Multiple Daily Doses Research Articles

Ultra-rapid Lispro (URLi) Reduces Postprandial Glucose Excursions vs. Humalog® in Patients with T1D at Multiple Meal-to-Dose Timing Intervals

URLi (LY900014), a novel ultra-rapid mealtime insulin in Phase 3 development, is shown to reduce postprandial glucose after subcutaneous injection. This 2-part, randomized, double-blind, Phase 1b study evaluated the differences in PK and PD between URLi and insulin lispro (Humalog®; HL) in 30 patients with T1D. Part A used a 6´period crossover design to evaluate safety and compare PK and postprandial glucose response to solid mixed meal tolerance tests (MMTT) with URLi or HL at different injection to mealtime intervals (-15, 0, and +15 min). Part B evaluated the safety, PK, and PD during 2 weeks of multiple daily dosing (immediately before a meal) in a parallel design. In Part A, URLi reduced glucose excursions (assessed as change in area under the concentration curve vs. time [∆AUC]) during the first 2 hours (∆AUC0-2h) and entire 5 hours (∆AUC0´5h) of the MMMT regardless of dose timing (Fig). URLi reduced ∆AUC0-2h by 103% (p=0.008), 39% (p=0.031), and 16% (p=0.096), and ∆AUC0-5h by 40% (p=NS), 44% (p=0.097), and 42% (p=0.026) vs. HL at -15, 0, and +15 min (significance level =0.1. The PK and PD profiles for URLi and HL were sustained after 2 weeks of outpatient dosing (Part B). Similar number of hypoglycemic events occurred between treatments during MMTTs. During 2 weeks of outpatient dosing, the number of events was lower for URLi vs. HL. Local tolerability was similar between treatments. Disclosure L. Plum-Moerschel: None. J. Leohr: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Employee; Spouse/Partner; Accenture. Stock/Shareholder; Spouse/Partner; Accenture. R. Liu: Employee; Self; Eli Lilly and Company. Employee; Spouse/Partner; Eli Lilly and Company. S. Reddy: None. M.A. Dellva: Employee; Self; Eli Lilly and Company. S. Lim: None. M. Loh: Employee; Self; Eli Lilly and Company. M.P. Knadler: Other Relationship; Self; Eli Lilly and Company. T. Hardy: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C.M. Kazda: Employee; Self; Eli Lilly and Company.

Distribution of pomalidomide into semen of healthy male subjects after multiple doses.

ObjectiveTo assess whether pomalidomide can distribute into human semen and its duration in human semen.MethodA phase 1, randomized, double-blind, placebo-controlled study (CC-4047-CP-006) was conducted to evaluate the safety, tolerability, and pharmacokinetics of pomalidomide (CC-4047) following multiple daily doses in healthy male subjects. Semen samples were collected on Day −1 and 4 hours after dosing on Day 4 to quantify the pomalidomide concentrations in ejaculate after multiple oral doses of pomalidomide.ResultOur study showed that pomalidomide was present in male subjects’ semen samples, and the average amount of pomalidomide in a single ejaculate 4 hours after dosing was less than 0.0022% of the daily 2 mg dose. There was a good correlation between the semen concentrations and the plasma concentrations, suggesting that the plasma concentration may be the main driving force for the distribution of pomalidomide into the seminal reservoirs. Simulation results suggest that pomalidomide was undetectable in semen 48 hours after stopping dosing.ConclusionBased on the results from this study, the pomalidomide prescribing information approved by the US Food and Drug Administration includes a statement that “pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.”

