Administration Interval Research Articles

Chronic spontaneous urticaria: a low-grade disseminated intravascular coagulation only partially reversed by Omalizumab

Chronic spontaneous urticaria (CSU) is a disorder characterized by wheals and/or angioedema. The coagulation cascade and inflammation pathways are closely linked together. The aim of our study was first to investigate the dynamics of clot formation in plasma (Clot Waveform Analysis, CWA) in a group of 47 patients with CSU along with other coagulative parameters dedicated to the study of hypercoagulability, such as D-Dimer, F 1 + 2 peptide, Fibrinogen, Platelet count and Mean Platelet Volume (MPV). Secondly, 23 out of 47 patients were treated with Omalizumab at four administration intervals from T0 to T4. A statistically significant increase in Activated Partial Thromboplastin (aPTT) ratio, D-Dimer, F1 + 2, Platelet count and MPV was found when compared with 53 healthy controls (HC). In contrast, the 2nd Derivative of aPTT showed lower values than those of the HC. No differences were found between 1st derivative of aPTT and Fibrinogen. D-Dimer only showed a significant difference between T0 and T3. An activation of both coagulation and fibrinolysis along with a weaker clot acceleration may be in agreement with a low-grade DIC. The accelerated turnover of platelets expressed by both an increase in platelet count and MPV further supports this pathway in CSU. Omalizumab does not affect the relationship between the immune and the hemostatic systems.

Nanoparticulate DNA scavenger loading methotrexate targets articular inflammation to enhance rheumatoid arthritis treatment

Abnormal high cell-free DNA (cfDNA) activates toll-like receptor 9 (TLR9) in immune cell's endosome to produce inflammatory cytokines that aggravate rheumatoid arthritis (RA). Previously, we successfully developed cationic nanoparticles (cNPs) relieving symptoms of RA rats by scavenging cfDNA, but the strong positive charges of cNPs may cause systemic toxicity during circulation via intravenous injection. Herein, we design cNP-pp-PEG to shield the nanoparticles with MMP2-sensitive peptide (pp) linked PEG, the cations are exposed only when PEG is removed by MMP2, which is enriched in the inflamed articular cavity. Taking advantage of the self-assembled cNP-pp-PEG, hydrophobic methotrexate (MTX) is loaded into its core through hydrophobicity interaction, obtaining MTX@cNP-pp-PEG. The engineered reagents exhibit lower toxicity, longer retention time and higher accumulation in inflamed joints comparing to its counterpart MTX@cNP-pp due to the hidden cationic charges. Moreover, the anti-inflamed activity of MTX strengthens the therapeutic efficiency of cNPs. The dual roles of cNPs as therapeutic agent and MTX carrier significantly enhance the therapeutic efficacy and extended administration interval to 4 days. This research addresses the issues of targeting inflamed joints, reducing the systemic toxicities of both cNPs and MTX, and extending administration interval, demonstrating an upgraded strategy for DNA scavenger application.

Giant Cell Tumor of Bone: Effect of Longer Dosing Intervals of Denosumab on Tumor Control and Bone-related Complications.

BackgroundDenosumab is an effective treatment for giant cell tumor of the bone (GCTB) but can cause clinically significant adverse effects. Current approved dosing is every 4 weeks after 3 weekly loading doses. We assessed whether alternative, longer dosing intervals are associated with differences in efficacy or bone toxicity.MethodsSingle institution retrospective chart review was conducted on patients with GCTB over 18 years old who received at least 1 year of standard denosumab dosing. Patients identified using a free-text search engine with keywords “giant cell tumor” and “denosumab” from January 1998 to August 2020.ResultsApproximately 37 patients with GCTB (19F, 18M) were identified with median age of 37 years (range 22-73). Dosing interval was increased in 38% (n = 14), with the most common final dosing interval 12 weeks (n = 8). Six patients (16%) had bone complications: osteonecrosis of the jaw (n =5), atypical fracture (n = 1), and nonhealing dental wounds (n = 2). All patients with bone complications were on the monthly dosing schedule, but there was no statistically significant difference compared to longer dosing intervals (P = .22). No statistically significant difference in median PFS was noted (P = .97). However, 5-year PFS was superior in patients treated with less frequent versus standard dosing of denosumab (P = .036).ConclusionsIncreasing the interval of denosumab dosing for GCTB provided similar tumor control compared to standard dosing and lower absolute number of bone toxicity events. Larger studies are needed to better define the optimal interval of denosumab administration and the effect on efficacy, toxicity, and associated healthcare expense.

