Research conducted on gestating women globally during trials

The aim of clinical research is to impart knowledge that will improve human health or improve understanding of human physiology. Although, till the end of 20 century pregnancy was always under exclusion criteria, now pervasive exclusion of pregnant women in clinical trials is currently not justified. Pregnancy brings in an array of anatomical, physiological and biochemical changes that can impact the pharmacokinetics of important medications. Pregnancy is often accompanied by chronic diseases like diabetes, hypertension, tuberculosis, HIV, depression which can require long term therapy. This indicates a need for studies being conducted exclusively in pregnant women. Current communication narrates ethical and regulatory aspects of inclusion of pregnant women in clinical trials.

Distinct Glucocorticoid Receptor Actions in Bone Homeostasis and Bone Diseases

Glucocorticoids (GCs) are steroid hormones that respond to stress and the circadian rhythm. Pharmacological GCs are widely used to treat autoimmune and chronic inflammatory diseases despite their adverse effects on bone after long-term therapy. GCs regulate bone homeostasis in a cell-type specific manner, affecting osteoblasts, osteoclasts, and osteocytes. Endogenous physiological and exogenous/excessive GCs act via nuclear receptors, mainly via the GC receptor (GR). Endogenous GCs have anabolic effects on bone mass regulation, while excessive or exogenous GCs can cause detrimental effects on bone. GC-induced osteoporosis (GIO) is a common adverse effect after GC therapy, which increases the risk of fractures. Exogenous GC treatment impairs osteoblastogenesis, survival of the osteoblasts/osteocytes and prolongs the longevity of osteoclasts. Under normal physiological conditions, endogenous GCs are regulated by the circadian rhythm and circadian genes display oscillatory rhythmicity in bone cells. However, exogenous GCs treatment disturbs the circadian rhythm. Recent evidence suggests that the disturbed circadian rhythm by continuous exogenous GCs treatment can in itself hamper bone integrity. GC signaling is also important for fracture healing and rheumatoid arthritis, where crosstalk among several cell types including macrophages and stromal cells is indispensable. This review summarizes the complexity of GC actions via GR in bone cells at cellular and molecular levels, including the effect on circadian rhythmicity, and outlines new therapeutic possibilities for the treatment of their adverse effects.

Personalized pharmacotherapy of arterial hypertension patients with musculoskeletal system diseases based on pharmacogenetic aspects

Pharmacotherapy in patients with comorbidity is a current issue for clinical practice. Combination of hypertension and musculoskeletal diseases can be found in 40% of outpatients, which requires simultaneous administration of different drugs. The main mechanisms of drug interactions are associated with pharmacokinetics or pharmacodynamics alterations. It has been proven that changes in drugs pharmacokinetics can be due to cytochromes P450 activity. The main symptom of musculoskeletal diseases is chronic pain, which requires long-term therapy with non-steroidal anti-inflammatory drugs (NSAIDs). The 2C19 isoenzyme takes part in metabolism of some NSAIDs. Losartan, the inhibitor of renin-angiotensinaldosterone system (RAAS), is also metabolized by the 2C9 isoenzyme and is quite often prescribed to outpatients to treat hypertension. Hence, an influence of genetic factors on efficacy and safety of antihypertensive drugs and NSAIDs combinations requires further studies.

The role of denosumab in the complex treatment of giant cell tumor of the spine: reducing of local recurrence rate, surgery time and blood loss

