The mammalian target of rapamycin (mTOR) inhibitor everolimus has a well-established pharmacokinetics profile. We conducted a randomized, single-center, open-label, two-sequence, two-period crossover study of healthy volunteers to assess the relative bioavailability of everolimus administered as one 5 mg tablet or five 1 mg tablets.
Subjects were randomized 1:1 to receive everolimus dosed as one 5 mg tablet or as five 1 mg tablets on day 1, followed by a washout period on days 8–14 and then the opposite formulation on day 15. Blood sampling for pharmacokinetic evaluation was performed at prespecified time points, with 17 samples taken for each treatment period. Primary variables for evaluation of relative bioavailability were area under the concentration–time curve from time zero to infinity (AUCinf) and maximum blood concentration (Cmax). Safety was assessed by reporting the incidence of adverse events (AEs).
Twenty-two participants received everolimus as one 5 mg tablet followed by five 1 mg tablets (n=11) or the opposite sequence (n=11). The Cmax of five 1 mg tablets was 48% higher than that of one 5 mg tablet (geometric mean ratio, 1.48; 90% confidence interval [CI], 1.35–1.62). AUCinf was similar (geometric mean ratio, 1.08; 90% CI, 1.02–1.16), as were the extent of absorption and the distribution and elimination kinetics. AEs, all grade 1 or 2, were observed in 54.5% of subjects.
Although the extent of absorption was similar, the Cmax of five 1 mg tablets was higher than that of one 5 mg tablet, suggesting these formulations lead to different peak blood concentrations and are not interchangeable at the dose tested.
absorption kinetics; healthy volunteers
The purpose of this study was to evaluate the pharmacokinetics, bioavailability, and safety of oral extended-release hydrocodone (HC-ER) when administered with food or alcohol.
Two single-center, open-label, randomized, crossover studies were conducted in healthy volunteers. In a two-period food-interaction study, 12 subjects received HC-ER 20 mg after an overnight fast and a high-fat meal. In a three-period alcohol-interaction study, 30 naltrexone-blocked subjects received HC-ER 50 mg with a 0%, 20%, or 40% alcohol/orange juice solution after an overnight fast. Pharmacokinetic parameters were derived from plasma concentrations of hydrocodone and its metabolites.
Exposure to hydrocodone after HC-ER 20 mg was similar in the fed and fasted states, as assessed by area under the plasma concentration versus time curve from time of dosing to time of last detectable concentration (AUC0–t; 316.14 versus 311.94 ng · h/mL); relative bioavailability (Frel) was 101.74%. Differences (fed versus fasted) in hydrocodone mean maximum plasma concentration (Cmax; 28.86 versus 22.74 ng/mL) and median time to Cmax (tmax; 6 versus 8 hours) were not clinically significant. Administration of 20% alcohol with HC-ER 50 mg did not increase systemic exposure relative to 0% alcohol (AUC0–t 878 versus 832 ng · h/mL; Frel 105%) or result in clinically meaningful changes in Cmax (51.8 versus 46.3 ng/mL) or tmax (5.44 versus 6.16 hours). Administration with 40% alcohol increased AUC0–t (1,008 ng · h/mL versus 832 ng · h/mL; Frel 120%) and Cmax (109 versus 46.3 ng/mL), and shortened tmax (2.43 versus 6.16 hours). Adverse events occurred in 10.0%, 24.1%, and 66.7% of subjects after 0%, 20%, and 40% alcohol, respectively.
HC-ER can be administered without regard to meals. While there was no evidence of “dose-dumping” (an unintended, rapid release in a short time period of all or most of the hydrocodone from HC-ER), even with 40% alcohol, as with all opioids, alcohol should not be ingested while using HC-ER.
