Significant Treatment-related Effects Research Articles

Engaging a New Treatment Paradigm: Elranatamab in Relapsed/Refractory Multiple Myeloma.

To review the therapeutic profile of elranatamab, a novel bispecific T-cell-redirecting therapy, in treating relapsed or refractory (R/R) multiple myeloma (MM). A PubMed search was conducted for English-language articles published from January 2000 through June 2024, using the search terms: PF-06863135, elranatamab, Elrexfio, and "Multiple Myeloma." Additional data were obtained from ClinicalTrials.gov and other pertinent publications and meeting abstracts. Clinical trials, guidelines, and prescribing information pertaining to elranatamab were included. The phase II MagentisMM-3 trial demonstrated an overall response rate of 61.0% (95% confidence interval, 51.8-69.6) in patients naïve to B-cell maturation antigen targeting therapy (cohort A, n = 123), establishing elranatamab monotherapy as a viable treatment option for patients with R/R MM who have received at least 4 prior lines of therapy. The duration of response and progression-free survival at 12 months were 75.3% and 56.6%, respectively. Despite the promising activity of elranatamab in R/R MM, the significant treatment-related adverse effects (AEs) associated with this therapy necessitate careful monitoring and expert management. Common AEs include cytokine release syndrome, neurotoxicity, hematologic toxicity, and infectious complications. The cost-effectiveness of elranatamab has yet to be evaluated. Elranatamab is approved by the Food and Drug Administration as a treatment option for patients with heavily pretreated R/R MM. Further studies are warranted to identify the optimal treatment strategy for elranatamab and other bispecific antibodies in the management of R/R MM.

Amorphous calcium carbonate as a novel potential treatment for osteoarthritis in dogs: a pilot clinical study.

Amorphous calcium carbonate (ACC) is a potential new treatment for canine osteoarthritis (OA) with novel mechanisms based on local pH modulation and targeting bone remodeling, inflammation, and pain. The aim of this pilot exploratory clinical study was to obtain initial data on the potential efficacy and safety of ACC in OA dogs and to determine if further investigation was appropriate using similar assessment methods. In this prospective, randomized, double-blind, controlled pilot study, 41 client-owned dogs were allocated in a 2:1 ratio to ACC: placebo given orally for 56 days. Efficacy assessments included improvements in pain and mobility using owner questionnaires [Canine Brief Pain Inventory (CBPI), Client Specific Outcome Measure (CSOM), and Veterinary Orthopedic Scores (VOS)]. Safety in the study population was monitored by veterinary examinations, clinical pathology, and adverse events. Fifty-three dogs were screened, of which 41 enrolled and served for the safety assessment. Thirty-six dogs were found evaluable for initial efficacy assessment. Three dogs given placebo (21.4%) and one given ACC (4.5%) were removed before day 56 due to owner-perceived pain and were considered treatment failures. There were no serious adverse events or clinically significant treatment-related effects in the study. Overall, ACC was found safe in the small study population. On day 56, proportionally more ACC than placebo dogs were treatment successes based on CBPI (45.5% vs. 21.4%) and CSOM (63.6% vs. 30.8%, respectively); however, these differences were not statistically significant (p = 0.15 and 0.06, respectively). On day 56, within the ACC group but not the placebo group, the CBPI, CSOM, and VOS assessments were lower compared to day 0 and day 14 (p < 0.05). The relatively small number of dogs limited the statistical power of the pilot study in evaluating the efficacy and safety of ACC. Study results support the conduct of larger, appropriately powered studies using similar assessments to confirm whether ACC may be a safe and effective treatment for OA in dogs.

Efficacy and safety of novel multifunctional M10 CAR-T cells in HIV-1-infected patients: a phase I, multicenter, single-arm, open-label study

Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.