Pharmacokinetic/pharmacodynamic-guided gentamicin dosing in critically ill patients: a revisit of the Hartford nomogram

The appropriateness of the Hartford nomogram based on 7 mg/kg gentamicin with administration interval adjustment is questioned in critically ill patients. This study aimed to perform a pharmacokinetic/pharmacodynamic (PK/PD) evaluation of the Hartford nomogram and to assess the influence of PK/PD indices on gentamicin dosing. Gentamicin data were extracted from a critical care database to construct the population PK model. Simulations were performed to evaluate the probability of target attainment (PTA) and risk of toxicity for the gentamicin Hartford nomogram. Cmax/MIC ≥ 10 and AUC/MIC ≥ 100 were the PK/PD targets considered, and the non-toxicity targets included concentration < 0.5 mg/L for at least 4 h within a dosing interval and trough concentration < 1 mg/L. A one-compartment model was optimal to describe gentamicin PKs, and creatinine clearance (CLCr) was included as a time-varying covariate on gentamicin clearance. The PTA of Cmax/MIC ≥ 10 (MIC=1 mg/L) for the Hartford nomogram was suboptimal after the first dose but was desirable (near or greater than 90%) at steady-state, and > 90% PTA based on AUC/MIC ≥ 100 was readily achieved after the first dose in patients with CLCr < 60 mL/min. Significant PTA differences between the PK/PD targets were observed at an MIC of 2 mg/L, but the PTAs were all low. The predicted risk of toxicity was high regardless of the applied toxicity targets. The Hartford nomogram provided adequate gentamicin exposure in critically ill patients with an MIC ≤ 1 mg/L by considering the combined PK/PD indices.

Interviewer Administration Corresponds to Self-Administration of the Vision Impairment in Low Luminance (VILL) Questionnaire.

PurposeTo quantify the impact of the mode of administration (MOA) on scores of the Vision Impairment in Low Luminance (VILL) questionnaire.MethodsThe VILL questionnaire was implemented using different MOAs (paper, interview, electronic), in addition to a demographical survey of adult participants recruited at an outpatient eye clinic, with the initial MOA being either paper or interview. Polytomous Rasch models were used to generate person measure scores for the three subscales of the VILL questionnaire (reading, VILL_R; mobility, VILL_M; and emotional, VILL_E). Measures of agreement among the different MOAs were calculated (self-administered paper/interview, self-administered paper/self-administered electronic, and interview/self-administered electronic). An age-matched analysis was performed to control for the impact of the initial MOA, administration interval, visual acuity, and self-reported hearing difficulties.ResultsWe included 309 participants (mean age, 63 ± 14 years; 61% female). Intra-class correlation coefficients were 0.930, 0.919, and 0.799 for paper versus interview assessment; 0.951, 0.959, and 0.916 for paper versus electronic; and 0.967, 0.955, and 0.907 for interview versus electronic assessment (VILL_R, VILL_M, and VILL_E, respectively). Mean differences were 0.35, 0.41, and 1.74 logits; 0.32, 0.18, and 0.68 logits; and 0.08, 0.22, and 0.63 logits, respectively. None of the mentioned factors significantly affected the results (corrected P ≥ 0.11).ConclusionsPaper, interview, and electronic MOAs of the VILL can be considered equivalent. Reporting across the main MOAs of self-administration (paper) and interviewer-administration was unaffected by better eye visual acuity and self-reported hearing difficulties.Translational RelevanceThe results support use of the VILL questionnaire with flexible modes of administration.

MBP-11901 Inhibits Tumor Growth of Hepatocellular Carcinoma through Multitargeted Inhibition of Receptor Tyrosine Kinases.

