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.

Preservative free travoprost and timolol fixed combination in the initial treatment of primary glaucoma: an assessment of hypotensive efficiency and safety

Purpose. To evaluate the efficacy and safety of Travapress Duo with respect to hypotensive results, changes in functional parameters, and adverse reactions. Material and methods. 30 patients aged 65–75 (averagely 71.3 ± 3.2 years) with a newly diagnosed primary open-angle glaucoma (POAG) received Travapress Duo in the evening, once a day. Goldman tonometry was performed during the screening, then 1 week, 1 month and 3 months from the treatment start. Static perimetry and optical coherence tomography (OCT) were performed before treatment and at the end of the 3rd month since the treatment start. Adverse events were recorded at each stage of the study.Results. As a result of a 3 month long therapy with Travapress Duo, a significant decrease in IOP was noted starting from the 1st week of instillations (by 34 %), after 1 month, by 35 % and after 3 months of observation by 36 %. By the end of the 3rd month of treatment, we noted an insignificant increase in visual acuity, a positive dynamic of the standard deviation and the standard deviation pattern, as well as OCT indicators, such as average thickness of the layer of retinal nerve fibers and the layer of retinal ganglion cells in the macula, stabilization of the thickness of the retinal ganglion cell complex layer and the size of the inner plexiform layer. One patient complained of discomfort and hyperemia by the end of the 1st week of drug instillation. No systemic side effects were noted during the follow-up, and in no case drug withdrawal was require. Conclusion. The preservative-free Travapress Duo drug displayed a high hypotensive efficacy, reducing the IOP to 36% of the initial value. The hypotensive effect was accompanied by indirect neuroprotection, which manifested itself in the positive changes observable in the results of functional studies with varying degrees of reliability. Travapress Duo is characterized by a low level of local side effects and can be recommended for both for the initial and long-term therapy of primary glaucoma of developed and advanced stages.

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.

Disorder of Sex Development, Mosaic Genetic Disorder 45x, 46xy: A Case Report

Background. Disorder of sex development (DSD) is a congenital disorder associated with interference in chromosomes, gonads, or sexes anatomically. Individual affected with DSD can be recognized since birth due to external genital ambiguity. Sexual chromosome DSD occurred because sexual chromosome numeric or structural disorder. Mosaic karyotype 45X/46XY is among the rare sexual chromosome DSD with incidence less than 1:15,000 live births. DSD individuals are susceptible to stigmatization. This can cause stress, negative emotion, and social isolation. Therefore, DSD individual management should be done as optimal as possible. Case Presentation: Twelve years old girl complaining a bump arose from anterior side of her genital resembles male genital since 4 years prior to admission without micturition and defecation complains. Patient has not experienced menarche. On external genital examination, we found the normal female external genital such as mons pubis, pubic hair, labia majora, labia minora, hymen, perineum, but without clitoris which in this case it is replaced by a glans of penis, arising from anterior commissure of labia majora area, with an urethral estuary. Before the management is done, patient underwent multidiscipline consultations and further examinations. Subsequently, it was approved that the joint conference formation consisting obstetric and gynecology, urologist, and pediatric endocrinologist to determine the optimal management for the patient. Conclusion: In this case, diagnosis was made with history taking, clinical examination, and supporting investigation such as ultrasound imaging and could be followed by biochemistry test, voiding cystourethrography or genitogram to determine next management. Counseling should be done in detail towards the family to know what action is best for the patient. Multidiscipline team was required to get the optimum result either in medical, ethical, or religious point of view. Surgery in this case was considered followed by long term therapy afterwards.

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.