Stereotactic high-dose irradiation for intramedullary metastases

To study the results of stereotactic high-dose irradiation for IMM considering local control of metastases, neurological status and life expectancy. Nineteen patients with 29 IMMs underwent high-dose irradiation (Cyber Knife G4 and TrueBeam STx devices) between 2016 and 2022. There were 1-10 fractions, radiation dose 14.0-35.0 Gy with isodose 70-100%. Local control and new spinal cord metastases were assessed using contrast-enhanced MRI. Clinical status and neurological functions were assessed using the Karnofsky and McCormick scales. Local control rates were 91% and 78% after 6 and 12 months, respectively. Overall survival after treatment was 7.3 months, 6- and 12-month overall survival - 58% and 37%, respectively. In addition, 8 patients were available for follow-up. Of these, 6 ones demonstrated improvement or stabilization of neurological function after treatment. The main cause of death was progression of the underlying disease. No significant treatment-related toxic effects were observed. High-dose irradiation is a safe, effective and time-saving treatment for IMM. Considering unadvisable surgical methods and chemotherapy for this pathology, we can recommend high-dose irradiation for patients with spinal cord metastases.

US Veterans Show Improvements in Subjective but Not Objective Sleep following Treatment for Posttraumatic Stress Disorder: Secondary Analyses from a Randomised Controlled Trial

Background. Sleep disturbances are a prominent feature of posttraumatic stress disorder (PTSD), and poorer sleep quality is associated with higher PTSD severity. This highlights the importance of monitoring sleep outcomes alongside PTSD symptoms in treatments targeting PTSD. Yet few studies monitor both sleep and PTSD outcomes, unless sleep is the primary treatment target. Furthermore, inconsistencies remain about the effects of first-line, evidence-based PTSD treatments on sleep. Methods. Here, we explored changes in sleep in secondary analyses from a randomised controlled trial that originally assessed the noninferiority of a breathing-based yoga practice (Sudarshan kriya yoga; SKY) to a first-line PTSD treatment (cognitive processing therapy (CPT)) for clinically significant PTSD symptoms among US veterans (intent-to-treat N = 85 ; per protocol N = 59 ). Sleep was assessed via subjective (self-reported sleep diary), PTSD symptom severity items (self-reported and clinician-administered insomnia/nightmare sleep items), and objective (wrist actigraphy) measures. Results. Following treatment, subjective sleep diary measures of quality, latency, and wake duration showed small effect size ( d = .24 − .39 ) improvements, with no significant differences between treatment groups. Significant improvements were also observed in PTSD sleep symptoms, though CPT ( d = .34 ) more reliably reduced nightmares while SKY (d = .44-.45) more reliably reduced insomnia. In contrast, there were no significant treatment-related effects for any of the actigraphy-measured sleep indices. Conclusions. To our knowledge, this is the first study to investigate sleep as an outcome of CPT or SKY for PTSD, across a combination of subjective diary, PTSD symptom severity, and objective actigraphic measures. Findings lend support to a growing body of evidence that trauma-focused psychotherapy for PTSD improves sleep and suggest that yoga-based interventions may also be beneficial for sleep among individuals with emotional or mental health disorders like PTSD. This trial is registered with NCT02366403.

Low-Dose Bevacizumab for the Treatment of Focal Radiation Necrosis of the Brain (fRNB): A Single-Center Case Series.

Focal radiation necrosis of the brain (fRNB) is a late adverse event that can occur following the treatment of benign or malignant brain lesions with stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS). Recent studies have shown that the incidence of fRNB is higher in cancer patients who received immune checkpoint inhibitors. The use of bevacizumab (BEV), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), is an effective treatment for fRNB when given at a dose of 5-7.5 mg/kg every two weeks. In this single-center retrospective case series, we investigated the effectiveness of a low-dose regimen of BEV (400 mg loading dose followed by 100 mg every 4 weeks) in patients diagnosed with fRNB. A total of 13 patients were included in the study; twelve of them experienced improvement in their existing clinical symptoms, and all patients had a decrease in the volume of edema on MRI scans. No clinically significant treatment-related adverse effects were observed. Our preliminary findings suggest that this fixed low-dose regimen of BEV can be a well-tolerated and cost-effective alternative treatment option for patients diagnosed with fRNB, and it is deserving of further investigation.