A Study of the Potential Interaction Between Bazedoxifene and Atorvastatin in Healthy Postmenopausal Women

An open-label, 3-period study was conducted in 30 healthy postmenopausal women (mean age, 58.4years) who received a single oral dose of atorvastatin 20mg on day 1 (period 1), multiple daily dosing of bazedoxifene 40mg on days 4-11 (period 2), and coadministration of atorvastatin 20mg+bazedoxifene 40mg on day 12 (period 3). Serial blood samples were collected (24hours after bazedoxifene and 72hours after atorvastatin) and assayed for bazedoxifene, atorvastatin, and its ortho-hydroxy and para-hydroxy metabolites. Pharmacokinetic parameters were calculated using noncompartmental methods. Bazedoxifene exposure was not altered with coadministration of atorvastatin 20mg (Cmax and AUCss were within bioequivalence limits). Similarly, atorvastatin and ortho-hydroxyatorvastatin exposure was equivalent with or without coadministration with bazedoxifene. Para-hydroxyatorvastatin concentrations were below the limit of quantitation under both conditions. Cmax for atorvastatin and ortho-hydroxyatorvastatin was 14% and 18% lower, respectively, and Tmax was 20% and 34% longer, respectively, with the combination compared with atorvastatin alone. There were no serious adverse events, and no subjects discontinued the study because of safety. No clinically significant pharmacokinetic interaction was observed between bazedoxifene and atorvastatin or its active metabolites, indicating they may be safely coadministered without dosage adjustment.

Topical drug delivery to the posterior segment of the eye: Dexamethasone concentrations in various eye tissues after topical administration for up to 15 days to rabbits

Delivering drug to the back of the eye remains a challenging task owning to the anatomical and physiological barrier of the eye. Today injection and implants are routinely used to treat diseases in the posterior segment of the eye. Both methods require repeated injection or insertion with potential complication such as retinal detachment, endophtalmitis and retinal haemorrhage, a better non-invasive approach is therefore needed. The aim of this study was to investigate if topically applied dexamethasone in cyclodextrin micro-suspension could deliver dexamethasone to the posterior segment of the eye in therapeutic concentrations in rabbits. Un-anesthetized pigmented rabbits were used in this study where they received eye drop in the left eye and were sacrificed 1, 2, 6 h after administration, and 7 and 15 days after receiving eye drop to the left eye 3 times a day. The result showed that dexamethasone was detectable in all ophthalmic tissues tested and at relatively high concentrations in tissues at the back of the eye. Furthermore, dexamethasone did not accumulate in the ocular tissues after multiple daily dosing for up to 15 days. This novel delivery technique could therefore be used to deliver lipophilic drug to the posterior segment of the eye.

Evaluation of efficacy and effects of daily dosing of diminazene aceturate in dogs experimentally infected with <i>Trypanosoma congolense</i>

Resistance to trypanocidal drugs or relapse of infection poses a big challenge to the effective treatment of trypanosomosis. This study investigated the efficacy and effect of multiple daily doses of diminazene aceturate (DA) in Nigerian indigenous dogs (NID) experimentally infected with Trypanosoma congolense (2.5 x 105). Fifteen NID of both sexes and mean weight of 9.4 0.98 kg were randomly divided into 3 equal groups. Group A dogs were infected but not treated. Groups B and C were infected with T. congolense, and treated with single and four multiple daily divided doses of 3.5 mg/kg of DA, respectively. Parasitaemia was detected in the infected dogs on day 10 post infection (pi) and treatment was instituted in Groups B and C dogs on day 17 pi. Parasitaemia was cleared on days 10 and 8 post-treatment in Groups B and C respectively. There was an increase in urea, creatinine, aminotransferase and aspartate aminotransferase levels in all the groups while, alkaline phosphatase, Packed Cell Volume and Red Blood Cells count decreased. There was relapse of infection in treated groups on day 25 post-treatment. We concluded that four multiple daily divided doses of DA (3.5 mg/kg) were not effective in preventing relapse of T. congolense infection in NID.Keywords: Diminazene aceturate multiple doses; trypanosomosis; biochemical changes; dogs

