Orthostatic Hypotension in Benign Prostatic Hyperplasia Patients and Its Association With Alpha-1 Antagonist Use: A Comprehensive Literature Review.

Orthostatic hypotension (OH) is frequently observed in benign prostatic hyperplasia (BPH) patients undergoing alpha-1 adrenergic antagonist (A1AA) therapy. While previous studies have acknowledged the prevalence of OH in BPH patients on A1AAs, limited data exist on ranking the safety of different A1AAs. This comprehensive review explores the underlying mechanisms of OH, examines numerous factors influencing its development, and provides insights into effective treatment strategies such as hydration, gradual postural changes, leg exercises, compression stockings, and tilt-table training for BPH management. The review highlights the significance of individualized care, interdisciplinary collaboration, and further research to optimize A1AA treatment, improve patient outcomes, and enhance quality of life.

P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells.

Glioma stem cells (GSC) exhibit plasticity in response to environmental and therapeutic stress leading to tumor recurrence, but the underlying mechanisms remain largely unknown. Here, we employ single-cell and whole transcriptomic analyses to uncover that radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of vascular endothelial-like and pericyte-like cell phenotypes. These vascular-like cells provide trophic support to promote proliferation of tumor cells, and their selective depletion results in reduced tumor growth post-treatment in vivo. Mechanistically, the acquisition of vascular-like phenotype is driven by increased chromatin accessibility and H3K27 acetylation in specific vascular genes allowing for their increased expression post-treatment. Blocking P300 histone acetyltransferase activity reverses the epigenetic changes induced by radiation and inhibits the adaptive conversion of GSC into vascular-like cells and tumor growth. Our findings highlight a role for P300 in radiation-induced stress response, suggesting a therapeutic approach to prevent glioma recurrence.

Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas.

BACKGROUND: Pediatric diffuse midline gliomas (DMGs) are incurable childhood cancers. The imipridone ONC201 has shown early clinical efficacy in a subset of DMGs. However, the anticancer mechanisms of ONC201 and its derivative ONC206 have not been fully described in DMGs. METHODS: DMG models including primary human in vitro (n = 18) and in vivo (murine and zebrafish) models, and patient (n = 20) frozen and FFPE specimens were used. Drug-target engagement was evaluated using in silico ChemPLP and in vitro thermal shift assay. Drug toxicity and neurotoxicity were assessed in zebrafish models. Seahorse XF Cell Mito Stress Test, MitoSOX and TMRM assays, and electron microscopy imaging were used to assess metabolic signatures. Cell lineage differentiation and drug-altered pathways were defined using bulk and single-cell RNA-seq. RESULTS: ONC201 and ONC206 reduce viability of DMG cells in nM concentrations and extend survival of DMG PDX models (ONC201: 117 days, P = .01; ONC206: 113 days, P = .001). ONC206 is 10X more potent than ONC201 in vitro and combination treatment was the most efficacious at prolonging survival in vivo (125 days, P = .02). Thermal shift assay confirmed that both drugs bind to ClpP, with ONC206 exhibiting a higher binding affinity as assessed by in silico ChemPLP. ClpP activation by both drugs results in impaired tumor cell metabolism, mitochondrial damage, ROS production, activation of integrative stress response (ISR), and apoptosis in vitro and in vivo. Strikingly, imipridone treatment triggered a lineage shift from a proliferative, oligodendrocyte precursor-like state to a mature, astrocyte-like state. CONCLUSION: Targeting mitochondrial metabolism and ISR activation effectively impairs DMG tumorigenicity. These results supported the initiation of two pediatric clinical trials (NCT05009992, NCT04732065).

Diffuse midline glioma: review of epigenetics.

PURPOSE: Our understanding of diffuse midline glioma (DMG) biology inclusive of diffuse intrinsic pontine glioma has been revolutionized by the discovery of novel mutations on the tails of histone 3, leading to the reclassification in 2016 of 'diffuse midline glioma, H3 K27M-mutant.' Given the abundance of basic, translational, and clinical information put forth in recent years, a review of the epigenetics of diffuse midline glioma is warranted. METHODS: Literature for the epigenetics of diffuse midline glioma published from 1989 to 2019 was reviewed by searching PubMed using the terms "diffuse intrinsic pontine glioma", "pontine glioma", or "midline glioma". The final references list was generated on the basis of originality and relevance to the broad scope of our review. RESULTS: The effects of H3K27M-mutation, while better understood, suggest multiple consequences on the chromatin landscape and DNA modification states, contributed to the progression of DMG. A rapid pace of translational development is occurring for epigenetic modifiers, and several classes of inhibitors have already made their way into clinical trial testing. As more agents become clinically accessible, immense effort is underway to understand the target effects, tumor penetration, and immune microenvironmental changes of epigenetic modification. CONCLUSION: We continue to seek a comprehensive understanding of the mechanisms that govern chromatin dysregulation and DNA modification in DMG, and in parallel we forge ahead with clinical testing of epigenetic modifiers. The determined efforts from bench to bedside, along with collaborative mindset and unified mission, will ultimately result in improved outcomes for DMG.

