Drug Dose Reduction Research Articles

Performance Analysis of Magnetic Nanoparticles during Targeted Drug Delivery: Application of OHAM

In recent years, the emergence of nanotechnology experienced incredible development in the field of medical sciences. During the past decade, investigating the characteristics of nanoparticles during fluid flow has been one of the intriguing issues. Nanoparticle distribution and uniformity have emerged as substantial criteria in both medical and engineering applications. Adverse effects of chemotherapy on healthy tissues are known to be a significant concern during cancer therapy. A novel treatment method of magnetic drug targeting (MDT) has emerged as a promising topical cancer treatment along with some attractive advantages of improving efficacy, fewer side effects, and reduce drug dose. During magnetic drug targeting, the appropriate movement of nanoparticles (magnetic) as carriers is essential for the therapeutic process in the blood clot removal, infection treatment, and tumor cell treatment. In this study, we have numerically investigated the behavior of an unsteady blood flow infused with magnetic nanoparticles during MDT under the influence of a uniform external magnetic field in a micro-tube. An optimal homotopy asymptotic method (OHAM) is employed to compute the governing equation for unsteady electromagnetohydrodynamics flow. The influence of Hartmann number (Ha), particle mass parameter (G), particle concentration parameter (R), and electro-osmotic parameter (k) is investigated on the velocity of magnetic nanoparticles and blood flow. Results obtained show that the electro-osmotic parameter, along with Hartmann’s number, dramatically affects the velocity of magnetic nanoparticles, blood flow velocity, and flow rate. Moreover, results also reveal that at a higher Hartman number, homogeneity in nanoparticles distribution improved considerably. The particle concentration and mass parameters effectively influence the capturing effect on nanoparticles in the blood flow using a micro-tube for magnetic drug targeting. Lastly, investigation also indicates that the OHAM analysis is efficient and quick to handle the system of nonlinear equations.

Design of experiments assisted the development of inclusion complexes of ramipril using hydrophilic carriers for enhancement of solubility and dissolution rate

The goal of the present study was to develop inclusion complexes and polymers dispersions of ramipril prepared by physical mixing, kneading, co-evaporation, and solvent evaporation methods to enhance drug solubility and dissolution rate, and thereby to reduce drug dose and side effects using selected hydrophilic carriers such as β-CD, PVP-K25, PEG 4000, and HPMC K100M. The prepared formulations were characterized for solubility and in-vitro drug release studies. The systematic optimization of formulations was performed using I-Optimal experimental design by selecting factors such as type of carriers (X1), drug: carrier ratio (X2), and method of preparation (X3), and response variables including percent yield (Y1), solubility (Y2), Carr’s index (Y3) and drug release in 30 min (Y4). Mathematical modeling was carried out using a quadratic polynomial model. The inclusion complex formulation (F27) was selected as an optimized batch by numerical desirability function and graphical optimization with the help of design space. The inclusion complex prepared by the co-evaporation method showed maximum drug solubility and released in pH 6.8 phosphate buffer compared to pure and other formulations. The inclusion complex is a feasible approach to improve the solubility, dissolution rate, bioavailability, and minimization of drugs’ gastrointestinal toxicity upon oral administration of ramipril.

Effect of thymoquinone on pharmacokinetics of 5-fluorouracil in rats and its effect on human cell line in vitro.

Thymoquinone (TQ) is one of the components extracted from Nigella sativa seeds and has antioxidant, anti-inflammatory, and anticancer effects. We evaluated the effect of TQ on 5-fluorouracil (5-FU) pharmacokinetics (PK) in vivo and in vitro on human colorectal cancer cell line. Ten Adult male Wistar rats were assigned to two groups. TQ treated group received intraperitoneal TQ once daily for 14 consecutive days (5mg/kg). Both groups received intraperitoneal 5-FU (50mg/kg) on day 15 and blood samples were collected from retro-orbital plexus. The pharmacokinetics parameters were analyzed using high-performance liquid chromatography (HPLC). Moreover, various concentrations of 5-FU, TQ, and combination of 5-FU and TQ were added to the HT-29 cell line and cell viability was measured using 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide colorimetric assay. The maximum serum concentration (Cmax), area under the curve (AUC), and time of maximum concentration (Tmax) of 5-FU in TQ treated group were significantly increased approximately by 61, 60, and 24% compared to the control group, respectively. The combination of 5-FU with TQ (0.284mM) showed a greater inhibitory effect on HT-29 cell growth compared to the alone 5-FU (0.027 and 0.055mM) administration. TQ increases the AUC, Cmax, and Tmax of 5-FU and has a synergistic effect on the PK of 5-FU. Moreover, low concentration of TQ enhances the inhibitory effects of 5-FU on cell growth in colorectal cancer cell line. This synergistic effect might enhance the anticancer effects of low concentration of 5-FU, leading to drug dose reduction and reduced systemic toxicity of this chemotherapeutic agent.