A Comprehensive 6-mo Prostate Cancer Patient Empowerment Program Decreases Psychological Distress Among Men Undergoing Curative Prostate Cancer Treatment: A Randomized Clinical Trial

BackgroundAlthough survival rates for newly diagnosed prostate cancer patients are very high, most of them will likely suffer significant treatment-related side effects, depression, or anxiety, affecting their quality of life. ObjectiveThe aim of this study was to examine the effects of a 6-mo online home-based physical, mental, and social support intervention, the Prostate Cancer Patient Empowerment Program (PC-PEP), on preventing psychological distress among men undergoing curative prostate cancer treatment. Design, setting, and participantsIn a crossover randomized clinical trial of 128 men aged 50–82 yr scheduled for curative prostate cancer surgery or radiotherapy (± hormone treatment), 66 received the 6-mo PC-PEP intervention and 62 were randomized to a waitlist-control arm and received the standard of care for 6 mo, and then PC-PEP to the end of the year. The PC-PEP intervention consisted of daily e-mails with video instructions providing education, patient activation, and empowerment on healthy living including physical and mental health, dietary recommendations, social support, physical and pelvic floor fitness, stress reduction using a biofeedback device, social connection and intimacy, and social support. Outcome measurements and statistical analysisThe primary outcome was nonspecific psychological distress (clinical cutoff ≥20) measured at baseline, and at 6 and 12 mo using the Kessler Psychological Distress Scale (K10). Results and limitationsAt 6 mo, patients in the waitlist-control group had 3.59 (95% confidence interval: 1.12–11.51) times higher odds for nonspecific psychological distress and need for psychological treatment than men who received the PC-PEP intervention. At 12 mo, the wait-list control group that received the intervention at 6 mo had higher psychological distress than the early group. ConclusionsPC-PEP delivered early following diagnosis significantly prevented the burden of psychological distress in men undergoing curative prostate cancer treatment compared with standard of care, or late (6 mo later) intervention. Patient summaryIn this report, we looked at the effectiveness of a program (Prostate Cancer Patient Empowerment Program: PC-PEP) developed with patients' engagement on the mental distress of patients awaiting curative treatment for their prostate cancer. The PC-PEP program lasted for 6 mo, and it prescribed, described, and demonstrated daily aerobic and strength training, kegels (pelvic floor training to help with urinary and sexual function), dietary changes that have been shown to be helpful in the prevention of prostate cancer and prostate cancer progression, stress reduction using a biofeedback device, as well as social and emotional support. All patients in the PC-PEP program were invited to a monthly video conference with the leads of the program who appeared in the 6 mo of daily videos prescribing the activities the patients were asked to watch and follow. The leads were a prostate cancer oncologist and a scientist in prostate cancer quality of life research. Half of the patients in this study received PC-PEP daily for the first 6 mo and were re-assessed at the end of the year. The other half received standard of care for 6 month and then received the intervention to the end of the year. The results of the study show that, at 6 mo, this intervention was effective at reducing the mental distress that accompanies a prostate cancer diagnosis and treatment compared with the standard of care. Mental distress was significantly reduced when the intervention was received early, compared with that received late (6 mo after scheduled curative treatment). We conclude that multi-faceted patient education and empowerment programming of this kind that is developed with patient engagement from the start is crucial to the care of patients diagnosed with prostate cancer and should be implemented in the standard of care. While treatment for prostate cancer is highly successful, side effects that accompany most treatments significantly affect the quality of life of patients. Here, we describe PC-PEP, a patient education and activation program that is cost effective, highly enforced by patients, and successful at reducing the impact of prostate cancer active treatment–related side effects on their psychological state. To learn more about this project, please visit www.pcpep.org. The program is now being tested in a phase 4 implementation trial throughout Canada and internationally (New Zealand), and is being expanded and tested for other types of cancer.

