Progestogens of varying androgenicity and cardiovascular risk factors in postmenopausal women receiving oestrogen replacement therapy

OBJECTIVE: Medroxyprogesterone (MP) was used as the progestogen in randomized clinical trials of postmenopausal hormone replacement on cardiovascular risk. To attempt to understand the lack of benefit in these trials, we have examined the effects of MP and two other progestogens, the less androgenic desogestrel (DG) and the more androgenic norethisterone (NE), on cardiovascular risk factors against a background of oestrogen therapy. DESIGN AND MEASUREMENTS: Thirty-four women were treated with conjugated equine oestrogens (CEE) 0.625 mg daily alone for 12 weeks, followed in random order by each of the three progestogens (DG 75 microg, MP 10 mg and NE 1 mg daily) given sequentially for three 12-week cycles while maintaining the same CEE treatment. We measured serum lipoproteins, paraoxonase activity, C-reactive protein (CRP), fibrinogen, fasting glucose and insulin levels at baseline, at the end of the oestrogen-only phase and at the end of each of the combined oestrogen and progestogen phases. RESULTS: The addition of progestogens to CEE maintained the oestrogen-induced reduction in apolipoprotein B (apo B) and lipoprotein (a) [Lp(a)], and further lowered total cholesterol (P < 0.01) and fibrinogen (P < 0.001). CEE raised serum triglyceride (P < 0.001) and CRP (P < 0.01) concentrations, which reverted towards pre-oestrogen levels with progestogens. Progestogens significantly reduced high density lipoprotein (HDL) cholesterol (P < 0.05). NE was associated with the greatest reduction in HDL cholesterol and apo A1, but was most effective in preserving paraoxonase activity and reducing the potentially unfavourable oestrogen-induced increases in triglycerides and CRP. CONCLUSION: Preconceptions that more androgenic progestogens necessarily have more unfavourable effects on cardiovascular risk factors may require revision.     

Properties of electromagnetic field focusing probe

The electromagnetic field focusing (EFF) apparatus consists of a radio frequency generator, solenoidal coil, and a hand-held or catheter probe. Applications such as aneurysm treatment, angioplasty, and neurosurgery in various models have been reported. The probe is operated in the near field (within one wavelength of an electromagnetic field source) of a coil inducing eddy currents in biological tissues, producing maximal convergence of the induced current at the probe tip. The probe produces very high temperatures depending on the wattage selected for the given radio frequency of output power. The high temperature can be used in cutting, cauterizing, or vaporizing. The EFF probe is comparable to different types of lasers and to bipolar and monopolar cautery. The EFF probe can be used with catheters or endoscopes. Objectives of this study were to determine what the thermal properties of the EFF probe are and how instrument parameters can be varied to obtain different temperatures in the tissue near the probe tip. In this study an F2 catheter was used as an insulated sheath and the tip of the guide wire was used as the probe tip. Different powers, wave forms, coil-to-probe distances, and probe-tip lengths were tested on a phantom that simulates tissue electrical properties. Some of the experiments were conducted under normal saline to simulate treatment of tissue with body fluids such as blood vessels or brain tissue under normal physiologic conditions. It is concluded that the EFF probe has the advantages of easy manipulation, relative safety, cost effectiveness, and a high degree of spatial control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Formulation development,in vitro and in vivo evaluation of microemulsion-based gel loaded with ketoprofen

Abstract

Background: Anti-inflammatory agents are widely used to relieve inflammation caused by various factors.

Aim: This study was initiated with the intention to deliver low aqueous soluble ketoprofen to enhance its solubility by developing microemulsion system as a template and then incorporating it into gel phase.

Materials and methods: Initially ketoprofen was solubilized into microemulsion preparation made up of clove oil, Tween 20 and propylene glycol as oil phase, surfactant and co-surfactant respectively, then it was incorporated into different concentration of gelling phase using gelling agents namely Carbopol 940, Carbopol 934 and hydroxypropyl methyl cellulose K₄M (HPMC K₄M). Formulated emulgels were evaluated for their physical appearance, pH, rheological properties, globule size, extrudability, drug content, spreadability, bioadhesion strength, in vitro and ex vivo drug release, skin irritation test and anti-inflammatory activity.

