High Lipid Solubility Research Articles

Comparison of the Efficacy Between Ultrasound-Guided Paravertebral Block and Erector Spinae Block for Postoperative Analgesia in Percutaneous Nephrolithotomy Using Levobupivacaine: A Prospective and Randomized Study.

Introduction Various techniques have been developed in the current era of regional anesthesia practice. With the advent of ultrasound, the visualization of needle and pleura in real time enables a better outcome with negligible adverse events. This study was designed to compare the efficacy between ultrasound-guided erector spinae plane block (ESPB) and paravertebral block (PVB) in percutaneous nephrolithotomy (PCNL) for the duration of postoperative analgesia with levobupivacaine, a local anesthetic with higher lipid solubility, making it more potent and resulting in a longer duration of action. Methods This prospective randomized single-blinded study enrolled 50 patients of ASA grades I and II, aged between 20 and 60 years, who were scheduled for PCNL under general anesthesia. Patients were divided into two groups of 25 each: group ESPB andgroup PVB, and 25 mL of 0.25% levobupivacaine was administered to both groups. They were primarily evaluated for the duration of postoperative analgesia. Total rescue analgesic requirements, hemodynamic parameters, and any adverse effects were also assessed. Results Both ESPB and PVB provided a significant duration of analgesia postoperatively. Demographic characteristics in both groups were comparable. The duration of postoperative analgesia in group ESPB was 746 ± 58.6 minutes when compared to group PVB, which is 768 ± 68.6 minutes (p = 0.08). Intravenous (IV) paracetamol was used as a rescue analgesic. The doses used were also comparable in both groups, with the visual analog score (VAS) being high after around 12 hours of surgery. The total rescue analgesic requirement was similar in both groups (group ESPB, 2.0 ± 1.6; group PVB, 2.2 ± 1.4; p = 0.51). There were no significant hemodynamic or other adverse effects in either group. Conclusion We conclude that both ESPBand PVB using isobariclevobupivacaine 0.25% as a local anesthetic are equally efficacious in providing effective postoperative analgesia in patients undergoing PCNL under generalanesthesia.

A ginsenoside G-Rg3 PEGylated long-circulating liposome for hyperglycemia and insulin resistance therapy in streptozotocin-induced type 2 diabetes mice

Ginsenoside (GS), one of the main active components in ginseng, can enhance insulin sensitivity, improve the function of islet β cells, and reduce cell apoptosis in the treatment of diabetes. However, the drawbacks of high lipid solubility, poor water solubility, and low oral availability in Ginsenoside Rg3 (G-Rg3) seriously limit further application of GS. In this work, a G-Rg3 PEGylated long-circulating liposome (PEG-L-Rg3) is designed and developed to improve symptoms in type 2 diabetic mice. The as-prepared PEG-L-Rg3 with a spherical structure shows a particle size of ∼ 140.5 ± 1.4 nm, the zeta potential of −0.10 ± 0.05 mV, and a high encapsulation rate of 99.8 %. Notably, in vivo experimental results demonstrate that PEG-L-Rg3 exhibits efficient ability to improve body weight and food intake in streptozotocin-induced type 2 diabetic mice. Moreover, PEG-L-Rg3 also enhances fasting insulin (FINS) and insulin sensitivity index (ISI). In addition, the glucose tolerance of mice is significantly improved after the treatment of PEG-L-Rg3, indicating that PEG-L-Rg3 can be a potential drug for the treatment of type 2 diabetes, which provides a new way for the treatment of type 2 diabetes using ginsenosides.

Human breast milk-derived phospholipid DOPE ameliorates intestinal injury associated with NEC by inhibiting ferroptosis.