Acute, repeated inhalation toxicity, respiratory system irritation, and mutagenicity studies of 1,1,2,2-tetrafluoroethane (HFC-134) as the impurity in the pharmaceutical propellant 1,1,1,2-tetrafluoroethane (HFA-134a)

HFC-134 is the main impurity of HFA-134a. In order to verify the rationality of HFC-134 limits in HFA-134a and ensure the safety of HFA-134a as propellant in pharmaceutical metered-dose inhalers, acute inhalation toxicity, seven-day repeat dose inhalation irritation study, 21-day repeat dose inhalation toxicity study and reverse mutation assay of HFC-134 were tested to evaluate its inhalation safety. In acute inhalation studies, Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 100 000, 200 000, 400 000, 600 000, and 800 000 ppm for 4 h. Based on the mortality incidence, the calculated four-hour LC50 value for HFC-134 is 532 069 ppm for males and 502 058 ppm for females and acute inhalation toxicity is manifested as the lung lobes turn dark red. Exposures to 836 ± 67 ppm for 4 hours/day 7 days/week continuously did not induce local irritation of the respiratory system in Sprague-Dawley rats. Sprague-Dawley rats were exposed nose-only to HFC-134 at levels of 0 (control), 203 929 ppm and 394 871 ppm 2 h/day for 21 consecutive days, no significant treatment-related adverse effects was noted. Results from Ames studies demonstrated that HFC-134 was not mutagenic. Although HFC-134 has a very low acute inhalation toxicity, considering that its acute inhalation toxicity is higher than that of HFA-134a, and due to the high frequency of use of MDI by asthma patients, acceptance criteria of HFC-134 as the impurity in aerosol propellant HFA-134a should be lower than 8-h TWA WEEL value of 1000 ppm to ensure the safety of the MDI.

El compromiso articular temporomandibular como causa de cefaleas agudas y crónicas y otros síntomas otoneurológicos

ObjectivesThe aim of this work is to introduce a new condition within temporomandibular disorders, temporomandibular joint compromise (TMJC), a mandibular movement limiting disorder of extra-articular traumatic cause, and evaluate the response rate and safety of treatment. The limiting cause of mandibular movement is the lack of space between the mandibular ramus and maxilla. The main symptoms of TMJC include headache, dizziness, and tinnitus. In many cases, the headache is previously diagnosed as a migraine. MethodsData were collected from 54 patients aged between 6 and 59 years that had a confirmed diagnosis of migraine according to the 3rd Edition of the International Headache Classification of the International Headache Society of 2018, and were treated for TMJC in a dental clinic. They also presented with other otolaryngological symptoms. A retrospective quasi-experimental study without a control group was carried out due to ethical considerations related to the harmless nature of the treatment. ResultsAfter treatment of TMJC, migraine symptoms disappeared in 52 patients (96.3%, P<.001), and persisted, although with clinical improvement, in 2 (3.7%). There was also an improvement in the other associated symptoms: dizziness disappeared in 23 out of 27 affected patients (85.21%, P<.001), and tinnitus disappeared in the 31 affected patients (100%, P<.001). No significant treatment-related side effects were observed. ConclusionsThis study shows the high rate of response and safety of the treatment of TMJC.

Evaluation of the neurotoxic effects of engineered nanomaterials in C57BL/6J mice in 28-day oral exposure studies

In recent years, concerns have emerged about the potential neurotoxic effects of engineered nanomaterials (NMs). Titanium dioxide and silver are among the most widely used types of metallic NMs. We have investigated the effects of these NMs on behaviour and neuropathology in male and female C57BL/6J mice following 28-day oral exposure with or without a 14-day post-exposure recovery. The mice were fed ad libitum with food pellets dosed with 10 mg/g TiO2, 2 mg/g polyvinylpyrrolidone-coated Ag or control pellets. Behaviour was evaluated by X-maze, open field, string suspension and rotarod tests. Histological alterations were analysed by immunohistochemistry and brain tissue homogenates were investigated for markers of oxidative stress, inflammation and blood-brain barrier disruption. Effects of the NMs on tyrosine and serine/threonine protein kinase activity in mouse brains were investigated by measuring kinase activity on peptide microarrays.Markers of inflammation, oxidative stress and blood-brain barrier integrity were not significantly affected in the male and female mice following exposure to Ag or TiO2. Both types of NMs also revealed no consistent significant treatment-related effects on anxiety and cognition. However, in the Ag NM exposed mice altered motor performance effects were observed by the rotarod test that differed between sexes. At 1-week post-exposure, a diminished performance in this test was observed exclusively in the female animals. Cortex tissues of female mice also showed a pronounced increase in tyrosine kinase activity following 28 days oral exposure to Ag NM. A subsequent Inductively Coupled Plasma - Mass Spectrometry (ICP-MS) based toxicokinetic study in female mice revealed a rapid and persistent accumulation of Ag in various internal organs including liver, kidney, spleen and the brain up to 4 weeks post-exposure. In conclusion, our study demonstrated that subacute exposure to foodborne TiO2 and Ag NMs does not cause substantial neuropathological changes in mice. However, the toxicokinetic and specific toxicodynamic findings indicate that long-term exposures to Ag NM can cause neurotoxicity, possibly in a sex-dependent manner.

