First Day Of Administration Research Articles

Dosing Characteristics of Recombinant Human Luteinizing Hormone or Human Menopausal Gonadotrophin-Derived LH Activity in Patients Undergoing Ovarian Stimulation: A German Fertility Database Study

Objectives: The aim of the study was to evaluate dosing of recombinant human luteinizing hormone (r-hLH) or human menopausal gonadotrophin (hMG)-derived medications with LH activity in ovarian stimulation (OS) cycles for in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Design: A non-interventional study was performed to analyse data from the German RecDate database (January 2007–December 2011). Participants/Materials, Setting, Methods: Starting/total r-hLH/hMG dose, OS duration/cycle number, r-hLH/hMG initiation day (first day of administration), and population/cycle characteristics were assessed in women (≥18 years) undergoing OS for IVF/ICSI using r-hLH or hMG-derived medications (excluding corifollitropin alfa, clomiphene citrate, letrozole, mini/micro-dose human chorionic gonadotrophin, and urofollitropin alone). Data were summarized descriptively. Results: 67,858 identified cycles utilized medications containing r-hLH (10,749), hMG (56,432), or both (677). Mean (standard deviation) OS duration with r-hLH and hMG was 10.1 (4.43) and 9.8 (6.16) days, respectively. Median (25th–75th percentile) r-hLH starting dose (75.0 [75.0–150.0] IU) was consistent across patients regardless of age, infertility diagnosis, or gonadotrophin-releasing hormone (GnRH) protocol. Median (25th–75th percentile) hMG-derived LH activity starting dose was 225.0 (150.0–300.0) IU, regardless of GnRH protocol, but was lower in women aged <35 years and those with ovulation disorders/polycystic ovary syndrome. Median (25th–75th percentile) total dose for r-hLH (750.0 [337.5–1,125.0] IU) and hMG-derived LH activity (1,575.0 [750.0–2,625.0] IU) varied according to patients’ age, infertility diagnosis, cycle number, and r-hLH/hMG initiation day. GnRH antagonist use resulted in a numerically higher median total hMG-derived LH activity dose than GnRH agonist use. Limitations: The data used in this study were taken from electronic medical records relating to a specific timeframe (2007–2011) and therefore may not accurately reflect current clinical practice; however, it is likely that the differences between the two compounds would be maintained. Additionally, secondary data sources may suffer from uniformity and quality issues. Conclusions: The standard of care for OS cycles is described with respect to IVF/ICSI treatment including an LH component in Germany during the specified timeframe.

Evaluation the effect of amitriptyline and/or ashwagandha on body weight in male rats

study aims to examine and compare the effects of amitriptyline and ashwagandha on body weight in male rats by measurement weight for 4 weeks after their exposure to these two compound. Materials and Methods: This study used twenty healthy adult male albino rats that were 8-10 weeks old and weighed 200-250g. The animals were randomly divided to 4 groups (n= 5 /group), Group 1: were served as a control group received distilled water orally (1.0ml/kg) group 2: were administered amitriptyline (10mg/kg/ orally) group 3: were administered (200mg/kg) of ashwagandha root extract and group 4: were co-administered amitriptyline (10mg/kg) and ashwagandha (200mg/kg). After 30 days of administration, The body weight was measured every week starting from the first day of administration to last week of experimental for all rats. Results: According to the one-way analysis of variance(ANOVA) showed significant differences in growth value in the co-administered Amitriptyline and ashwagandha group ( 1.48±0.09) significantly increased in comparison with control group (1.27 ± 0.04) at week 4, otherwise, there is no significant differences in growth among groups at other periods at p value ≤0.05. Conclusion: Amitriptyline induced oxidative stress causing increased in body weight during experimental periods. Administration ashwagandha alone non-significant effect on body weight but when co-administration with amitriptyline significantly increase in body weight.