Iontophoretic delivery of lidocaine hydrochloride through ex-vivo human skin.

Background: Iontophoresis is one of the widely used noninvasive and painless transdermal drug delivery technique.Objective: Transdermal delivery of Lidocaine Hydrochloride using continuous and modulated iontophoresis were evaluated across human skin ex-vivo and further assessed for skin tolerance in-vivo in the Swiss albino mice.Methods: Continuous DC was modified into modulated DC by introducing ON-OFF time in continuous DC. Iontophoresis studies were conducted on human skin samples for 60 min.Results: Drug permeation of 2% lidocaine HCl was enhanced in current density-, duty cycle- and time-dependent manner across human skin. The lidocaine HCl concentration obtained with modulated DC and continuous DC iontophoresis were about three-fold and four-fold higher than passive group respectively for all current densities across human skin. Continuous DC iontophoresis was found to be more effective than modulated DC. However, no significant difference was observed in transport of lidocaine HCl between 75% and 100% (continuous) duty cycle at all current density. Further, in-vivo reversibility studies with mice confirmed that modulated iontophoresis was well tolerated by the tissue and the injury caused is transient and reversible.Conclusion: For clinical application, modulated DC iontophoresis with 75% duty cycle at 0.5 mA/cm2 current density would be recommended.

Effect of epidural clonidine on characteristics of spinal anaesthesia in patients undergoing gynaecological surgeries: A clinical study.

BACKGROUND AND AIMS: Combined spinal-epidural (CSE) anaesthesia is being increasingly used for effective post-operative analgesia. This study was designed to evaluate the effect of epidural clonidine on characteristics of spinal anaesthesia for gynaecological surgeries. METHODS: This was a prospective randomised, double-blind, controlled study involving sixty patients belonging to American Society of Anesthesiologists Physical Status I and II who underwent gynaecological surgeries were randomly divided into clonidine (C) group and saline (S) group of thirty each. All patients received CSE anaesthesia. Ten minutes before subarachnoid block (SAB), Group C received clonidine 150 µg diluted to 5 ml in normal saline (NS) and Group S received NS epidurally. Hyperbaric bupivacaine (15 mg) was administered intrathecally for both groups after epidural injection. Sensory and motor block characteristics, analgesia, sedation and haemodynamics were observed. Statistical analysis was performed using appropriate tests. RESULTS: Epidural clonidine produced faster onset (37.83 ± 8.58 s in Group C compared to 50.33 ± 8.80 s in Group S, P = 0.001) and prolonged duration of sensory block (241.17±18.65 minutes in group C compared to 150.33±19.16 minutes in group S, P = 0.001). Time for two segment regression of sensory block was193.67 ± 19.82 min in Group C and 109.33 ± 18.56 min Group S (P < 0.001). The duration of analgesia was 299.00 ± 43.38 min in Group C and 152.50 ± 21.04 min in Group S (P < 0.001). Haemodynamics and sedation scores were comparable between two groups. CONCLUSION: Administration of clonidine epidurally, 10 min before SAB, caused early onset and prolonged duration of motor blockade and analgesia, without any significant post-operative complication.

Transdermal delivery of methotrexate: past, present and future prospects.

Mehotrexate has been reported as an immunosuppressant and an antimetabolite widely used in the treatment of rheumatoid arthritis and psoriasis. However, it causes various toxicities and has low bioavailability when taken orally, thus, it is desirable that the drug be delivered transdermally. The water solubility and charged structure of methotrexate, however, limits its use via the transdermal route mainly due to the highly organized microstructure of the stratum corneum. Hence, various technologies, such as chemical enhancers, iontophoresis, electroporation, ultrasound and microneedles, either alone or in combination, are being explored to enhance its permeability by disrupting the barrier property of the skin. The present article discusses the past, present and future of transdermal delivery of methotrexate.

Biophysical assessment of DC iontophoresis and current density on transdermal permeation of methotrexate.

