Continuous Drug Administration Research Articles

Computational modeling of schedule-specific chemotherapy outcomes in mouse tumor model

Despite the rapid development of new innovative strategies in cancer treatment like immunotherapy, chemotherapy still remains a common choice in many cases. Standard protocols of chemotherapeutic administration rely on a maximal tolerated dose paradigm, however there is growing evidence that this approach is not always optimal. Alternative scheduling, like metronomic - low dose continuous drug administration - were recently proved their efficacy. The space of available variants of drug administration protocols is prohibitively large to be explored empirically, and there is an urgent need of predictive mathematical models for rational chemotherapeutic scheduling design. In this work we tested the ability of the minimal pharmacokinetic-pharmacodynamics model to describe schedule-specific tumor volume time evolution in different mouse tumor models.

Effect of anti-diabetic drugs in dialysis patients with diabetes: a nationwide retrospective cohort study

BackgroundType 2 diabetes mellitus is common in patients undergoing dialysis. However, the association between anti-diabetic drug use and survival outcomes is rarely discussed. We aimed to investigate whether continued anti-diabetic medication use affects the survival of diabetic dialysis patients and whether different hypoglycemic drug use influences prognosis.MethodsUsing a nationwide database, we enrolled patients with incident end-stage renal disease under maintenance dialysis during 2011–2015 into the pre-existing diabetes dialysis (PDD), incident diabetes after dialysis (IDD), and non-diabetic dialysis (NDD) groups. The PDD group was further subclassified into patients who continued (PDD-M) and discontinued (PDD-NM) anti-diabetic drug use after dialysis.ResultsA total of 5249 dialysis patients were examined. The PDD-NM group displayed a significantly higher mortality rate than the IDD, PDD-M, and NDD groups (log-rank test P < 0.001). The PDD-M group had a significantly lower risk of death, regardless of insulin (P < 0.001) or oral hypoglycemic agent (OHA) (P < 0.001) use. Initial insulin administration or OHA had no statistically significant effect on overall mortality in the IDD group. But OHA use had better survival trends than insulin administration for the older (P = 0.02) and male subgroups (P = 0.05).ConclusionsFor dialysis patients with diabetes, continuous administration of anti-diabetic drugs after dialysis and choice of medication may affect outcomes.

SS-31 efficacy in a mouse model of Friedreich ataxia by upregulation of frataxin expression.

Friedreich ataxia (FRDA) is a serious hereditary neurodegenerative disease, mostly accompanied with hypertrophic cardiomyopathy, caused by the reduced expression of frataxin (FXN). However, there is still no effective treatment. Our previous studies have shown that SS-31, a mitochondrion-targeted peptide, is capable to upregulate the expression of FXN and improve the mitochondrial function in cells derived from FRDA patients. To further explore the potential of SS-31, we used the GAA expansion-based models, including Y47 and YG8R (Fxn KIKO) mice, primary neurons and macrophages from the mice and cells derived from FRDA patients. After once-daily intraperitoneal injection of 1mg/kg SS-31 for 1 month, we observed the significant improvement of motor function. The vacuolation in dorsal root ganglia, lesions in dentate nuclei and the lost thickness of myelin sheath of spinal cord were all repaired after SS-31 treatment. In addition, the hypertrophic cardiomyocytes and disarrayed abnormal Purkinje cells were dramatically reduced. Interestingly, we found that SS-31 treatment upregulated FXN expression not only at the translational levels as observed in cell culture but also at mRNA levels in vivo. Consequently, mitochondrial morphology and function were greatly improved in all tested tissues. Importantly, our data provided additional evidence that the maintenance of the therapeutic benefits needed continuous drug administration. Taken together, our findings have demonstrated the effectiveness of SS-31 treatment through the upregulation of FXN in vivo and offer guidance of the potential usage in the clinical application for FRDA.

Antipsychotics for elderly with psychosis: Deprescribe or continue?