Cognitive functional therapy and non-steroidal anti-inflammatory drugs in the treatment of low back pain

A multidisciplinary approach including drug and non-drug methods is recommended for the treatment of chronic low back pain (CLBP). Kinesiotherapy, psychological methods, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be highly effective for CLBP. All of the listed methods contribute to significant relief and relief of pain, increase the patient’s social and physical activity, and improve the emotional state. Psychological methods help patients cope with catastrophizing pain, increase daily activities, and reduce the likelihood of disease recurrence. Results from clinical studies and systematic reviews demonstrate the effectiveness of psychological techniques such as cognitive behavioral therapy (CBT) and mindfulness therapy (mindfulness) in the treatment of CLBP. Cognitive Functional Therapy (CFT) is a promising new psychological method that was created on the basis of CPT. Clinical studies have been conducted confirming the efficacy of CFT in CLBP. CFT is aimed at regular therapeutic exercises, normalization of motor activity with avoidance of excessive physical and static exertion, avoidance of sedentary lifestyle and normalization of sleep, which is often disturbed in chronic back pain. In practice, patients with CLBP often have low adherence to increased physical activity during the day, to therapeutic exercises. In most cases, this is due to the fact that in the first days of increased physical activity there is an increase in pain. Patients mistakenly fear further progression of pain and disease. Prescribing NSAIDs usually results in pain reduction as early as the first days of administration, so patients with chronic musculoskeletal pain have an increased desire to engage in physical activity and therapeutic exercises. The choice of a particular NSAID medication is made individually, taking into account the co-morbidities and the risk of possible side effects. We discuss the use of nimesulide in CLBP.

Клинический случай пациентки с синдромом раздраженного кишечника

Синдром раздраженного кишечника (СРК) занимает одно из лидирующих мест по распространенности среди заболеваний органов пищеварения. В статье представлен клинический случай пациентки М. с диагнозом СРК с преобладанием диареи, установленным в соответствии с Римскими критериями IV 2016 г. Согласно этому документу, B. infantis 35624 (Альфлорекс) обладает способностью значительно уменьшать все симптомы СРК (абдоминальную боль/дискомфорт, вздутие, диарею, запор). С учетом этого пациентке М. назначен препарат Альфлорекс. Альфлорекс показал высокую эффективность в купировании всех симптомов СРК у пациентки уже с первых дней приема. Учитывая высокий уровень безопасности, удобство приема (1 раз/сутки), препарат В. infantis 35624 (Альфлорекс) открывает новые перспективы для пациента и врача в успешном контроле симптомов СРК.

Long Term Response to Circulating Angiogenic Cells, Unstimulated or Atherosclerotic Pre-Conditioned, in Critical Limb Ischemic Mice.

Critical limb ischemia (CLI), the most severe form of peripheral artery disease, results from the blockade of peripheral vessels, usually correlated to atherosclerosis. Currently, endovascular and surgical revascularization strategies cannot be applied to all patients due to related comorbidities, and even so, most patients require re-intervention or amputation within a year. Circulating angiogenic cells (CACs) constitute a good alternative as CLI cell therapy due to their vascular regenerative potential, although the mechanisms of action of these cells, as well as their response to pathological conditions, remain unclear. Previously, we have shown that CACs enhance angiogenesis/arteriogenesis from the first days of administration in CLI mice. Also, the incubation ex vivo of these cells with factors secreted by atherosclerotic plaques promotes their activation and mobilization. Herein, we have evaluated the long-term effect of CACs administration in CLI mice, whether pre-stimulated or not with atherosclerotic factors. Remarkably, mice receiving CACs and moreover, pre-stimulated CACs, presented the highest blood flow recovery, lower progression of ischemic symptoms, and decrease of immune cells recruitment. In addition, many proteins potentially involved, like CD44 or matrix metalloproteinase 9 (MMP9), up-regulated in response to ischemia and decreased after CACs administration, were identified by a quantitative proteomics approach. Overall, our data suggest that pre-stimulation of CACs with atherosclerotic factors might potentiate the regenerative properties of these cells in vivo.

What if melatonin could help patients with severe COVID-19?

What if melatonin could help patients with severe COVID-19?