Neonatal necrotizing enterocolitis (NEC) is a severe inflammatory bowel disease that commonly affects premature infants. Breastfeeding has been proven to be one of the most effective methods for preventing NEC. However, the specific role of lipids, the second major nutrient category in human breast milk (HBM), in intestinal development remains unclear. Our preliminary lipidomic analysis of the HBM lipidome revealed that dioleoyl phosphatidylethanolamine (DOPE) is not only abundant but also shows high solubility in lipids, endowing it with significant biological utility. Experimental results confirmed that DOPE significantly reduces the mortality of neonatal rats, ameliorates impairment of intestinal barrier function, and alleviates the expression of intestinal inflammatory factors IL-1β and IL-6. Furthermore, DOPE promotes the migration and proliferation of intestinal epithelial cells, thereby enhancing the integrity of the intestinal barrier function in vitro. The progression of NEC is linked with the onset of ferroptosis. Our cellular-level analysis of lipid peroxide and iron ion concentrations revealed that DOPE significantly reduces the indicators of ferroptosis, while also modulating the expression of pivotal ferroptosis-associated factors, including SLC7A11, GPX4, and ACSL4. Hence, this research on DOPE is expected to provide novel insights into the bioactive lipids present in HBM.

Druggable genomic landscapes of high-grade gliomas.

Despite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging. Using glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug's clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50). Among 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs' half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively). While multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.

Lycopene-Loaded Solid Lipid Nanoparticles: Preparation, Characterization, ROS-Scavenging, and In vitro Anti-Melanogenesis Evaluations

Background: Lycopene, a natural antioxidant from carotenoids, is produced by plants and microorganisms. It has been investigated in many studies in relation with potential health effects. Objective: Due to the high lipid-solubility of lycopene, its skin penetration is challenged. Therefore, in the present study, lycopene was loaded into lipid nanoparticles to improve penetration and pharmacological properties. Methods: Solid lipid nanoparticles (SLNs) containing lycopene were prepared and anti-tyrosinase properties were studied in the present study. The formulation was investigated in terms of drug release and antityrosinase properties. Determination of encapsulation efficiency was performed directly. Electron microscopy was used to examine the shape of the nanoparticles. Subsequently, the rate of drug release was investigated by the cell diffusion method. The present study applied cytotoxicity tests, cellular tyrosinase inhibition, melanin content, and free radical level to evaluate the effect of formulations on melanogenesis inhibition, and western blot assay was used to determine tyrosinase and MITF levels. Results: The results from particle size investigation for LYC-SLNs were 151.1 ± 2.3, and exploring the data of electron microscopy showed that the shapes of nanoparticles were spherical, and the encapsulation efficiency was 85.76 ± 2.75%. In determining the anti-tyrosinase effects of LYC-SLNs, a significant reduction in cellular tyrosinase activity and melanin and ROS levels were observed; It is also worth noting that LYC-SLNs reduced melanin production with minimal toxicity against melanoma cells. Conclusion: In general, the results confirm that SLNs can be an efficient delivery platform for the topical delivery of lycopene as a natural anti-oxidant and anti-melanogenic agent.

The effect of intravenous lipid emulsion (ILE) on the pharmacokinetic/toxicokinetic dispositions of ivermectin and carprofen in rabbits.

Intravenous lipid emulsion (ILE) has been widely used as an effective antidote in both veterinary and human medicine for the treatment of acute intoxications caused by drugs and pesticides with high lipid solubility. This study was conducted to investigate the effect of ILE co-administration on the kinetic dispositions of ivermectin (IVM) and carprofen (CRP) following intravenous bolus administration at subtoxic doses in rabbits.Twenty-four male New Zealand rabbits weighing 2.78 ± 0.2kg were used in this study. Rabbits were divided into four groups (Group 1: IVM and Group 2: IVM + ILE or Group 3: CRP and Group 4: CRP + ILE), each group consisting of 6 animals. In the IVM study, Group 1 received IVM (0.6mg/kg) alone while Group 2 received IVM (0.6mg/kg) and ILE (2.5ml/kg). In the CRP study, Group 3 received CRP (12mg/kg) alone while Group 4 received CRP (12mg/kg) and ILE (2.5ml/kg). In both drug groups, ILE was administered 3 times as an i.v. bolus at the 10th min and repeated 4th and 8th h after the drug administration. Blood samples were collected from the auricular vein at various times after drug administration. The drug concentrations in plasma samples were determined by high-pressure liquid chromatography. Kinetic parameters were calculated using a non-compartmental model for both CRP and IVM.The C0 and area under the concentration-time curve from zero up to ∞ (AUC0-∞) values were significantly greater with ILE co-administration (2136ng/ml and 360.84ng.d/ml) compared to the IVM alone (1340.63ng/ml and 206ng.d/ml), respectively. Moreover, the volume of distribution (Vdss) and clearance (Cl) of IVM were reduced by approximately 42% and 46% with ILE co-administration compared to IVM alone resulting in a reduction of the distribution and slower elimination, respectively. Similar differences in C0, and Vdss values were also observed in CRP with ILE co-administration compared to CRP alone. ILE co-administration changed significantly the kinetic profile of both IVM and CRP in rabbits, supporting the lipid sink theory in which highly lipid-soluble compounds are absorbed into the lipid phase of plasma from peripheral organs such as the heart and brain affected by the acute toxicity of the compounds.

