Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

BACKGROUD: Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. METHODS: This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. RESULTS: Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/µL), quality of life, and pain, were not apparent. CONCLUSIONS: A single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.

Multiple Dosing and Preactivation of Mesenchymal Stromal Cells Enhance Efficacy in Established Pneumonia Induced by Antimicrobial-Resistant Klebsiella pneumoniae in Rodents.

Antimicrobial-resistant (AMR) bacteria, such as Klebsiella species, are an increasingly common cause of hospital-acquired pneumonia, resulting in high mortality and morbidity. Harnessing the host immune response to AMR bacterial infection using mesenchymal stem cells (MSCs) is a promising approach to bypass bacterial AMR mechanisms. The administration of single doses of naïve MSCs to ARDS clinical trial patient cohorts has been shown to be safe, although efficacy is unclear. The study tested whether repeated MSC dosing and/or preactivation, would attenuate AMR Klebsiella pneumonia-induced established pneumonia. Rat models of established K. pneumoniae-induced pneumonia were randomised to receive intravenous naïve or cytomix-preactivated umbilical cord MSCs as a single dose at 24 h post pneumonia induction with or without a subsequent dose at 48 h. Physiological indices, bronchoalveolar lavage (BAL), and tissues were obtained at 72 h post pneumonia induction. A single dose of naïve MSCs was largely ineffective, whereas two doses of MSCs were effective in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, while reducing bacteria and injury in the lung. Cytomix-preactivated MSCs were superior to naïve MSCs. BAL neutrophil counts and activation were reduced, and apoptosis increased. MSC therapy reduced cytotoxic BAL T cells, and increased CD4+/CD8+ ratios. Systemically, granulocytes, classical monocytes, and the CD4+/CD8+ ratio were reduced, and nonclassical monocytes were increased. Repeated doses of MSCs-particularly preactivated MSCs-enhance their therapeutic potential in a clinically relevant model of established AMR K. pneumoniae-induced pneumosepsis.

Antibiotics for preventing infection at the surgical site: Single dose vs. multiple doses.

Background: Surgical site infections are common and expensive infections that can cause fatalities or poor patient outcomes. To prevent these infections, antibiotic prophylaxis is used. However, excessive antibiotic use is related to higher costs and the emergence of antimicrobial resistance. Objectives: The present meta-analysis aimed to compare the effectiveness of a single dosage versus several doses of antibiotics in preventing the development of surgical site infections. Methods: PubMed was used to find clinical trials evaluating the effectiveness of a single dosage versus several doses of antibiotics in avoiding the development of surgical site infections. The study included trials that were published between 1984 and 2022. Seventy-four clinical trials were included in the analysis. Odds ratios were used to compare groups with 95% confidence intervals. The data were displayed using OR to generate a forest plot. Review Manager (RevMan version 5.4) was used to do the meta-analysis. Results: Regarding clean operations, there were 389 surgical site infections out of 5,634 patients in a single dose group (6.90%) and 349 surgical site infections out of 5,621 patients in multiple doses group (6.21%) (OR = 1.11, lower CI = 0.95, upper CI = 1.30). Regarding clean-contaminated operations, there were 137 surgical site infections out of 2,715 patients in a single dose group (5.05%) and 137 surgical site infections out of 2,355 patients in multiple doses group (5.82%) (OR = 0.87, lower CI = 0.68, upper CI = 1.11). Regarding contaminated operations, there were 302 surgical site infections out of 3,262 patients in a single dose group (9.26%) and 276 surgical site infections out of 3,212 patients in multiple doses group (8.59%) (OR = 1.11, lower CI = 0.84, upper CI = 1.47). In general, there were 828 surgical site infections out of 11,611 patients in a single dose group (7.13%) and 762 surgical site infections out of 11,188 patients in multiple doses group (6.81%) (OR = 1.05, lower CI = 0.93, upper CI = 1.20). The difference between groups was not significant. Conclusion: The present study showed that using a single-dose antimicrobial prophylaxis was equally effective as using multiple doses of antibiotics in decreasing surgical site infections.

Pharmacokinetics of carprofen following single and repeated intravenous administrations of different doses in sheep.