203. Opportunities for Antimicrobial Stewardship in Febrile Neutropenia

BackgroundEmerging evidence suggests antibiotics may be safely discontinued before neutropenia resolves in patients without identifiable infection. We estimated the volume of encounters and antibiotic use for future stewardship interventions shortening FN treatment duration.MethodsThis retrospective cohort study used electronic health records from inpatient encounters on the hematologic malignancies ward at Duke University Hospital from 5/21/2018 to 12/31/2019 where patients received at least one antibiotic for an indication of “neutropenic fever.” The primary outcome was length of therapy (LOT) of broad Gram-negative (GN) agents, including cefepime, piperacillin-tazobactam, meropenem, or aztreonam. FN LOT was counted by calendar day, starting with the first day of administration of a broad GN agent and ending with antibiotic discontinuation or hospital discharge. Encounters with at least one positive blood culture (positive cohort) were compared to those with no positive blood cultures (negative cohort) to assess if culture positivity was associated with differences in FN LOT. We included the first FN LOT from each encounter in the negative cohort and the FN LOT associated with the first positive blood culture in the positive cohort. We used descriptive statistics and a Gaussian density function to calculate the percent of encounters exceeding FN LOT of 14 days and the percent of broad GN agent days.ResultsWe evaluated 15,678 GN antibiotic administrations from 471 unique FN encounters. Blood culture results were available for 443 encounters— 122 (27.5%) in the positive cohort, and 321 (72.5%) encounters in the negative cohort. Thirty percent of encounters (36/122) in the positive cohort received more than one GN treatment course, compared to 10% (32/321) of those in the negative cohort. FN LOT was significantly longer in the positive cohort (median 10.5, IQR 13 days vs. 6, IQR 8 days, p < 0.001). Among encounters with negative cultures, 57 (17.8%) had a first FN LOT greater than 14 days, accounting for 44% of broad GN agent days within that population (Figure 1).Gram-Negative Antibiotic Therapy in Blood Culture-Negative Febrile Neutropenia ConclusionNearly 20% of blood culture-negative encounters received initial GN treatment courses exceeding 14 days, representing a sizeable target for antimicrobial stewardship interventions focused on FN treatment duration.DisclosuresRebekah W. Moehring, MD, MPH, Agency for Healthcare Quality and Research (Grant/Research Support)Centers for Disease Control and Prevention (Grant/Research Support)

Various immuno-related adverse events after IPI+NIVO therapy; a case report of metastatic choroidal melanoma

Abstract Background Choroidal melanoma with metastasis is known to have a poor prognosis with no established standard therapy. Recently there are some case reports that combination therapy of IPI and NIVO is effective, but with high incidence of immune-related adverse events (irAE). Case presentation A 53-year-old man presented with choroidal melanoma of the right eye and underwent stereotactic radio surgery but eighteen months later developed diffuse hepatic metastases. He was treated with combination therapy of IPI and NIVO, but he developed hyposalivation from the next day of first administration, and grade 3 hepatic disorder after 2 cycles. After 3 days administration of mPSL 125mg followed by PSL 0.5mg/kg, his hepatic enzymes normalized, then we started steroid tapering. At the dose of 30mg, he developed grade 4 Stevens-Johnson syndrome, for which 3 days pulse therapy of mPSL 1mg was effective. We re-escalated PSL to 1mg/kg and tapered carefully. At the dose of 15mg, MRI showed progression of liver metastasis. We decided to resume nivolumab monotherapy three months after termination of IPI+NIVO therapy, but it resulted in grade 3 diarrhea. Lower gastrointestinal endoscopy found seemingly normal mucosa, but histological examination showed inflammatory cell infiltration with hemorrhage, which means irAE. Now he is continuing steroid therapy at 15mg of PSL. Conclusion Our patient developed various irAEs after IPI+NIVO therapy for metastatic choroidal melanoma. Each irAEs responded to corticosteroid therapy, but unexpected severe irAEs occurred even with high dose steroid. As a result, prolonged steroid therapy is often needed to control various irAEs, and in those cases, we have to take extra attention to adverse events of steroids such as opportunistic infections.

Conservation of Steroidogenic Effect of the Low-Molecular-Weight Agonist of Luteinizing Hormone Receptor in the Course of Its Long-Term Administration to Male Rats.

Abstract-It was shown that the thienopyrimidine derivative TP03, a low-molecular-weight agonist of the luteinizing hormone receptor (LHR), during the treatment of male rats for 7 days steadily increased the production of testosterone (T), whose elevated level was retained for 7 days, and increased the expression of the gene for LHR, which indicates the maintenance of the sensitivity of Leydig cells to gonadotropins. At the same time, the steroidogenic effect of human chorionic gonadotropin (hCG), which significantly increased the T level on the first day of administration, was further weakened, which was accompanied by a decrease in the expression of the gene for LHR in the testes, indicating the development of resistance of Leydig cells to hCG. Along with this, in the case of hCG administration, a compensatory increase in the expression of genes of the steroidogenic enzymes, such as cytochrome P450scc and dehydrogenase 3β-HSD, was shown in the testes, while in the case of TP03 administration this effect was absent.

Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients

BackgroundThis study investigated the pharmacokinetics, pharmacodynamics, and safety of multiple doses of evocalcet in Japanese secondary hyperparathyroidism (SHPT) patients receiving hemodialysis.MethodsIn this multicenter, open-label study, conducted between August 2013 and March 2014, 27 patients received multiple doses of 1 and 4 mg evocalcet for 14 days, followed by an extension period of multiple doses of 8 and 12 mg evocalcet for 7 days using an intra-patient dose escalation protocol. Pharmacodynamic parameters consisted of measurement of intact parathyroid hormone (PTH), serum-corrected calcium, serum phosphorus and intact fibroblast growth factor 23 concentrations. Safety was assessed by analysis of adverse events.ResultsPlasma evocalcet levels reached steady state 3 days after the first day of administration. Pharmacodynamic analyses showed that evocalcet effectively reduced intact PTH and serum-corrected calcium levels. Adverse events (AEs) occurred in 29.6 and 62.5% of patients receiving multiple doses of 1 or 4 mg, respectively. The AE ‘blood calcium decreased’ occurred in eight patients (33.0%) after multiple doses of 4 mg. All events were mild, except for one patient with a moderate AE (abnormal liver function) and one patient with a severe adverse drug reaction (blood calcium decreased).ConclusionMultiple doses of evocalcet reduced intact PTH levels with a concomitant decrease in serum calcium levels. Evocalcet was well tolerated in SHPT patients receiving hemodialysis.

Anti-Parkinsonian and anti-dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists.

We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT-390 and AT-403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression. Binding affinity and functional efficacy of AT-390 and AT-403 at the opioid receptors were determined in radioligand displacement assays and in GTPγS binding assays respectively, conducted in CHO cells. Their anti-Parkinsonian activity was evaluated in 6-hydroxydopamine hemi-lesioned rats whereas the anti-dyskinetic properties were assessed in 6-hydroxydopamine hemi-lesioned rats chronically treated with levodopa. The ability of AT-403 to inhibit the D1 receptor-induced phosphorylation of striatal ERK was investigated. AT-390 and AT-403 selectively improved akinesia at low doses and disrupted global motor activity at higher doses. AT-403 palliated dyskinesia expression without causing sedation in a narrow therapeutic window, whereas AT-390 delayed the appearance of abnormal involuntary movements and increased their duration at doses causing sedation. AT-403 did not prevent the priming to levodopa, although it significantly inhibited dyskinesia on the first day of administration. AT-403 reduced the ERK phosphorylation induced by SKF38393 in vitro and by levodopa in vivo. NOP receptor stimulation can provide significant albeit mild anti-dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT-403 could be a potent and selective tool to investigate the role of NOP receptors in vivo.

Sodium 2-(4-amino-(5-(furan-2-yl)-1,2,4-triazole-3-ylthio)acetate, synthesis, study of biochemical indicators of blood serum cows in its use