An overview of insulin therapy in pharmacotherapy of diabetes mellitus type I

Type 1 diabetes mellitus is a chronic disease, which characterizes itself with body’s inability to produce insulin from pancreas. This condition can happen from different autoimmune processes, which subsequently leads into destruction of beta cells in pancreas, the cells responsible for production of insulin. This condition account for about 5-10% of all different forms of diabetes, which should be taken very seriously since its incidence seems to be increasing worldwide and it can result in different devastating short and long-term complications. Management and approaches in patients with type 1 DM is of major concern worldwide since in the lack of proper management these patients cannot survive. Therefore, it is very important to have a multidisciplinary health management team that can have full focus on every aspect of this condition from continuous glucose monitoring, meal planning, screening for different complications to insulin therapy, which is the mainstay in treatment of patients in this group. American Diabetes Association (ADA) suggests using patient’s age in establishment of glycaemic goals, with targets for pre-prandial, bedtime and haemoglobin A1c levels. It is very important to educate patients on how to adjust the level of their insulin injection according to the amount of carbohydrate intake, premeal blood glucose, and anticipated activity. Insulin is and will remain the most important treatment approach in patients suffering from type 1 DM. According to recommendations of ADA, it is best when patients with type 1 DM are treated with multiple daily doses of insulin injections, such as three to four daily basal and prandial injections, or continuous subcutaneous insulin infusion devices should be used.

Pharmacokinetics of multiple doses of transdermal flunixin meglumine in adult Holstein dairy cows.

A transdermal formulation of the nonsteroidal anti-inflammatory drug, flunixin meglumine, has been approved in the United States and Canada for single-dose administration. Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33mg/kg every 24hr for three total treatments. Plasma flunixin concentrations were determined using high-pressure liquid chromatography with mass spectroscopy (HPLC-MS). Pharmacokinetic analysis was completed on each individual animal with noncompartmental methods using computer software. The time to maximum drug concentration (Tmax) was 2.81hr, and the maximum drug concentration was 1.08μg/ml. The mean terminal half-life (T½) was determined to be 5.20hr. Clearance per fraction absorbed (Cl/F) was calculated to be 0.294L/hrkg-1 , and volume of distribution of fraction (Vz/F) absorbed was 2.20L/kg. The mean accumulation factor was 1.10 after three doses. This indicates changes in dosing may not be required when giving multiple doses of flunixin transdermal. Further work is required to investigate the clinical efficacy of transdermal flunixin after multiple daily doses.

Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections

Guaifenesin, a mucoactive drug, acts by loosening mucus in the airways and making coughs more productive. It is used for relief of wet cough and chest congestion due to the common cold, and remains the only legally marketed expectorant in the US (per OTC Monograph). An ingredient in numerous over-the-counter (OTC) cough/cold medications, guaifenesin has a secondary indication for use in stable chronic bronchitis (professional indication). Clinical pharmacology and patient studies support the clinical utility of guaifenesin in respiratory conditions where mucus hypersecretion is prevalent: acute upper respiratory tract infections (URTIs), stable chronic bronchitis, and possibly rhinosinusitis. Guaifenesin has a well-established and favorable safety and tolerability profile in adult and pediatric populations. Its dosing range (200–400 mg 4-hourly, up to 6× daily) allows flexible dose titration to allow an increase of plasma concentrations. Multiple daily doses are needed to maintain 24-h therapeutic effect with immediaterelease formulations. Extended-release guaifenesin tablet formulations are available, providing convenience with 12-hourly dosing and portability compared to liquids. Guaifenesin is considered as a safe and effective expectorant for the treatment of mucus-related symptoms in acute URTIs and stable chronic bronchitis. Its clinical efficacy has been demonstrated most widely in chronic respiratory conditions, where excess mucus production and cough are more stable symptoms. Progress is being made to establish clinical models and measures that are more appropriate for studying symptomatic relief with guaifenesin in acute respiratory infections. This will help generate the up-to-date and high-quality data needed to optimize guaifenesin’s effectiveness in established uses, and in new respiratory indications associated with mucus hypersecretion.