opioid; food interaction; alcohol interaction; bioavailability; norhydrocodone; hydromorphone
The present study aimed to examine the enantiomer-selective pharmacokinetics (PK), relative bioavailability (Frel), and sex effects of various oral dosage forms of racemic alpha-lipoic acid (ALA). In an open-label, randomized, four-period, four-sequence crossover study, 24 healthy adult subjects (12 males and 12 females) received single doses of 600 mg of ALA in fasted state at four different occasions as follows: three 200 mg tablets (T 200); two 300 mg tablets (T 300); one 600 mg tablet (T 600); and a racemic ALA solution (OS). All tablet formulations (Thioctacid HR) were considered test treatments, while the OS (Thioctacid, 600 T) served as the reference treatment. Serial blood samples were collected over 8 hours postdose to quantify R-(+)- and S-(−)-ALA enantiomer plasma concentrations for the PK evaluation. The maximum observed plasma concentration (Cmax) and total exposure (area under the curve [AUC]0–t) were compared between treatments by analysis of variance. Weight-normalized Cmax and the AUC data of male and female study subjects were applied to examine the presence of sex effects. All treatments displayed rapid absorption of both enantiomers with median time to maximum concentration (tmax) values ranging from 0.33–0.5 hours. The Frel of all tablet formulations was comparable, with R-(+)-enantiomer Cmax test/reference ratios ranging from 36% (T 600) to 43% (T 200), and R-(+)-enantiomer AUC test/reference ratios ranging from 64% (T 600) to 79% (T 300), indicating a favorable Frel of all tablet formulations, especially in terms of the total extent of absorption (AUC). An examination of weight-normalized female/male Cmax and AUC sex ratios for both ALA enantiomers indicated the absence of a significant sex effect for Cmax, as well as 20%–26% and 25%–32% higher R-(+)- and S-(−)-ALA enantiomer AUC outcomes in females when compared to males. The observed modest sex effect was comparable for both ALA enantiomers and across all formulations, and it did not appear to require a dose adjustment in clinical practice.
alpha-lipoic acid; thioctic acid; enantiomers; sex effect; formulation effect; bioavailability
When l-dopa use began in the early 1960s for the treatment of Parkinson’s disease, nausea and reversible dyskinesias were experienced as continuing side effects. Carbidopa or benserazide was added to l-dopa in 1975 solely to control nausea. Subsequent to the increasing use of carbidopa has been the recognition of irreversible dyskinesias, which have automatically been attributed to l-dopa. The research into the etiology of these phenomena has identified the causative agent of the irreversible dyskinesias as carbidopa, not l-dopa. The mechanism of action of the carbidopa and benserazide causes irreversible binding and inactivation of vitamin B6 throughout the body. The consequences of this action are enormous, interfering with over 300 enzyme and protein functions. This has the ability to induce previously undocumented profound antihistamine dyskinesias, which have been wrongly attributed to l-dopa and may be perceived as irreversible if proper corrective action is not taken.
vitamin B6; PLP; irreversible; pyridoxal 5’-phosphate
Currently, there are no direct comparisons of apixaban and rivaroxaban, two new oral direct factor Xa inhibitors approved for management of thromboembolic disorders.
Compare the pharmacokinetics and anti-factor Xa activity (AXA) of apixaban and rivaroxaban.
In this randomized, open-label, two-period, two-treatment crossover study, healthy subjects (N=14) received apixaban 2.5 mg twice daily (BID) and rivaroxaban 10 mg once daily (QD) for 4 days with a ≥4.5-day washout. Plasma samples were obtained for pharmacokinetic and AXA assessments; parameters were calculated using noncompartmental methods.
Median time-to-maximum concentration was 2 hours for both compounds, and the mean half-life was 8.7 and 7.9 hours for apixaban and rivaroxaban, respectively. Daily exposure, the area under the curve (AUC(0–24)), appeared similar for rivaroxaban (1,094 ng · h/mL) and apixaban (935 ng · h/mL), whereas mean peak-to-trough plasma concentration ratio was 3.6-fold greater for rivaroxaban (16.9) than apixaban (4.7). Coefficient of variation for exposure parameters (AUC0–24, Cmax, Cmin) was 20%–24% for apixaban versus 29%–46% for rivaroxaban. Peak AXA, AXA AUC(0–24), and AXA fluctuation were ~2.5-, 1.3-, and 3.5-fold higher for rivaroxaban than apixaban, respectively. Trough concentrations and AXA were lower for rivaroxaban (10 ng/mL and 0.17 IU/mL vs 17 ng/mL and 0.24 IU/mL for apixaban, respectively). Rivaroxaban exhibited a steeper concentration–AXA response (slope: 0.0172 IU/ng vs 0.0134 IU/ng for apixaban, P<0.0001).