Development, Characterization and Evaluation of Phytosomal Gel of Curcumin for the Treatment of Topical Fungal Infection

An innovative approach to the delivery of phytoconstituents and plant extracts for therapeutic and cosmetic purposes constitutes a herbal medication delivery system. However, their bioavailability is low because of their high molecular size and low lipid solubility. Turmeric (Curcuma longa) and Curcuma xanthorrhiza oil contain the active component curcumin, also known as diferuloylmethane. This medication can kill or inhibit the growth of bacteria, fungi, viruses, and fungi, and it can reduce inflammation, lower blood sugar, and speed the healing of wounds. In this study, we created a phytosomal gel containing Curcumin and analyzed its efficacy. Anti-solvent precipitation was used to create Curcumin phytosomes in three separate batches with varying drug-to-soya lecithin ratios. Several tests, including those of yield, solubility, drug content, entrapment efficiency, and in vitro drug release, were conducted on phytosomal formulations. Based on a number of evaluation criteria, the formulation F1 was chosen as the optimal formulation to include into a gel basis of varying proportions utilizing carbopol 940 and PEG400 as polymers. This formulation contained drug extract: soya lecithin in the ratio 1:1. Maximum drug absorption (98.19%) was observed after 8 hours in the improved formulation (G2). 45 days of stability testing was conducted at 40oC ±20oC, 70±5%.RH The drug's potency, pH, dispersibility, extrudability, viscosity, or in-vitro diffusion profile all remained unchanged. The Curcumin phytosomal gel was found to have a superior diffusion and stability profile, making it an appealing vehicle for the delivery of the various phytoconstituents.

Efficacy of brivacetam as an anti-epileptic in patients with epilepsy, with special reference to previous exposure to levetiractam

Brivaracetam (BRV) is a new antiepileptic drug (AED) approved for adjunctive treatment of focal (partial-onset) seizures in adults. It is a selective, high-affinity ligand for synaptic vesicle 2A (SV2A) with much higher affinity than Levetiracetam (LEV). It has a high lipid solubility and rapid brain penetration, and has been shown to have potent broad-spectrum antiepileptic activity in animal models. The aim of the study was to evaluate the efficacy and tolerability of BRV in everyday clinical practice. This observational study included 35 participants, suffering from different types of epilepsy. Patients were observed over a period of 1 year and data was collected using an interview design model. After the initial interview, a final interview took place after 1 year. Various parameters studied included demographic parameters, seizure frequency and duration, any side effects such as behavioral issues. This study included total 35 patients. The mean age of the participants was 33 years (range 3 – 90 years). Approximately 63% patients demonstrated a decrease in seizure frequency after switching to Brivacetam. Out of these patients, 76% patients were those patients, who were earlier treated with Levetiracetam, and it was discontinued either due to inadequate control of seizures or prominent side-effects. Brivaracetam also improved emotional balance in the treated patients (treatment naïve or Levetiracteam associated behavioral issues).Brivaracetam seems to be an effective and safe antiepileptic drug in the routine clinical setting.