Objective. To assess the effect of the combined treatment method including preoperative denosumab therapy on the results of treatment of patients with giant cell tumors of the spine.Material and Methods. A single-center retrospective-prospective study of a series of clinical cases included 15 patients with giant cell tumors of vertebrae. The average follow-up period was 56 months. A total of 11 patients received denosumab therapy according to the following scheme: 120 mg subcutaneously on the 1st, 8th, 15th and 28th days of the first month and then once every 28 days. Surgical options included marginal resection, segmental resection, or en-bloc resection with or without spinal reconstruction/stabilization. In the case of locally advanced and inoperable disease, long-term therapy with denosumab was carried out until the disease progressed or serious adverse events appeared.Results. Thoracic vertebrae were involved in 7 (46.6 %) of 15 cases, lumbar in 4 (26.7 %) and cervical in 4 (26.7 %). Local recurrence rate after surgery alone was 40 % (2/5), average time to recurrence onset was 4.5 months. No relapses were observed after combined treatment performed in four patients. Disease progression during long-term denosumab therapy for inoperable disease recurrence was not recorded (0/7). The average number of denosumab injections before surgery and during long-term therapy was 15 and 24 injections, respectively. Denosumab therapy allows reducing the duration of surgery and the volume of blood loss.Conclusion. Combined therapy of giant cell vertebral tumor allows to reduce the risk of recurrence of the disease, as well as to reduce surgery duration and blood loss. Long-term continuous therapy for inoperable cases allows achieving long-term stabilization of the effect. Due to the rarity of giant cell tumors of the spine, a further prospective recruitment of patients is required to study the efficacy and safety of combined therapies.

Recent Advances in the Local Drug Delivery Systems for Improvement of Anticancer Therapy

: The conventional anticancer chemotherapies not only cause serious toxic effects, but also produce resistance in tumor cells exposed to long-term therapy. Usually, the killing of metastasized cancer cells requires long-term therapy with higher drug doses, because the cancer cells develop resistance due to the induction of poly-glycoproteins (P-gps) that act as a transmembrane efflux pump to transport drugs out of the cells. During the last few decades, scientists have been exploring new anticancer drug delivery systems such as microencapsulation, hydrogels, and nanotubes to improve bioavailability, reduce drug-dose requirement, decrease multiple drug resistance, and to save normal cells as non-specific targets. Hopefully, the development of novel drug delivery vehicles (nanotubes, liposomes, supramolecules, hydrogels, and micelles) will assist to deliver drug molecules at the specific target site and reduce the undesirable side effects of anticancer therapies in humans. Nanoparticles and lipid formulations are also designed to deliver small drug payload at the desired tumor cell sites for their anticancer actions. This review will focus on the recent advances in the drug delivery systems, and their application in treating different cancer types in humans.

Ultrasound-guided Perineural Dextrose Injection for Treatment of Superior Cluneal Nerve Entrapment: Serial Case Report

Background: Superior cluneal nerve entrapment is a neuropathic condition caused by the inclusion of the superior cluneal nerve that contributes to one of the causes of lower back pain leading to high morbidity. Several therapeutic modalities are available for superior cluneal nerve entrapment, including medications, physiotherapy, perineural injection, and surgery. Perineural injection with 5% dextrose has become therapeutic alternative in many cases of neuropathy, but its long-term effectiveness is unknown. Case Presentation: This study described four patients with superior cluneal nerve entrapment with severe pain intensity treated with ultrasonography guided perineural 5% dextrose injection, resulting in significant clinical improvement during the 6-month evaluation. Conclusion: Perineural injection can be considered as long-term therapy in patients with superior cluneal nerve entrapment who have failed other conventional therapies.

Experience of long-term use of denosumab in women with osteoporosis and various concomitant diseases

Background: Possible differences in the results of planned RCTs and real clinical practice were the reason for the analysis of long-term therapy with denosumab in patients with osteoporosis (OP) of various origins on an outpatient basis.Aim: To assess the effectiveness of long-term administration of denosumab in terms of the effect on BMD and markers of bone metabolism, tolerance and consequences of drug withdrawal in patients with OP of various etiologies.Materials And Methods: A retrospective analysis of the outpatient records of women with OP of various etiology, who were observed at the FSBI «NMRC TPM» from 1 to 10 years and regularly received denosumab 60 mg once every 6 months subcutaneously (at least 2 injections), was carried out. All completed examination and anthropometric research; DXA of the lumbar spine and proximal femur (PF); laboratory tests: marker of bone resorption CTx (β-crosslaps) in blood serum; survey on the presence of adverse events.Results: The study included 148 patients who were divided into 2 groups: 1 (N=98) - did not take anti-osteoporotic therapy (AT), 2 (N=50) - who took AT before the appointment of denosumab. Long-term therapy with denosumab was associated with a steady and reliable increase in BMD in the spine and PF, as well as a decrease in the concentration of CTx of both those who didn’t take and who previously took AT. In 54% of patients BMD in the spine reached values of osteopenia, in 43.4% of women target BMD values in the femoral neck were determined. During the first year of therapy, there was a decrease in the concentration of CTx by 67% in those who didn’t take AT and by 58% in those who had previously taken AT. Discontinuation of denosumab therapy without subsequent administration of AT was associated with a significant decrease in BMD in the spine (by 4.4-8.2%) during the first year after discontinuation of the drug.Conclusion: Denosumab therapy effectively increases BMD in the spine and PF and decreases CTx levels both in untreated patients and in those who previously received AT. It is necessary to discontinue therapy, further management of the patient should be discussed to prevent «withdrawal syndrome».