Curcumin Nanoparticles Enhance Antioxidant Efficacy of Diclofenac Sodium in Experimental Acute Inflammation.

We investigated the in vivo effect of curcumin nanoparticles (nC) in addition to diclofenac sodium on local edema and oxidative stress parameters in carrageenan-induced paw edema on rats. Seven groups were investigated: control group (C), the acute inflammation (AI) group, an AI group treated with Diclofenac (AID, 5 mg/kg b.w. Diclofenac sodium), two AI groups treated with cC (conventional Curcumin)—AIC200 and AIcC200D (D = Diclofenac, 200 represent the concentration of active substance expressed in mg/kg b.w.), and two AI groups with nC (Curcumin nanoparticles)—AIC200 and AIcC200D. Serum and tissue oxidative stress was assessed by measuring five parameters. Curcumin nanoparticles alone and in combination with D better reduced the paw edema than D alone (p < 0.027). The rats treated with D and nC (AIcC200D) had the highest inhibition percentage on edema, reaching the maximum level of inhibition (81%) after 24 h. Conventional curcumin and nC presented antioxidant effects in acute inflammation, with significantly better results obtained for nC. The pro-oxidant markers were reduced up to 0.3 by the cC and up to 0.4 times by the nC and both solutions increased the antioxidant markers up to 0.3 times. The nC enhanced the antioxidative efficacy of D, as this combination reduced the pro-oxidant markers up to 1.3 times. Curcumin nanoparticles could represent a therapeutic option in association with classical nonsteroidal anti-inflammatory medication in acute inflammation, as they might offer a reduction of drug dose and possible limitation of their associated side effects.

COVID-19 Pandemic Impact on Severe Alopecia Areata Patients

Introduction: The pandemic of COVID-19 has several implications for patients with chronic stress-sensitive diseases such as alopecia areata (AA). On the other hand, the vulnerability of AA patients using immunosuppressives to a more severe infection is in the shadow of ambiguity. This teledermatology study aimed to evaluate the course and outcome of AA in patients during this challenging period. Methods: Patients with AA who had previously received systemic therapy included in this study. Information about demographic data, AA history, characteristics, and treatments, hair loss progression, Corona Disease Anxiety Scale (CDAS), adherence to protective measures against the COVID-19, possible infection, and its features obtained via a telephone call. Results: A total of 57 patients participated. The majority (84.2%) of the participants had mild anxiety assessed by CDAS. Two patients (3.5%) had got infected with COVID-19. Twenty-one (36.8%) participants experienced hair loss progression. Hair loss progression correlated with drug dose reduction (OR: 46.09, 95% CI 5.48–387.14, p < 0.001) although it did not influence by the level of anxiety evaluated by the CDAS (p > 0.05). Conclusion: The anxiety perceived by severe AA patients about COVID-19 is mild; however, many experience hair loss progressions owing to their drug dose reduction.

