Dosage of Lipid Emulsions as an Antidote to Lipid-Soluble Substances

Introduction: Lipid emulsions are increasingly used as an antidote to lipophilic drug intoxications. The dose recommended by the American Society of Regional Anesthesia is used primarily for the treatment of local anesthetic systemic toxicity. There is insufficient information about what the dose of lipid emulsions (LE) should be in other intoxications depending on their severity. Aim: To determine the LE dose in a shock or haemodynamic instability in patients with acute exogenous intoxications treated with LE. Materials and methods: Forty-nine patients with acute lipophilic drug intoxications were treated with LE in the Clinic of Toxicology at the Naval Hospital in Varna. Statistical analysis was performed using the statistical functions of Excel 2016 and the Statistica 7.0 software package. Results: The percentage of patients receiving a low dose of LE of 0.3 ml/kg (93.87%) was significantly higher than the percentage of patients treated with a medium (2.04%) and a high dose (4.08%) of LF. The high dose of LE of 1.5 ml/kg recommended by the American Society of Regional Anesthesia was administered to two patients (4.08%). In severe intoxications with exotoxic shock, the rate of LE administration varies from 20 ml/h to 40 ml/h. Conclusions: In severe intoxications with cardiotoxic syndrome and haemodynamic instability, LE should be used in the dose as suggested by the American Society of Regional Anesthesia. It is possible to use lower doses of LE in the range of 0.3–0.6 ml/kg in all moderate poisonings administered by continuous intravenous infusion for 12-24-48 hours. No side effects were observed at these doses.

Influence of Massage and Skin Hydration on Dermal Penetration Efficacy of Nile Red from Petroleum Jelly—An Unexpected Outcome

The study aimed at comparing the influence of direct and indirect skin hydration as well as massage on the dermal penetration efficacy of active compounds. Nile red was used as a lipophilic drug surrogate and was incorporated into Vaseline (petroleum jelly). The formulation was applied with and without massage onto either dry skin or pre-hydrated, moist skin. It was expected that the occlusive properties of Vaseline in combination with massage and enhanced skin hydration would cause a superposition of penetration-enhancing effects, which should lead to a tremendous increase in the dermal penetration efficacy of the lipophilic drug surrogate. Results obtained were diametral to the expectations, and various reasons were identified for causing the effect observed. Firstly, it was found that Vaseline undergoes syneresis after topical application. The expulsed mineral oil forms a film on top of the skin, and parts of it penetrate into the skin. The lipophilic drug surrogate, which is dissolved in the mineral oil, enters the skin with the mineral oil, i.e., via a solvent drag mechanism. Secondly, it was found that massage squeezes the skin and causes the expulsion of water from deeper layers of the SC. The expulsed water can act as a water barrier that prevents the penetration of lipophilic compounds and promotes the penetration of hydrophilic compounds. Based on the data, it is concluded that dermal penetration is a complex process that cannot only be explained by Fick’s law. It is composed of at least three different mechanisms. The first mechanism is the penetration of active ingredients with their solvents into the skin (convection, solvent drag), the second mechanism is the penetration of the active ingredient via passive diffusion, and the third mechanism can involve local penetration phenomena, e.g., the formation of liquid menisci and particle-associated penetration enhancement, which occur upon the evaporation of water and/or other ingredients from the formulation on top of the skin.

Acute exposure to extracellular BTP2 does not inhibit Ca2+ release during EC coupling in intact skeletal muscle fibers