Target animal safety evaluation of a novel topical combination of esafoxolaner, eprinomectin and praziquantel for cats.

The safety profile of NexGard® Combo, a novel topical product for cats combining esafoxolaner, eprinomectin and praziquantel, for the treatment and prevention of internal and external parasites, was evaluated in kittens, in two margin-of-safety studies (Studies #1 and #2), and in an oral tolerance study (Study #3). In the margin of safety studies, kittens were dosed several times topically with multiples of the maximum exposure dose (1×): in Study #1, 3× and 5× doses four times at 2-week intervals; in Study #2, 1×, 3× and 5× doses six times at 4-week intervals. In Study #3, kittens were dosed orally once with a 1× dose. Furthermore, in Study #1, another group of kittens was dosed topically twice at a 4-week interval with a formulation of esafoxolaner as the sole active ingredient dosed at 23×. Physical examinations and clinical pathology analyses were performed throughout the studies, followed by necropsy and detailed histopathological evaluation in Studies #1 and #2. No significant treatment related effects were observed in the three studies, except for one occurrence of reversible neurological signs attributed to eprinomectin in one cat after the third 5× dose in Study #2, with clinical signs observed nine hours after dosing, pronounced for a few hours, significantly improved the next day, and absent 2 days after dosing. In conclusion, NexGard® Combo was demonstrated safe in kittens following repeated topical administrations and following oral ingestion, and very high topical doses of esafoxolaner were well tolerated.

Dextran sulfate sodium mouse model of inflammatory bowel disease evaluated for systemic genotoxicity via blood micronucleus and Pig-a gene mutation assays

Inflammatory bowel disease (IBD) is an important risk factor for gastrointestinal cancers. Inflammation and other carcinogenesis-related effects at distal, tissue-specific sites require further study. In order to better understand if systemic genotoxicity is associated with IBD, we exposed mice to dextran sulfate sodium salt (DSS) and measured the incidence of micronucleated cells (MN) and Pig-a mutant phenotype cells in blood erythrocyte populations. In one study, 8-week-old male CD-1 mice were exposed to 0, 1, 2, 3 or 4% w/v DSS in drinking water. The 4-week in-life period was divided into four 1-week intervals-alternately on then off DSS treatment. Low volume blood samples were collected for MN analysis at the end of each week, and cardiac blood samples were collected at the end of the 4-week period for Pig-a analyses. The two highest doses of DSS were observed to induce significant increases in reticulocyte frequencies. Even so, no statistically significant treatment-related effects on the genotoxicity biomarkers were evident. While one high-dose mouse showed modestly elevated MN frequencies during the DSS treatment cycles, it also exhibited exceptionally high reticulocyte frequencies (e.g. 18.7% at the end of the second DSS cycle). In a second study, mice were treated with 0 or 4% DSS for 9-18 consecutive days. Exposure was continued until rectal bleeding or morbidity was evident, at which point the treatment was terminated and blood was collected for MN analysis. The Pig-a assay was conducted on samples collected 29 days after the start of treatment. The initial blood specimens showed highly elevated reticulocyte frequencies in DSS-exposed mice (mean ± SEM = 1.75 ± 0.10% vs. 13.04 ± 3.66% for 0 vs. 4% mice, respectively). Statistical analyses showed no treatment-related effect on MN or Pig-a mutant frequencies. Even so, the incidence of MN versus reticulocytes in the DSS-exposed mice were positively correlated (linear fit R2 = 0.657, P = 0.0044). Collectively, these results suggest that in the case of the DSS CD-1 mouse model, systemic effects include stress erythropoiesis but not remarkable genotoxicity. To the extent MN may have been slightly elevated in a minority of individual mice, these effects appear to be secondary, likely attributable to stimulated erythropoiesis.