FORMULATION DEVELOPMENT AND EVALUATION OF NIOSOMAL GEL OF COLLECTIVE ANTI-FUNGAL AGENTS

Objectives: Tea tree oil (TTO) and Eucalyptus oil (EO) are essential oils derived from the leaves and terminal branches of Melaleuca alternifolia and Eucalyptus globulus. Both oils have narrative topical antifungal agents. Niosomal vesicles were chosen for Tea tree and EO dispersion in this investigation because of their ability to protect enclosed drugs, reduce drug dose amount, target drug delivery, increase residence time and penetration. Methods: TTO and EO containing niosomes were made using a modified thin-film hydration process and Carbopol 934 as a gelling agent to produce a smooth antifungal niosomal gel. Results: TTO and EO entrapment efficiency was found to be 84.89±0.19% and 86.86±0.57%, respectively, and percent cumulative drug diffusion of TTO and EO was found to be 84.21% and 85.22% in the prepared optimized batch [N9]. Transmission electron microscopy revealed vesicular, spherical particles in the nano range with a smooth surface. The optimum batch [N9] of niosomal gel was made with 1% w/w carbopol 934. TTO 84.9% and EO 86.89%, respectively, were found to have prolonged drug release in an in vitro release investigation utilizing the dialysis bag method. The G9 batch niosomal gel was found to be stable by performing an accelerated stability study for 3 months. Conclusion: It was concluded that the best formulation batch G9 shows better-sustained release, enhanced residence time, and stability.

Effects of Recovery-Orientation on the Use of Forced Medication and Maximum Daily Drug Dose: The "Weddinger Modell".

Objective: The aim of the present study was to analyze the effects of the implementation of the Recovery-orientated psychiatric care concept “Weddinger Modell” on the incidence of forced medication, the total number of forced medication incidents per affected case, the maximum dose of a singular forced medication and the maximum voluntary daily drug dose of different psychotropic drugs administered during an inpatient stay.Methods: This retrospective case-control study included 234 patients. A pre/post-comparison of patients on two acute psychiatric wards before (control group, n = 112) and after (intervention group, n = 122) the implementation of the Weddinger Modell in 2010 was performed. Patient data was selected at two reporting periods before and at two reporting periods after 2010.Results: No significant differences were found in the incidence of forced medication and the total number of forced medications. A significant reduction of the maximum forced medication dose of haloperidol in the intervention group was seen. Furthermore, the analysis of the intervention group showed a significant reduction of the maximum voluntary daily drug doses of clozapine, haloperidol and risperidone.Discussion: The results indicate that the implementation of the Weddinger Modell had no effect on the incidence of forced medication, but it can help to improve the approach to psychotropic drugs. Despite the reduction of mechanical coercive measures by the model, as shown in a previous study, there is no increase in forced medications or administered drug doses. Focus on Recovery helps in reducing coercion in acute psychiatric care.

Safety and Efficacy of Tenalisib Given in Combination with Romidepsin in Patients with Relapsed/Refractory T-Cell Lymphoma: Final Results from a Phase I/II Open Label Multi-Center Study

