed the grade of crystallization in individual mixtures of seven local anesthetics (bupivacaine, ropivacaine, lidocaine, procaine, chloroprocaine, mepivacaine, prilocaine) with or without four adjuvants (sodium bicarbonate, dexamethasone, clonidine, fentanyl) using a semiquantitative light microscopy scale (ranging from 0 to 5), repeatedly for up to 60 min and performed correlation analysis between grade of crystallization and initial solution pH.
RESULTS
Of the 50 mixtures tested, 26 showed grades of crystallization ≥4 at admixture and 41 showed grades of crystallization ≥4 after 60 min. The addition of adjuvants to local anesthetic mixtures did not substantially change the grades of crystallization. Bupivacaine has a slightly lower precipitation tendency, compared with ropivacaine. A moderate relationship was found between initial pH and grade of crystallization after 15 min for the adjuvant mixtures (R=0.33, p=0.04), but not at other time points.
DISCUSSION
The preparation of local anesthetic (±adjuvant) mixtures leads to high grades of crystallization, which increase over 60 min and appear independent of solution pH. The risk of mixing medications with unknown physical or chemical compatibility profiles in regional anesthesia should be critically appraised and its clinical significance elucidated in future translational research.
PubMed: 38443138
DOI: 10.1136/rapm-2023-105229