Preclinical pharmacokinetics of a promising antineoplastic prototype piperazine-containing compound (LQFM018) in rats by a new LC-MS/MS bioanalytical method

LQFM018 is a novel antineoplastic prototype, showing an expressive drug-triggered K562 leukemic cells death mechanism, through necroptotic signaling. Due to its promising effect, this study aimed to evaluate the pharmacokinetics of LQFM018 in rats, using a new validated bioanalytical LC-MS/MS-based method. Chromatographic column was an ACE® C18 (100 mm × 4.6 mm, 5 µm) eluted by a mobile phase composed of ammonium acetate 2 mM and formic acid 0.025%:methanol (50:50, v/v), under flow of 1.2 mL/min and injection volume of 3.0 µL. LQFM018 was extracted from rat plasma by a simple liquid–liquid method, using MTBE solvent. Rats were administered intraperitoneally at LQFM018 100 mg/kg dose and blood samples were collect at times of 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9 h. Bioanalytical-LC-MS/MS-based method was rapid, high throughput and sensitive with a good linearity ranging from 10 (LLOQ) to 15000 ng/mL, besides precise and accurate, ranging of 0.8–7.3% and 96.8–107.6%, respectively. The prototype LQFM018 was rapid and well absorbed, and highly distributed, apparently due to its high lipid solubility. These features are primordial for an anticancer agent in the treatment of deep tumors, such as bone marrow neoplasms, in which the drug might permeate easily tissue barriers. Also, LQFM018 has demonstrated a high clearance, according to a low t1/2in rats, indicating a relative fast elimination phase related to a possible intense hepatic biotransformation. These information support further studies to establish new understands on pharmacokinetics of promising antineoplastic prototype LQFM018 from preclinical and clinical evaluations.

ASSESSMENT OF EFFICACY OF PRE-OPERATIVE TRANSDERMAL FENTANYL PATCH IN POST -OPERATIVE ANALGESIA IN PATIENTS UNDERGOING ABDOMINAL SURGERIES UNDER GENERALANAESTHESIA – A PROSPECTIVE RANDOMISED CONTROLLED STUDY

Abdominal surgeries done under general anaesthesia is associated with severe pain in the post-operative period. There are many drugs that can be administered to alleviate post-operative pain. Opioids are an essential to the mitigation of visceral pain associated with abdominal surgeries. Apart from needles and epidural catheters which are invasive, transdermal drug delivery systems are novel, non-invasive, and is associated with increased patient comfort. Among drugs that can be delivered by transdermal route fentanyl is an effective opioid analgesic that has a high potency and high lipid solubility making it suitable for transdermal delivery1. This study attempts at the evaluation of the analgesic efcacy of fentanyl patch applied pre-operatively in alleviation of post-operative pain in patients undergoing abdominal surgeries under general anaesthesia

Transdermal opioids for acute postoperative pain: A road less travelled!

