Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans

Background: Ketamine is rapidly metabolized to norketamine and hydroxynorketamine (HNK) metabolites. In female mice, when compared to males, higher levels of ( 2R,6R;2S,6S)-HNK have been observed following ketamine treatment, and higher levels of ( 2R,6R)-HNK following the direct administration of ( 2R,6R)-HNK. Aim: The objective of this study was to evaluate the impact of sex in humans and mice, and gonadal hormones in mice on the metabolism of ketamine to form norketamine and HNKs and in the metabolism/elimination of ( 2R,6R)-HNK. Methods: In CD-1 mice, we utilized gonadectomy to evaluate the role of circulating gonadal hormones in mediating sex-dependent differences in ketamine and ( 2R,6R)-HNK metabolism. In humans (34 with treatment-resistant depression and 23 healthy controls) receiving an antidepressant dose of ketamine (0.5 mg/kg i.v. infusion over 40 min), we evaluated plasma levels of ketamine, norketamine, and HNKs. Results: In humans, plasma levels of ketamine and norketamine were higher in males than females, while ( 2R,6R;2S,6S)-HNK levels were not different. Following ketamine administration to mice (10 mg/kg i.p.), Cmax and total plasma concentrations of ketamine and norketamine were higher, and those of ( 2R,6R;2S,6S)-HNK were lower, in intact males compared to females. Direct ( 2R,6R)-HNK administration (10 mg/kg i.p.) resulted in higher levels of ( 2R,6R)-HNK in female mice. Ovariectomy did not alter ketamine metabolism in female mice, whereas orchidectomy recapitulated female pharmacokinetic differences in male mice, which was reversed with testosterone replacement. Conclusion: Sex is an important biological variable that influences the metabolism of ketamine and the HNKs, which may contribute to sex differences in therapeutic antidepressant efficacy or side effects.

Application of science and technology for farmer groups facing the cabbage caterpillar explosion in The Village of Sembalun Lawang, East Lombok Regency.

The implementation of science and technology for community (IbM) farmer groups who are facing the problem of the cabbage caterpillar population explosion was carried out in Sembalun Lawang Village, East Lombok Regency. The IbM activity was designed based on the agreement between the IbM team and the Village Head of Sembalun Lawang together with the Sangka Bira Farmers Group and the Sebun Kedit Farmers Group in Sembalun Lawang Village. IbM activities are carried out with the stages of socialization, practice, and tutorials with various media used including blackboards, LCDs, manuals (leflet), seeds, saplings, specimens, and leaf dry powder of jayanti plants (S. sesban). Partners also provide media for this IbM activity, which includes cabbage plantations and water facilities. The results achieved at this stage are that farmers in Sembalun Lawang Village recognize jayanti plants as a source of natural insecticides, are skilled at drying leaves properly and making leaf solutions from Jayanti plants and trying to apply them as natural insecticides to control cabbage caterpillars on cabbage plants. The results of trials by farmers showed that direct administration of 50 ppm Jayanti leaf solution could kill 52 to 56% of cabbage caterpillars on cabbage plants. If the Jayanti leaf solution was stored for the previous 24 hours, then 50 ppm of the solution could only kill 15 to 16% of cabbage caterpillars. After participating in this IbM activity, the farmers were also able to identify the type of parasitoid insect, Diadegma semiclausum, which can control the cabbage caterpillar population. The outputs of this IbM activity include 1) Farmer's Guide Book (leflet) Making and Application of Insecticides from Jayanti Plants for Integrated Control of Cabbage Caterpillars, 2) IbM results publication at national seminars (poster presenter certificate), and 3) Publication of IbM results in national scientific journal (submitted). The next stage to be carried out is to monitor and continue the mentoring (tutorial) by the team to IbM participants in the implementation of Jayanti plant cultivation and the manufacture and use of Jayanti insecticide in controlling cabbage caterpillars on cabbage plantations in Sembalun Lawang Village, East Lombok Regency.The implementation of science and technology for community (IbM) farmer groups who are facing the problem of the cabbage caterpillar population explosion was carried out in Sembalun Lawang Village, East Lombok Regency. The IbM activity was designed based on the agreement between the IbM team and the Village Head of Sembalun Lawang together with the Sangka Bira Farmers Group and the Sebun Kedit Farmers Group in Sembalun Lawang Village. IbM activities are carried out with the stages of socialization, practice, and tutorials with various media used including blackboards, LCDs, manuals (leflet), seeds, saplings, specimens, and leaf dry powder of jayanti plants (S. sesban). Partners also provide media for this IbM activity, which includes cabbage plantations and water facilities. The results achieved at this stage are that farmers in Sembalun Lawang Village recognize jayanti plants as a source of natural insecticides, are skilled at drying leaves properly and making leaf solutions from Jayanti plants and trying to apply them as natural insecticides to control cabbage caterpillars on cabbage plants. The results of trials by farmers showed that direct administration of 50 ppm Jayanti leaf solution could kill 52 to 56% of cabbage caterpillars on cabbage plants. If the Jayanti leaf solution was stored for the previous 24 hours, then 50 ppm of the solution could only kill 15 to 16% of cabbage caterpillars. After participating in this IbM activity, the farmers were also able to identify the type of parasitoid insect, Diadegma semiclausum, which can control the cabbage caterpillar population. The outputs of this IbM activity include 1) Farmer's Guide Book (leflet) Making and Application of Insecticides from Jayanti Plants for Integrated Control of Cabbage Caterpillars, 2) IbM results publication at national seminars (poster presenter certificate), and 3) Publication of IbM results in national scientific journal (submitted). The next stage to be carried out is to monitor and continue the mentoring (tutorial) by the team to IbM participants in the implementation of Jayanti plant cultivation and the manufacture and use of Jayanti insecticide in controlling cabbage caterpillars on cabbage plantations in Sembalun Lawang Village, East Lombok Regency.