Maintenance treatment with antipsychotics remains the key principle in the long-term management of psychotic disorders. For some patients, it means life-long use of medication. Continuous drug administration helps to prevent relapses, maintain remission, and achieve functional recovery. Moreover, epidemiological data suggest that antipsychotic treatment significantly reduces mortality rates of schizophrenia patients. On the other hand, some authors argue that antipsychotic drugs may lose its efficacy over time, their long-term exposure results in more harm than benefit. Especially elderly patients are more sensitive to side effects. Several studies which followed-up patient cohorts over the span of several decades found that there are schizophrenia patients who can achieve good functional outcome and full recovery without antipsychotic treatment. Therefore, it is paramount to identify those individuals, particularly among elderly psychotic patients, who can thrive and benefit from timely antipsychotic discontinuation.DisclosureNo significant relationships.

Drug Penetration Enhancement Techniques in Transdermal Drug Delivery System: A Review

Transdermal Drug Delivery System (TDDS) is described as a self-contained or discrete dosage form that is applied to the intact skin. This rout of drug administration of drugs through the skin for therapeutic use is an alternative approach to oral, intravascular, subcutaneous, and transmucosal routes. The delivery of drugs through the skin to the systemic circulation provides a convenient route of administration for a variety of clinical indications. Transdermal Drug Delivery System allows continuous drug administration, use of drugs with short biological half lives, avoids increases hepatic first pass elimination and rapid termination of medication by removing the transdermal drug delivery system from the skin. Various transdermal technologies may be applied for different categories of pharmaceuticals used for the treatment of disorders of the skin or for systemic effects to treat diseases of other organs. Several transdermal products and applications include hormone replacement therapy, contraception, pain management, angina pectoris, smoking cessation, and neurological disorders such as Parkinson's disease. The most commonly used transdermal system is the skin patch using various types of technologies. Stratum corneum is the outermost layer of the skin and it is the main barrier layer for permeation of drug in transdermal delivery of drugs. So, to circumvent the barrier properties of stratum corneum and to increase the flux of drug through skin membrane various penetration enhancement techniques are used in transdermal drug delivery system. The review presents different physical and chemical methods in penetration enhancement approaches and to optimize the transdermal delivery system.

Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome

BackgroundThe last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.Case presentationWe report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung’s deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.ConclusionsThis case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.

Impact of air temperature and drug concentration on liquid emission from elastomeric pumps

BackgroundElastomeric pumps (EPs) are devices that allow quantitative and continuous drug administration without the need for electronic control, and they are used by being filled with anticancer agents. Although the package inserts of several manufacturers that provide EPs describe the relationship between the flow rate per unit time and temperature, the solution is only saline solution or 5% glucose solution, and data on anticancer drugs have not been published. In this study, we focused on 5-fluorouracil (5-FU), a drug frequently used in cancer chemotherapy, and examined the effect of changes in standard of EPs and temperature on drug emission.MethodsWe evaluated the EP data of patients treated with Baxter Infusor® LV5 and SV2.5 in terms of emission rate, relationship between 5-FU prescription amount and emission rate, and relationship between emission rate and monthly air temperature in LV5 and SV2.5. The number of EPs sampled in the study was N = 5708 (n = 2988 for LV5 and n = 2720 for SV2.5).ResultsIn LV5, the emission rate varied from 88 to 97% (median 94.0%), whereas in SV2.5, the emission rate was observed as 97 to 98% (median 97.4%). The 5-FU prescription amount and the emission rate were not correlated in LV5 and SV2.5, respectively (LV5; y = − 0.0015x + 97.305, R2 = 0.0226, SV2.5; y = − 0.001x + 100.25, R2 = 0.0466). LV5 showed a higher emission rate in the months with higher air temperature and a lower emission rate in the month with lower air temperature. In addition, LV5 showed a significant reduction in emission rate compared with SV2.5 in all months (P < 0.001).ConclusionsIn this study, we clarified that air temperature is an important factor that affects the drug emission of EPs. Therefore, it is necessary to examine the conditions for total fluid volume suitable for the air temperature in each region and to provide sufficient information to patients.

