Unacceptable Adverse Effects Research Articles

Efficacy and safety of intralesional triamcinolone acetonide alone and its combination with 5‐ fluorouracil in keloids and hypertrophic scars: Randomized, parallel group, and double blinded trial

AbstractBackgroundTreatment of keloids and hypertrophic scars is challenging. The current first‐line treatment is a steroid which has high resistance and recurrence rate along with unacceptable adverse effects. Different studies involving the combination of TAC and 5‐FU that have been done so far showed better treatment outcomes in terms of efficacy and safety.ObjectiveThe objective of this study was to compare the efficacy and safety of intralesional triamcinolone acetonide alone and its combination with 5‐fluorouracil in patients with keloids and hypertrophic scars at 12 weeks follow‐up.MethodsIn this randomized parallel group double‐blinded clinical trial, we enroled 66 cases of keloids and hypertrophic scars randomly allocated into two treatment groups. Patients received an intralesional injection of triamcinolone acetonide (20 mg/mL) in Group A and an intralesional injection of a combination of triamcinolone acetonide (20 mg/mL) and 5‐fluorouracil (25 mg/mL) in Group B for every 2 weeks until 10 weeks and the final evaluation was done at 12 weeks follow‐up.ResultsThere was a reduction in all the parameters at every follow‐up visit in both groups. The ≥50% reduction in height, reduction in the VSS and POSAS scores, and good to excellent subjective improvement reported by both the patients and the observer were significantly greater in the combination group compared to TAC alone group. The response rate was faster and complications were lesser in the combination group as compared to TAC alone group.LimitationSingle‐centred, no long‐term follow‐up, and recurrence could not be assessed.ConclusionTAC alone and its combination with the 5‐FU both were effective in keloids and hypertrophic scars. Yet, the TAC and 5‐FU combination treatment was more efficacious with a faster response rate and safer than the TAC alone treatment.

The ConSoil project: An integrated framework for monitoring plant protection product residues in agricultural soil

AbstractPlant Protection Products (PPPs) are widely used to maintain high productivity and protect crops, but can have unintended toxic effects on beneficial non‐target soil organisms. To avoid unacceptable adverse effects of PPPs on soil organisms, a prospective risk assessment is carried out, which focuses on individual substances and their effects on a few individual species or groups. However, the reality of agricultural soils consists of complex networks of organisms exposed to mixtures of several PPP active substances. It is therefore essential to monitor PPP residues in soils. This paper describes the ConSoil project and its proposed framework for monitoring PPP residues in Swiss Agricultural soils which includes and integrates (1) risk‐based reference values for PPP residues in soil and (2) indicators of their effects on long‐term soil fertility. For risk‐based reference values, a proposal has been developed to derive Soil Guideline Values (SGVs) for PPP residues and a mixture risk assessment concept is being developed. Regarding indicators, a toolbox of ecological and ecotoxicological indicators will be proposed to reflect the protection goal of long‐term soil fertility in agricultural soils. For this objective, standardised and/or well‐established bioindicator methods will be selected for the key soil organisms that support soil fertility. To integrate SGVs and the biomonitoring toolbox, an adapted TRIAD approach is proposed, where generic SGVs are used as a screening tool to identify monitoring sites potentially at risk and to trigger more detailed monitoring. Detailed monitoring will refine the SGVs based on site‐specific characteristics and implement the bioindicator toolbox to measure the effects of PPP residues and their risk to long‐term soil fertility. As a novel integrated framework, it is essential to use the data generated in detailed assessments to calibrate and refine the SGVs and bioindicator tools and improve the monitoring over time.

Antiproliferative effect of Solanum nigrum L. water extract on breast can-cer cells: potential roles of apoptosis and oxidative stress.

Breast cancer is the most progressive cancer among women worldwide. The currently available chemotherapeutic agents induce severe unacceptable adverse effects in breast cancer patients. In this context, natural medicinal herbs are gaining importance to find non-toxic effective anticancer drugs. Solanum nigrum is one of the major traditional medicinal plants widely used in Ayurveda for the treatment of various diseases. This study investigated the anticancer effect of Solanum nigrum water extract (SNWE) against MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines. SNWE significantly induced oxidative stress-mediated apoptotic cell death in a concentration-dependent manner. Real-time PCR results illustrated the upregulation of proapoptotic genes and downregulation of antiapoptotic genes after SNWE treatment in MCF-7 and MDA-MB-231 cell lines. Immunofluorescence analysis showed increased expressions of apoptotic markers like p53, Caspase3 and BAX by SNWE treatment. In conclusion, the findings of this study indicate the antiproliferative effect and apoptosis-inducing property of SNWE in both cell lines. Further studies are warranted on testing the anticancer activity of S. nigrum L. using animal models of cancer.

Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients

BackgroundBempedoic acid, an ATP citrate lyase inhibitor, reduces low-density lipoprotein (LDL) cholesterol levels and is associated with a low incidence of muscle-related adverse events; its effects on cardiovascular outcomes remain uncertain.MethodsWe conducted a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects (“statin-intolerant” patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.ResultsA total of 13,970 patients underwent randomization; 6992 were assigned to the bempedoic acid group and 6978 to the placebo group. The median duration of follow-up was 40.6 months. The mean LDL cholesterol level at baseline was 139.0 mg per deciliter in both groups, and after 6 months, the reduction in the level was greater with bempedoic acid than with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid. The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P=0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P=0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P=0.001). Bempedoic acid had no significant effects on fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.ConclusionsAmong statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). (Funded by Esperion Therapeutics; CLEAR Outcomes ClinicalTrials.gov number, NCT02993406.)

Precious Gene: The Application of RET-Altered Inhibitors.

The well-known proto-oncogene rearrangement during transfection (RET), also known as ret proto-oncogene Homo sapiens (human), is a rare gene that is involved in the physiological development of some organ systems and can activate various cancers, such as non-small cell lung cancer, thyroid cancer, and papillary thyroid cancer. In the past few years, cancers with RET alterations have been treated with multikinase inhibitors (MKIs). However, because of off-target effects, these MKIs have developed drug resistance and some unacceptable adverse effects. Therefore, these MKIs are limited in their clinical application. Thus, the novel highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been accelerated for approval by the Food and Drug Administration (FDA), and clinical trials of TPX-0046 and zetletinib are underway. It is well tolerated and a potential therapeutic for RET-altered cancers. Thus, we will focus on current state-of-the-art therapeutics with these novel RET inhibitors and show their efficacy and safety in therapy.

A pharmacokinetic-pharmacodynamic model for chemoprotective agents against malaria.

Chemoprophylactics are a vital tool in the fight against malaria. They can be used to protect populations at risk, such as children younger than the age of 5 in areas of seasonal malaria transmission or pregnant women. Currently approved chemoprophylactics all present challenges. There are either concerns about unacceptable adverse effects such as neuropsychiatric sequalae (mefloquine), risks of hemolysis in patients with G6PD deficiency (8-aminoquinolines such as tafenoquine), or cost and daily dosing (atovaquone-proguanil). Therefore, there is a need to develop new chemoprophylactic agents to provide more affordable therapies with better compliance through improving properties such as pharmacokinetics to allow weekly, preferably monthly, dosing. Here we present a pharmacokinetic-pharmacodynamic (PKPD) model constructed using DSM265 (a dihydroorotate dehydrogenase inhibitor with activity against the liver schizonts of malaria, therefore, a prophylaxis candidate). The PKPD model mimics the parasite lifecycle by describing parasite dynamics and drug activity during the liver and blood stages. A major challenge is the estimation of model parameters, as only blood-stage parasites can be observed once they have reached a threshold. By combining qualitative and quantitative knowledge about the parasite from various sources, it has been shown that it is possible to infer information about liver-stage growth and its initial infection level. Furthermore, by integrating clinical data, the killing effect of the drug on liver- and blood-stage parasites can be included in the PKPD model, and a clinical outcome can be predicted. Despite multiple challenges, the presented model has the potential to help translation from preclinical to late development for new chemoprophylactic candidates.

Will immune therapy cure acute myeloid leukemia?