Organic electrolytic photocapacitors for stimulation of the mouse somatosensory cortex

Objective. For decades electrical stimulation has been used in neuroscience to investigate brain networks and been deployed clinically as a mode of therapy. Classically, all methods of electrical stimulation require implanted electrodes to be connected in some manner to an apparatus which provides power for the stimulation itself. Approach. We show the use of novel organic electronic devices, specifically organic electrolytic photocapacitors (OEPCs), which can be activated when illuminated with deep-red wavelengths of light and correspondingly do not require connections with external wires or power supplies when implanted at various depths in vivo. Main results. We stimulated cortical brain tissue of mice with devices implanted subcutaneously, as well as beneath both the skin and skull to demonstrate a wireless stimulation of the whisker motor cortex. Devices induced both a behavior response (whisker movement) and a sensory response in the corresponding sensory cortex. Additionally, we showed that coating OEPCs with a thin layer of a conducting polymer formulation (PEDOT:PSS) significantly increases their charge storage capacity, and can be used to further optimize the applied photoelectrical stimulation. Significance. Overall, this new technology can provide an on-demand electrical stimulation by simply using an OEPC and a deep-red wavelength illumination. Wires and interconnects to provide power to implanted neurostimulation electrodes are often problematic in freely-moving animal research and with implanted electrodes for long-term therapy in patients. Our wireless brain stimulation opens new perspectives for wireless electrical stimulation for applications in fundamental neurostimulation and in chronic therapy.

A Randomized Open Clinical Study of the Atherosclerosis Treatment Information Video Effect on Adherence to Long-Term Therapy in Patients with Cardiovascular Diseases

Aim. Study the effect of a study video, which was created by researchers and devoted to the atherosclerosis development and the effect of statin therapy on atherosclerotic plaque, on adherence to long-term therapy in patients with high or very high risk of cardiovascular complications.Material and methods. 120 patients admitted to hospital with cardiovascular diseases were included in the study. Patients were randomized into 2 groups: in the main group (n=60), the information video edited by the researchers was shown to patients on the eve of discharge, in addition to a printed brochure on lifestyle and diet modification, and in the control group (n=60), patients were given only a standard brochure. The motivating video shows the damage to the cardiovascular system by the atherosclerotic process and the beneficial effect on the body of constant intake of statins. After 1 and 3 months after discharge from the hospital, telephone calls were made, after which the patients had to visit the center for an objective examination by a researcher and control of laboratory parameters. After 1 month, 110 patients visited the center, after 3 months, 98 respondents visited the center.Results. The group with the information video demonstration noted more frequent adherence to medical recommendations compared to the control: after 1 month, 52 (96%) patients continued treatment versus 48 (86%) patients, 3 months after discharge 48 (96%) patients continued treatment versus 38 (79%) patients (p<0.05). After 1 month, 38 (70%) patients in the intervention group continued taking statins versus 29 (43%) respondents in the control group (p<0.05), 3 months after discharge, 40 (80%) patients in the intervention group continued to take statins versus 33 (69%) control patients (p<0.09).Conclusion. Demonstration of a motivating video about the effect of statins on the atherosclerosis course increases patient adherence to medicinal therapy, including adherence to statins.