Standard Multiple and Single Daily Dosing of Amikacin in Premature Infants

Background: Bacterial sepsis is highly prevalent among premature infants. Amikacin is an antibiotic widely recommended for the treatment of neonatal sepsis, one of the consequences of which might be nephrotoxicity. The present study aimed to compare the efficacy and nephrotoxicity of multiple daily dosing (MDD) and once-daily dosing (ODD) of amikacin in preterm infants suspected of sepsis. Methods: This triple-blind, randomized, controlled clinical trial was conducted on 40 premature infants suspected of sepsis, who were randomly divided into two groups. In addition to ampicillin, one group was administered with the standard daily dose, and the other group received an ODD of intravenous amikacin. Maximum and minimum serum levels of amikacin and urine neutrophil gelatinase-associated lipocalin (NGAL) were measured in both groups. Data were extracted and analyzed based on the research hypothesis and literature review. Results: No significant differences were observed between the study groups in terms of gender, gestational age, mode of delivery, birth weight, and Apgar score. After the intervention, mean plasma creatinine reduced in both groups, while the mean reduction was significantly higher in the group administered with the ODD of amikacin (P=0.0001). However, mean changes in the urine NGAL had no significant difference between the groups (P=0.635). Minimum and maximum serum levels of amikacin in the study groups indicated a more significant reduction in mean level of the infants administered with the ODD of amikacin compared to the MDD group (P=0.0001). Conclusion: Considering the higher maximum and lower minimum levels of amikacin in the neonates receiving the daily dosage regimen, it seems that this regimen is more effective in the treatment of sepsis in preterm infants. Moreover, no significant difference was observed in the efficacy and nephrotoxicity of the daily amikacin dosing in the premature infants suspected of sepsis compared to those treated by multiple doses of amikacin.

Safety of intravenous tobramycin in combination with a variety of anti-pseudomonal antibiotics in children with cystic fibrosis.

Objectives:Previous studies have examined renal safety of once daily intravenous tobramycin in individuals with cystic fibrosis. This has been mainly in combination with ceftazidime in an adolescent or adult population. In this report, we describe our institutional experience of once daily intravenous tobramycin in combination with a variety of second anti-pseudomonal antibiotics in children with cystic fibrosis.Methods:We present a retrospective review including children with cystic fibrosis, who were admitted for a pulmonary exacerbation from January 2009 to December 2011, and treated using intravenous tobramycin. A literature review of once daily intravenous aminoglycoside dosing in cystic fibrosis was performed to compare our results to existing literature.Results:A total of 35 subjects were divided into once daily dosing (n = 20) versus multiple daily dosing (n = 15) groups. Mean age was 11.3 years (± 5.7) for the once daily dosing group and 13.1 years (± 4.4) for the multiple daily dosing group (p = 0.34). All subjects had normal baseline serum creatinine at admission (once daily dosing 0.49 ± 0.14 mg/dL vs multiple daily dosing 0.62 ± 0.23 mg/dL, p = 0.07). All subjects received intravenous tobramycin, and most received piperacillin-tazobactam as their second anti-pseudomonal antibiotic (once daily dosing 45% and multiple daily dosing 40%). There was no significant change in serum creatinine in either group during antibiotic treatment (once daily dosing 0.08 ± 0.12 mg/dL vs. multiple daily dosing 0.06 ± 0.10 mg/dL, p = 0.43). All subjects had significant improvement in lung function following intravenous antibiotic therapy.Conclusion:We show that both once daily dosing and multiple daily dosing of intravenous tobramycin in combination with a variety of second anti-pseudomonal antibiotics were safe in terms of nephrotoxicity in children with cystic fibrosis. These findings are important given existing literature mainly examines once daily tobramycin in combination with ceftazidime, a cephalosporin, and the majority of our patients were on tobramycin with piperacillin-tazobactam, an extended spectrum penicillin plus beta-lactam. This contributes new information not previously examined in a pediatric cystic fibrosis population.

Bis-choline tetrathiomolybdate in patients with Wilson's disease: an open-label, multicentre, phase 2 study