Flavonoids in Benign Prostate Hypertrophy: Identification in Herbal Preparations and Molecular Docking Approach

The benefits of phytotherapy in Benign prostatic hyperplasia (BPH) are of interest where they may lack side effects at long-term therapy. Through plant-derived preparations are Saw palmetto and Pumpkin seed oil. Evidence suggests that fatty acids, phytosterols, tocopherols, and flavonoids are the active components responsible for alleviating BPH symptoms. Flavonoids are reported to inhibit BPH through different mechanisms. Reducing inflammation and lowering reactive oxygen species are amongst the proposed mechanisms. In vitro studies highlighted the role of flavonoids in 5-alpha reductase II (5ARII) inhibitory activity. In this study, herbal preparations known to treat BPH were subjected to LC/MS/MS analysis integrated with multiple reaction monitoring (MRM) to identify the content of flavonoids. A molecular docking study was conducted on the assigned flavonoids to predict the binding mode and interaction with the targeted 3D- crystal structure of the human 5ARII enzyme. Results showed the existence of seven flavonoids and a polyphenol compound. Sakuranetin, Isorhamnetin, and Chlorogenic acid were not reported before. Molecular docking outcomes revealed that Astragalin, Isoquercitrin, Quercetin, and Chlorogenic acid have similar binding affinity to the reference Finasteride compound. These findings suggest flavonoids as potent potential inhibitors of 5ARII and could proceed to in vitro investigations.

Determination of Factors Influencing Physical Therapy Treatment Compliance

Background: Compliance to long term therapy is the extent to which a person's behavior - taking medication, following a diet or executing lifestyle changes, corresponds with agreed recommendations from a health care provider. Aim: To determine the factors influencing physical therapy treatment compliance and relation of age and gender on compliance. Study Design: Observational study. Methodology: Study conducted for 6 months in public sector hospitals of twin cities of Pakistan. Non-probability convenient sampling technique was used. Data was collected by interviewing the patients, using self-structured questionnaire. 141 patients attending physical therapy treatment in outpatient department for more than three days and willing to participate in the study, were included in the study. Patient who visited OPD for first time, pediatric patient and indoor patients were excluded. Data was analyzed by SPSS software, version 25 as qualitative variables were expressed as frequencies and percentages. Results: Most of patient could not adhere to physical therapy because of unavailability of time (60.28%), lengthy follow up (46.10%), boredom with exercise (23.4%), unavailability of respective gender (23.4%), long distance between home and hospital (20.6%), Physical contact with therapist during session (15.6%) and fear of modality (7.8%). Most patients within age group of 29-42 and 43-56 responded that frequent visits to hospital to attend multiple sessions of physical therapy were the reason they left physical therapy sessions and had unavailability of time to attend physical therapy sessions. Conclusion: We concluded that frequent visits to hospital to attend multiple sessions of physical therapy and unavailability of time are two main factors that led to poor compliance to physical therapy treatment. Keywords: Barriers, Compliance and Physical Therapy Treatment

Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

Fungal infections are underestimated threats that affect over 1 billion people, and Candida spp., Cryptococcus spp., and Aspergillus spp. are the 3 most fatal fungi. The treatment of these infections is performed with a limited arsenal of antifungal drugs, and the class of the azoles is the most used. Although these drugs present low toxicity for the host, there is an emergence of therapeutic failure due to azole resistance. Drug resistance normally develops in patients undergoing azole long-term therapy, when the fungus in contact with the drug can adapt and survive. Conversely, several reports have been showing that resistant isolates are also recovered from patients with no prior history of azole therapy, suggesting that other routes might be driving antifungal resistance. Intriguingly, antifungal resistance also happens in the environment since resistant strains have been isolated from plant materials, soil, decomposing matter, and compost, where important human fungal pathogens live. As the resistant fungi can be isolated from the environment, in places where agrochemicals are extensively used in agriculture and wood industry, the hypothesis that fungicides could be driving and selecting resistance mechanism in nature, before the contact of the fungus with the host, has gained more attention. The effects of fungicide exposure on fungal resistance have been extensively studied in Aspergillus fumigatus and less investigated in other human fungal pathogens. Here, we discuss not only classic and recent studies showing that environmental azole exposure selects cross-resistance to medical azoles in A. fumigatus, but also how this phenomenon affects Candida and Cryptococcus, other 2 important human fungal pathogens found in the environment. We also examine data showing that fungicide exposure can select relevant changes in the morphophysiology and virulence of those pathogens, suggesting that its effect goes beyond the cross-resistance.