Background: Tenalisib (RP6530), a highly selective PI3K δ/γ and SIK3 inhibitor has shown promising activity as a single agent in T Cell lymphoma (TCL) and a differentiated safety profile (Huen A et al., Cancers,2020). In vitro studies in TCL cell lines showed synergistic activity when tenalisib was combined with romidepsin. A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics, and efficacy in patients with relapsed/refractory (R/R) TCL peripheral (PTCL) and cutaneous T cell lymphoma (CTCL) (NCT03770000).Methods: This was a multi-center, open label study. We performed a Phase I, 3+3 dose escalation study to determine the MTD/recommended Phase II dose (RP2D), and a dose expansion study in both the subtypes separately (PTCL and CTCL). Patients received tenalisib at doses ranging from 400-800 mg BID (fasting), orally in combination with romidepsin at doses ranging from 12-14 mg/m 2, intravenously, given on Days 1,8 and 15 of a 28-day cycle.Results: Thirty-three patients (16 PTCL and 17 CTCL) who received more than 1 prior therapy were enrolled in the study; 9 in dose escalation and 24 in dose expansion. Of the 33 patients, 64% were refractory to their last therapy. The median number of prior therapies was 3. Most patients (67%) had stage III/IV disease at time of enrolment.No dose limiting toxicity (DLT) was reported during dose escalation; tenalisib 800 mg BID with romidepsin 14 mg/m 2 (given on Days 1, 8, and 15) was chosen as the RP2D.The most frequent treatment emergent adverse events (TEAEs) were nausea (All: 73% and ≥G3:0%), thrombocytopenia (All:57% and ≥G3:21%), fatigue (All: 54% and ≥G3:6%), AST elevation (All:33% and ≥G3:6%) ALT elevation (All:27% and ≥G3:18%), neutropenia (All: 27% and ≥G3:15%), vomiting (All:27% and ≥G3:0%), decreased appetite (All: 27% and ≥G3:0%). There were no unexpected TEAEs. Among CTCL patients, five related TEAEs led to drug discontinuation were sepsis, ALT elevation, GGT elevation, rash, and dysgeusia. None of the PTCL patients discontinued the study drug due to related TEAEs. Incidences of TEAEs leading to drug interruption (72%) and dose reduction (45%) of any the drugs in the combination were similar in PTCL and CTCL groups.Based on C max and AUC, dose proportional exposure of tenalisib was observed from doses 400-800 mg BID. Co-administration of romidepsin with tenalisib did not significantly alter the PK of either agent.Of the 33 patients enrolled, 27 (12 PTCL and 15 CTCL) who received at least 1 dose of study drug and provided at least 1 post-baseline efficacy assessment were considered evaluable for efficacy as per protocol. The overall response rate (ORR) was of 63%; 7 (26%) patients achieved CR and 10 (37%) patients had PR (Table 1). The median duration of response (DoR) was 5.03 months (range: 2.16 months-Not Reached).In twelve evaluable PTCL patients, the ORR was 75% with 6 CR (50%) and 3 PR (25%). Among 15 evaluable CTCL patients, 8 responded with an ORR of 53.3%, 1 CR (6.7%) and 7 PR (46.7%). The median DoR was 5.03 (range: 2.16 months-Not Reached) for PTCL and 3.8 months (1.9-18.86) for CTCL. Three of the six (50%) PTCL patients with CR were bridged to transplant.Six patients who benefitted with the treatment and completed the protocol were enrolled in an open-label compassionate medication study after Cycle 7 and are being followed up.Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising anti-tumor activity in patients with R/R TCL. Based on these encouraging results, further development of this combination in PTCL patients in being planned. [Display omitted] DisclosuresHuen: Rhizen: Research Funding; Elorac: Research Funding; Kyowa Kirin: Research Funding; Tillium: Research Funding; Innate: Research Funding; Galderma: Research Funding; Miragen: Research Funding. Ai: Kymria, Kite, ADC Therapeutics, BeiGene: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Alderuccio: ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Puma Biotechnology: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member. Kuzel: Cardinal Health: Membership on an entity's Board of Directors or advisory committees; Exelixis: Membership on an entity's Board of Directors or advisory committees; Genomic Health: Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme Genomic Health Tempus laboratories Bristol Meyers Squibb: Honoraria; Abbvie: Other; Curio Science: Membership on an entity's Board of Directors or advisory committees; AmerisourceBergen Corp: Membership on an entity's Board of Directors or advisory committees; CVS: Membership on an entity's Board of Directors or advisory committees; Tempus Laboratories: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data Monitoring Committee Membership; Amgen: Other: Data Monitoring Committee Membership; SeaGen: Other: Data Monitoring Committee Membership; Medpace: Other: Data Monitoring Committee Membership.

Risk Management Assessments of Adverse Drug Reactions: A Systematic Review of the Literature

Abstract Background Improving the quality of life of patients is a key concern in public health. In the context of improving therapeutic compliance, quality of life of patients undergoing anti-tuberculosis treatment, and prevention of antibiotic resistance, we conducted this systematic review to support risk minimization actions. Methods A literature review of risk management strategies targeting adverse drug reactions to anti-tuberculosis drugs was conducted, including published observational studies. Two independent reviewers identified studies through Medline, Scopus, and Web of Science. The methodological quality of the included studies was assessed using criteria defined by the Newcastle Ottawa Scale. Results Seven studies were included in this review, which identified four risk management strategies (psychological intervention, reduction of drug dose with or without prescription of adjunctive medications, change of medication, permanent or temporary discontinuation of medication). The strategies adopted were dependent on the nature and severity of the adverse events. All drugs responsible for serious adverse events were changed or discontinued. Three studies had a moderate risk of methodological bias. Conclusions Strategies to minimize the risk of adverse drug reactions and improve adherence to therapy have a strong potential to improve adherence to therapy, improve patient quality of life, and reduce antibiotic resistance. However, high-level evidence on the effectiveness of strategies to minimize the risk of adverse events is limited. Key messages Strategies to manage the risk of adverse drug reactions have a strong potential benefit for TB patients on treatment; and improve adherence to treatment. High-level evidence on the effectiveness of strategies to minimize the risk of adverse events is limited.