Dear Editor, Transdermal delivery system (TDS) is a simple, reliable, noninvasive analgesic delivery method that has been used extensively for chronic pain management. After application, drug in TDS forms a depot in the upper layers of skin that slowly increases serum concentration.[4] Both fentanyl and buprenorphine have high lipid solubility and low molecular weight which makes them ideal candidates for a TDS. The perceived advantages of TDS for acute postoperative pain include sustained blood level of the drug and reduced side effects. Transdermal buprenorphine (TDB) provides convenient once-weekly dosing, has ceiling effect for respiratory, lower abuse potential, and does not require dose alterations patients with renal dysfunction, unlike fentanyl (full μ-opioid receptor agonist).[1] Khandelwal et al. compared two doses of buprenorphine (10 μgh-1 and 20 μgh-1) with fentanyl (25 μgh-1) in adult patients undergoing lower limb arthroscopic surgery.[2] They found TDB patch (20 μgh-1) to be an effective postoperative analgesic without any significant undesirable effects. The concentration of TDS drugs tends to be higher in the first 24 h and several factors like variability in body temperature, factors that increase cutaneous blood flow (warming blanket, sepsis or regional anesthesia), previous opioid use, hemodynamics, and patient’s general condition may make TDS opioid absorption unpredictable.[3] There have been reports of serious, life-threatening respiratory depression and death following transdermal fentanyl.[4] Buprenorphine is 60 times while fentanyl is 100 times as potent as morphine and the duration of action for fentanyl (3d) and TBD (7d) is different. So, equianalgesic doses of both[ratio 3:5]should be compared but the authors in the study have used a non-equianalgesic dosage (10:25 and 20:25). The peak effect comes in 12 h (fentanyl) to 24 h (buprenorphine). So, the patches are generally applied a day before surgery, but this may not be the ideal scenario in daycare settings. Alternative analgesics should be started till the effect of TDS drugs comes in 12–24 h, whereas in the index study, the usual analgesics were withheld the day before surgery when the patches were applied.[2] Many dose formulations are available and according to recommendations from the manufacturer, opioid-naive patients should initially receive the lowest strength patch.[5] Authors of present study evaluating the use of TDS in postoperative pain management concluded that further prospective randomized studies are required to conclusively find the optimum dose.[2] TDS are amenable to abuse, serious side effects like respiratory depression, and cognitive dysfunction, may increase duration of hospital stay and overall cost of daycare procedures. Despite their success for chronic pain management, TDS opioids for acute postoperative pain is a new and off-label use and should be undertaken if the benefits outweigh the risks involved. The main rebuke for TDS is its lack of titrability, long latency for onset, and slow offset making it an inferior alternative compared to other commonly used modes of analgesic delivery such as patient-controlled analgesia. Moreover, they are an expensive alternative to parenteral and oral drugs and may not be ideal in our setting. Hence, we would urge caution in the indiscriminate usage of TDS as a sole modality of postoperative analgesia until further robust evidence proves the contrary. Whenever chosen, they should be used in monitored settings for opioid naïve patients. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

P17.04.B Combination of Trofosfamide and Etoposide in Recurrent Glioma

Abstract Background Disease relapse almost inevitably occurs in patients with adult-type diffuse glioma. Standard of care treatment options at tumor relapse are still not well defined. Frequently used drugs for adult-type diffuse glioma recurrence include lomustine (CCNU) and bevacizumab. Few studies indicate that the combination of trofosfamide/etoposide, given their high lipid solubility with good blood-brain barrier penetrance, may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide/etoposide treatment at disease recurrence of patients with adult-type diffuse glioma. Material and Methods We collected clinicopathological data from adult patients with adult-type diffuse glioma treated with the combination of trofosfamide/etoposide at the Division of Clinical Neurooncology at the University Hospital Essen. Only those patients were considered eligible who received trofosfamide/etoposide treatment for more than four weeks (one course). Trofosfamide (100mg/m2/day) and Etoposide (25mg/m2/day) was administered orally in a “one week on, one week off” scheme. A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors (number of previous treatments, MGMT promoter methylation, IDH mutation status, KPS, age, extent of resection) served as control. We collected toxicity data as it pertained to CTCAE (Common Terminology Criteria for Adverse Events, version 5.0) and survival data to explore putative efficacy. Results A total of 33 patients were eligible for this analysis. In the IDH wild-type glioblastoma (n=18) subgroup, median progression-free survival (3.8 months versus 2.9 months, HR: 2.09, 95% CI: 1.010-4.312, p=0.0227; PFS-6: 39% versus 6%) and median overall survival (10.4 months versus 5.7 months, HR: 3.05, 95% CI: 1.393-6.655, p=0.0008) were significantly prolonged as compared to the control cohort. In a multivariable Cox regression analysis, treatment with trofosfamide/etoposide emerged as statistically significant prognostic marker regarding progression-free survival and overall survival. We observed high-grade adverse events (CTCAE grade≥III ) in 21 (64%) of all recurrent glioma patients with hematotoxicity comprising most adverse events (n=18, 86%). Lymphopenia was by far the most observed hematotoxic adverse event (n=13, 62%). Among non-hematologic high-grade adverse events was transaminase elevation (n=3, 14%). Conclusion This study provides first indication that the combination of trofosfamide/etoposide is safe in patients with adult-type diffuse gliomas and may be associated with prolonged survival in adult patients with recurrent IDH wildtype glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.