Wilson's disease is a genetic disorder in which copper accumulates in the liver, brain, and other tissues. Therapies are limited by efficacy, safety concerns, and multiple daily dosing. Bis-choline tetrathiomolybdate (WTX101) is an oral first-in-class copper-protein-binding molecule that targets hepatic intracellular copper and reduces plasma non-ceruloplasmin-bound copper (NCC) by forming tripartite complexes with albumin and increasing biliary copper excretion. We aimed to assess the efficacy and safety of WTX101 in the initial or early treatment of patients with Wilson's disease. We did this open-label, phase 2 study at 11 hospitals in the USA and Europe. We enrolled patients (≥18 years) with Wilson's disease who were untreated or had received no more than 24 months of treatment with chelators or zinc, had a Leipzig score of 4 or more, and had NCC concentrations above the lower limit of the normal reference range (≥0·8 μmol/L). Eligible patients received WTX101 monotherapy at a starting dose of 15-60 mg/day on the basis of baseline NCC concentrations for the first 4-8 weeks, with response-guided individualised dosing for the remaining weeks up to week 24. Investigators, other hospital personnel, and patients were aware of the identity of the treatment. The primary endpoint was change in baseline NCC concentrations corrected for copper in tetrathiomolybdate-copper-albumin complexes (NCCcorrected) at 24 weeks, with treatment success defined as achievement or maintenance of normalised NCCcorrected (≤2·3 μmol/L [upper limit of normal]) or achievement of at least a 25% reduction in NCCcorrected from baseline at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT02273596. Between Nov 24, 2014, and April 27, 2016, 28 patients were enrolled and received WTX101; 22 (79%) patients completed the study up to week 24. At 24 weeks, 20 (71%, 95% CI 51·3-86·8; p<0·0001) of 28 patients met the criteria for treatment success: 16 (57%) treated with WTX101 either achieved or maintained normalised NCCcorrected concentrations and 4 (14%) had at least a 25% reduction from baseline NCCcorrected. Mean NCCcorrected was reduced by 72% from baseline to week 24 (least squares mean difference -2·4 μmol/L [SE 0·4], 95% CI -3·2 to -1·6; p<0·0001). No cases of paradoxical drug-related neurological worsening were recorded. Liver function was stable in all patients, although reversible increased concentrations of asymptomatic alanine or aspartate aminotransferase, or γ-glutamyltransferase, without increased bilirubin, occurred in 11 (39%) of 28 patients who received at least 30 mg/day. 11 serious adverse events were reported in seven (25%) patients and included psychiatric disorders (six events in four patients), gait disturbance (one event), elevated liver aminotransferases (two events in two patients, one with agranulocytosis), and decline in neurological functioning (one event, likely due to natural disease progression although causality could not be ruled out). The seven serious adverse events categorised as psychiatric disorders and as gait disturbance were assessed as unlikely to be related to the study drug, whereas the remaining four events were possibly or probably related. Our findings indicate that WTX101 might be a promising new therapeutic approach for Wilson's disease, with a unique mode of action. In view of its once-daily dose and favourable safety profile, WTX101 could improve the treatment of patients with this debilitating condition. Wilson Therapeutics AB.

Clinical efficacy of piperacillin/tazobactam in the treatment of complicated skin and soft tissue infections

ABSTRACTIntroduction: Complicated skin and soft tissue infections (cSSTIs) are skin and soft tissue infections (SSTIs) that involve deep soft tissue. cSSTIs often require surgical intervention and/or hospitalization. cSSTIs are associated with significant mortality and morbidity, and carry a significant burden on health care systems. Piperacillin/tazobactam has been regarded as a standard treatment for cSSTIs because of its antibiotic spectrum, safety and clinical efficacy. Several antibiotics, as compared to piperacillin/tazobactam, have been evaluated in the treatment of cSSTIs.Areas covered: This review summarizes randomized controlled trials (RCTs) evaluating the clinical efficacy of piperacillin/tazobactam for the treatment of cSSTIs.Expert opinion: Piperacillin/tazobactam, which covers most causative organisms in cSSTIs, is the drug of choice for the treatment of cSSTIs. Other options such as ertapenem and moxifloxacin may be reasonable where multiple daily dosing or intravenous administration is inappropriate. But in general, they should be avoided as an empirical treatment because of their highly association with resistant bacteria, which are becoming a global threat. Therefore, piperacilin/tazobactam is appropriate as an empirical therapy for the treatment of SSTIs and should be de-escalated as soon as causative organisms are identified, their drug-sensitivity results are available, and clinical condition becomes stable.

Continuous Glucose Monitoring with Multiple Daily Insulin Treatment: Outcome Studies.