Introduction. Heterocyclic system of 1,2,4-triazole is interesting and has a popularity among scientists around the world every year. Most attention today is attracted to the compounds formed by a combination of 1,2,4-triazole and various structural residues of an aliphatic, aromatic, heterocyclic nature. Recent publications on the study of physical, chemical and biological properties of 1,2,4-triazole substituted prove the obvious relevance of the search for potential pharmacologically active molecules is among the water-soluble derivatives of 1,2,4-triazole. It should be noted that 1,2,4-triazole derivatives are successfully used in veterinary practice as original domestic drugs.The aim of our work was to synthesize the sodium 2-(4-amino-(5-(furan-2-yl)-1,2,4-triazole-3-ylthio) acetate for which we decided to provide a comparative screening studies on determination of some biochemical parameters of cows blood serum and determine the possibility of its further implementation.Materials and methods of research. As the starting compound for the synthesis it was used a 2-(4-amino-(5-(furan-2-yl)-1,2,4-triazol-3-ylthio) acetic acid. The obtained compound is an individual white crystalline substance, which is soluble in water but insoluble in organic solvents.Results and discussion. At the first day of administration of sodium 2-(4-amino-(5-(furan-2-yl)-1,2,4-triazole-3-ylthio) acetate in experimental animals it was recorded significant increase in total protein content of the serum, γ-globulin, reduction of enzyme activity of lactate dehydrogenase and alkaline phosphatase.On the third day it was marked increase in total protein, γ-globulin, and decrease of activity of LDH and LF. On the seventh day in the experimental animals was recorded increase of total protein and γ-globulins. Decreased activity of LDH and exercise therapy.Conclusions. First we synthesized sodium 2-(4-amino-(5-(furan-2-yl)-1,2,4-triazol-3-ylthio) acetate whose structure is confirmed by complex physical and chemical analysis methods. According to the results of the experiment revealed that intramuscular administration of 1 % aqueous solution of sodium 2-(4-amino-(5-(furan-2-yl)-1,2,4-triazole-3-ylthio) acetate cows enhances total protein, γ-globulin, reduce LDH activity in cow blood serum and LF. Thus, this salt is a perspective in future implementation and can be recommended as a compound which has antioxidant, hepatoprotective, immunomodulating activity by increasing the basic biochemical indicators.

Abstract P3-12-04: Is 6 hour monitoring for administration related reactions after first administration of subcutaneous trastuzumab necessary? A single institution audit

Abstract Background: Subcutaneous (sc) trastuzumab has demonstrated non-inferiority to intravenous (iv) trastuzumab and is preferred by patients and providers. Serious administration related reactions (ARRs) such as hypotension, respiratory distress etc. were not reported in the pivotal HannaH study. However, the summary of product characteristics (SPC) advises that patients should be observed for ARRs for 6 hours post the first injection (and 2 hours post subsequent injections), similar to the iv formulation. Methods: We conducted an audit of patients commencing sc trastuzumab at our institution. Medical notes of each patient were reviewed to record adverse events reported on the day of first administration or at the subsequent visit. In addition all patients were interviewed by telephone and questioned regarding adverse events with first or subsequent injections. Results: 39 patients were identified, 32 had received prior iv trastuzumab. Patients received a mean of 12 injections. In total patients received 470 sc trastuzumab injections, associated with a recommended 1,096 hours of observation as per SPC. 3 injections (0.6%) were associated with ARRs within 24 hours, all on the first cycle. 2 patients (5%) experienced injection site reactions immediately post injection and 1 patient had injection site pain during the injection. 1 patient experienced pyrexia and dry cough 24 hours post injection and was hospitalized for respiratory tract infection. No patient experienced a reaction between 2 and 6 hours post first injection. There were no serious ARRs. Conclusions: ARRs related to sc trastuzumab are usually immediate, mild and self-limiting. Observing patients for 6 hours post first injection and 2 hours post subsequent injections represents an inefficient use of healthcare resources. Citation Format: Karmali S, Hughes N, Galiauskas R, Cook J, Murphy K, Bird BR, Murphy CG. Is 6 hour monitoring for administration related reactions after first administration of subcutaneous trastuzumab necessary? A single institution audit [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-12-04.

Sustained-release microspheres of amifostine for improved radio-protection, patient compliance, and reduced side effects

A biweekly administration of sustained-release microsphere dosage form of amifostine, a radioprotective drug used in radiotherapy, was performed to examine the feasibility to minimize injection frequency and blood concentration-associated side effects. Model animal trials indicated that this subcutaneously injecting microspheres, 50–100 μm in diameter, achieved bi-weekly prolonged radio-protective efficacy and, at the same time, significantly reduced skin irritation than the solution form of amifostine given by the same administration route. In addition, the hypertension associated with blood concentration of amifostine was not observed in the drug-treated rats. The animals given the amifostine microspheres and amifostine showed significantly differences in white blood cell, red blood cell, hematocrit, hemoglobin and spleen tissue histopathology after exposed under a cobalt-60 γ-radiation at a dose rate of 1.0 Gy/min for 6 min. The in vitro release profile of amifostine from the micropsheres showed a minor initial burst (less than 20% of total drug loading in the first day of administration), consisting with the side effects observations. The results suggest that amifostine encapsulated in sustained-release microspheres may be an ideal dosage form for prolonged radio-protective efficacy and improved patient compliance.