Effect of Continued Perioperative Anticoagulant Therapy on Bleeding Outcomes Following Robot-assisted Radical Prostatectomy

To assess the impact of continued perioperative anticoagulant drug administration on bleeding and complications in patients undergoing robot-assisted radical prostatectomy. Between January 2014 and January 2020, 620 patients with prostate cancer underwent robot-assisted radical prostatectomies and were retrospectively reviewed. Fourteen patients who discontinued antithrombotic therapy were excluded. Among the 606 included patients, 31 continued anticoagulant therapy during the perioperative phase (anticoagulant group). The anticoagulant group outcomes were compared with those of patients who continued clopidogrel and prasugrel (thienopyridine group = 13), aspirin monotherapy (aspirin group = 61), and no chronic antithrombotic agent (control group = 501). The primary outcome was the incidence of bleeding complications requiring transfusion, additional intervention, or readmission. Secondary outcomes were the incidence of thrombotic complications, estimated blood loss, and overall complication rates. Among the 31 patients in the anticoagulant group, 20 (65%) used directed oral anticoagulants, 11 (35%) used warfarin, and 5 used combined aspirin. Only 1 (3%) patient in the anticoagulant group required postoperative transfusion, and none required additional interventions or readmission. No significant differences were detected between the anticoagulant and other groups (anticoagulant vs thienopyridine, aspirin, and control groups) regarding bleeding complications (3% vs 8%, P = .51; 0%, P = .34; 0.4%, P = .17, respectively), thrombotic complications (3% vs 0%, P = .70; 2%, P = .56; 0.2%, P = .11, respectively), estimated blood loss (200 vs 100 mL, P = .63; 175 mL, P = .64; 165 mL, P = .74, respectively), or other high-grade complications (6% vs 0%, P = .49; 2%, P = .26; 3%, P = .24, respectively). Perioperative continuation of anticoagulant use is feasible for patients undergoing robot-assisted radical prostatectomy.

Brunner's Gland Adenocarcinoma in an Aged Western Gorilla (Gorilla gorilla)

A 50-year-old male western gorilla (Gorilla gorilla) presented with severe bradypragia, anorexia and vomiting. Despite continuous administration of antiphlogistic analgesic drugs and supportive care, the animal died and was submitted for post-mortem examination. Macroscopically, a large mass was located in the duodenum. The mucosal surface of the duodenum was irregular and thickened, and the lumen narrowed. The duodenal lesion was identified as a tubular adenocarcinoma and the neoplastic cells were strongly positive for cytokeratin AE1/AE3, cytokeratin 7, cytokeratin 19 and mucin-6 protein. Ultrastructurally, the apical cytoplasm of neoplastic cells had electron dense granules and apical microvilli. This is the first reported case of Brunner's gland adenocarcinoma in a gorilla.

Mo1730 CONTINUOUS ADMINISTRATION OF ANTITHROMBOTIC DRUGS DOES NOT EXACERBATE ACUTE LOWER GASTROINTESTINAL BLEEDING: POST-HOC ANALYSIS OF A MULTICENTER RANDOMIZED CONTROLLED TRIAL