Megacolon in inflammatory bowel disease: response to infliximab

Megacolon is a serious complication of inflammatory bowel disease that often requires a colectomy. Infliximab is a therapeutic alternative when conventional treatment fails, before resorting to surgery. Its use is currently based on the publication of isolated cases. We present a series of 12 patients with megacolon treated with infliximab, five with signs of systemic toxicity. Seventy-five percent of the patients avoided a colectomy during their acute episode after early infliximab treatment, 2.45 days after the megacolon diagnosis. There was a greater risk of surgery among patients with ulcerative colitis and toxicity criteria. Two more patients required follow-up surgery despite long-term infliximab treatment. No patient suffered significant treatment-related adverse effects or significant post-surgery complications.

Evaluation of Sub-acute and Sub Chronic Toxicity Profile of the Aqueous Leaf Crude Extract of Melanthera Scandens (Schumach &amp; Thonn) in Wistar Rats

Aims: Although Melanthera scandens is a plant widely used in traditional medicine for the management of seizures, stomach ulcers and sores, dysmenorrhea, diabetes and malaria, there was scanty information about its safety. There was, therefore, a need to evaluate the sub-acute and subchronic toxicity studies of this plant which would reflect on its safety.&#x0D; Methodology: This was an experimental laboratory study. The research was conducted at Kampala International University-Western Campus at the Pharmacology laboratory from February to June 2017. The sub-acute toxicity was evaluated after administering daily oral doses of M. scandens crude extract (250, 500 and 1000 mg/kg) for 28 days and 90 days for subchronic study, after which the effect on haematological, biochemical and histopathological parameters were assessed in male and female Wistar rats (five of each sex).&#x0D; Results: Sub-acute toxicity results revealed that there was a significant decrease in the AST between the male Wistar rats that received 250 mg/kg (P= .005) and those that received 500 mg/kg (P= .05) as compared with the control group. Subchronic studies showed a significant increase in ALP (P= .05) at 1000 mg/kg compared with 500 mg/kg. Terminal necropsy did not reveal any treatment-related histopathological findings. There were also no toxicologically significant treatment-related effects on haematological parameters. The sub-acute toxicity results suggest that doses of 250mg/kg and 500mg/kg are safe and could be hepatoprotective due to reduced levels of AST and ALP, while the subchronic toxicity study results suggest that doses greater than 1000 mg/kg could be toxic to the plasma membrane, liver cells or endoplasmic reticulum due to increased ALP levels at this dose.&#x0D; Conclusion: The M. scandens crude extract did not cause significant toxicity on haematological and histopathological indices, after sub-acute and subchronic administration in Wistar rats.

Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?

The main objective of the study was to assess the effect of age on target tissue total gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective was to assess the potential developmental and long-term consequences of GBCA administration during neonatal and juvenile periods. A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either gadoterate or gadodiamide were administered concurrently by the intravenous route to healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the blood-brain barrier is functional as in humans after birth. The tests were conducted on 5 juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats. Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats were characterized by histopathological examination (including immunohistochemistry for glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by fluorescence microscopy. All tests were performed blindly on randomized animals. Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in adult rats having received gadodiamide. Persisting (up to completion of the study) T1 hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem ratio was observed in adult rats compared with juvenile rats, whereas no difference was noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in the gadodiamide-treated groups than in the gadoterate groups. No age-related differences were observed except in bone marrow where total Gd concentrations in gadodiamide-treated juvenile rats were higher than those measured in adults and similar to those measured in cortical bone tissue. No significant treatment-related effects were observed in histopathological findings or in development, behavior, and biochemistry parameters. However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the balance beam test, a high number of trials were excluded in the gadodiamide group because rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic effect. No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide. Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect, whereas Gd distribution in bone marrow was influenced by age. Further studies are required to assess the form of the retained Gd and to investigate the potential risks associated with Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of age, total Gd concentration in the brain and bone was 10- to 30-fold higher after administration of gadodiamide compared with gadoterate.