Continuous glucose monitoring (CGM) is developing into an increasingly useful tool for glucose monitoring and therapeutic guidance in the treatment of diabetes. Multiple daily doses of insulin (MDI) is the most common method for intensive insulin treatment of type 1 diabetes and is also becoming more common in the treatment of type 2 diabetes as an increasing population with type 2 diabetes experiences progressive beta cell loss. The clinical evidence demonstrating the benefit of CGM in the outcomes of patients treated with MDI is becoming clearer, particularly with the recent completion of several randomized clinical trials addressing both type 1 and 2 diabetes. This evidence is reviewed.

A Preclinical Translational Study of the Cardioprotective Effects of Plasma-Derived Alpha-1 Anti-trypsin in Acute Myocardial Infarction.

The area of myocardial infarction continues to expand for hours after reperfusion. The injured but viable myocardium may be salvaged if the signals leading to cell death are interrupted. Activation of the caspase-1 inflammasome in the heart shortly after ischemia-reperfusion contributes to the final infarct size. Plasma-derived α-1 anti-trypsin (AAT) has shown to inhibit inflammasome formation in vitro and in vivo. To explore the potential translational clinical value of AAT as a therapeutic, we conducted a series of preclinical experiments designed to simulate clinically relevant scenarios. Adult male CD1 mice were used. The left anterior descending coronary artery was ligated for 30 or 75 minutes followed by reperfusion, to explore different severity of ischemic injury. Plasma-derived AAT (Prolastin C) was administered intraperitoneally after reperfusion, without pretreatment, exploring 3 different doses (60, 120, and 180 mg/kg). In a subgroup of mice, we administered Prolastin C with a delay of 30 minutes after reperfusion to simulate the clinical context of delayed administration, and we also used a model of permanent coronary artery ligation without reperfusion. Finally, we tested whether a single dose at reperfusion was sufficient to maintain a benefit in the longer term (7 days). Infarct size was measured by 3 different and independent methodologies: pathology, plasma levels of troponin I, and wall motion abnormalities at echocardiography. Prolastin C given at reperfusion after 30 minutes of ischemia provided a powerful reduction in infarct size (>50% reduction in all methodology used, all P < 0.01) without a clear dose-dependent response. Prolongation of ischemia to 75 minutes nor a delay in treatment by 30 minutes after reperfusion had any negative impact on Prolastin C effects. A single dose given at reperfusion was as effective as multiple daily doses. When given to the mouse without reperfusion, Prolastin C failed to reduce infarct size. Plasma-derived AAT (Prolastin C) given as an adjunct to reperfusion powerfully limits the final infarct size across a wide range of experiments in the mouse reproducing clinically relevant scenarios, such as variable duration of ischemia, delay in administration in the drug, and a large therapeutic index.

Once versus twice daily aspirin after coronary bypass surgery: a randomized trial

Background Acetyl-salicylic acid (ASA) hyporesponsiveness occurs transiently after coronary artery bypass graft (CABG) surgery and may compromise the effectiveness of ASA in reducing thrombotic graft failure. A reduced response to ASA 81 mg once-daily after CABG surgery is overcome by four times daily ASA dosing. Objectives To determine whether ASA 325 mg once-daily or 162 mg twice-daily overcomes a reduced response to ASA 81 mg once-daily after CABG surgery. Methods Adults undergoing CABG surgery were randomized to ASA 81 mg once-daily, 325 mg once-daily or 162 mg twice-daily. The primary outcome was median serum thromboxane B2 (TXB2 ) level on postoperative day 4. We pooled the results with those of our earlier study to obtain better estimates of the effect of ASA 325 mg once-daily or in divided doses over 24 h. Results We randomized 68 patients undergoing CABG surgery. On postoperative day 4, patients randomized to receive ASA 81 mg once-daily had a median day 4 TXB2 level of 4.2 ng mL-1 (Q1, Q3: 1.5, 7.5 ng mL-1 ), which was higher than in those randomized to ASA 162 mg twice-daily (1.1 ng mL-1 ; Q1, Q3: 0.7, 2.7 ng mL-1 ) and similar to those randomized to ASA 325 mg once-daily (1.9 ng mL-1 ; Q1, Q3: 0.9, 4.7 ng mL-1 ). Pooled data showed that the median TXB2 level on day 4 in groups receiving ASA 162 mg twice-daily or 81 mg four times daily was 1.1 ng mL-1 compared with 2.2 ng mL-1 in those receiving ASA 325 mg once-daily. Conclusions Multiple daily dosing of ASA is more effective than ASA 81 mg once-daily or 325 mg once-daily at suppressing serum TXB2 formation after CABG surgery. A twice-daily treatment regimen needs to be tested in a clinical outcome study.