Currently, there is no established guideline for the continue or discontinue of antithrombotic drugs such as antiplatelet drugs and anticoagulants for patients with gastrointestinal bleeding. Previous retrospective reports suggest that the continuation of antithrombotic drugs increase the risk of early rebleeding. However, discontinuation of antithrombotic drugs has been suggested as a possibility of increased cerebrocardiovascular events and mortality. We conducted a multicenter randomized controlled trial (RCT) on the usefulness of early colonoscopy for acute lower gastrointestinal bleeding (ALGIB) in collaboration with 14 facilities. In the present study, we compared the effects of continuation and discontinuation of antithrombotic drugs for ALGIB as a post-hoc analysis of the RCT. Among 162 patients who visited the hospital for ALGIB between June 2016 and May 2018, 87 were taking antithrombotic drugs. We divided the patients into antithrombotic drugs continuation (n=55) and discontinuation (n=32) groups when they underwent colonoscopy. As a post-hoc analysis, the early rebleeding rate (within 30 days), blood transfusion, the stigmata of recent hemorrhage (SRH) identification rate, additional treatment (endoscopy, interventional radiology, surgery), and adverse events (thrombosis and mortality) were compared between the two groups. Student’s t-test was used for continuous variables, and chi-square test was used for categorical variables. Mantel-Haenszel analysis was performed by adjusting facilities and operators. There was no difference in the type of antithrombotic drugs and bleeding source in the patient background. The early rebleeding rate was not significantly different between the continuation (14.5%) and discontinuation groups (3.1%) (P = 0.14, 95% confidence interval [CI]: -22.1% to -10.3%). The SRH identification rate was not significantly different between the continuation (23.6%) and discontinuation groups (25.0%) (P = 0.98, 95% CI: -19.5% to -19.1%). Blood transfusion, additional treatment such as endoscopic hemostasis or surgery or interventional radiology was not significantly different in either group. No mortality or thrombosis occurred in either group within the 30-day observation period. Reports regarding the continuation of antithrombotic drugs and the course of bleeding such as early rebleeding and blood transfusion were rare. Furthermore, the use of patient data from multicenter RCT is novel. Continuous administration of antithrombotic drugs did not exacerbate ALGIB. This suggests that colonoscopy with continued antithrombotic drug administration should be considered.

Evaluation of a Novel Boron-Containing α-D-Mannopyranoside for BNCT.

Boron neutron capture therapy (BNCT) is a unique anticancer technology that has demonstrated its efficacy in numerous phase I/II clinical trials with boronophenylalanine (BPA) and sodium borocaptate (BSH) used as 10B delivery agents. However, continuous drug administration at high concentrations is needed to maintain sufficient 10B concentration within tumors. To address the issue of 10B accumulation and retention in tumor tissue, we developed MMT1242, a novel boron-containing α-d-mannopyranoside. We evaluated the uptake, intracellular distribution, and retention of MMT1242 in cultured cells and analyzed biodistribution, tumor-to-normal tissue ratio and toxicity in vivo. Fluorescence imaging using nitrobenzoxadiazole (NBD)-labeled MMT1242 and inductively coupled mass spectrometry (ICP-MS) were performed. The effectiveness of BNCT using MMT1242 was assessed in animal irradiation studies at the Kyoto University Research Reactor. MMT1242 showed a high uptake and broad intracellular distribution in vitro, longer tumor retention compared to BSH and BPA, and adequate tumor-to-normal tissue accumulation ratio and low toxicity in vivo. A neutron irradiation study with MMT1242 in a subcutaneous murine tumor model revealed a significant tumor inhibiting effect if injected 24 h before irradiation. We therefore report that 10B-MMT1242 is a candidate for further clinical BNCT studies.

Modeling the Residence Time Distribution of Integrated Continuous Bioprocesses.

In response to the biopharmaceutical industry advancing from traditional batch operation to continuous operation, the Food and Drug Administration (FDA) has published a draft for continuous integrated biomanufacturing. This draft outlines the most important rules for establishing continuous integration. One of these rules is a thorough understanding of mass flows in the process. A computer simulation framework is developed for modeling the residence time distribution (RTD) of integrated continuous downstream processes based on a unit-by-unit modeling approach in which unit operations are simulated one-by-one across the entire processing time, and then combined into an integrated RTD model. The framework allows for easy addition or replacement of new unit operations, as well as quick adjustment of process parameters during evaluation of the RTD model. With this RTD model, the start-up phase to reach steady state can be accelerated, the effects of process disturbances at any stage of the process can be calculated, and virtual tracking of a section of the inlet material throughout the process is possible. A hypothetical biomanufacturing process for an antibody was chosen for showcasing the RTD modeling approach.