Simple SummaryAlthough various treatments such as surgery and chemotherapy exist for advanced or unresectable HCC, most patients suffer from intractable diseases, having a poor prognosis. While immunotherapy using immune checkpoint inhibitors was recently proposed for HCC, only a small percentage of patients respond. Thus, there remains an unmet need for the development of therapeutic agents for the treatment of liver cancer. Here, we presented multi-RTKi MBP-11901, an innovative targeted anticancer agent for HCC, suggesting it as a new therapeutic strategy for the treatment of liver cancer.Hepatocellular carcinomas (HCCs) are aggressive tumors with a poor prognosis. Approved first-line treatments include sorafenib, lenvatinib, and a combination of atezolizumab and bevacizumab; however, they do not cure HCC. We investigated MBP-11901 as a drug candidate for HCC. Cell proliferation and cytotoxicity were evaluated using normal and cancer human liver cell lines, while Western blotting and flow cytometry evaluated apoptosis. The anticancer effect of MBP-11901 was verified in vitro through migration, invasion, colony formation, and JC-1 MMP assays. In mouse models, the tumor volume, tumor weight, and bodyweight were measured, and cancer cell proliferation and apoptosis were analyzed. The toxicity of MBP-11901 was investigated through GOT/GPT and histological analyses in the liver and kidney. The signaling mechanism of MBP-11901 was investigated through kinase assays, phosphorylation analysis, and in silico docking simulations. Results. MBP-11901 was effective against various human HCC cell lines, leading to the disappearance of most tumors when administered orally in animal models. This effect was dose-dependent, with no differences in efficacy according to administration intervals. MBP-11901 induced anticancer effects by targeting the signaling mechanisms of FLT3, VEGFR2, c-KIT, and PDGFRβ. MBP-11901 is suggested as a novel therapeutic agent for the treatment of advanced or unresectable liver cancer.

Direct Observation Approach for Medication Errors Detection in an Educational Hospital

Background: Mistakes occur inevitably, but medication errors can cause catastrophic consequences such as death, which accentuates investigation through presumptive sources and possible solutions for the prevention of errors that took place before.&#x0D; Methods: Twelve different medical wards of an educational hospital were analyzed using the direct disguised observation (DDO) method for administration step and chart review for prescription step. Each ward was randomly chosen, and the time at which the researcher presented oneself to each ward was contingent. The researcher observed the medicine continuously from the time prescribed by the physician until the drug finally entered the patient's body.&#x0D; Results: Of 1350 dose of drugs, which were evaluated; 65% of data was collected in the morning shift (n=867), 28.6% in the afternoon shift, 6.4% of the night shift. About one-third of the physician orders were defective and did not contain all six parameters (drug name, dosage form, dose, measuring unit, administration route, and intervals of administration). Interpretation of the administration phase revealed 69% of drugs were erroneously administered due to errors detected as wrong route, omission, wrong dose, wrong time, and unauthorized dose.&#x0D; Conclusion: Our findings exhibit errors in the pivotal stages of the therapy process. Clear instructions and protocols should be implemented for hospital technicians, nurses, and physicians to avoid irreparable detriments caused by medication errors.

Analysis of Variables that Influence the Success Rates of Induction of Labor with Misoprostol: A Retrospective Observational Study.

Determine the predictive criteria for success in inducing labor for live fetuses using misoprostol in pregnant women. Secondarily, the objective is to determine the rates of vaginal or cesarean delivery, duration of induction, interval of administration of misoprostol, the main causes of induction of labor and indication for operative delivery. Medical records of 873 pregnant women admitted for cervical maturation from January 2017 to December 2018 were reviewed in a descriptive observational study of retrospective analysis, considering the following response variables: age, parity, Bishop Index, doses of misoprostol, labor induction time. Logistic regression models were used to predict success with misoprostol in non-operative deliveries. Of the 873 patients evaluated, 72% evolved with vaginal delivery, 23% of the cases were cesarean, 5% forceps or vacuum-extractor. For non-operative delivery the predictive variables at admission were age, parity, gestational age and dilation. During hospitalization, fewer vaginal touches, amniotomy or amniorrhexis with clear fluid lead to a shorter induction time and a greater chance of non-operative delivery. False positives and false negatives of the model were always below 50% and correct answers above 65%. At admission, age less than 24 years, previous normal births, lower the gestational age and greater the dilation, were predictive of greater probability of non-operative delivery. During hospitalization, the less vaginal touches and occurrence of amniotomy/amniorrhexis with clear liquid indicate shorter induction time. Future studies with a prospective design and analysis of other factors are necessary to assess the replicability, generalization of these findings.