Retrospective analysis of skin photosensitivity induced by pirfenidone.

Knowledge regarding the association between photosensitivity and pirfenidone is based mainly on case reports. The purpose of this article was to evaluate the clinical characteristics of photosensitivity associated with pirfenidone. We collected studies on photosensitivity induced by pirfenidone published from 2008 to 31 August 2021 in Chinese and English for a retrospective analysis. The median age was 70years (range 57-80) in 22 patients with pirfenidone-induced photosensitivity. The dose at the onset of symptoms ranged from 600 to 2403mg for the treatment of idiopathic pulmonary fibrosis. Pirfenidone-induced photosensitivity occurred within 1week in some patients and up to 8months in others. The most common clinical manifestation of photosensitivity caused by pirfenidone was itching on body parts exposed to sunlight (back of hands, face, neck, and limbs) in 15 patients followed by erythema in 13 patients. Histopathological examination revealed necrotic keratinocytes, lymphocytic inflammatory cell infiltrate, hyperkeratosis and liquefaction degeneration in 5 patients. The photosensitivity test showed a markedly decreased minimum erythema dose (MED) of 7-228mJ/cm2 UV-B in 4 patients and 4.86-12J/cm2 UV-A in 5 patients. The clinical symptoms were significantly improved or completely relieved with a median time of 4weeks (range 1-8) after drug withdrawal, dose reduction or systemic and topical glucocorticoid therapy. Clinicians should be aware of the potential phototoxic effects of pirfenidone and should inform patients to take pirfenidone during (or after) a meal, avoid sun exposure, wear protective clothing, and apply broad-spectrum sunscreen with high ultraviolet UVA and UVB protection.

P-194: Pomalidomide-based therapy in Relapsed/Refractory Multiple Myeloma: a real-world single-center experience

P-194: Pomalidomide-based therapy in Relapsed/Refractory Multiple Myeloma: a real-world single-center experience

P-210: Oral ixazomib (Ixa), IV daratumumab (Dara), and dexamethasone (dex; IDd) in relapsed/refractory multiple myeloma (RRMM) patients (pts) with 1–3 prior therapies: phase 2 study interim analysis (IA)

<h3>Background</h3> Proteasome inhibitors (PIs) & monoclonal antibodies are backbones of RRMM treatment; Ixa is approved with lenalidomide-dex for pts with ≥1 prior therapy, & Dara is approved in various regimens, including with bortezomib-dex (DVd). In CASTOR (DVd vs Vd), Vd was limited to 8 cycles; however, prolonged PI therapy is associated with improved outcomes. The IDd regimen with oral Ixa may enable longer-term PI therapy than with DVd. We evaluate IDd using a treat-to-progression approach. <h3>Methods</h3> Ixa/Dara-naive RRMM pts receive Ixa 4 mg (days 1, 8, 15), Dara 16 mg/kg (days 1, 8, 15, 22, cycles 1–2; days 1, 15, cycles 3–6; day 1, cycles 7+), & dex 20 mg (days 1, 2, 8, 9, 15, 16, 22, 23) in 28-day cycles. The primary endpoint is ≥ very good partial response (VGPR) rate; secondary endpoints include overall response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), & safety. We report data from the 2nd IA, conducted after ~50% of PFS events had occurred (data cutoff: 1/1/2021). <h3>Results</h3> 61 pts were enrolled (median age 69 y, 19.7% aged ≥75 y; 19.7% International Staging System stage III; 26.2% high-risk cytogenetics [del(17p), t(4;14), t(14;16)], 42.6% expanded high-risk cytogenetics [high-risk &/or amp1q21]); 59.0/26.2/14.8% of pts had received 1/2/3 prior lines. At data cutoff, pts had received a median of 16 IDd cycles; 37.7% were ongoing. Relative dose intensity (RDI) of Ixa, Dara, & dex was 20%) TEAEs were diarrhea (39.3%), anemia (27.9%), thrombocytopenia (26.2%), & fatigue (21.3%); common (>5%) G≥3 TEAEs were pneumonia (11.5%), thrombocytopenia (11.5%), & anemia (8.2%). Infections & Infestations TEAEs were seen in 57.4% of pts (G≥3 24.6%) and were serious in 26.2%, including pneumonia (9.8%) and COVID-19/pneumonia (4.9%). Rate of peripheral neuropathy (PN) was 18.0% (1.6% G≥3). PN was 28.6% & 12.5% in pts with & without history of PN, respectively. Study drug dose modifications, reductions & discontinuations due to TEAEs were required in 57.4% (Ixa 36.1%, Dara 34.4%, dex 41.0%), 32.8%, & 9.8% of pts, respectively. Four pts died on study due to sudden death, COVID-19 pneumonia, septic shock, & COVID-19 (none were considered study drug-related). <h3>Conclusion</h3> These IA data suggest IDd has a positive risk-benefit profile in RRMM pts, with a ≥VGPR rate of 30.5%, median PFS of 17.0 m, & a low rate of discontinuation due to TEAEs. The final analysis of this ongoing study is expected in 2022.