INTRODUCTION: The effect of DC iontophoresis using low (0.2 mA/cm(2)) and high current density (0.5 mA/cm(2)) on transdermal permeation of methotrexate loaded into polyacrylamide hydrogel patch was investigated. RESULTS: Flux of 20.57 ± 1.02 µg/cm(2)/h and 36.8 ± 2.21 µg/cm(2)/h was achieved with low and high current density DC iontophoresis, respectively. Attenuated total reflectance-Fourier Transform infrared (ATR-FTIR) spectra and microscopic studies of the treated skin samples supported the permeation results. A greater decrease in the peak height of asymmetric, symmetric C-H stretching vibration and ester peak was noticed with 0.5 mA/cm(2) current density as compared to 0.2 mA/cm(2) current density samples. Furthermore, an increase in the ratio of amide I and amide II bands from 2.6 to 11 with increase in current density was noticed, thus indicating that hydration levels are associated with iontophoresis and play an important role in increasing the drug permeation. Scanning electron microscopy revealed increase in pore size of the hair follicles. Light microscopy studies of the skin samples treated with low current density DC iontophoresis demonstrated epidermal thinning and focal disruptions, spongiosis and appendageal dilatations. With higher current density, disruption of epidermis in almost half of the sectioned area, loss of appendages and fractured collagen in the dermis was noticed. Moreover, the reversibility studies conducted in vivo on mice revealed that the recovery process had started within 24 h and is complete in 48 h for lower current density treated animals. However, the histological changes associated with 0.5 mA/cm(2) current density were not reversible in 48 h and edema, appendageal dilatations along with focal disruption of epidermis persisted. CONCLUSION: Hence our study suggests that high density current is not well-tolerated by the skin.

Studies on in vitro and in vivo transdermal flux enhancement of methotrexate by a combinational approach in comparison to oral delivery.

BACKGROUND: Methotrexate (MTX) causes systemic toxicity thereby limiting its use; hence, transdermal delivery would be a possible alternative. METHOD: A comparative in vitro/in vivo study was done to see the effect of the two-tier system of chemical and physical enhancers. MTX was loaded into polyacrylamide-based hydrogel patch to see the effect of enhancers. RESULT: Flux enhancement (161%) of MTX was achieved when ternary mixture of ethyl acetate:menthol:ethanol (1:1:1) was used in combination with square-wave iontophoresis for 1 hour. Lower flux enhancement of 71%, 83%, and 93.5% was obtained in vitro with neat ethyl acetate, its binary composition with ethanol, and its ternary composition with ethanol and menthol, respectively, as compared to passive. However, with square-wave iontophoresis, it increased to 126%, 140%, and 161%, respectively. The mechanism of flux enhancement was supported by biophysical tools such as attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), and histopathology. ATR-FTIR studies demonstrated split in the asymmetric C-H vibration and amide II band with terpenes and iontophoresis, respectively. Additionally binary and ternary mixture of ethyl acetate demonstrated absence of ester peak accounting for lipid extraction. SEM of the skin samples treated with chemical enhancers in combination with square-wave iontophoresis showed both swelling and increased pore size of hair follicles, thus supporting higher permeation. Histopathological studies on treated skin samples of albino mice demonstrated epidermal thinning and focal disruptions, spongiosis, dermal edema, and appendageal dilatations. In vivo studies on mice demonstrated plasma concentration of 18.79 microg/mL with ternary mixture of ethyl acetate in combination with square wave, which is twofold higher to oral delivery. The reversibility studies conducted in vivo on mice demonstrated that the histological changes induced by the above-mentioned enhancers were transient and reversible in 48 hours. CONCLUSION: The above results indicate that the above-mentioned enhancers are safe and well tolerated by the skin.

STD sensor based on nucleic acid functionalized nanostructured polyaniline.

STD (sexually transmitted disease, Gonorrhoea) sensor based on nucleic acid probe (from Opa, a multi-copy gene of Neisseria gonorrhoeae) functionalized nanostructured-polyaniline coated onto indium-tin-oxide-coated glass plate has been fabricated using avidin-biotin as cross-linking agent. This DNA functionalized electrode can specifically detect upto 0.5 x 10(-15)M of complementary target within 60s of hybridization time at 25 degrees C by differential pulse voltammetry (DPV) using methylene blue as electro-active DNA hybridization indicator. This highly sensitive and specific nucleic acid functionalized nanostructured-polyaniline electrode can distinguish presence of N. gonorrhoeae from Neisseria meningitidis and Escherichia coli culture and spiked samples from the urethral swabs of the patients.