The knowns and unknowns of the efficacy of neem oil (Azadirachta indica) used as a preventative measure against Leishmania sand fly vectors (Phlebotomus genus)

Since domestic dogs are the main reservoir hosts of Leishmania infantum throughout the world, they are the main focus in terms of controlling zoonotic visceral leishmaniosis. To protect dogs from leishmaniosis, chemical repellents of durable efficacy are available in the form of collars, spot-on and sprays. However, the negative effects of chemical pesticides on the environment are well established as they affect animals and plants. This phenomenon has created the need for safer and more environmentally friendly substitutes. Plant extract-based insecticides and/or repellents have therefore been increasingly used by pet owners and veterinarians. Several botanical products have been tested as insecticides and/or repellents against a variety of bloodsucking arthropods that transmit human diseases. Among the products tested against Leishmania vectors, neem oil containing azadirachtin is the most studied. This study reviews the scientific literature concerning the efficacy of neem oil (azadirachtin-based products) against phlebotomine sand fly bites. A questionnaire was also administered to assess Italian veterinarians’ attitudes to the use of neem oil. The survey was anonymous and consisted of three closed-ended questions.According to the data reported in the literature, the efficacy of neem oil in reducing the risk of sand fly bites has been tested against Phlebotomus papatasi, Phlebotomus perniciosus, Phlebotomus argentipes, Phlebotomus orientalis and Phlebotomus bergeroti. The efficacy of the products tested was expressed in percentages, ranging from 74.9% to 100%. The protection time was only available for six out of eight studies, ranging from “only during the first hour” (minimum protection time) to “all night” (expected maximum protection time). As regards the attitude to recommending the use of neem oil, 208 veterinarians participated in the online survey. Of the 126 veterinarians who recommended natural products, 119 (94.44%) reported that they recommended the use of neem oil-based products.Considering the limited data on the duration of protection and the dose of the active ingredient, more studies are required on the efficacy of neem oil-based products in reducing the risk of contracting canine leishmaniosis. These studies should also refer specifically to the concentration of the active ingredient as well as the interval of administration. Until such results are available, the use of azadirachtin-based products as the only topical products for the prevention of leishmaniosis in dogs is not recommended.

Role of albumin in the treatment of decompensated liver cirrhosis.

Albumin has been used primarily as a plasma expander, since it leads to an increase in the circulating blood volume. Current generally recommended indications for albumin therapy in cirrhotic patients are the prevention of circulatory dysfunction after large-volume paracentesis, the prevention of hepatorenal syndrome (HRS) in patients with spontaneous bacterial peritonitis (SBP), and the management of HRS in combination with vasoconstrictors. Yet, new indications for albumin have been tested in the recent years and are outlined in this short review. New data show that albumin both supports the circulation and reduces systemic inflammation. In addition, to its oncotic function, it acts as an antioxidant, radical scavenger, and immune modulator. These nononcotic properties explain why long-term albumin administration in patients with decompensated cirrhosis may be useful in the prevention of associated complications (acute-on-chronic liver failure, infections). New data show that long-term albumin therapy in patients with cirrhosis and ascites improves survival, prevents complications, simplifies ascites management, and lowers hospitalization rates. The so-called disease-modifying effects of long-term albumin therapy may have a favorable effect on the course of the disease. Nevertheless, the optimal dosage and administration intervals have not yet been finally defined. Albumin therapy is effective in the indications already recommended by the guidelines. A possible extension of the indication for albumin administration in non-SBP infections and as long-term therapy is promising, but should be confirmed by further studies.

Effect of Dosage and Time Interval of Application of Liquid Organic Fertilizer Gamal Leaves on Growth and Yield of Mustard Plants (Brassica Juncea L.)