Apixaban 2.5 mg BID demonstrated less intersubject variability in exposure, lower AXA AUC, and higher trough and smaller peak-to-trough fluctuations in plasma concentration and AXA, suggesting more constant anticoagulation compared with rivaroxaban 10 mg QD. However, the clinical impact of these differences on the relative efficacy and safety of apixaban and rivaroxaban remains to be determined.
apixaban; pharmacodynamics; pharmacokinetics; rivaroxaban; safety
In severe alcohol withdrawal (AW), benzodiazepines may be inadequate to control symptoms. In many situations, benzodiazepine dosing escalates despite no additional efficacy and introduces potential toxicities. Severe cases of AW may require additional agents to control symptoms. Case reports and studies have shown benefits with dexmedetomidine and propofol in severe AW, but these agents have not been compared with one another. This study compares the effects of dexmedetomidine and propofol on benzodiazepine and haloperidol utilization in patients with AW.
A retrospective chart review was completed on 41 patients with AW who received adjunctive dexmedetomidine or propofol. The primary objective was to compare benzodiazepine and haloperidol utilization before and after initiation of dexmedetomidine or propofol. Secondary measures included AW and sedation scoring, analgesic use, intensive care unit length of stay, rates of intubation, and adverse events.
Among the dexmedetomidine and propofol groups, significant reductions in benzodiazepine (P≤0.0001 and P=0.043, respectively) and haloperidol (P≤0.0001 and P=0.026, respectively) requirements were observed. These reductions were comparable between groups (P=0.933 and P=0.465, respectively). A trend toward decreased intensive care unit length of stay in the dexmedetomidine group (123.6 hours vs 156.5 hours; P=0.125) was seen. Rates of intubation (14.7% vs 100%) and time of intubation (19.9 hours vs 97.6 hours; P=0.002) were less in the dexmedetomidine group. Incidence of hypotension was 17.6% in the dexmedetomidine group vs 28.5% in the propofol group. Incidence of bradycardia was 17.6% in the dexmedetomidine group vs 0% in the propofol group. No differences were observed in other secondary outcomes.
In patients with severe AW who require sedation, both dexmedetomidine and propofol have unique and advantageous properties. Both agents appear to have equivalent efficacy in reducing AW-related symptoms and benzodiazepine and haloperidol requirements. These results should be validated in a larger, prospective trial.
dexmedetomidine; propofol; benzodiazepines; alcohol; withdrawal
The only indication for carbidopa and benserazide is the management of L-3,4-dihydroxyphenylalanine (L-dopa)-induced nausea. Both drugs irreversibly bind to and permanently deactivate pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, and PLP-dependent enzymes. PLP is required for the function of over 300 enzymes and proteins. Virtually every major system in the body is impacted directly or indirectly by PLP. The administration of carbidopa and benserazide potentially induces a nutritional catastrophe. During the first 15 years of prescribing L-dopa, a decreasing Parkinson’s disease death rate was observed. Then, in 1976, 1 year after US Food and Drug Administration approved the original L-dopa/carbidopa combination drug, the Parkinson’s disease death rate started increasing. This trend has continued to the present, for 38 years and counting. The previous literature documents this increasing death rate, but no hypothesis has been offered concerning this trend. Carbidopa is postulated to contribute to the increasing Parkinson’s disease death rate and to the classification of Parkinson’s as a progressive neurodegenerative disease. It may contribute to L-dopa tachyphylaxis.
L-dopa; levodopa; vitamin B6; pyridoxal 5′-phosphate
The potential for ezogabine/retigabine (EZG/RTG) and its N-acetyl metabolite (NAMR) to inhibit the transporter protein P-glycoprotein-(P-gp)-mediated digoxin transport was tested in vitro. EZG/RTG did not inhibit P-gp. However, NAMR inhibited P-gp in a concentration-dependent manner. Based on these in vitro results, NAMR had the potential to inhibit P-gp at therapeutic doses of EZG/RTG (600–1,200 mg/day). As digoxin has a narrow therapeutic index, inhibition of digoxin clearance may have an impact on its safety.