There is considerable recent progress in using immune therapy to treat lymphoid including monoclonal antibodies, antibody-drug and -radionuclide conjugates, bi-specific antibodies and chimeric antigen receptor T-cells (CAR-T-cells). Targets of these therapies are B-cell lineage-specific antigens such as CD19, CD20 and BCMA, not cancer-specific antigens. Given these immune therapy advances in lymphoid cancers one might expect similar success using immune therapy to treat acute myeloid leukemia (AML). However, this is not so. There is only one FDA-approved therapy of myeloid cancers, gemtuzumab ozogamicin (Myelotarg®) for AML approved > 10 years ago. Why this discordance? The answer lies in two considerations: (1) lack of a robust AML-specific target antigen(s); and (2) unacceptable adverse effects resulting from non-specificity of lineage-specific antigens such as CD33 and CD124. Also, most data suggest less immune surveillance against myeloid cancers compared with lymphoid cancers. For example, AML cells have an average of 0.28 mutation per megabase of DNA compared with 8.15 mutations for lung cancer, 40-fold less. The exception is the anti-AML effect associated with haematopoietic cell transplants, so-called graft- versu s-leukaemia (G v L). However, this effect occurs only in an allogeneic setting and is difficult or impossible to distinguish from graft- versus -host disease (G v HD). We can envision potential anti-AML immune therapy using two strategies: (1) antibodies; and (2) cell therapies. Synthetic biology may offer a solution to the problem of the lack of an AML-specific target antigens. I discuss the current state of immune therapy of AML and potential future directions. So, will immune therapy cure AML? Stand by.

Comparative efficacy of high-frequency repetitive transcranial magnetic stimulation to left dorsolateral prefrontal cortex as an augmentation strategy versus pharmacological augmentation in non-psychotic, unipolar, treatment-resistant depression: A randomized controlled trial.

Depression causes significant morbidity, disability and mortality, along with socioeconomic losses. Patients with depression who don't remit even with the second trial of anti-depressants need optimization, combination or augmentation strategies. Pharmacological strategies sometimes have unacceptable adverse effects. The aim of this study is to compare the efficacy of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) to left dorsolateral prefrontal cortex (DLPFC) with that of pharmacological augmentation strategies in unipolar non-psychotic treatment-resistant depression. This is a randomized controlled trial. Cases of unipolar, non-psychotic, treatment-resistant depression between ages 20 and 60 years were taken. The study period was from November 2016 to May 2018. Cases diagnosed as per ICD-10 criteria by a qualified psychiatrist. Cases of treatment-resistant depression (100) were divided into two arms by using a random number generator: rTMS arm and treatment as usual (TAU) arm. HF-rTMS to left DLPFC (rTMS group) and pharmacological augmentation with lithium, serotonin-dopamine antagonist, buspirone or thyroxine. In the rTMS arm, 44 patients and in TAU arm 41 completed the study. After 4 weeks of treatment augmentation, rTMS and TAU groups showed response rates of 52% and 46%, respectively. The difference between the two groups in terms of number of responders at the end of 4 weeks is not statistically significant. Additionally, factors associated with good response to rTMS were absence of a family history of psychiatric illness, no concomitant psychoactive substance use, being first episode of depression and mild-moderate severity of illness. The study did not find rTMS augmentation to be significantly better than standard pharmacological augmentation therapies.

Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus, and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, and their many side effects are well-documented. A group of compounds, the azoles, have activity against A fumigatus, and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been used in aerosolised form to treat invasive infection with A fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. This is an update of a previously published review. The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis: 1. improve clinical status compared to placebo or standard therapy (no placebo); and 2. do not have unacceptable adverse effects. If benefit was demonstrated, we planned to assess the optimal type, duration, and dose of antifungal therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, and abstract books of conference proceedings. Date of the most recent search of the Group's Trials Register was 28 September 2021. We searched ongoing trials registries, most recently on 11 March 2022. Earlier, we also approached pharmaceutical companies regarding possible unpublished trials. Published or unpublished randomised controlled trials, in which antifungal treatments were compared to either placebo or no treatment, or where different doses of the same treatment were used in the treatment of ABPA in people with cystic fibrosis. The searches identified six trials; none of which met the inclusion criteria for the review. We included no completed randomised controlled trials. There is currently one ongoing trial, which we may find eligible for a future update. At present, there are no randomised controlled trials that evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis, although one trial is currently ongoing. Trials with clear outcome measures are needed to properly evaluate the use of corticosteroids in people with ABPA and cystic fibrosis.

How Protective to the Environment is the Pesticide Risk Assessment and Registration Process in the United States?