The purpose of this study was to determine the effect of the dose and time interval of applying organic Gamal leaf fertilizer on the growth and yield of mustard (Brassica junceaL). The study was conducted from March 2019 to May 2019 at the STIPER East Kutai Agrotechnology Experimental Garden. The design used was a Completely Randomized Design (CRD), with a factorial pattern, where the treatment of giving a dose of organic Gamal leaf fertilizer consisted of 4 treatments, namely: D0 = 0 ml L- 1, D1 = 40 ml L-1, D2 = 80 ml L-1, D3 = 120 ml L-1, while the time interval treatment consisted of 3 treatments, namely I1 = once every 3 days, I2 = once every 5 days, I3 = 7 days once. All treatments were repeated 3 times. Data were analyzed by analysis of variance followed by the smallest significant difference test at a significance level of 5%. The variables observed included the height of the mustard plant, the number of leaves of the mustard plant, the fresh weight per plant of the mustard greens. There was no interaction between the dosage of liquid organic fertilizer of Gamal leaves and the time interval of administration of all the variables measured. significantly to plant height (8.332), number of leaves (7.911) and fresh weight (7.027), while the time interval treatment had a significant effect only on plant height (8.076) and number of leaves (7.683).

Inhalable cryptotanshinone spray-dried swellable microparticles for pulmonary fibrosis therapy by regulating TGF-β1/Smad3, STAT3 and SIRT3 pathways

Cryptotanshinone (CTS) is a promising therapeutic option for pulmonary fibrosis (PF). However, clinical applications of CTS are limited owing to high photosensitivity and poor oral bioavailability. Pulmonary drug delivery, especially sustained pulmonary drug delivery, is promising for local treatment of chronic lung diseases. In this study, CTS was encapsulated in an optimized chitosan/L-leucine-based swellable microparticles (SMs) system, which exhibited an appropriate aerosolization performance, sustained release and storage stability. SMs enhanced the in vitro anti-fibrosis efficacy of CTS as shown by the improved cellular uptake. The effect of PF status on in vivo fate of the pulmonary delivered drug was also assessed. Pharmacokinetics and tissue distribution of oral and pulmonary delivery CTS in bleomycin-induced PF rats were compared. Pulmonary delivery exhibited high drug concentrations in pulmonary lesion areas, with reduced exposure to blood and non-targeted tissues after administration at a significantly lower dose compared with oral delivery. Moreover, PF pathological status enhanced activity of SMs, implying that pulmonary delivery was highly effective for PF treatment. Compared to oral delivery, Inhaled SMs showed comparable or even better efficacies at approximately 60-fold low dose compared with oral delivery. A sustained efficacy was observed under a prolonged administration interval (corresponding to half the total dose). Inhalation safety of SMs was established, and important mechanism-related signaling pathways against PF were investigated in vitro and in vivo. In summary, the findings showed that the developed CTS-loaded sustained pulmonary delivery system is a safe and effective strategy for chronic PF treatment.

Desensitization for the prevention of drug hypersensitivity reactions.

Drug desensitization is the temporary induction of tolerance to a sensitized drug by administering slow increments of the drug, starting from a very small amount to a full therapeutic dose. It can be used as a therapeutic strategy for patients with drug hypersensitivity when no comparable alternatives are available. Desensitization has been recommended for immunoglobulin E (IgE)-mediated immediate hypersensitivity; however, its indications have recently been expanded to include non-IgE-mediated, non-immunological, or delayed T cell-mediated reactions. Currently, the mechanism of desensitization is not fully understood. However, the attenuation of various intracellular signals in target cells is an area of active research, such as high-affinity IgE receptor (FcɛRI) internalization, anti-drug IgG4 blocking antibody, altered signaling pathways in mast cells and basophils, and reduced Ca2+ influx. Agents commonly requiring desensitization include antineoplastic agents, antibiotics, antituberculous agents, and aspirin/nonsteroidal antiinflammatory drugs. Various desensitization protocols (rapid or slow, multi-bag or one-bag, with different target doses) have been proposed for each drug. An appropriate protocol should be selected with the appropriate concentration, dosage, dosing interval, and route of administration. In addition, the protocol should be adjusted with consideration of the severity of the initial reaction, the characteristics of the drug itself, as well as the frequency, pattern, and degree of breakthrough reactions.