The State of the Art of Theranostic Nanomaterials for Lung, Breast, and Prostate Cancers.

The synthesis and engineering of nanomaterials offer more robust systems for the treatment of cancer, with technologies that combine therapy with imaging diagnostic tools in the so-called nanotheranostics. Among the most studied systems, there are quantum dots, liposomes, polymeric nanoparticles, inorganic nanoparticles, magnetic nanoparticles, dendrimers, and gold nanoparticles. Most of the advantages of nanomaterials over the classic anticancer therapies come from their optimal size, which prevents the elimination by the kidneys and enhances their permeation in the tumor due to the abnormal blood vessels present in cancer tissues. Furthermore, the drug delivery and the contrast efficiency for imaging are enhanced, especially due to the increased surface area and the selective accumulation in the desired tissues. This property leads to the reduced drug dose necessary to exert the desired effect and for a longer action within the tumor. Finally, they are made so that there is no degradation into toxic byproducts and have a lower immune response triggering. In this article, we intend to review and discuss the state-of-the-art regarding the use of nanomaterials as therapeutic and diagnostic tools for lung, breast, and prostate cancer, as they are among the most prevalent worldwide.

Valproate-associated hair abnormalities: Pathophysiology and management strategies.

To review the literature on valproate-associated hair abnormalities and the available treatment options. We searched PubMed and Google Scholar with keywords including "valproate", "valproic acid", "hair", "alopecia", and "effluvium," supplemented with hand search from cross-references. We included all types of studies including case reports in this review. The pathophysiology of hair loss includes telogen effluvium, biotin, mineral deficiency, and possibly hyperandrogenism. Diagnosis is based on history of hairloss or abnormalities following valproate treatment, and is confirmed by use of simple clinical tests such as pull test and modified wash test. Treatment involvesreassurance and advice on hair care, and if possible drug discontinuationordose reduction. Medications such as biotin and other vitamins with mineralssupplementation is effective for most individuals with hair loss. Other treatment options are agomelatine, topical valproate or minoxidil, though these lack evidence. Hair abnormalities with valproate are common, benign adverse effects, and management includes general measures and specific treatment options.

Prophylactic Role of Mandukasan and OM Chanting Patients Who Survives with Diabetes

Diabetes Mellitus is one of the most chronic non-communicable diseases in the enire world. Yoga is an part of Indian culture which doing ancient times by our rishi munis. Nowadays science has been considered yoga for management of various diseases i.e. hypertension, diabetes, asthma. In this case study had been conducted to understand effect of yoga in type 2 diabetics. Yoga group were put through mandukasanasana and mandukasan with OM chanting for 40 days. Biochemical parameters was performed i.e. FBG, PPBG and HbA1C. It can be concluded that mandukasan with OM chanting has been helpful as an adjunct to medical therapy to minimize the biochemical parameters. Yoga therapy helpful for the status of diabetics in terms of reduction of drug doses, physical and mental alertness and prevention of various complications related to diabetes.&#x0D; Keywords: Mandukasan, OM Chanting, Diabetes