Soil-transmitted helminths and schistosomiasis among pre-school age children in a rural setting of Busia County, Western Kenya: a cross-sectional study of prevalence, and associated exposures

BackgroundSoil-transmitted helminths (STH) and schistosomiasis continue to cause serious health problems among affected communities. To ensure that infection transmission levels are reduced, repeated mass drug administration at regular intervals has been recommended by World Health Organization. Pre-school age children (PSAC) have been neglected both in terms of research activities and in control programmes in the past for reasons that they carry insignificant infection levels. The current study determined risk factors that contribute to differences in infection prevalence among enrolled and non-enrolled PSAC in Busia County, western Kenya.MethodsThis was a comparative cross-sectional study that compared STH and Schistosoma mansoni infections among enrolled and non-enrolled PSAC in Busia County. Simple random sampling was used to select study participants. A total of 327 enrolled and 326 non-enrolled PSAC (n = 653) were recruited from five participating schools, and the neighboring villages. Statistical analysis was performed using STATA version 14 (STATA Corporation, College Station, TX, USA). Differences in proportions were assessed using the z-test statistic for testing sample proportions. Univariable and multivariable logistic regression were used to test the associations between the variables.ResultsThe prevalence of STH and Schistosoma mansoni infection was 17.0% (95%CI: 13.1–22.1), and 11.8% (95%CI:11.0–12.9) respectively. Specific STH species prevalence were 12.9% (95%CI:7.0–23.5) for Trichuris trichiura, 8.3% (95%CI:8.2–8.3) for Ascaris lumbricoides, and 1.2% (95%CI:1.2–1.2) for hookworms. Prevalence of T. trichiura was higher among enrolled PSAC 16.9% (95%CI: 6.8–41.9); p = 0.003, compared to the non-enrolled 8.9% (95%CI:4.3–18.2). From univariable analysis, lack of improved water source for drinking OR 2.01, (95%CI:1.29–3.13); p = 0.002, and not wearing shoes OR 3.42, (95%CI:1.14–10.29); p = 0.028, were some of the significant factors associated with STH infection. While for multivariable analysis, bathing/swimming in a river daily, aOR 3.99 (95%CI:1.98–8.06); p = 0.001 was a key significant factor for S. mansoni infections.ConclusionThere was high prevalence of STH infection among enrolled PSAC despite having participated in the national school-based deworming programme. Hence the need for continued mass drug administration to reduce the intensity of infections among these age group. In addition, further research maybe needed to identify drivers of STH infection particularly T. trichiura among PSAC.

Co-transplantation of Vascularized Thymic Graft with Kidney in Pig-to-Nonhuman Primates for the Induction of Tolerance Across Xenogeneic Barriers.

Using advanced gene editing technologies, xenotransplantation from multi-transgenic alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of renal xenograft survival, ranging from days to greater than several months for life-supporting kidneys and >2years in a heterotopic non-life-supporting cardiac xenograft model. However, continuous administration of multiple immunosuppressive drugs continues to be required, and attempts to taper immunosuppression have been unsuccessful. These data are consistent with previous reports indicating that the human-anti-porcine T cell response is similar or stronger than that across allogeneic barriers. Due to the strength of both the innate and adaptive immune responses in xenotransplantation, the level of continuous immunosuppression needed to control these responses and prolong xenograft survival has been associated with prohibitive morbidity and mortality. These facts provide compelling rationale to pursue a clinically applicable strategy for the induction of tolerance.Mixed chimerism and thymic tissue transplantation have both achieved xenogeneic tolerance in pig-to-mouse models, and both have recently been extended to pig-to-baboon models. Although these strategies are promising in small animal models, neither direct intravenous injection of porcine bone marrow cells nor direct fetal thymic tissue transplantation into recipients was able to achieve >2days chimerism following BM Tx or the engraftment of thymic tissues across xenogeneic barriers in pig-to-nonhuman primate models. Several innovative procedures have been largely developed by Kazuhiko Yamada to overcome these failures. These include vascularized thymic transplantation, combined with either thymokidney (TK) or vascularized thymic lobe (VTL) transplantation. Utilizing the strategy of transplanting vascularized thymic grafts with kidney from the same GalT-KO donor without further gene modification, we have achieved longer than 6 months survival of life-supporting kidneys in a baboon. Notably, the recipient became donor specific unresponsive and developed new thymic emigrants. In this chapter, we introduce a brief summary of our achievements to date toward the successful induction of tolerance by utilizing our novel strategy of vascularized thymic transplantation (including thymokidney transplantation), as well as describe the step-by-step methodology of surgical and in vitro procedures which are required for this experiment.