An open-label, single-center, two session, fixed-sequence study was conducted to assess the effect of co-administration of therapeutic doses of EZG/RTG on digoxin pharmacokinetics in healthy adults. In session 1, subjects received a single dose of digoxin 0.25 mg. In session 2, EZG/RTG was up-titrated over 6 weeks. Digoxin 0.25 mg was co-administered at EZG/RTG steady-state doses of 600, 900, and, based on tolerability, 1,050/1,200 mg/day. Blood samples were collected over 144 hours for determination of digoxin, EZG/RTG, and NAMR concentrations. Urine samples were collected over 48 hours for determination of digoxin concentrations.
Of 30 subjects enrolled, 29 were included in the pharmacokinetic analysis. Compared with digoxin alone, co-administration with EZG/RTG led to small increases in the digoxin plasma area under the concentration–time curve (AUC)0–120 at doses of 600, 900, and 1,050/1,200 mg (geometric mean ratio 1.08, 90% confidence interval [CI] 1.01–1.15; 1.18, 90% CI 1.10–1.27; 1.13, 90% CI 1.05–1.21, respectively). Safety was consistent with previous repeat-dose studies of EZG/RTG in healthy subjects.
Co-administration of EZG/RTG across the therapeutic range resulted in small, non-dose-dependent and non-clinically relevant increases in digoxin systemic exposure, suggesting that digoxin dose adjustment is not necessary.
digoxin; retigabine; ezogabine; drug–drug interactions
Arbekacin sulfate (ABK), an aminoglycoside antibiotic, was discovered in 1972 and was derived from dibekacin to stabilize many common aminoglycoside modifying enzymes. ABK shows broad antimicrobial activities against not only Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) but also Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. ABK has been approved as an injectable formulation in Japan since 1990, under the trade name Habekacin, for the treatment of patients with pneumonia and sepsis caused by MRSA. The drug has been used in more than 250,000 patients, and its clinical benefit and safety have been proven over two decades. ABK currently shows promise for the application for the treatment of multidrug-resistant Gram-negative bacterial infections such as multidrug-resistant strains of P. aeruginosa and Acinetobacter baumannii because of its synergistic effect in combination with beta-lactams.
synergistic effect; Habekacin; MRSA; multidrug-resistant Gram-negative bacteria
Melatonin (N-acetyl-5-methoxytryptamine) is widely known as “the darkness hormone”. It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review.
MT1/MT2 ligands; circadian rhythms; melatonin
The Institute of Medicine has reported that medication errors are the single most common type of error in health care, representing 19% of all adverse events, while accounting for over 7,000 deaths annually. The frequency of medication errors in adult intensive care units can be as high as 947 per 1,000 patient-days, with a median of 105.9 per 1,000 patient-days. The formulation of drugs is a potential contributor to medication errors. Challenges related to drug formulation are specific to the various routes of medication administration, though errors associated with medication appearance and labeling occur among all drug formulations and routes of administration. Addressing these multifaceted challenges requires a multimodal approach. Changes in technology, training, systems, and safety culture are all strategies to potentially reduce medication errors related to drug formulation in the intensive care unit.
medication safety; drug design; drug formulation; patient safety
The objective of this study was to evaluate the extent of renal adverse effects caused by ibuprofen or indomethacin in order to choose the safer drug to administer to preterm infants.
The following three parameters of renal function were taken into consideration: 1) the urine output; 2) the serum creatinine concentration; and 3) the frequency of oliguria. The bibliographic search was performed using PubMed and Embase databases as search engines.
Urine output ranged from 3.5±1.2 to 4.0±1.4 mL/kg/h after ibuprofen treatment, and from 2.8±1.1 to 3.6±1.4 mL/kg/h after indomethacin treatment. The values for ibuprofen are significantly (P<0.05) higher than those for indomethacin. The serum creatinine concentrations ranged from 0.98±0.24 to 1.48±0.2 mg/dL after ibuprofen treatment, and from 1.06±0.24 and 2.03±2.10 mg/dL after indomethacin treatment. The values for ibuprofen are significantly (P<0.05) lower than those for indomethacin. The frequency of oliguria ranged from 1.0% to 9.6% (ibuprofen) and from 14.8% to 40.0% (indomethacin), and was significantly lower following ibuprofen than indomethacin administration. In infants with body weight lower than 1,000 g, oliguria appeared in 5% (ibuprofen) and 40% (indomethacin; P=0.02).