Peripheral neuropathy in patients with multiple myeloma: molecular effects of bortezomib

Multiple myeloma (MM) is a B cell neoplasm characterized by uncontrolled growth of malignant plasma cells within the bone marrow . The introduction of new treatment regimens and medicinal substances, particularly proteasome inhibitors (e.g. bortezomib or carfilzomib) and immunomodulatory drugs (e.g. lenalidomide, pomalidomide, and monoclonal antibodies), have radically changed MM therapy by improving the response rate and progression-free survival. However, these potentially effective drugs are associated with a number of side effects, the most serious of which include peripheral neuropathy, which appears in 40% of MM patients with bortezomib treatment and up to 70% with thalidomide treatment during long-term exposure. Usually, symptoms of neuropathy disappear after drug discontinuation or dose reduction. However, as a result, the effectiveness of the treatment is lowered and survival time is reduced. The pathogenesis of chemotherapy-induced peripheral neuropathy is not fully understood. Current research focuses on areas such as the change in the expression of genes responsible for the proper functioning of the nervous system, neuroprotective protein factors, oxidative stress, pro-inflammatory factors and epigenetic changes (miRNA, DNA methylation or histone acetylation). Thoroughly elucidating the mechanisms responsible for the development of chemotherapy-induced peripheral neuropathy will allow us to reduce/eliminate this side effect and improve quality of life for patients.

Neoadjuvant treatment as a window to chemotherapy driven alterations to the genome and transcriptome of high-grade serous ovarian cancer

<h3>Objectives:</h3> The growing use of neoadjuvant chemotherapy to treat advanced stage high-grade serous ovarian cancer (HGSOC) creates an opportunity to better understand chemotherapy-induced mutational and gene expression changes. A tumor's response to chemotherapy may provide prognostic information or allow prediction of future response to therapy. We performed a cohort study to assess changes in the tumor genome and transcriptome in women receiving neoadjuvant chemotherapy and explored the role of the AP-1 pathway on chemotherapy response. <h3>Methods:</h3> In our single-institution study, we included 50 patients with stage IIIC or IV HGSOC who received neoadjuvant chemotherapy and had archived pre- and post-chemotherapy tumor samples. We performed whole exome RNA-sequencing and panel sequencing of 596 cancer-related genes from FFPE specimens. Significantly differentially expressed genes (DEGs) between pre- and post-chemotherapy samples were identified using paired statistical analysis (GFOLD). An AP-1 inhibitor, SR 11302, was used to explore the in vitro role of AP-1 signaling on chemotherapy response. <h3>Results:</h3> Following tissue and sequencing quality control, the final patient cohort consisted of a total of 32 paired DNA and 20 paired RNA samples from pre- and post-neoadjuvant chemotherapy. Eighteen patients within the cohort had both DNA and RNA available. Mutations in <i>TP53</i> were identified in 31/32 patients. There was a shift in mutational class after chemotherapy from C>G to C>T (p=0.035). Gene expression analyses found that most DEGs were upregulated by chemotherapy, primarily in the chemotherapy resistant specimens. Several genes were solely upregulated in chemotherapy resistant patients, including AP-1 transcription factor family genes (FOS, FOSB, FRA-1), genes implicated in chemotherapy resistance (DUSP1, SERPINE1, MEOX2, ERRFI1), and genes previously associated with cell survival (CCL14, HAS1, NR4A1). The in vitro role of AP-1 was demonstrated by observing an increase in c-Jun expression after treatment with paclitaxel, but not carboplatin. Combining paclitaxel or carboplatin with SR 11302 decreased the IC50 of both therapies. Pairing these therapies additionally demonstrated synergistic effects with a favorable combination index of <1, at effect sizes >75% for paclitaxel and >90% for carboplatin. Additionally, favorable drug dose reduction indices were found at large effect sizes. These observations were most pronounced with the SR 11302 and paclitaxel combination. <h3>Conclusions:</h3> Genomic analysis of tumors before and after chemotherapy did not reveal any consistent mutations associated with chemotherapy response. Gene expression analysis suggested a link between upregulation of the AP-1 pathway in chemotherapy resistant patients after treatment. In vitro experiments indicated that AP-1 inhibition synergizes with standard cytotoxic agents, particularly paclitaxel, and might be a novel approach to overcome or delay paclitaxel resistance in HGSOC.