The Safety Profile of Single Daily Dose of Aminoglycosides in Comparison with Multiple Daily Dose

To overcome the problems which associated with the standard multiple daily doses (MDD)&#x0D; of aminoglycosides (AGs) like high incidence of toxicity(nephrotoxicity, ototoxicity)(5-25%) and high cost, an alternative approach was developed which was single daily dose (SDD).This new regimen was designed to maximize bacterial killing by optimizing the peak concentration/minimum inhibitory concentration(MIC)ratio and to reduce the potential for toxicity. The study includes 75 patients selected randomly, 50 of them received SDD regimen of age range of 17-79 years and the remaining received MDD regimen of age range of 13-71 years. The study was designed to evaluate the safety of SDD regimen in comparison with MDD regimen. All the patients in SDD group received a constant dose of 5-mg/kg/day of gentamicin and 20mg/kg/day of amikacin with a drug administration interval based on estimated creatinine clearance(CLcr): if ≥60 ml//min every 24 hours (q24h), 59- 40 ml/ min every 36hours and 39- 30 ml/min every 48 hours.The calculated dose was diluted with 0.9% normal saline or 5% dextrose to 50-100 ml and given as intravenous infusion over 30-60 minutes. In SDD group , the mean length of therapy was 6.4±1.73 days .Gentamicin accounted for 96% of the aminoglycoside use, and the majority(58%) of patients received the drug every 24 hours.The 36- and -48 hours intervals were used for 34 and 8% of the population, respectively.While in MDD group , the mean length of therapy was 5.0±0.91 days. Gentamicin accounted for all (100%) of aminoglycoside use, and all of the patients received the drug every 8 hours. No clinically apparent ototoxicity and nephrotoxicity were observed in the patients in the SDD group, in contrast to the patients in MDD group, in whom 4 patients (16%) were developed nephrotoxicity and 1 patient (4%) was developed ototoxicity. The obtained results indicate that SDD regimen was safer through decreasing the incidence of both nephrotoxicity and ototoxicity.For statistical analysis, ANOVA test was used with P&lt;0.01.Each mean was expressed as mean±SEM(Standard Error of Mean).&#x0D; Key words: Aminoglycosides, Single Daily Dose, Nephrotoxicity and Ototoxicity.

Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. This is an update of a previously published review. To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: 24 June 2016. All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis. The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study; authors also assessed the quality of the evidence using the GRADE criteria. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. Fifteen studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants (aged 5 to 50 years) were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One study had a low risk of bias for all criteria assessed; the remaining three included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias.There was no significant difference between treatment groups in: forced expiratory volume in one second, mean difference 0.33 (95% confidence interval -2.81 to 3.48, moderate quality evidence); forced vital capacity, mean difference 0.29 (95% confidence interval -6.58 to 7.16, low quality evidence); % weight for height, mean difference -0.82 (95% confidence interval -3.77 to 2.13, low quality evidence); body mass index, mean difference 0.00 (95% confidence interval -0.42 to 0.42, low quality evidence); or in the incidence of ototoxicity, relative risk 0.56 (95% confidence interval 0.04 to 7.96, moderate quality evidence). The percentage change in creatinine significantly favoured once-daily treatment in children, mean difference -8.20 (95% confidence interval -15.32 to -1.08, moderate quality evidence), but showed no difference in adults, mean difference 3.25 (95% confidence interval -1.82 to 8.33, moderate quality evidence). The included trials did not report antibiotic resistance patterns or quality of life. Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Once daily aerosolised tobramycin in adult patients with cystic fibrosis in the management of Pseudomonas aeruginosa chronic infection