Performance of modern syringe infusion pump assemblies at low infusion rates in the perioperative setting

BackgroundSyringe infusion pumps are used for the precise continuous administration of intravenous drugs. Their compliance and mechanical deficiencies have been found to cause considerable start-up delays, flow irregularities during vertical displacement, as well extensive delays of occlusion alarms at low infusion rates. The aim of this study was to evaluate the performance of several modern syringe infusion pumps at low infusion rates and the impact on drug concentration. MethodsSeven currently marketed syringe infusion pump assemblies were assessed in an in vitro study during start-up, vertical displacement manoeuvres, and infusion line occlusion at a set flow rate of 1 ml h−1. The measured data were used as input for a pharmacokinetic simulation modelling plasma concentration during a standard neonatal continuous epinephrine infusion. ResultsThe mean time from starting the infusion pump to steady-state flow varied from 89 to 1622 s. The zero-drug delivery time after lowering the pump ranged from 145 to 335 s. In all assemblies tested, occlusion alarm delays and measured flow irregularities during vertical displacement manoeuvres resulted in relevant deviations in plasma epinephrine concentration (>25%) as calculated by the pharmacokinetic simulation model. ConclusionProblems with the performance of syringe infusion pump assemblies can have considerable impact on plasma drug concentration when highly concentrated short-acting cardiovascular drugs are administered at low flow rates. The problems, which affected all assemblies tested, are mainly related to the functional principle of syringe infusion pumps and will only partially be solved by incremental improvements of existing equipment.

Controlled, non-inferiority trial of bupivacaine liposome injectable suspension.

Recently, a bupivacaine liposome injectable suspension (BLIS) became commercially available in the veterinary market that may provide local analgesia for 72 h. The purpose of this study was to compare a BLIS incisional block with a control protocol in cats after ovariohysterectomy (OHE). The hypothesis was that a BLIS block would provide equivalent pain relief. This study was designed as a randomized, double-blind, non-inferiority trial. Students performed an OHE followed by a two-layer incisional and body wall block with either standard bupivacaine (control) or BLIS. Postoperatively, cats in the control group received robenacoxib, whereas the BLIS cats received saline. All cats were evaluated using the feline Glasgow Composite Measure Pain Scale (GCMPS) at multiple time points postoperatively. There were 24 control cats and 23 BLIS cats. One cat from each group required rescue medication. The mean GCMPS scores were low and the groups were equivalent at all time points (P <0.05). This study showed that BLIS was equivalent to the control group up to 42 h and pain scores remained low up to 68 h after surgery. BLIS incisional block is equivalent to a control pain protocol and reduces the need for continued postoperative drug administration.