Sexual function and depressive symptoms in men with hypoprolactinaemia secondary to overtreatment of prolactin excess: A pilot study

BackgroundLow prolactin levels have been found to impair libido and arousal, as well as to reduce wellbeing in young women. ObjectiveThe aim of this study was to investigate whether drug-induced hypoprolactinaemia affects male sexual function and depressive symptoms. MethodsThe study population consisted of three groups of young and middle-aged men. Two groups were treated with dopamine agonists because of previous hyperprolactinaemia but differed in current prolactin levels, which were <3ng/ml (n=12; group 1) or within the reference range (3–20ng/ml) (n=20; group 2). The control group (group 3) included 24 dopamine agonist-naïve normoprolactinaemic men. During the study, doses of dopaminergic agents in group 1 were reduced by 25–50% compared to doses before the start of the study. Circulating levels of prolactin, testosterone, free calculated testosterone, dehydroepiandrosterone-sulphate, oestradiol and gonadotropins were measured upon enrolment in the study and six months later. Moreover, at the beginning and the end of the study, all men enrolled completed questionnaires assessing sexual functioning (IIEF-15) and depressive symptoms (BDI-II). ResultsGroup 1 differed from groups 2 and 3 in domain scores for sexual desire and erectile function, and in the overall BDI-II score. It was also characterised by lower levels of total testosterone and calculated free testosterone. Reduction of drug doses normalised sexual desire and erectile function, reduced BDI-II scores and increased prolactin as well as total and free calculated testosterone. Groups 2 and 3 did not differ from each other in sexual functioning, depressive symptoms or hormone levels. ConclusionsThe results obtained indicate that men with dopamine agonist-induced hypoprolactinaemia are characterised by impaired sexual functioning and reduced wellbeing. These disturbances are a consequence of subnormal prolactin levels and do not seem to reflect adverse effects of dopamine agonists.

Primary results of the randomized trial of metformin administration in polycystic kidney disease (TAME PKD)

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by growth of kidney cysts and glomerular filtration rate (GFR) decline. Metformin was found to impact cystogenesis in preclinical models of polycystic disease, is generally considered safe and may be a promising candidate for clinical investigation in ADPKD. In this phase 2 two-year trial, we randomly assigned 97 patients, 18-60 years of age, with ADPKD and estimated GFR over 50 ml/min/1.73 m2, in a 1:1 ratio to receive metformin or placebo twice daily. Primary outcomes were medication safety and tolerability. Secondary outcomes included estimated GFR decline, and total kidney volume growth. Thirty-eight metformin and 39 placebo participants still received study product at 24-months. Twenty-one participants in the metformin arm reduced drug dose due to inability to tolerate, compared with 14 in the placebo arm (not significant). Proportions of participants experiencing serious adverse events was similar between the groups. The Gastrointestinal Symptoms Rating Scale score was low at baseline and did not significantly change over time. The annual change for estimated GFR was -1.71 with metformin and -3.07 ml/min/1.73m2 per year with placebo (mean difference 1.37 {-0.70, 3.44} ml/min/1.73m2), while mean annual percent change in height-adjusted total kidney volume was 3.87% in metformin and 2.16% per year in placebo, (mean difference 1.68% {-2.11, 5.62}). Thus, metformin in adults with ADPKD was found to be safe and tolerable while slightly reducing estimated GFR decline but not to a significant degree. Hence, evaluation of efficacy requires a larger trial, with sufficient power to detect differences in endpoints.

Preliminary Results from an Ongoing Phase 1/2 Study of INCB053914, a Pan-Proviral Integration Sites for Moloney Virus (PIM) Kinase Inhibitor, in Patients with Advanced Hematologic Malignancies

Preliminary Results from an Ongoing Phase 1/2 Study of INCB053914, a Pan-Proviral Integration Sites for Moloney Virus (PIM) Kinase Inhibitor, in Patients with Advanced Hematologic Malignancies