The media, public, and other stakeholders are generally unaware of the degree of protection provided to the environment by the current pesticide registration process in the United States. Each pesticide product must meet extensive fate and toxicological data requirements (typically 100+ studies) to be considered by the U.S. Environmental Protection Agency (EPA). The EPA uses that information to conduct ecological, human health, and benefits assessments and make decisions on whether to register pesticides and, if so, under what conditions. The assessments rely on conservative assumptions, models, and inputs to consistently err on the side of caution throughout the pesticide registration process. The rigorous compliance requirements specified in the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and Endangered Species Act (ESA) are designed to preclude unacceptable adverse effects. However, this reality seldom, if ever, makes headlines. Pesticides are not causing the dire widespread apocalyptic effects often portrayed by some media outlets. Rather, pesticides have been doing what they were intentionally designed to do, controlling pests and increasing yields, within the stringent limitations of registered labels. The continually evolving pesticide registration process was originally predicated on the unintended adverse effects neither anticipated nor considered over 50 years ago, due to insufficient regulation and oversight at the time. However, the contemporary regulatory paradigm in the U.S. is data rich and analysis intensive by design, and perhaps understandably, biased towards ensuring environmental protection when registering pesticides. https://doi.org/10.21423/jrs-v09i2moore

158. Pain plan implementation for elective spine surgery: effect of patient opioid history categorization on inpatient and outpatient opioid use, length of stay, pain scores, and clinic resource utilization

<h3>BACKGROUND CONTEXT</h3> Opioid use is common after spine surgery, posing serious risks. Past experience with opioid pain medication is variable for patients undergoing elective spine surgery, which may have an effect on pain management. <h3>PURPOSE</h3> To analyze if pain plan categorization based on prior opioid experience is predictive of opioid use, length of stay (LOS), patient-reported pain scores, and pain management related clinic resource utilization following elective spine surgery. <h3>STUDY DESIGN/SETTING</h3> In an effort to minimize opioid use, the Madison pain plan was developed and implemented for patients undergoing elective spine surgery at UW Health in Madison, WI. The pain plan was built collaboratively with patients preoperatively, based on prior patient opioid experience. The plan includes intraoperative, postoperative, and planned discharge pain management medications. Patients are categorized based on their previous opioid experiences as follows: Category 1 – no previous opioid experience; Category 2 – previous opioid experience with adequate pain control and no adverse side effects; Category 3 – previous opioid experience with unacceptable pain control and/or adverse side effects; Category 4 – currently taking opioids preoperatively. <h3>PATIENT SAMPLE</h3> The study population consisted of patients ≥ 18 years of age undergoing elective spine surgery with two surgeons during the study period. <h3>OUTCOME MEASURES</h3> Primary outcome measures were inpatient opioid quantities, outpatient opioid prescription quantities, LOS, patient-reported pain scores, as well as frequency and complexity of clinic communication encounters. <h3>Methods</h3> A retrospective cohort study was performed for the outcome measures in patients within the 4 different pain plan categories over a one-year period (n=313). Extensive demographic data was collected to confirm group comparison validity. A biostatistician performed all statistical analyses. <h3>Results</h3> A regression model was used to control for patient age, and surgeon covariates. There was no difference in LOS or complexity of communication encounters amongst groups. Inpatient and outpatient opioid use were statistically significant (p<0.001) amongst the categories, with prescription quantities being greatest in Category 4, followed by Categories 2, 3, and 1, respectively. Inpatient opioid use had statistically significant differences when comparing Category 1 vs 2, 1 vs 4, and 3 vs 4 and outpatient opioid prescription quantities had statistically significant differences when comparing Category 1 vs 4, 2 vs 4, and 3 vs 4. Patient-reported pain scores were also significant (p<0.001) when comparing Category 1 vs 4, 2 vs 4, and 3 vs 4, and followed the same trend as opioid quantities. The number of communication encounters was significant (p=0.006) for Category 3 vs 4 only. <h3>Conclusions</h3> The pain plan was developed to collaboratively address postoperative pain control with patients. We feel that this approach sets expectations and limits. We expected both Category 3 and 4 patients to have the greatest opioid consumption, but this proved to be true only for Category 4. Category 3 and 4 patients required substantially more effort to build the pain plan, and we believe this extra effort is responsible for Category 3 patients showing characteristics similar to Category 1 and 2 patients. pain plan categorization based on patient-reported opioid experience is an effective tool for postoperative pain management at our institution. <h3>FDA DEVICE/DRUG STATUS</h3> This abstract does not discuss or include any applicable devices or drugs.