Indomethacin is associated with more severe renal adverse effects than ibuprofen. Ibuprofen is less nephrotoxic than indomethacin and should be used to treat patent ductus arteriosus in preterm infants. Immaturity increases the frequency of adverse effects of indomethacin.
ibuprofen; indomethacin; patent-ductus-arteriosus; renal-side-effects
The subject of this literature review is the alleged relationship between L-tyrosine, phenelzine, and hypertensive crisis. Phenelzine (Nardil®) prescribing information notes: “The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crises (see WARNINGS). Therefore, patients being treated with NARDIL should not take […] L-tyrosine […]”. Interest in the scientific foundation of this claim was generated during routine patient care. A comprehensive literature search of Google Scholar and PubMed revealed no reported cases of hypertensive crisis associated with concomitant administration of L-tyrosine and phenelzine. Review of current US Food and Drug Administration nutritional guidelines relating to ongoing phenelzine studies reveals no mention and requires no consideration of L-tyrosine ingestion in combination with phenelzine. This paper is intended to provide an objective review of the science to then allow the reader to formulate the final opinion.
hypertensive crisis; phenelzine; tyrosine; tyramine; stroke; phenelzine
We examined the potential effect of sex and age on warfarin dosing in ambulatory adult patients.
We conducted a retrospective chart review of patients attending an anticoagulation clinic. We included patients anticoagulated with warfarin for atrial fibrillation or venous thromboembolism who had a therapeutic international normalized ratio of 2–3 for 2 consecutive months. We excluded patients who had been on any drug that is known to have a major interaction with warfarin, smokers, and heavy alcohol consumers. Out of 340 screened medical records, 96 met the predetermined inclusion criteria. The primary outcome assessed was warfarin total weekly dose (TWD).
There was a statistically significant difference in the TWD among the ages (P<0.01); older patients required lower doses. However there was no statistically significant difference in the TWD between sexes (P=0.281).
Age was found to have a significant effect on warfarin dosing. Even though women did require a lower TWD than men, this observation was not statistically significant.
warfarin; INR; anticoagulation; vitamin K antagonists; age
Microdialysis is a valuable technique for studying the distribution of drugs into interstitial fluid, the target site for a pharmacologic effect. Due to incomplete equilibrium, retrodialysis is a method used to correct for relative recovery. The impact of two-drug combinations on probe recovery, however, remains unknown.
In vitro microdialysis was conducted for five antibiotics (avibactam, cefepime, ceftaroline, piperacillin-tazobactam, and vancomycin), representing three empiric antimicrobial regimens, to assess the impact of two-drug combinations on probe recovery. Recoveries were compared between single and two-drug treatments.
Recoveries by gain and loss were linear with their molecular weight. During all gain experiments, recoveries were similar when tested alone or in combination with another antibiotic. Unacceptable differences in recovery by loss were observed for cefepime in the presence of vancomycin (−21%) and vancomycin in the presence of piperacillin-tazobactam (−22%).
Differences among in vitro recovery by loss suggest two-drug combinations may impact dialysate recovery during in vivo retrodialysis procedures, particularly when larger molecular weight drugs (ie, vancomycin) are involved. Importantly, there were no differences during gain experiments. In vitro studies, as performed here, should be conducted for each potential two-drug combination, prior to their combined use for in vivo retrodialysis.