Results: Microemulsion had shown globule size 396?nm, pH 6–6.7, viscosity 29.4?cps and zeta potential ?12?mV indicating good stability. Formulated emulgels showed good physical appearance, skin acceptable pH 6–6.9, non-Newtonian shear thinning system, drug content 99.28?±?0.16%, bioadhesion strength 48.4 gram force, globule size 473?nm, spreadability 22.96?gm.cm/s, good extrudability, in vitro release, ex vivo release did not showed any irritation reaction and possess a good anti-inflammatory activity.

Conclusions: Selected batch showed enhanced drug release (92.42?±?4.66%) as compared to marketed gel (65.94?±?3.30). Similarly ex vivo release of formulation showed 72.22% release through mice skin compared with marketed gel. Formulations followed Korsmeyer–Peppas diffusion kinetic model. It was observed from the results that the formulated emulgel can provide promising delivery of ketoprofen.     

Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization

Abstract

Intranasal thermosensitive gel for rasagiline mesylate (RM) was developed for effective treatment of Parkinson’s disease. Intranasal gels were prepared by combination of poloxamer 407 and poloxamer 188 (1:1) with mucoadhesive polymers (carbopol 934?P and chitosan). The formulations were evaluated for sol–gel transition temperature, in-vitro drug release and in-vivo mucociliary transit time. Further, optimal intranasal gel formulations were tested for in-vivo pharmacokinetic behavior, nasal toxicity studies and brain uptake studies. It was found that optimal formulations had acceptable gelation temperature (28–33?°C) and adequate in-vitro drug release profile. Pharmacokinetic study in rabbits showed significant (p?<?0.05) improvement in bioavailability (four- to six-folds) of the drug from intranasal gels than oral solution. Chronic exposure studies in Wistar rats showed that these intranasal gels were non-irritant and non-toxic to rat nasal mucosa. Estimation of RM in rat brain tissue showed significant (p?<?0.01) improvement in uptake of RM form intranasal gel formulations than nasal solution.     

Engineering of polymer–surfactant nanoparticles of doxycycline hydrochloride for ocular drug delivery

Abstract

Context: Physiologic barriers of the eye, short precorneal drug residence time and poor corneal penetration are the few reasons for reduced ocular bioavailability.

Objective: This study was aimed to develop novel polymer–surfactant nanoparticles of hydrophilic drug doxycycline hydrochloride (DXY) to improve precorneal residence time and drug penetration.

Materials and methods: Nanoparticles were formulated using emulsion cross-linking method and the formulation was optimized using factorial design. The prepared formulation was characterized for particle size, ζ potential, encapsulation efficiency, in vitro drug release and ex vivo drug diffusion studies. The antibacterial activity studies were also carried out against Escherichia coli and Staphylococcus aureus using the cup-plate method. In vivo eye irritation study was carried out by a modified Draize test in rabbits.

Results and discussion: The particle size was found to be in the range of 331–850?nm. About 45–80% of the drug was found to be encapsulated in the nanoparticles. In vitro release demonstrated sustained release profile. Lower flux values in case of nanoparticles as compared to DXY pure drug solution in ex vivo diffusion studies confirmed the sustained release. The nanoparticles were found to be significantly effective (p?<?0.001) than DXY aqueous solution due to sustained release of doxycycline from nanoparticles in both the E. coli and S. aureus strains. The formulation was found to be stable over entire stability period.

Conclusion: The developed formulation is safe and suitable for sustained ocular drug delivery.     