Post-marketing safety evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir: A drug-use investigation in patients with high risk factors.

Peramivir, the only injectable anti-influenza neuraminidase inhibitor medically available in Japan at present, is considered first-line treatment in patients with high risk factors for influenza exacerbation. We conducted a drug-use investigation of peramivir in inpatients with high risk factors (old age, pregnancy, and underlying disease such as chronic respiratory disease) from January 2010 to March 2013. Data of 772 patients from 124 facilities across Japan were collected; peramivir's safety in 770 patients and effectiveness in 688 patients were examined. In total, 412 adverse events were observed in 219 patients (28.4%). Of these, 155 events were adverse drug reactions (ADRs) observed in 98 patients (12.7%). Major ADRs (≥2%) were increased aspartate aminotransferase (5.1%), increased alanine aminotransferase (3.8%) and decreased white blood cell count (2.5%). Fourteen serious ADRs were observed in 12 patients (1.6%). All serious ADRs were resolved or improved except for two events for which outcomes were unknown. Multivariate analyses revealed that ADR incidences were significantly associated with these four backgrounds of patients: medical history, no influenza vaccination, renal impairment and other infection(s). With regard to its effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration, which was the same as in other previous surveillance studies. This surveillance study indicated the safety of peramivir in the treatment of influenza inpatients with high risk factors under routine clinical settings.

Repeated injections of orexin-A developed behavioral tolerance to its analgesic effects in rats.

Reduction of pharmacological effectiveness or tolerance appears following repeated administration of many analgesic drugs. We investigated tolerance to anti-nociceptive effects of orexin-A, an endogenous potent analgesic peptide using the hot-plate test. Orexin-A was microinjected ICV (intracerebroventricular) with an interval of 12 hr for 7 continuous days and its anti-nociceptive responses were measured on days 1, 4 and 7 using the hot-plate test following the first day of administration. Orexin-A was used at a dose of 100 pmol to induce analgesic effects. ICV administration of orexin-A produced an effective anti-nociception on the first day of experiment as measured by hot-plate 5, 15, and 30 min after the injection, in comparison with both baselines (hot-plate test one day before the beginning of orexin-A administration and control, saline-administrated group). However, repeated administration of orexin-A on the following days revealed a significant reduction in this analgesic effect during day 4 to day 7. However, to rule out any associative tolerance resulting from learning related to experimental procedures and/or environmental cues, a single injection of orexin-A was administrated to animals of control group (which were receiving saline during 7 days of experiments) and the analgesic effect was observed. These results, for the first time, indicated the appearance of tolerance to anti-nociceptive effects of orexin-A, following repeated administrations of this agent.

Post-marketing safety and effectiveness evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir (I): a drug use investigation.

Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. We conducted a drug use investigation of peramivir from October 2010 to February 2012 and evaluated its safety and effectiveness under routine clinical settings. We collected data of 1309 patients from 189 facilities across Japan and examined safety in 1174 patients and effectiveness in 1158 patients. In total, 143 adverse events were observed with an incidence rate of 7.33% (86/1174). Of these, 78 events were adverse drug reactions (ADRs) with an incidence rate of 4.34% (51/1174). The most frequently reported ADRs were diarrhea, vomiting, and nausea, with incidence rates of 1.87% (22/1174), 0.85% (10/1174), and 0.68% (8/1174), respectively. Moreover, no ADR was reported as serious. ADR onset was within 3 days after the start of peramivir administration in 91.0% (71 events) of the 78 ADRs, and ADRs were resolved or improved within 7 days after onset in 96.2% (75 events) of the 78 ADRs. Neither patient characteristics nor treatment factors appeared to significantly affect drug safety. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. The present study demonstrates the safety and effectiveness of peramivir under routine clinical settings.

Post-marketing safety and effectiveness evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir. II: a pediatric drug use investigation.

Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. In October 2010, an additional indication for pediatric use was approved. We conducted a pediatric drug use investigation of peramivir from October 2010 to February 2012 and evaluated its real-world safety and effectiveness in pediatric patients. We collected the data of 1254 peramivir-treated pediatric patients from 161 facilities across Japan and examined the safety in 1199 patients and effectiveness in 1188 patients. In total, 245 adverse events were observed with an incidence rate of 14.01% (168/1199). Of these, 115 events were adverse drug reactions (ADRs) with an incidence rate of 7.67% (92/1199). Common ADRs were diarrhea and abnormal behavior, with incidence rates of 2.50% (30/1199) and 2.25% (27/1199), respectively. Fourteen serious ADRs were observed in 12 patients (1.00%), including 5 cases each of abnormal behavior and neutrophil count decreased. While 87.0% (100 events) of ADRs occurred within 3 days after the initiation of peramivir administration, 87.8% (101 events) resolved or improved within 7 days after onset. Multivariate analyses indicated that the presence or absence of underlying diseases/complications was significantly related to ADR incidence. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. Thus, this study confirms the pediatric safety of peramivir without any concerns about effectiveness under routine clinical settings.

Naturalistic Effects of Five Days of Bedtime Caffeine Use on Sleep, Next-Day Cognitive Performance, and Mood.

Background: Disruptive effects of caffeine on sleep have previously been reported, although measures of next-day mood and performance have rarely been included. The present study aims to evaluate the effects of caffeine on sleep and associated next-day effects in a naturalistic field setting. Methods: Nineteen participants (daily caffeine intake 0-141 mg), assessed as good sleepers, took part in a randomized, placebo-controlled, double-blind, 2-week crossover study to assess the effects of bedtime caffeine use (250 mg) on sleep and next-day cognitive performance and mood, which were assessed on a mobile phone in the morning and afternoon. Sleep was assessed objectively (actiwatch) and subjectively (sleep diary). Results: Caffeine's effects on sleep were largely restricted to the first day of administration, with actigraphically measured reduced sleep efficiency, increased activity score and fragmentation index, decreased self-rated sleep quality, and an increased occurrence of participants waking early; only decreased sleep efficiency remained over the week. Effects on next-day performance and mood were evident over the whole week, although despite disrupting sleep, accuracy on a working memory task was higher after caffeine than placebo administration. Conclusions: Caffeine disrupted sleep, although when assessing next-day performance, which may have been affected by the presence of residual caffeine, performance appeared better after caffeine compared to placebo, although this was most likely due to prevention of the effects of overnight withdrawal from caffeine rather than representing a net benefit. Furthermore, partial tolerance developed to the effects of caffeine on sleep.

Effect of memantine on L-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson’s disease

An increasing body of experimental evidence demonstrates that the glutamatergic system is involved in the genesis of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Indeed, the N-methyl-d-aspartate (NMDA) receptor antagonist amantadine is the only anti-dyskinetic compound used in patients, albeit with limited efficacy and side effects. In this study, we investigated the anti-dyskinetic properties of memantine, a non-competitive NMDA receptor antagonist in clinical use for the treatment of dementia, in the 6-hydroxy-dopamine (6-OHDA)-lesion rat model of Parkinson’s disease. For comparison, parallel experiments were also performed with amantadine.First, we investigated the acute effect of different doses of memantine (5, 10, 15 and 20mg/kg), and amantadine (10, 20, 40, 60mg/kg) on established dyskinesia induced by L-DOPA (6mg/kg plus benserazide). Results showed that both memantine and amantadine produced a significant reduction of LID. Afterward, drug-naïve and L-DOPA-primed 6-OHDA-lesioned rats were sub-chronically treated with daily injections of L-DOPA (6mg/kg plus benserazide) alone, or in combination with the effective doses of memantine, while amantadine was tested in already dyskinetic rats. Results showed that memantine significantly dampened dyskinesia in both drug-naïve and L-DOPA-primed rats, but only during the first few days of administration. In fact, the anti-dyskinetic effect of memantine was completely lost already at the fifth administration, indicating a rapid induction of tolerance. Interestingly, a 3-week washout period was not sufficient to restore the anti-dyskinetic effect of the drug. Similarly, amantadine was able to dampen already established dyskinesia only during the first day of administration. Moreover, memantine partially decreased the therapeutic effect of L-DOPA, as showed by the result of the stepping test. Finally, loss of the anti-dyskinetic effect of memantine was associated to increased synaptic GluN2A/GluN2B ratio at striatal synaptic membranes.Our results are in line with clinical observations suggesting that NMDA receptor blockade may only be transiently effective against LID in PD patients.