microdialysis; retrodialysis; combination therapy
Carfilzomib, a selective proteasome inhibitor approved in the USA in 2012, is a single agent for relapsed and refractory multiple myeloma. Carfilzomib is administered as a 2–10-minute infusion on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle at a starting dose of 20 mg/m2 for cycle 1 and a target dose of 27 mg/m2 thereafter. In the pivotal Phase II study (PX-171-003-A1), carfilzomib 20/27 mg/m2 provided durable responses in a heavily pretreated population with relapsed and refractory multiple myeloma (n=266), with an overall response rate of 22.9% and a median duration of response of 7.8 months. In an integrated safety analysis of four Phase II studies, common adverse events (32.7%–55.5%) included fatigue, anemia, nausea, thrombocytopenia, dyspnea, and diarrhea. Grade 3/4 adverse events were generally hematologic and included thrombocytopenia (23.4%), anemia (22.4%), and lymphopenia (18.1%). Serious adverse events included pneumonia (9.9%), acute renal failure (4.2%), pyrexia (3.4%), and congestive heart failure (3.4%). New or worsening peripheral neuropathy was infrequent (13.9% overall, 1.3% grade 3, no grade 4). This review discusses findings of the integrated safety analysis and provides practical experience from a single institution in managing treatment-related and disease-related adverse events. Individualized treatment with proactive management of side effects and complications allows patients with advanced multiple myeloma to remain on carfilzomib for extended periods.
carfilzomib; relapsed; refractory; myeloma; safety; adverse events; toxicity
Hyperuricemia has been proposed to be a risk factor for cardiovascular disease and chronic kidney disease. Since diabetes is often complicated by hypertension and hyperuricemia, efficient therapeutic strategy against these two complications is very important in diabetic treatment. It has been reported that the antihypertensive drug, irbesartan, inhibits the renal uric acid reabsorptive transporters, URAT1 and GLUT9; this result suggests that irbesartan decreases serum uric acid level (SUA).
Subjects and methods
A retrospective study of 107 patients with hypertension and diabetes was performed to analyze the effects of irbesartan on blood pressure, estimated glomerular filtration rate (eGFR), and SUA. The follow-up period was 6–12 months. Seventy percent of the patients were diagnosed with diabetic nephropathy stage II–IV. We excluded patients treated with drugs that influenced SUA. The multiple logistic regression analysis was introduced to identify the relative factors for SUA decline. The time-dependent SUA changes were examined in a mixed-linear model.
Irbesartan reduced blood pressure significantly after 1, 6, and 12 months’ treatment. No subject showed significant change in eGFR from baseline level throughout the period. The multiple logistic regression analysis revealed that SUA baseline significantly influenced SUA decline after 6–12 months. In patients whose SUA baseline was ≥5.9 mg/dL, the SUA was significantly decreased from 6.6±0.16 mg/dL to 6.2±0.16 mg/dL (P=0.010), after 12 months’ irbesartan treatment. In the SUA baseline <5.9 mg/dL group, the SUA did not show significant change over the monitoring period.
Our results demonstrate that irbesartan reduces the risk of hyperuricemia. No decline in renal function was observed after the initiation of irbesartan treatment. The present report determines the criteria of SUA baseline for introducing an antihyperuricemic effect using irbesartan. Its antihypertensive effect coupled with SUA decline would be effective for the treatment of hypertension complicated by hyperuricemia.
angiotensin-receptor blocker; diabetes; hypertension; hyperuricemia; serum uric acid
Chronic kidney disease (CKD) is associated with a high risk of cardiovascular disease complications. Therefore, medical institutions conduct educational hospitalization for early treatment and education of CKD patients. However, patients who have been discharged after achieving educational targets can end up showing poor symptoms at home. There also have been several cases of rehospitalization or disease aggravation. In this study, we analyzed rehospitalized patients who were discharged from the hospital after CKD educational hospitalization and investigated the purpose of analyzing rehospitalization factors.
Materials and methods
This was an observational case-control study conducted at Yokosuka Kyousai Hospital. We performed univariate analysis using patient background features and laboratory data between a rehospitalization group and a no-rehospitalization group. Next, we performed multiple logistic regression analysis using the results of the univariate analysis.
From the results of this study, we identified independent risk factors, such as serum albumin level, heart-failure complications, and estimated glomerular filtration rate (eGFR). Moreover, the serum Alb level was identified as the most important risk factor for rehospitalization. Therefore, we considered that it is important to live a life that makes it possible to maintain CKD stage G3b for a long time after discharge, because the cutoff level of eGFR is 31 mL/minute/1.73 m2.