Effects of Momordica charantia (Bitter Melon) on Ischemic Diabetic Myocardium.

Objective: A rat model is here used to test a hypothesis that Momordica charantia (Bitter melon (BM)) extract favorably alters processes in cardiovascular tissue and is systemically relevant to the pathophysiology of type 2 diabetes (T2DM) and related cardiovascular disease. Methods: Male Lean and Zucker Obese (ZO) rats were gavage-treated for six weeks with 400 mg/kg body weight bitter melon (BM) extract suspended in mucin–water vehicle, or with vehicle (Control). Animals were segregated into four treatment groups, 10 animals in each group, according to strain (Lean or ZO) and treatment (Control or BM). Following six-week treatment periods, peripheral blood was collected from selected animals, followed by sacrifice, thoracotomy and mounting of isolated working heart setup. Results: Body mass of both Lean and ZO rats was unaffected by treatment, likewise, peripheral blood fasting glucose levels showed no significant treatment-related effects. However, some BM treatment-related improvement was noted in postischemic cardiac functions when Lean, BM-treated animals were compared to vehicle treated Lean control rats. Treatment of Lean, but not ZO, rats significantly reduced the magnitude of infarcted zone in isolated hearts subjected to 30 min of ischemia followed by 2 h of working mode reperfusion. Immunohistochemical demonstration of caspase-3 expression by isolated heart tissues subjected to 30 min of ischemia followed by 2 h of reperfusion, revealed significant correlation between BM treatment and reduced expression of this enzyme in hearts obtained from both Lean and ZO animals. The hierarchy and order of caspase-3 expression from highest to lowest was as follows: ZO rats receiving vehicle > ZO rats receiving BM extract > Lean rats treated receiving vehicle > Lean rats administered BM extract. Outcomes of analyses of peripheral blood content of cardiac-related analytics: with particular relevance to clinical application was a significant elevation in blood of ZO and ZO BM-treated, versus Lean rats of total cholesterol (high density lipoprotein HDL-c + low density lipoprotein LDL-c), with an inferred increase in HDL-c/LDL-c ratio—an outcome associated with decreased risk of atherosclerotic disease. Conclusions: BM extract failed to positively affect T2DM- and cardiovascular-related outcomes at a level suggesting use as a standalone treatment. Nevertheless, the encouraging effects of BM in enhancement of cardiac function, suppression of post-ischemic/reperfused infarct size extent and capacity to modulate serum cholesterol, will likely make it useful as an adjuvant therapy for the management of T2DM and related cardiovascular diseases.

Transcranial Focused Ultrasound in Functional Neurosurgery for Essential Tremor and Parkinson’s Disease: A Review Article

PURPOSE: Transcranial magnetic resonance guided focused ultrasound (MRgFUS) is a new development in the field of functional neurosurgery. A comprehensive review of the current literature was performed to evaluate of transcranial MRgFUS in treatment of essential tremor (ET) and Parkinson’s disease.METHODS: Articles available in electronic databases of PubMed, and Web of Science, as of July 2016 were reviewed. The strategy included a combination of key words 'MRgFUS', 'tremor', 'Parkinson', 'brain', ' head ', 'tumor', 'transcranial' and 'focused ultrasound' in the title and abstract of the manuscripts. In addition transcranial MRgFUS systems and cost-effectiveness of treatment were assessed. Finally, the major findings are summarized.RESULTS: Fifty-eight articles met the inclusion criteria for review. Among these, 15 studies eligible for inclusion in this review. The synthesis of the data demonstrated that, transcranial MRgFUS have been successfully used for treatment of essential tremor and Parkinson’s disease. Lesions were created under real-time MRI guidance, with peak temperatures of between 52° C and 63° C. Adverse events during transcranial MRgFUS reported such as headache, dizziness, vertigo, lip paresthesia, and hypogeusia. However, there were no significant treatment-related complications or side effects. At present, one of the limitations of transcranial MRgFUS is high price of treatment. However, continued advances in technology can be expected to further refine the high price market of transcranial MRgFUS.CONCLUSION: The findings showed that essential tremor and Parkinson’s disease can be effectively treated with transcranial MRgFUS method. Long-term clinical data are forthcoming.