Regional Anesthesia Facilitates the Early Recognition of Local Anesthetic Toxicity

Rising concerns regarding the potential long-term neurocognitive effects of general anesthetic agents have renewed an interest in using regional anesthesia instead of general anesthesia in infants. Although generally safe and effective, the primary risk associated with regional anesthesia relates to the use of large doses of local anesthetic agents and the potential for local anesthetic systemic toxicity (LAST). We present three infants who suffered LAST after receiving regional anesthesia instead of general anesthesia. The early signs and symptoms were quickly identified in the awake state thereby allowing for cessation of continuous drug administration and a rapid response to treat LAST before progression to severe sequelae. J Med Cases. 2019;10(11):338-342 doi: https://doi.org/10.14740/jmc3393

Optimal EPO dosing in hemodialysis patients using a non-linear model predictive control approach

Anemia management with erythropoiesis stimulating agents is a challenging task in hemodialysis patients since their response to treatment varies highly. In general, it is difficult to achieve and maintain the predefined hemoglobin (Hgb) target levels in clinical practice. The aim of this study is to develop a fully personalizable controller scheme to stabilize Hgb levels within a narrow target window while keeping drug doses low to mitigate side effects. First in-silico results of this framework are presented in this paper. Based on a model of erythropoiesis we formulate a non-linear model predictive control (NMPC) algorithm for the individualized optimization of epoetin alfa (EPO) doses. Previous to this work, model parameters were estimated for individual patients using clinical data. The optimal control problem is formulated for a continuous drug administration. This is currently a hypothetical form of drug administration for EPO as it would require a programmable EPO pump similar to insulin pumps used to treat patients with diabetes mellitus. In each step of the NMPC method the open-loop problem is solved with a projected quasi-Newton method. The controller is successfully tested in-silico on several patient parameter sets. An appropriate control is feasible in the tested patients under the assumption that the controlled quantity is measured regularly and that continuous EPO administration is adjusted on a daily, weekly or monthly basis. Further, the controller satisfactorily handles the following challenging problems in simulations: bleedings, missed administrations and dosing errors.

Voluntary exercise is motivated by ghrelin, possibly related to the central reward circuit.

We previously reported that voluntary exercise contributed to the amelioration of abnormal feeding behavior with a concomitant restoration of ghrelin production in a rat model of obesity, suggesting a possible relationship between exercise and appetite-regulating hormones. Ghrelin is known to be involved in the brain reward circuits via dopamine neurons related to motivational properties. We investigated the relevance of ghrelin as an initiator of voluntary exercise as well as feeding behavior. The plasma ghrelin concentration fluctuates throughout the day with its peak at the beginning of the dark period in the wild-type (WT) mice with voluntary exercise. Although predominant increases in wheel running activity were observed accordant to the peak of plasma ghrelin concentration in the WT mice, those were severely attenuated in the ghrelin-knockout (GKO) mice under either ad libitum or time-restricted feeding. A single injection of ghrelin receptor agonist brought about and reproduced a marked enhancement of wheel running activity, in contrast to no effect by the continuous administration of the same drug. Brain dopamine levels (DAs) were enhanced after food consumption in the WT mice under voluntary exercise. Although the acceleration of DAs were apparently blunted in the GKO mice, they were dramatically revived after the administration of ghrelin receptor agonist, suggesting the relevance of ghrelin in the reward circuit under voluntary exercise. These findings emphasize that the surge of ghrelin plays a crucial role in the formation of motivation for the initiation of voluntary exercise possibly related to the central dopamine system.

Evaluating ibrutinib in the treatment of symptomatic Waldenstrom's macroglobulinemia.

Waldenstrom’s macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma with indolent course and prolonged disease course. The first-in-class Bruton’s tyrosine kinase inhibitor, ibrutinib, has shown significant activity and a distinct adverse event profile among both newly diagnosed and relapsed/refractory WM patients. Interestingly, clinical responses to ibrutinib have been shown to be dependent on patients’ MYD88 and CXCR4 mutational status. The recent outcomes of the Phase III iNNOVATE trial showed that the combination of ibrutinib with rituximab resulted in a significantly prolonged progression-free survival compared with rituximab monotherapy, which provides a novel therapeutic option in the clinical practice especially for the rituximab-refractory WM patients. However, the need for continuous drug administration along with the unique toxicity manifestations may render the patient management challenging. Furthermore, our understanding of the underlying resistant mechanisms to ibrutinib is currently being evolved.