Disease Activity-Guided Stepwise Tapering but Not Discontinuation of Biologics Is a Feasible Therapeutic Strategy for Patients with Ankylosing Spondylitis: Real-World Evidence.

To analyze the history of biologics usage in patients with ankylosing spondylitis (AS) in China and to evaluate the impact of drug reduction and withdrawal on disease activity. Drug administration intervals and disease activity indexes in patients with AS who regularly used etanercept (ETN) biosimilars for more than 1 year and those who withdrew the drugs during the same period in a single center were analyzed retrospectively. A total of 108 patients with AS who used ETN biosimilars for more than a year were recruited in this study for analysis. (1) Overall, 98.1% patients with AS increased the intervals between drug administrations, averaging from 4.57 ± 0.15days during 0-3months to 8.53 ± 0.43days during 3-6months, and to 10.49 ± 0.39days during 6-12months. Compared with the baseline parameters, after 3-month and 12-month treatments disease activities were improved significantly, including Patient Global Assessment (PTGA), overall back pain, nocturnal pain, fatigue, Ankylosing Spondylitis Disease Activity Score-C-Reactive Protein (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Functional Index (BASFI). (2) Only 59.3% used ETN biosimilars with full dose (3.5days' interval) in the first 3months. At baseline, disease activities of these patients were higher than those with reduced dose (5.9days' interval). However, at 12months of drug administration there was no significant difference in the overall length of drug administration intervals and disease activities between the two groups. (3) Twenty patients with low disease activity (LDA) discontinued therapy spontaneously; after 3months, 55% of them experienced disease recurrence (∆ASDAS ≥ 0.9). Spontaneous dose reduction was a common phenomenon among patients with AS in China, which becomes more notable with increasing relief of symptoms. Most patients could maintain an LDA state after dose reduction. Compared with dose reduction, ETN biosimilar withdrawal was more likely to induce disease recurrence. Therefore, disease activity-guided individualized stepwise tapering may become one of the feasible therapeutic strategies for AS in the future.

CB1-RECEPTOR ANTAGONIST SR-141716A MODULATES LOCOMOTOR ACTIVITY IN OBX-RATS

Dysfunction of the endocannabinoid system has been related to depressive-like behavior. In our study, bilateral olfactory bulbectomy (OBX) was used as an animal model of depression. We evaluated the effect of the selective CB1-antagonist SR-141716A (Rimonabant) on the exploratory and locomotor activity of OBX-rats. Rimonabant was administered intragastrically for 14 days to OBX-rats, divided into 3 experimental groups, where the drug was given before; immediately (1-14 days) after; or 14 days (14-28 day) after OBX. Exploratory and locomotor activity of OBX-rats was tested in an Opto-Varimex apparatus. SR-141716A, administered subchronically, intragastrically exerted locomotor stimulating effects in OBX- and sham-operated rats, while the exploratory activity was not affected. The time interval for the drug administration is of significance for the manifestation of the effects on locomotor activity in OBX-rats. SR-141716A applied 14 days before OBX or after the development of a depressive-like state (14-28 days after OBX), but not immediately after OBX (1-14 days) aggravated the OBX-induced hyperlocomotor state.

The Relationship between Area of Necrosis with Degree of Lymphocytes Infiltration in Breast Rattus norvegicus Induced by DMBA

Breast cancer is one of the leading causes of death in women in the world. According to WHO, the incidence of breast cancer is about 2.1 million. The high mortality rate is often influenced by various reasons, one of which is the prognosis in patients. The level of lymphocyte infiltration in tumor cell tissue has been shown to correlate with a better prognosis in patients, while necrotic tissue found in breast cancer often shows worse prognostic value. To determine the relationship between the area of necrosis with the degree of infiltration of lymphocytes in the breast of Rattus norvegicus induced by DMBA. Method: True experimental study with post-test only controlled group design method using 40 Wistar strains of female (Rattus norvegicus) mice 12-13 weeks old. The technique for taking uses simple random sampling. Examining 2 variables, namely the dependent variable area of necrosis and the independent variable degree of lymphocyte infiltration. The treated group is injected with subcutaneous DMBA 10 mg/Kg BW between the two lower nipples during the middle of the fifth week with a three-week interval of administration to reach 14 times the total administration. Cancer tissue is taken in the fifth week. Data are analyzed by the Spearman test. Results: This study shows no relationship (P&gt; 0.05) between the area of necrosis with the degree of lymphocyte infiltration. Conclusions: There is no relationship the area of necrosis with the degree of lymphocytes infiltration in breast Rattus norvegicus Induced by DMBA.