Selective transferrin coating as a facile strategy to fabricate BBB-permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer in vivo

Brain metastases are a most disturbing situation for breast cancer patients as there is basically no adequate treatment available. Any potential drug formulation has to be able to cross the blood-brain barrier (BBB) and specific to metastatic brain tumors without causing unacceptable adverse effects. Here, we developed transferrin-functionalized chimeric polymersomes carrying siRNA against polo-like kinase 1 (Tf@TBP-CPs-siPLK1) for treating brain metastatic MDA-MB 231 triple negative breast cancer (TNBC) xenografts in mice. To facilitate the loading of siPLK1, chimaeric polymersomes (CPs) were designed with spermine in the watery core and transferrin-binding peptide (TBP) at the surface, enabling attachment of transferrin after the siRNA loading step and thereby circumventing interference of transferrin with siRNA loading. Tf@TBP-CPs-siPLK1 encapsulating 3.8 wt% siRNA had a mean size of about 50 nm and a neutral zeta potential in phosphate buffer (PB). By virtue of the presence of transferrin, Tf@TBP-CPs demonstrated greatly (ca. 5-fold) enhanced internalization in MDA-MB 231 cells and transcytosis in the endothelial (bEnd.3) monolayer model in vitro as well as markedly improved accumulation in the orthotopically xenografted MDA-MB 231 tumor in the brain in vivo compared with control CPs lacking transferrin, supporting that transferrin mediates efficient BBB penetration and high specificity towards MDA-MB 231 cells. As a result, Tf@TBP-CPs-siPLK1 effectively inhibited tumor progression and prolonged the lifespan of the mice significantly. Selective transferrin coating appears to be a particularly facile strategy to fabricate BBB-permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer.

Emerging Technologies in Spinal Surgery: Ultra-Low Radiation Imaging Platforms.

Spine surgery has seen tremendous growth in the past 2 decades. A variety of safety, practical, and market-driven needs have spurred the development of new imaging technologies as necessary tools for modern-day spine surgery. Although current imaging techniques have proven satisfactory for operative needs, it is well-known that these techniques have negative consequences for operators and patients in terms of radiation risk. Several mitigating techniques have arisen in recent years, ranging from lead protection to radiation-reducing protocols, although each technique has limits. A hitherto-problematic barrier has been the fact that efforts to diminish radiation emission come at the cost of reduced image quality. To describe new ultra-low radiation imaging modalities that have the potential to drastically reduce radiation risk and minimize unacceptable adverse effects. A literature review was performed of articles and studies that used either of 2 ultra-low radiation imaging modalities, the EOS system (EOS-Imaging S.A., Paris, France) and LessRay (NuVasive, San Diego, CA). Both ultra-low radiation imaging modalities reduce radiation exposure in the preoperative and perioperative settings. EOS provides 3-dimensional reconstructive capability, and LessRay offers intraoperative tools that facilitate spinal localization and proper visual alignment of the spine. These novel radiation-reducing technologies diminish patient and surgeon exposure, aid the surgeon in preoperative planning, and streamline intraoperative workflow.

Pesticides are the dominant stressors for vulnerable insects in lowland streams

Despite elaborate regulation of agricultural pesticides, their occurrence in non-target areas has been linked to adverse ecological effects on insects in several field investigations. Their quantitative role in contributing to the biodiversity crisis is, however, still not known. In a large-scale study across 101 sites of small lowland streams in Central Europe, Germany we revealed that 83% of agricultural streams did not meet the pesticide-related ecological targets. For the first time we identified that agricultural nonpoint-source pesticide pollution was the major driver in reducing vulnerable insect populations in aquatic invertebrate communities, exceeding the relevance of other anthropogenic stressors such as poor hydro-morphological structure and nutrients. We identified that the current authorisation of pesticides, which aims to prevent unacceptable adverse effects, underestimates the actual ecological risk as (i) measured pesticide concentrations exceeded current regulatory acceptable concentrations in 81% of the agricultural streams investigated, (ii) for several pesticides the inertia of the authorisation process impedes the incorporation of new scientific knowledge and (iii) existing thresholds of invertebrate toxicity drivers are not protective by a factor of 5.3 to 40. To provide adequate environmental quality objectives, the authorisation process needs to include monitoring-derived information on pesticide effects at the ecosystem level. Here, we derive such thresholds that ensure a protection of the invertebrate stream community.