Molecular dynamics simulation of α‐gliadin in ethanol/aqueous organic solvents

SummaryGliadin is an important protein present in cereals. Owing to its solubility in alcohol, gliadin contributes significantly to the field of food industry. However, at present, it is challenging to study the structural characteristics of gliadin at the molecular level because the exact 3‐D structure cannot be obtained using experimental methods. In this study, an α‐gliadin model was constructed by combining homology modelling, ab initio modelling, and threading methods to study the structural properties of gliadin in ethanol aqueous solution. Our results indicated that glutamine is a key element of α‐gliadin. Also, α‐gliadin exhibited relatively low hydrophilicity and high lipid solubility. Molecular dynamics simulations suggested that there are hydrogen bonds and van der Waals forces existed between α‐gliadin and ethanol molecules. This study has explored the structure of wheat gliadin and its conformation in different ethanol solutions and provides a deeper understanding towards the deacetylation mechanism and potential applications of α‐gliadin in the food industry.

A Case of High Dose Metoprolol Poisoning; Case Report and Literature Review

β-Blockers are prescribed by physicians for many medical reasons (hypertension, long-term prophylaxis of angina pectoris, myocardial infarction, stable heart failure treatment, cardiac arrhythmias, etc.). Although cases of β-blocker poisoning have a low rate of 0.9% among all poisoning cases, they have a high mortality rate. In β-blocker poisoning with high lipid solubility; seizures, respiratory depression, coma, resistant bradycardia-hypotension and shock may occur. Metoprolol, a type of β-blocker, is a selective β1-adrenoceptor antagonist with sympathomimetic effect. It is also reported that metoprolol is the 2nd most commonly prescribed β-blocker after bisoprolol all over the world. This article aims to present a case who took high-dose metoprolol for suicidal purposes and to examine metoprolol poisoning and its treatment in the light of current literature.

Discovery of metal-based complexes as promising antimicrobial agents.

The antimicrobial resistance (AMR) is an intractable problem for the world. Metal ions are essential for the cell process and biological function in microorganisms. Many metal-based complexes with the potential for releasing ions are more likely to be absorbed for their higher lipid solubility. Hence, this review highlights the clinical potential of organometallic compounds for the treatment of infections caused by bacteria or fungi in recent five years. The common scaffolds, including antimicrobial peptides, N-heterocyclic carbenes, Schiff bases, photosensitive-grand-cycle skeleton structures, aliphatic amines-based ligands, and special metal-based complexes are summarized here. We also discuss their therapeutic targets and the risks that should be paid attention to in the future studies, aiming to provide information for researchers on metal-based complexes as antimicrobial agents and inspire the design and synthesis of new antimicrobial drugs.

In Vitro Human Skin Absorption of Solvent-deposited Solids: Niacinamide and Methyl Nicotinate

A quantitative understanding of the dose dependence of topical delivery is important to cosmetic and dermatological product development and to risk assessment for hazardous chemicals contacting the skin. Despite considerable research, predictive capability in this area remains limited. To this end we conducted an experimental skin absorption study of two closely related skin care agents, niacinamide (nicotinamide, NA) and methyl nicotinate (MN), and analyzed the results quantitatively using a transient diffusion model described separately (Yu et al. submitted for publication). Radiolabeled test compounds were solvent-deposited onto ex vivo human skin mounted in Franz diffusion cells over a dose range exceeding 4.5 orders of magnitude, and permeation was measured over a 1-4 day period. At low doses, the permeation rate of NA was approximately 60-fold lower than that of its lower melting, more lipophilic analog, MN; at high doses an even greater difference was observed. The difference can be qualitatively explained based on higher lipid solubility and lower crystallinity of MN relative to NA. Dissolution-limited mass transfer through a lipid layer at the SC surface is suggested. Relevance of the results to practical skin care formulations was confirmed by a parallel study of NA in an o/w emulsion.