P433 Intravenous ustekinumab as maintenance treatment is effective in patients with partial or loss of response to optimized ustekinumab sc

Abstract Background Ustekinumab is an effective drug in Crohn′s Disease (CD) and most frequently used dose is subcutaneous (sc), 90 mg /, 8 weeks. With the usual sc doses (90 mg every, 8–12 weeks) some patients will only partially respond or experience secondary loss of response. In this situation, shortening of the administration interval (e.g., every, 4 or, 6 weeks) or a reinduction dose has been proposed. Another unexplored option is intravenous (IV) administration at regular intervals when shortening sc dose is not effective enough. Methods We conducted a retrospective study to evaluate the effectiveness of IV ustekinumab at regular intervals (usually every, 4–6 weeks) in patients with insufficient efficacy or loss of response to, 90 mg sc every, 4–6 weeks. All patients had active Ulcerative colitis (UC) or Crohn′s disease (CD) defined by partial Mayo score (pMS) or Harvey Bradshaw Index (HBI)&amp;gt;, 4 points and/or persistent biomarker elevation (calprotectin&amp;gt;, 250 µg/g) and/or endoscopic or radiological evidence of disease activity. We obtained data from, 79 patients (73 CD and, 6 with ulcerative colitis (UC)). Levels of fecal calprotectin before and after starting ustekinumab IV was available for, 44 patients and trough levels of drug for, 48 patients. Results Baseline characteristics of the included patients are shown in Table, 1. Complicated forms (B2-B3;, 60,6%) predominated and perianal disease was present in, 35.4% of patients. Only, 3 patients were naïve to biological treatments, 41.8% had received at least one and, 54,5% more than, 2. The mean follow-up after the first IV administration was, 13.22 months (IQR, 2–37 months). Last dose used before the start of ustekinumab IV was, 90 mg /, 6 weeks in, 31.6% and, 90 mg /, 4 weeks in, 68.4% of the patients. After, 12 weeks of the first IV dose, 43% of patients achieve clinical remission (HBI&amp;lt;5 or pMS, 2) and, 59.5% at the end of follow-up. Basal fecal calprotectin decreased significantly at month, 12 and at end of follow-up (612.6 mg/kg vs, 384.1 mg/kg vs, 222 mg/kg; p = 0.0002 and p=0,0048 respectively) (Figure, 1). Drug levels at the beginning of IV administration were, 2.6 mcg/ml (IQR, 0.13-11-69) and a significant increase from baseline was observed (week, 12–16:, 9.09 mcg/ml and after, 1 year:, 10.7 mcg/ml; both p &amp;lt;0,001). At the end of the follow-up, 81% of patients maintain the treatment (figure 2). Conclusion Patients who lose response to the intensified dose of ustekinumab sc could benefit from intravenous administration as maintenance treatment. This strategy achieves clinical remission in, 60% of the patients and allows to maintain the treatment in, 80% of them for at least, 12 months.

The association of high Vancomycin trough concentration with acute kidney injury during combination therapy of Piperacillin/Tazobactam and Vancomycin