We believe that it is important to educate patients, their families, and medical staff on the importance of early detection and treatment, and we consider that this approach is important to inclusively protect the kidney.
albumin; glomerular filtration rate; cardiovascular disease; stages of chronic kidney disease
The purpose of this study was to investigate the effect of glibenclamide dose escalation on blood glucose and insulin in patients with poorly controlled type 2 diabetes.
Twenty-two subjects with type 2 diabetes were administered increasing doses (0, 2.5, 5, 10, and 20 mg/day) of glibenclamide at 2-week intervals. Glibenclamide, glucose, and insulin determinations were performed.
The decrease in mean blood glucose from zero dose was 20%, 22%, 26%, and 28% for doses of 2.5, 5, 10, and 20 mg/day, respectively, which was significant from zero dose to 2.5 mg/day (P≤0.001). There were no significant decreases in glucose concentration beyond 2.5 mg/day. The percentage increase in mean insulin from zero dose was 51%, 58%, 44%, and 33% for 2.5, 5, 10, and 20 mg/day respectively. Mean blood insulin increased significantly from zero dose to 2.5 mg/day (P≤0.001). There were no significant increases in mean insulin concentration beyond 2.5 mg/day.
The results of this study suggest that increasing doses of glibenclamide do not produce a proportional increase in insulin secretion or a proportional decrease in blood glucose concentration.
type 2 diabetes; glibenclamide; dose-escalation; insulin; glucose
The pharmacology of single doses of acetylsalicylic acid (ASA) administered intravenously (250 or 500 mg) or orally (100, 300, or 500 mg) was evaluated in a randomized, placebo-controlled, crossover study.
Blood and urine samples were collected before and up to 24 hours after administration of ASA in 22 healthy volunteers. Pharmacokinetic parameters and measurements of platelet aggregation were determined using validated techniques.
A comparison between administration routes showed that the geometric mean dose-corrected peak concentrations (Cmax/D) and the geometric mean dose-corrected area under the curve (AUC0–∞/D) were higher following intravenous administration of ASA 500 mg compared with oral administration (estimated ratios were 11.23 and 2.03, respectively). Complete inhibition of platelet aggregation was achieved within 5 minutes with both intravenous ASA doses, reflecting a rapid onset of inhibition that was not observed with oral dosing. At 5 minutes after administration, the mean reduction in arachidonic acid-induced thromboxane B2 synthesis ex vivo was 99.3% with ASA 250 mg intravenously and 99.7% with ASA 500 mg intravenously. In exploratory analyses, thromboxane B2 synthesis was significantly lower after intravenous versus oral ASA 500 mg (P<0.0001) at each observed time point up to the first hour after administration. Concentrations of 6-keto-prostaglandin1α at 5 and 20 minutes after dosing were also significantly lower with ASA 500 mg intravenously than with ASA 500 mg orally.
This study demonstrates that intravenous ASA provides more rapid and consistent platelet inhibition than oral ASA within the first hour after dosing.
intravenous acetylsalicylic acid; oral acetylsalicylic acid; pharmacodynamics; pharmacokinetics; platelet aggregation; cyclooxygenase-1; thromboxane formation
Olprinone decreases the cardiac preload and/or afterload because of its vasodilatory effect and increases myocardial contractility by inhibiting phosphodiesterase III.
The objective of this study was to characterize the population pharmacokinetics of olprinone after a single continuous infusion in healthy male volunteers.
We used 500 plasma concentration data points collected from nine healthy male volunteers for the study. The population pharmacokinetic analysis was performed using the nonlinear mixed effect model (NONMEM®) software.
The time course of plasma concentration of olprinone was best described using a two-compartment model. The final pharmacokinetic parameters were total clearance (7.37 mL/minute/kg), distribution volume of the central compartment (134 mL/kg), intercompartmental clearance (7.75 mL/minute/kg), and distribution volume of the peripheral compartment (275 mL/kg). The interindividual variability in the total clearance was 12.4%, and the residual error variability (exponential and additive) were 22.2% and 0.129 (standard deviation). The final pharmacokinetic model was assessed using a bootstrap method and visual predictive check.