The inhibitor of store-operated Ca2+ entry (SOCE) BTP2 was reported to inhibit ryanodine receptor Ca2+ leak and electrically evoked Ca2+ release from the sarcoplasmic reticulum when introduced into mechanically skinned muscle fibers. However, it is unclear how effects of intracellular application of a highly lipophilic drug like BTP2 on Ca2+ release during excitation–contraction (EC) coupling compare with extracellular exposure in intact muscle fibers. Here, we address this question by quantifying the effect of short- and long-term exposure to 10 and 20 µM BTP2 on the magnitude and kinetics of electrically evoked Ca2+ release in intact mouse flexor digitorum brevis muscle fibers. Our results demonstrate that neither the magnitude nor the kinetics of electrically evoked Ca2+ release evoked during repetitive electrical stimulation were altered by brief exposure (2 min) to either BTP2 concentration. However, BTP2 did reduce the magnitude of electrically evoked Ca2+ release in intact fibers when applied extracellularly for a prolonged period of time (30 min at 10 µM or 10 min at 20 µM), consistent with slow diffusion of the lipophilic drug across the plasma membrane. Together, these results indicate that the time course and impact of BTP2 on Ca2+ release during EC coupling in skeletal muscle depends strongly on whether the drug is applied intracellularly or extracellularly. Further, these results demonstrate that electrically evoked Ca2+ release in intact muscle fibers is unaltered by extracellular application of 10 µM BTP2 for <25 min, validating this use to assess the role of SOCE in the absence of an effect on EC coupling.

Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine

As advanced synthetic technology has enabled drug candidate development with complex structure, resulting in low solubility and membrane permeability, the strategies to improve poorly absorbed drug bioavailability have attracted the attention of pharmaceutical companies. It has been demonstrated that nitric oxide (NO), a vital signaling molecule that plays an important role in various physiological systems, affects intestinal drug absorption. However, NO and its oxidants are directly toxic to the gastrointestinal tract, thereby limiting their potential clinical application as absorption enhancers. In this study, we show that sodium nitroprusside (SNP), an FDA-approved vasodilator, enhances the intestinal absorption of lipophilic drugs in the proximal parts of the small intestine in rats. The SNP pretreatment of the rat gastrointestinal sacs significantly increased griseofulvin and flurbiprofen permeation in the duodenum and jejunum but not in the ileum and colon. These SNP-related enhancement effects were attenuated by the co-pretreatment with dithiothreitol or c-PTIO, an NO scavenger. The permeation-enhancing effects were not observed in the case of antipyrine, theophylline, and propranolol in the duodenum and jejunum. Furthermore, the SNP treatment significantly increased acidic glycoprotein release from the mucosal layers specifically in the duodenum and jejunum but not in the ileum and colon. These results suggest that SNP increases lipophilic drug membrane permeability specifically in the proximal region of the small intestine through disruption of the mucosal layer.

Comprehensive Review On Nanomicelles Drug Delivery System

Many novel drug molecules in a clinical study as well as many existing drug molecules are lipophilic or hydrophobic in nature and thus they usually shows low bioavailability, poor absorption properties, low permeation as well as inability to reach at effective therapeutic concentration in blood. To overcome this problem, nanomicelles is the break through drug delivery system in which a lipophilic drug can be incorporated in polymeric micelles or surfactant micelles that can provide high solubility as well as high bioavailability. Due to the fact that Micelles have inner lipophilic core and outer hydrophilic shell as well as the inner lipophilic core provide space for incorporation for lipophilic drug, it enhances permeability of the lipophilic drug even at depth and also at target site. The present article provides overview of various applications of nanomicelles, it’s advantages as well as limitations, methods of preparations and various approaches for applications of nanomicelles.

Oleosome: A novel carrier for drug delivery, its stability issues, probable approaches for their stabilization, and associated Patents in Pharmaceutical Field

: Oleosomes are oil containing micro-carriers of natural origin that is comprised of special Oleosin proteins embedded with a monolayer of phospholipids and having triacylglycerol core. Due to their unique structure and non-toxic to the biological system these oil carriers are becoming very eye-catching in the field of formulation development in the field of pharmacy. Consequently, it offers emoliency, occlusivity, self-emulsification, an antioxidant and film-forming property which leads to controlled and sustained release of encapsulated bio-actives. It is also feasible to load oil-soluble ingredients such as fragrance, vitamins (retinol), and lipophilic drug moieties inside the core. Being a natural carrier, it shows some stability issues (leakage of oil from the core, oxidation of the loaded oil, aggregation of oil droplets) which are controllable. In this review, we have focused on the various stability issues, techniques (coating, surface modification, solvents) to overcome those problems, how to load any lipophilic drug into the oil core, and linked patent research works in the field of formulation development.