Analysis of the Toxic Effects of Bisphenol A on the Groups of Vertebrate Animals: a Comprehensive Review of Research 2015-2021

The toxic effects of Bisphenol A (BPA) have been studied in individual experimental animals under different conditions. However, without a systematic approach, it is difficult to compare and analyse the results because of differences in doses (concentration), dosing periods (exposure), research methods, and the effects of BPA. We systematically compared and analysed recent research (between 2015 and 2021) that examined the effects of BPA on individual experimental vertebrates (fishes, amphibians, birds, and mammals). We divided the experiments into two categories: experiments on fish and amphibians by indirect administration, and experiments on birds and mammals by direct administration. The deleterious effects of exposure to BPA were classified into two types: morphological and anatomical effects, and physiological and neurocognitive effects. Experimental animals that had less weight, were younger, and were farther away from humans in evolutionary relationships, showed toxic effects even if they were exposed to low concentrations of BPA in the short term. Long-term administration of a small amount of BPA and short-term administration of a large amount of BPA also showed severe toxic effects. When the parents absorbed BPA during puberty, just before fertilisation, or during pregnancy, toxic effects were transmitted from dosed parents to offspring. With increasing amounts of BPA production and waste, there is a growing possibility that animals in various ecosystems will be exposed to BPA. Therefore, it is necessary to identify the harmful effects of BPA on various animals and the conditions under which it affects them. We hope that the results reported here will contribute to the development of standardized study designs for BPA research, to ensure that results can be more readily compared.

In vivo Pooled Screening: A Scalable Tool to Study the Complexity of Aging and Age-Related Disease

Biological aging, and the diseases of aging, occur in a complex in vivo environment, driven by multiple interacting processes. A convergence of recently developed technologies has enabled in vivo pooled screening: direct administration of a library of different perturbations to a living animal, with a subsequent readout that distinguishes the identity of each perturbation and its effect on individual cells within the animal. Such screens hold promise for efficiently applying functional genomics to aging processes in the full richness of the in vivo setting. In this review, we describe the technologies behind in vivo pooled screening, including a range of options for delivery, perturbation and readout methods, and outline their potential application to aging and age-related disease. We then suggest how in vivo pooled screening, together with emerging innovations in each of its technological underpinnings, could be extended to shed light on key open questions in aging biology, including the mechanisms and limits of epigenetic reprogramming and identifying cellular mediators of systemic signals in aging.