We developed a population pharmacokinetic model of olprinone in healthy male adults. The bootstrap method and visual predictive check showed that this model was appropriate. Our results might be used to develop the population pharmacokinetic model in patients.
phosphodiesterase III inhibitor; men; pharmacokinetic model
Multiple sclerosis (MS) is a disease of the central nervous system that is characterized by the demyelination of neuronal axons. Four different patterns of demyelination have been described, showing the heterogeneity in the immunopathologic processes involved in the demyelination. This review will focus on reactive oxygen species (ROS)-related inflammation in MS. Special emphasis will be placed on the nuclear factor erythroid-2-related factor 2 (Nrf2) as it regulates the transcription of ROS-protective genes. In the cytosol, Nrf2 binds to Keap1 (Kelch-like ECH-associated protein 1), and together they are degraded by the 26S proteasome after ubiquitination. If challenged by ROS Nrf2, binding to Keap1 is abrogated, and it translocates into the nucleus. Here it binds to the antioxidant response element and to a small protein termed Maf (musculoaponeurotic fibrosarcoma oncogene homolog). This leads to an enhanced transcription of ROS protective genes and represents the physiological answer against ROS challenge. It has been shown that dimethyl fumarate (DMF) has the same effect and leads to an enhanced transcription of ROS-protective genes. This response is mediated through a reduced binding of Nrf2 to Keap1, thus resulting in a higher level of free Nrf2 in the cytosol. Consequently, more Nrf2 translocates to the nucleus, promoting transcription of its target genes. DMF has been used for the treatment of psoriasis for many years in Germany without the occurrence of major side effects. In psoriasis, DMF reduces ROS-related inflammation in skin. A DMF analog, BG-12, was recently approved for the treatment of relapsing-remitting MS by the European Union and the US Food and Drug Administration. As an oral formulation, it gives patients a convenient and effective alternative to the injectable immune modulators in the long-term treatment of MS.
MS; fumaric acid ester; ROS
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2; encoded in humans by the NFE2L2 gene) is a transcription factor that regulates the gene expression of a wide variety of cytoprotective phase II detoxification and antioxidant enzymes through a promoter sequence known as the antioxidant-responsive element (ARE). The ARE is a promoter element found in many cytoprotective genes; therefore, Nrf2 plays a pivotal role in the ARE-driven cellular defense system against environmental stresses. Agents that target the ARE/Nrf2 pathway have been tested in a wide variety of disorders, with at least one new Nrf2-activating drug now approved by the US Food and Drug Administration. Examination of in vitro and in vivo experimental results, and taking into account recent human clinical trial results, has led to an opinion that Nrf2-activating strategies – which can include drugs, foods, dietary supplements, and exercise – are likely best targeted at disease prevention, disease recurrence prevention, or slowing of disease progression in early stage illnesses; they may also be useful as an interventional strategy. However, this rubric may be viewed even more conservatively in the pathophysiology of cancer. The activation of the Nrf2 pathway has been widely accepted as offering chemoprevention benefit, but it may be unhelpful or even harmful in the setting of established cancers. For example, Nrf2 activation might interfere with chemotherapies or radiotherapies or otherwise give tumor cells additional growth and survival advantages, unless they already possess mutations that fully activate their Nrf2 pathway constitutively. With all this in mind, the ARE/Nrf2 pathway remains of great interest as a possible target for the pharmacological control of degenerative and immunological diseases, both by activation and by inhibition, and its regulation remains a promising biological target for the development of new therapies.
Nrf2; detoxification; antioxidant
The launch of first-generation protease inhibitors (PIs) is a major step forward in HCV treatment. However, the major advance is up to now restricted to genotype 1 (GT-1) patients. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors include nucleoside/nucleotide inhibitors (NIs) and non-nucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with protease inhibitors can cure GT-1b null responders in an interferon-free regimen. Besides, several studies demonstrate that interferon (IFN)-free regimens with direct-acting antiviral agent combinations are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, quadruple regimen with PR is able to cure almost all GT-1 null responders. The development of pan-genotypic direct-acting antiviral agents (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment.
SVR; direct antiviral agents; host-targeting agents; interferon-free regimen; pangenotypic activity; cirrhosis