Effects of Lemon and Seville Orange Juices on the Pharmacokinetic Properties of Sildenafil in Healthy Subjects.

PurposeSeveral severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose.MethodsWe conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration.ResultsCompared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30–60) and 18 % (90 % CI 108–129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63–75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study.ConclusionsAlthough it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.

IMPS-35UNUSUAL TUMOR INFILTRATING LYMPHOCYTES IN DE NOVO GLIOBLASTOMA FOLLOWING PRE-TREATMENT WITH ANTI-PD-L1 THERAPY FOR PRECEDING METASTATIC NSCLC: CASE PRESENTATION WITH DISCUSSION

The use of immunotherapy, specifically immune checkpoint inhibitors, is a rapidly emerging and evolving treatment modality for many solid tumor types. In this abstract, we describe a case of a 70 year old male with history of PD-L1 expressing metastatic poorly differentiated NSCLC treated with anti-PD-L1 therapy who was subsequently diagnosed with a glioblastoma with evidence of unexpected tumor infiltrating lymphocytes (TILs). The lung cancer was initially treated with combination chemotherapy with excellent response. This regimen was stopped prematurely due to significant treatment-related side effects. He then received the investigational anti-PD-L1 monoclonal antibody, MPDL3280A (Roche), under the Phase II Trial of MPDL3280A for PD-L1 positive locally advanced or metastatic NSCLC (NCT02031458). He experienced partial response without significant treatment-related side effects. Two weeks after completion of his 9th cycle of the study drug, he experienced altered mental status, personality changes, and confusion. A contrast brain MRI demonstrated a multifocal, rim-enhancing, left frontal lobe lesion with corpus callosal involvement. Of note, CT brain imaging prior to anti-PD-L1 study enrollment showed no evidence of abnormal enhancement. Stereotactic biopsy was performed with pathology showing glioblastoma with significant reactive lymphoid component noted (majority of lymphoid cells CD20 positive, scattered lymphocytes CD3 positive). He then underwent near image complete resection with pathology again demonstrating glioblastoma with 20-70% tumor necrosis, with 3 genomic alterations (CDKN2A/B loss; APCI1307K; TERT promoter – 124C > T) identified on Foundation One (Cambridge, MA) Next Generation Sequencing. This is the first reported case of a patient treated with anti-PD-L1 therapy for a high grade malignancy, who then developed a de novo glioblastoma with unusual biopsy findings of CD20 and CD3 positive TILs. Although more correlative studies are currently being performed, the immune implications for the use of immunotherapy for pre-treatment of glioblastomas may correspond to improved treatment response and patient outcomes.

In vivo antiarthritic activity of Rosa centifolia L. flower extract.

Introduction:Rosa centifolia L. (Rosaceae) have been used for the treatment of joint pain and rheumatoid arthritis (RA) in the traditional system of medicine.Aim:In this study, the antiarthritic activity of the alcoholic extract from the floral parts of R. centifolia was investigated.Materials and Methods:The anti-inflammatory and antiarthritic activity of R. centifolia alcoholic extract (RCAE: 32, 64, and 128 mg/kg) was evaluated using the carrageenan-induced paw edema and complete Freund's adjuvant (CFA) induced arthritis model. Serum from arthritic rats was collected for the estimation of pro-inflammatory cytokine levels. Further, the safety of RCAE was evaluated in an acute and sub-acute (28-day) oral toxicity study.Results:RCAE (64 and 128 mg/kg) significantly (P < 0.01) inhibited carrageenan-induced paw edema at 1, 3, and 6 h post carrageenan challenge and demonstrated significant (P < 0.01) antiarthritic activity on days 3, 7, 14, and 21 day following CFA immunization. Further, RCAE (128 mg/kg) treatment also produced a significant (P < 0.01) decrease in circulating pro-inflammatory cytokine levels as compared with control. Further, no toxicologically significant treatment-related effects were observed in the oral sub-acute toxicity study conducted with the extract.Conclusion:The result of study demonstrates the antiarthritic activity of R. centifolia and validates its traditional use for the treatment of RA.