Regional timber supply for shipbuilding and maintenance of war fleets in Cadiz: methods, agents and phases (1717-1736)

In the period of 1717-1736, the southern peninsular forests became a new resource frontier at the service of the Spanish Navy, in the context of the Bourbon Reforms. The timber supply for shipbuilding and maintenance of war fleets in Cádiz was made through four methods: direct administration by commissioned services; purchase from regional middlemen merchants; articulation between contractors and direct administration; articulation with the Royal Exchequer. The rhythm of supply was the reflex of different needs and constraints in three phases: maintenance of fleets during the period of consolidation of Cádiz as a naval and commercial center (1717-1727); the first shipbuilding series (1728-1731); the impact of the 30’s Mediterranean campaigns and the shipbuilding production of Ciprian Autran (1731-1736).

Treatment of Fetal Arrhythmias

Fetal arrhythmias are mostly benign and transient. However, some of them are associated with structural defects or can cause heart failure, fetal hydrops, and can lead to intrauterine death. The analysis of fetal heart rhythm is based on ultrasound (M-mode and Doppler echocardiography). Irregular rhythm due to atrial ectopic beats is the most common type of fetal arrhythmia and is generally benign. Tachyarrhythmias are diagnosed when the fetal heart rate is persistently above 180 beats per minute (bpm). The most common fetal tachyarrhythmias are paroxysmal supraventricular tachycardia and atrial flutter. Most fetal tachycardias can be terminated or controlled by transplacental or direct administration of anti-arrhythmic drugs. Fetal bradycardia is diagnosed when the fetal heart rate is slower than 110 bpm. Persistent bradycardia outside labor or in the absence of placental pathology is mostly due to atrioventricular (AV) block. Approximately half of fetal heart blocks are in cases with structural heart defects, and AV block in cases with structurally normal heart is often caused by maternal anti-Ro/SSA antibodies. The efficacy of prenatal treatment for fetal AV block is limited. Our review aims to provide a practical guide for the diagnosis and management of common fetal arrythmias, from the joint perspective of the fetal medicine specialist and the cardiologist.

The Rediscovery of Honey for Skin Repair: Recent Advances in Mechanisms for Honey-Mediated Wound Healing and Scaffolded Application Techniques

Honey is a honey-bee product obtained mainly by the enzymatic processing of nectar from a variety of plants, which leads to the wide range of colours and flavours available on the market. These organoleptic and nutritional features are influenced by the chemical composition, which in turn depends on the botanical origin. Bioactive compounds account for honey beneficial activity in medical applications, which explains the extensive use of honey in ethno-pharmacology since antiquity, from cough remedies to dermatological treatments. Wound healing is one of the main therapeutic uses of honey, and various design options in pharmaceutical technology such as smart delivery systems and advanced dressings are currently being developed to potentiate honey’s valuable properties for better performance and improved final outcome. In this review, we will focus on the latest research that discloses crucial factors in determining what properties are most beneficial when considering honey as a medicinal product. We will present the most recent updates on the possible mechanisms responsible for the exceptional effects of this ageless therapeutical remedy on skin repair. Furthermore, the state-of-the-art in application techniques (incorporation into scaffolds as an alternative to direct administration) used to enhance honey-mediated wound-healing properties are explored.