BackgroundCo-administration of Piperacillin/Tazobactam (PIPC/TAZ) and Vancomycin (VCM) as an antibiotic therapy for severe infectious diseases increases the risk of nephrotoxicity. We retrospectively investigated the utility of monitoring VCM trough concentration in early stage of developing acute kidney injury (AKI) on this combination therapy. MethodsWe enrolled all infectious disease patients who were managed with concurrent PIPC/TAZ and VCM. The record of dosage and the administration interval of each antibiotic and its clinical parameters, as well as the VCM trough concentrations, blood culture for bacteria, and serum creatinine values, were collected. VCM trough concentration was measured during the initial 48–72 h of VCM administration. Nephrotoxicity was evaluated as the degree of AKI. ResultsA total of 47 patients fulfilling the criteria were registered, and AKI developed in 10 patients. There was no statistical difference between the AKI and non-AKI groups with regard to age, height, weight, basal creatinine level, body surface area, body mass index, PIPC/TAZ dose, VCM dose, gender, artificial management, and death within around 30 days. The VCM trough level was increased significantly in the AKI group (mean [standard deviation {SD}]: 25.9 [7.8] μg/mL) compared to that in the non-AKI group (mean [SD]: 15.7 [6.9] μg/mL) (p = 0.003). During the clinical course, renal function returned to normal levels in three out of four AKI stage 2 patients, whereas only partial recovery was achieved in all AKI stage 3 patients. ConclusionsA high VCM trough concentration may have an influence on the occurrence of AKI during combination therapy of PIPC/TAZ and VCM. Careful monitoring of VCM trough concentration will be required to prevent AKI progression.

Drug Utilization Evaluation of Colistin: A Retrospective Study

Background: Colistin, is used as the last treatment line for infections concluded from multiple drug-resistant gram-negative microorganisms. Increased consumption of colistin leads to resistance to this antibiotic in many countries. This study investigated the usage pattern of colistin administration in a selected hospital in Iran. Methods: This study was conducted in a selected hospital in Ahvaz. Inclusion criteria were all patients who received colistin during this time according to the health information system. Patients who were received less than three doses of colistin were excluded from the study. Prescription of colistin in all patients was evaluated according to the protocol extracted from the last version of Lexicomp written by Wolters Kluwer. The descriptive and analytical statistics were carried out by the R software. Results: Among 27 patients who received colistin, pneumonia (30%) was the main diagnoses. Colistin administration was based on the microbiological culture data in 70% of cases. Considering the involved microorganism, most cases were Acinetobacter spp., followed by Klebsiella spp. Loading dose was prescribed for seven (26%) patients. In only five (19%) cases, colistin dosing, including loading dose, maintenance dose, and the interval of colistin administration, was appropriate during the study time. Increasing in serum creatinine was seen in two (7.4%) patients. In 29.4% of patients, the combination of colistin and carbapenems was observed. Conclusion: Given the lack of appropriate dose adjustment of colistin that may lead to incidence of resistance and adverse effect, applying of the specialist clinical pharmacist will be suggested.

Effect of Different MPTP Administration Intervals on Mouse Models of Parkinson's Disease.

Objective To research the effect of different 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration intervals on the behavior and pathology of mouse models of Parkinson's disease. Methods Eighteen C57 male mice were divided into a control group, subacute model group, and chronic model group (6 mice per group). Animal models of Parkinson's disease were built according to MPTP administration. The behavior of mice was determined through an open-field test and pole test. Tyrosine hydroxylase expression in brain tissues was checked by immunohistochemistry and western blot. Result In the open-field test, the total activity distance in the chronic model group (1271.05 ± 207.93 cm) was reduced significantly compared with that of the control group (1964.21 ± 379.77 cm), while the distance had no significant differences in the subacute model group (1950.57 ± 273.54 cm). At the same time, the number of times the mice crossed the center grid in the chronic model group (3.17 ± 1.17) was reduced compared with that in the control group (11.67 ± 6.65), while there were few differences in the subacute model group (9.33 ± 2.81). In the pole test, the climbing time (8.49 ± 1.44 s) and total rest time (103.64 ± 26.57 s) of mice in the chronic model group were longer than those in the control group, respectively (4.31 ± 0.70 s, 45.21 ± 14.36 s), while there were no significant differences in the subacute model group (4.51 ± 0.48 s, 52.44 ± 25.98 s). Besides, compared with the control group, TH expression in the subacute model group and chronic model group was reduced notably, and the changes of TH expression in the chronic model group were more significant. Conclusion There is a little loss of midbrain dopaminergic neurons in the subacute Parkinson's disease mouse models induced by continuous MPTP administration, but there is no effect on the behavior. Long interval MPTP-induced chronic Parkinson's disease mouse models lose a lot of dopaminergic neurons, which is accompanied by anxiety-like behaviors in addition to motor dysfunction.