Immune checkpoint inhibitors in patients with solid tumors and poor performance status: A prospective data from the real-world settings

Immune checkpoint inhibitors (ICIs) are rapidly being incorporated as treatment option either alone or in combination with chemotherapy in most of the solid tumors. Since there is very limited data of ICI in patients with poor performance status (PS) from the real world settings, we performed a retrospective audit of patients who received ICI and report the analysis based on ECOG PS of these patients.This study is a retrospective audit of a prospectively collected database of patients receiving ICIs for advanced solid tumors in any line between August 2015 and November 2018 at Tata Memorial Hospital, Mumbai, India. All statistical calculations were performed using SPSS statistical software for windows version 20.0.A total of 155 patients who received ICIs during the specified period were evaluated for this study. Baseline ECOG PS 0–1 (n = 103, 66.4%) patients was associated with median OS 9.1 (95% CI [confidence interval], 4.4-NR) months when compared to ECOG 2–4 (n = 52, 33.5%) which had a median OS of 2.9 (95% CI; 1.8–5.5) months (HR, 1.7, 95% CI, 1.1–2.7, log rank P = .017). The disease control rate for the poor PS group was 34.6%. However, 27.3% patients (95% CI: 20.3–34.3) were still alive at 1 year. Median OS in patients with PS 2 was 3.7 months (95% CI: 0–11.6) as compared to 1.8 months (95% CI: 0.2–3.4) for those with PS 3–4 (HR-2.0; 95% CI: 1.0–3.9, P = .041). The tolerance to ICIs was good with no grade 3/4 toxicities in 44 (84.6%) patients.Immune checkpoint inhibitors are a safe and effective therapeutic option even in solid tumor patients with poor performance status.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Interactions between host and gut microbiota in domestic pigs: a review

ABSTRACT

It is well established that pig gut microbiota plays a critical role in maintaining metabolic homeostasis as well as in a myriad of physiological, neurological and immunological functions; including protection from pathogens and digestion of food materials – some of which would be otherwise indigestible by the pig. A rich and diverse gut microbial ecosystem (balanced microbiota) is the hallmark of good health; while qualitative and quantitative perturbations in the microbial composition can lead to development of various diseases. Alternatively, diseases caused by stressors or other factors have been shown to negatively impact the microbiota. This review focuses primarily on how commensal microorganisms in the gastrointestinal tract of pigs influence biochemical, physiological, immunological, and metabolic processes within the host animal.     

Ultrasensitive and bifunctional ZnO nanoplates for an oxidative electrochemical and chemical sensor of NO2: implications towards environmental monitoring of the nitrite reaction

Herein, we focused on the one pot synthesis of ZnO nanoplates (NP edge thickness of ∼100 nm) using a chemical emulsion approach for chemical (direct) and electrochemical (indirect) determination of NO₂. The structural and morphological elucidation of the as-synthesized ZnO NPs was carried out by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive analysis of X-ray (EDAX), thermogravimetric analysis (TGA) and BET-surface area measurements. The XRD studies of the as-synthesised NPs reveal that ZnO NPs have a Wurtzite type crystal structure with a crystallite size of ∼100 nm. Such ZnO NPs were found to be highly sensitive to NO₂ gas at an operating temperature of 200 °C. Electrocatalytic abilities of these ZnO NPs towards NO₂/NO₂⁻ were verified through cyclic voltammetry (CV) and linear sweep voltammetry (LSV) using aqueous 1 mM NO₂⁻ (nitrite) in phosphate buffer (pH 7) solution. The results revealed enhanced activity at an onset potential of 0.60 V vs. RCE, achieved at a current density of 0.14 mA cm⁻². These ZnO NPs show selective NO₂ detection in the presence of other reactive species including CO, SO₂, CH₃OH and Cl₂. These obtained results show that this chemical route is a low cost and promising method for ZnO NPs synthesis and recommend further exploration into its applicability towards tunable electrochemical as well as solid state gas sensing of other toxic gases.

Herein, we focused on the one pot synthesis of ZnO nanoplates (NP edge thickness of ∼100 nm) using a chemical emulsion approach for chemical (direct) and electrochemical (indirect) determination of NO₂.