The SHREAD gene therapy platform for paracrine delivery improves tumor localization and intratumoral effects of a clinical antibody

The goal of cancer-drug delivery is to achieve high levels of therapeutics within tumors with minimal systemic exposure that could cause toxicity. Producing biologics directly in situ where they diffuse and act locally is an attractive alternative to direct administration of recombinant therapeutics, as secretion by the tumor itself provides high local concentrations that act in a paracrine fashion continuously over an extended duration (paracrine delivery). We have engineered a SHielded, REtargeted ADenovirus (SHREAD) gene therapy platform that targets specific cells based on chosen surface markers and converts them into biofactories secreting therapeutics. In a proof of concept, a clinically approved antibody is delivered to orthotopic tumors in a model system in which precise biodistribution can be determined using tissue clearing with passive CLARITY technique (PACT) with high-resolution three-dimensional imaging and feature quantification within the tumors made transparent. We demonstrate high levels of tumor cell–specific transduction and significant and durable antibody production. PACT gives a localized quantification of the secreted therapeutic and allows us to directly observe enhanced pore formation in the tumor and destruction of the intact vasculature. In situ production of the antibody led to an 1,800-fold enhanced tumor-to-serum antibody concentration ratio compared to direct administration. Our detailed biochemical and microscopic analyses thus show that paracrine delivery with SHREAD could enable the use of highly potent therapeutic combinations, including those with systemic toxicity, to reach adequate therapeutic windows.

Effects of Sodium Chloride-Rich Mineral Water on Intestinal Epithelium. Experimental Study

Since knowledge concerning the cellular and tissue substrate that explains the therapeutic action of mineral waters is generally very scarce, we address the different effects that Lanjarón-Capuchina mineral water exerts on the intestinal epithelium in an experimental model as a prototype of the sodium chloride-rich mineral waters used in digestive disorders. In the experimental protocol, two groups of five adult Wistar rats received unrestricted mineral water in their diet or mineral water directly into the gastrointestinal tract through a catheter. A third control group was given a standard diet and water ad libitum. Intestinal samples for scanning electron microscopy were analyzed according to standardized methods. The observations carried out by microscope after the administration of the sodium chloride-rich mineral water clearly indicate that the hypertonic action of this mineral water affects the structure of the intestinal epithelium. It modifies the microvilli absorption in terms of the groups of enterocytes and the secretion of goblet cells, but it particularly affects the epithelial renewal process, accelerating and stimulating cell extrusion. The type of extrusion mechanism observed by microscope allows us to affirm that, although this increased after direct administration, it does not generate an epithelial disruption as it occurs in other circumstances with other extrusion modalities.

Impact of Food and Drink Administration Vehicles on Paediatric Formulation Performance Part 2: Dissolution of Montelukast Sodium and Mesalazine Formulations

Paediatric medicines are not always age-appropriate, causing problems with dosing, acceptability and adherence. The use of food and drinks as vehicles for medicine co-administration is common practice, yet the impact on drug bioavailability, safety and efficacy remains unaddressed. The aim of this study was to use in vitro dissolution testing, under infant simulating conditions, to evaluate the effect of co-administration with vehicles on the dissolution performance of two poorly soluble paediatric drugs. Dissolution studies of mesalazine and montelukast formulations were conducted with mini-paddle apparatus on a two-stage approach: simulated gastric fluid followed by addition of simulated intestinal fluid. The testing scenarios were designed to reflect daily administration practices: direct administration of formulation; formulation co-administered with food and drinks, both immediately after mixing and 4 h after mixing. Drug dissolution was significantly affected by medicine co-administration with vehicles, compared to the direct administration of formulation. Furthermore, differences were observed on drug dissolution when the formulations were mixed with different vehicles of the same subtype. The time between preparation and testing of the drug-vehicle mixture also impacted dissolution behaviour. Drug dissolution was shown to be significantly affected by the physicochemical properties and composition of the vehicles, drug solubility in each vehicle and drug/formulation characteristics. Ultimately, in this study, we show the potential of age-appropriate in vitro dissolution testing as a useful biopharmaceutical tool for estimating drug dissolution in conditions relevant to the paediatric population. The setup developed has potential to evaluate the impact of medicine co-administration with vehicles on paediatric formulation performance.