It is estimated that about 60–70% of Cystic Fibrosis patients develop Pseudomonas aeruginosa chronic infection,with progressive loss of lung function, as well as increased antibiotic resistance and mortality. The current strategy is to maintain lung function by chronic suppressive antipseudomonas antibiotic therapy. Tobramycin inhalation solution was the first approved aerosolised antibiotic to be used against P. aeruginosa; inhalatory tobramycin frequency of administration is twice daily and inhalation time is estimated to be 15 to 20 min. From the pharmacokinetic point of view, aminoglycosides are dose-dependent antibiotics and therefore once-daily dosing intravenous regimens have shown to be superior to the conventional multiple daily dosing. Therefore, there is no pharmacological reason to prefer the b.i.d administration as it is usually performed in current clinical practice. Should this be confirmed also for inhalatory route, the use of once-daily dosed aerosolized tobramycin could be an important step in making treatment burden easier in CF patients. The aim of this proof of concept study was to explore the effectiveness of treatment with once daily inhaled tobramycin in reducing P. aeruginos a density in sputum of chronically infected patients.

Switching L-dopa Therapy from Pulsatile to Pulse Administration Reduces Motor Complications in Parkinson's Disease.

To evaluate the severity of wearing-off and dyskinesia in patients with complicated Parkinson disease (PD) after switching L-dopa oral therapy from a "pulsatile" administration, consisting in intermittent multiple daily small doses of the drug, to a "pulse" administration, consisting in standard oral doses given at specific interdose intervals. Thirty-four PD patients with motor complications were monitored twice with standardized waking day motor status evaluations using the Unified Parkinson Disease Rating Scale-Motor Examination (UPDRS-ME) and the Abnormal Involuntary Movement Scale (AIMS) after switching L-dopa administration modality from "pulsatile" to "pulse." To quantify predictable motor fluctuations, a Wearing Off Index was computed based on changes in treatment response magnitude. On the whole, after switching from "pulsatile" to "pulse" administration, there was a reduction in number of L-dopa daily doses and an increase in the amount of the dosage of the single doses, AIMS maximum score decreased without increasing motor disability. More specifically, in predominant fluctuating patients, there was a significant reduction in UPDRS-ME average score as well as in Wearing Off Index. In predominant dyskinetic patients, there was a significant reduction in average and maximum AIMS scores with no changes in average and maximum UPDRS-ME scores. Switching L-dopa therapy from "pulsatile" to "pulse" modality may reduce the severity of wearing-off and dyskinesia in complicated PD.

Ceftriaxone for the Treatment of Methicillin-susceptible Staphylococcus aureus Bacteremia: A Case Series.

Methicillin-susceptible Staphylococcus aureus (MSSA) causes 45% of S. aureus bloodstream infections (BSI) and is the most important cause of BSI-associated death. The standard of care therapy is an anti-staphylococcal penicillin or cefazolin, but dosing frequencies for these agents are often infeasible; multiple daily doses tie up infusion lines and are impractical for outpatient antibiotic infusion. Ceftriaxone represents a promising alternative, with once daily dosing and a short infusion time. Currently, treatment with ceftriaxone for invasive MSSA infections is infrequent, with minimal data supporting the clinical utility of ceftriaxone for MSSA BSI. In this case series, we identified 15 patients receiving ceftriaxone for treatment of MSSA BSI, either following standard of care therapy or as initial therapy. Patients were evaluated for clinical cure (CC)(clearance of BSI and normalization of white blood cell count) and microbiological cure (MC)(clearance of blood cultures and no recurrence of organism within 60 days). CC was observed in seven patients, with MC observed in all patients. Only one patient was readmitted to the hospital. This case series provides vital data to support ceftriaxone for treatment of MSSA BSI. With few readmissions and recurrences of infection, ceftriaxone was an effective option for maintenance therapy after resolution of the BSI. Ceftriaxone appears to be a viable alternative for the treatment of MSSA BSI.