β-adrenoceptor antagonists and nightmares: A pharmacoepidemiological-pharmacodynamic study.

To compare different β-adrenoceptor antagonists for the risk of reporting nightmare. The study involved two approaches: first, we investigated in VigiBase®, the World Health Organization Individual Case Safety Report (ICSR) database, the disproportionality between exposure to each β-adrenoceptor antagonists and reports of nightmares between 1967 and 2019. Second, in a pharmacoepidemiological-pharmacodynamic analysis, we assessed whether use of β-adrenoceptor antagonists with moderate and high lipid solubility or strong 5-HT1A affinity were associated with an increased risk of reporting nightmares. We conducted multivariate logistic regression to estimate reporting odds ratios (RORs) of nightmares compared to all other adverse drug reactions. Of the 126,964 reports recorded with β-adrenoceptor antagonists, 1138 (0.9%) were nightmares. The highest risk of reporting a nightmare was found with exposure of pindolol (adjusted ROR 2.82, 95%CI, 2.19-3.61), metoprolol (1.89, 1.66-2.16), and alprenolol (1.77, 1.06-2.97). Compared to use of low lipid solubility β-adrenoceptor antagonists, use of moderate or high lipid solubility β-adrenoceptor antagonists were significantly more associated with nightmare reports (aROR moderate vs. low 1.72, 95%CI 1.47-2.00 and aROR high vs. low 1.84, 95%CI 1.53-2.22). Use of moderate or high 5-HT1A affinity of β-adrenoceptor antagonists was associated with an increased ROR of nightmares compared with low 5-HT1A affinity of β-adrenoceptor antagonists (aROR moderate vs. low 1.22, 95%CI 1.04-1.43 and aROR high vs. low 2.46, 95%CI 1.93-3.13). In our large pharmacovigilance study, nightmares are more frequently reported for pindolol and metoprolol, and among β-adrenoceptor antagonists with high lipid solubility and high 5-HT1A receptor affinity.

Novel Facet of an Old Dietary Molecule? Direct Influence of Caffeine on Glucose and Biogenic Amine Handling by Human Adipocytes.

Caffeine is a plant alkaloid present in food and beverages consumed worldwide. It has high lipid solubility with recognized actions in the central nervous system and in peripheral tissues, notably the adipose depots. However, the literature is scant regarding caffeine’s influence on adipocyte functions other than lipolysis, such as glucose incorporation into lipids (lipogenesis) and amine oxidation. The objective of this study was to explore the direct effects of caffeine and of isobutylmethylxanthine (IBMX) on these adipocyte functions. Glucose transport into fat cells freshly isolated from mice, rats, or humans was monitored by determining [3H]-2-deoxyglucose (2-DG) uptake, while the incorporation of radiolabeled glucose into cell lipids was used as an index of lipogenic activity. Oxidation of benzylamine by primary amine oxidase (PrAO) was inhibited by increasing doses of caffeine in human adipose tissue preparations with an inhibition constant (Ki) in the millimolar range. Caffeine inhibited basal and insulin-stimulated glucose transport as well as lipogenesis in rodent adipose cells. The antilipogenic action of caffeine was also observed in adipocytes from mice genetically invalidated for PrAO activity, indicating that PrAO activity was not required for lipogenesis inhibition. These caffeine inhibitory properties were extended to human adipocytes: relative to basal 2-DG uptake, set at 1.0 ± 0.2 for 6 individuals, 0.1 mM caffeine tended to reduce uptake to 0.83 ± 0.08. Insulin increased uptake by 3.86 ± 1.11 fold when tested alone at 100 nM, and by 3.21 ± 0.80 when combined with caffeine. Our results reinforce the recommendation of caffeine’s potential in the treatment or prevention of obesity complications.