Drug desensitization in the coronavirus disease 2019 pandemic era: Local success to widespread potential

Drug desensitization in the coronavirus disease 2019 pandemic era: Local success to widespread potential

How I treat immune thrombocytopenia – a global view

How I treat immune thrombocytopenia – a global view

Acute antidepressant activity of ciprofloxacin and levofloxacin by using tail suspension test in swiss albino mice

Introduction: Depression is a psychological disorder of serious nature characterized by loss of interest in all most all the activities of life. In spite of many drugs available in the market, yet their is still search for newer drugs as the earlies drugs are known for its drawbacks like delayed onset of action and carries unacceptable adverse effects. Objectives: Our previous study with Ciprofloxacin and Levofloxacin have shown antidepressant activity by forced swim test in Swiss albino mice, hence we want to reconfirm the same in different models. Materials and Method: Swiss albino mice were divided randomly in to six groups of which each weighing 20-25 gm and the groups are as follows, Group I: 1% Gum acacia, 10ml/kg (Control), Group II: Imipramine (Standard), 10mg/kg, Group III and IV, Ciprofloxacin 25 & 50 mg/kg respectively, Group V & VI, Levofloxacin, 25 & 50 mg served as test group respectively. Each mouse was suspended by using a metal rod placed 50cm above the surface and its tail was pasted on to rod by an adhesive tape approximately 1cm away from the tip. Its mobility and immobility time was recorded discarding the initial 2minutes and considering the last 4 minutes of observation. Decrease in immobility time was considered to be having antidepressant effect. Results: Immobility duration based on mean± SD was 86.67 ± 2.61 sec for control, 52.50 ± 5.95 sec for Imipramine, 63.50 ± 19.00 sec and 67.17 ± 10.21 sec for Ciprofloxacin 25mg/kg and 50mg/kg respectively. Similarly, immobility duration for Levofloxacin was 68.67 ± 14.41 sec and 69.00 ± 18.85 sec respectively. Conclusion: Ciprofloxacin and Levofloxacin has not shown antidepressant activity by tail suspension test in Swiss albino mice. Keywords: Antidepressant, Ciprofloxacin, Levofloxacin, Tail suspension test

Treatment Rationale and Design for APPLE (WJOG11218L): A Multicenter, Open-Label, Randomized Phase 3 Study of Atezolizumab and Platinum/Pemetrexed With or Without Bevacizumab for Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer

BackgroundFirst-line treatment of non–small-cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with an immune checkpoint inhibitor (ICI). Bevacizumab is expected to enhance not only chemotherapy but also the efficacy of ICIs through blockade of vascular endothelial growth factor–mediated immunosuppression. We have now designed a randomized phase 3 study (APPLE, WJOG11218L, JapicCTI-194565) to evaluate the additional effect of bevacizumab administered together with platinum combination therapy and the ICI atezolizumab in patients with advanced nonsquamous NSCLC. Patients and MethodsCytotoxic chemotherapy–naive patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive either atezolizumab plus pemetrexed/carboplatin or atezolizumab, pemetrexed/carboplatin, and bevacizumab. Patients with genetic driver alterations such as those affecting EGFR or ALK are included if they have experienced disease progression or unacceptable adverse effects during treatment with at least one approved tyrosine kinase inhibitor. After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab is administered for up to 2 years until evidence of disease progression or development of unacceptable toxicity. The primary end point is progression-free survival. ConclusionThis is a phase 3 study to investigate the effect of adding bevacizumab to an ICI and platinum/pemetrexed combination therapy. If the primary objective is achieved, this study will provide a new standard treatment for cytotoxic chemotherapy–naive patients with advanced nonsquamous NSCLC.

Stopping and switching antipsychotic drugs.

SUMMARYIn general, specialist advice should be sought when stopping or switching antipsychoticsWhile antipsychotics are often needed long term, there are circumstances when clinicians, patients and families should reconsider the benefits versus the harms of continuing treatmentWithdrawal syndromes, relapse and rebound can occur if antipsychotics are discontinued, especially if they are stopped abruptly. Generally, they should be reduced and stopped slowly, ideally over weeks to monthsRelapse of psychosis and exacerbation occur in most patients with psychotic disorders, occasionally with drastic consequences. Sometimes this occurs many months after stopping antipsychoticsSwitching from one antipsychotic to another is frequently indicated due to an inadequate treatment response or unacceptable adverse effects. It should be carried out cautiously and under close observation

Regulation of apoptosis in the ischemic penumbra in the first day post-stroke.

Regulation of apoptosis in the ischemic penumbra in the first day post-stroke.