The ability of fentanyls and other opioids to increase EMG amplitude in respiratory muscles correlates with their agonist efficacy

Acute overdose deaths involving fentanyls have been dramatically increasing in the USA since 2013. These potent opioids depress respiratory drive and produce rigidity in the intercostal muscles and diaphragm (resulting in what is referred to as Wooden Chest Syndrome) as well as in glottic and supraglottic muscles which further reduces the ability to breathe. In this study we have sought to characterise the ability of various opioid agonists to induce respiratory muscle rigidity using electromyographic (EMG) recording. EMG amplitude was recorded simultaneously from diaphragm, external and internal intercostal muscles of P21 male Wistar rats, using an in situ decerebrated and arterially perfused preparation. First, the effects of fentanyl and morphine on respiratory muscle EMG were studied using a dose of each agonist that depressed respiratory rate by approximately 40%. Fentanyl produced a marked increase in EMG amplitude during expiration in all three respiratory muscles whereas the effect of morphine was very slight. In order to understand whether the difference between fentanyl and morphine related to differences in chemical structure, lipid solubility or agonist intrinsic efficacy we studied the effects of a range of opioids that differed in these characteristics – carfentanil and fentanyl (piperidine derivatives, high lipid solubility, high efficacy), alfentanil (piperidine derivative, moderate lipid solubility, high efficacy) norbuprenorphine (thebaine derivative, high lipid solubility, high efficacy), levorphanol (morphinan, high lipid solubility, low efficacy), morphine and hydromorphone (morphine derivatives, low lipid solubility, low efficacy). With doses of each that produced around 40% depression of respiratory rate we observed that the rank order of ability to increase internal and external intercostal muscle EMG amplitude was carfentanil = fentanyl = norbuprenorphine > alfentanil = hydromorphone > morphine = levorphanol but for the diaphragm the rank order was fentanyl > alfentanil = norbuprenorphine ≥ hydromorphone > carfentanil ≥ morphine = levorphanol. These results suggest that the ability of opioid agonists to increase respiratory muscle EMG amplitude and therefore respiratory muscle rigidity does not depend solely on either chemical structure or lipid solubility of the agonist. For the intercostal muscles there is a better correlation with agonist efficacy. Why the effect of carfentanil on the diaphragm is weak remains to be elucidated.

Comparison of Transdermal Fentanyl Patch and Intravenous Fentanyl for Postoperative pain relief in patients undergoing major abdominal surgeries under general Anaesthesia

Pain is a common feature for many disease processes which has association with actual or impending tissue damage. Acute postoperative pain, moderate-to-severe is still a problem, despite the progress in pain management. New technologies in pain management are being used as alternatives to IV routes because of its limitations. The transdermal route is a novel system which uses iontophoresis for the drug delivery directly via the skin by a low-intensity electrical field. Among opioids, fentanyl is the most common and because of its low molecular weight, smaller structure, high lipid solubility and high analgesic potency it could be a good choice for transdermal use. Objectives: The primary objective of this study is to evaluate the efficacy of fentanyl dermal patch with intravenous fentanyl for postoperative analgesia in major abdominal surgeries under general anaesthesia. The secondary objective is to assess the side effects associated with transdermal fentanyl patch. Methods: 50 patients of ASA I and II posted for elective abdominal surgeries, randomly allocated into two groups, IV group (n=25), received intravenous fentanyl and TFP group (n=25), receiving 25mcg/hr Duragesic patch applied on upper arm 10 hours before the surgery and were monitored for pain by VAS scale and for side effects i.e, respiratory depression, pruiritis, nausea and vomiting. The patients received inj. Paracetamol 1gm as rescue analgesia when the VAS score> 5. The pain scores, time for rescue analgesia, the complications were noted and analysed by using Windows SPSS 17 version. Results: Pain intensity scores showed a statistically significant difference between the two groups, with VAS score lower in TFP (3.80±0.12) when compared to I.V (4.67±1.18). The mean time interval for the first rescue analgesia was significantly greater in TFP (345.50±33.34) than in I.V (58.10±12.88). The side effects i.e, respiratory depression, pruritis, nausea and vomiting were significantly lower with TFP. Conclusion: Transdermal patch of fentanyl of 25 microgram/hour put 10hours prior to surgery provides an effective, safe and non-invasive method of postoperative pain relief after major abdominal surgery.