The aim of this study was to determine the pharmacokinetics of carprofen following single and repeated intravenous (IV) administrations at 1.4 and 4 mg/kg doses in sheep. The study was carried out on twelve sheep in two experiments as single- and multiple-dose pharmacokinetics. In experiment 1, carprofen was administered via IV at single doses of 1.4 (n = 6) and 4 mg/kg (n = 6) in a randomized parallel design. In experiment 2, the same dose groups in experiment 1 following the 21-day washout period received intravenously carprofen every 24 h for 5 days. Plasma concentrations were measured using high-performance liquid chromatography-UV and analyzed by a two-compartment open model. After the single administration of 1.4 mg/kg dose, the t1/2α , t1/2el , MRT, ClT , Vdss , and AUC were 0.62 h, 27.57 h, 38.78 h, 2.72 ml/h/kg, 105.26 ml/kg, and 515.12 h*µg/ml, respectively. Carprofen at a single dose of 4 mg/kg showed prolonged t1/2el and MRT, and increased Vdss . On day 5 after the repeated administration of the 1.4 mg/kg dose, the t1/2α , t1/2el , MRT, ClT , Vdss , and AUC were 1.12 h, 57.48 h, 82.18 h, 0.55 ml/h/kg, 45.43 ml/kg, and 2532 h*µg/ml, respectively. Carprofen at a repeated dose of 4 mg/kg showed increased ClT and Vdss and decreased AUC/dose. Although the long t1/2ʎz in single and multiple IV dose studies suggest the possibility of its effective use, the IV route may not be practical in sheep. Therefore, oral and subcutaneous routes of carprofen in sheep would be more valuable in clinical settings.

Sequential dosing of convalescent COVID-19 plasma with significant temporal clinical improvements in a persistently SARS-COV-2 positive patient.

The current global pandemic, SARS-CoV-2 infection, is still extending across the world affecting millions of lives to the date. While new successful vaccines are available with promising outcomes to minimize the spread and to reduce the severity of the disease, optimal therapeutic options still remain elusive. COVID-19 convalescent plasma (CCP) is an investigational treatment option which studies suggesting signals of efficacy and favorable outcomes only for patients treated very early in course of the disease. Benefits of the use of CCP later in the disease remain highly debated and therefore are not common practice. We hereby report a case of severe SARS-CoV-2 infection in a young male patient with prolonged COVID-19 positivity who received repeat doses of CCP treatments later in the disease with temporal clinical improvement. This patient's case highlights the need of further studies evaluating efficacy of repeated dosing of CCP. This also suggests a potential of successful use of CCP later in the disease in selected COVID-19 patients.

Pharmacokinetics of doxycycline after oral administration of multiple doses in dogs.

The aim of this study was to determine the pharmacokinetic parameters of doxycycline in dogs and assess the efficacy of an oral drug dosage regimen of 10 mg/kg daily for 28 days through Pharmacokinetic/Pharmacodynamic (PK/PD) target analysis based on Monte Carlo simulation, using previously published data for the zoonotic pathogen Staphylococcus pseudintermedius. After a multiple-dosage regimen, the accumulation index was 1.88 ± 0.82. The Cmaxss and Cminss values were 5.18 ± 1.81 µg/ml and 1.91 ± 1.35 µg/ml, respectively. There were statistically significant differences for Cmax, Cmin at 24 hr, MRTt, AUCt and AUC∞ between days 1 and 28. The Cminss value was over the MIC of the principal pathogens, and Cmaxss was higher than the resistance values (>2 µg/ml). For AUC/MIC indices of 12, 25 and 40, the cumulative fraction responses (CFR) were 94.01%, 69.55% and 60.86%, respectively; for an MIC value of 2 µg/ml, the corresponding probability of target attainment (PTA) was 99.94%, 84.78% and 45.16%, respectively. Doxycycline was used against numerous localized infections in different organs and tissues. For the strains with MIC < 1 µg/mL, PTA was close to 100%, even for the most demanding ones, specifically 94.98% for an index of 40% and 99.9% for an index of 25.

Comparison of Repeated Doses of C-kit-Positive Cardiac Cells versus a Single Equivalent Combined Dose in a Murine Model of Chronic Ischemic Cardiomyopathy.

Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 106 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 × 106 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 106 cells each) can be fully replicated by a single combined dose of 3 × 106 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 106) and vehicle × 2; or (3) three doses of CPCs (1 × 106 each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 ± 0.6% (p < 0.001 vs. the vehicle group, 27.3 ± 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 ± 0.6%) than in the combined-dose group (4.8 ± 0.8%), although the difference was not statistically significant (p = 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group (p = 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (-32.7%, 182.6 ± 15.1 µm2 vs. 271.5 ± 27.2 µm2, p < 0.05, in the risk region and -28.5%, 148.5 ± 12.1 µm2 vs. 207.6 ± 20.5 µm2, p < 0.05, in the noninfarcted region). LV weight/body weight ratio and LV weight/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.

Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS.

The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson's disease while AChE plays a major role in Alzheimer's disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats' brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses' study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid-liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats' plasma (10-3100 ng/mL) and rats' brain tissue (15-2900 ng/mL) using liquid-liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats' plasma and rats' brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats' plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.

Pharmacokinetic study of methylnaltrexone after single and multiple subcutaneous administrations in healthy Chinese subjects.

1. Pharmacokinetics of methylnaltrexone (MNTX) were evaluated after subcutaneous administrations (s.c.) in healthy Chinese subjects. 2. In a cross-over single dose study, 12 subjects were given 0.075, 0.15, and 0.3 mg/kg of MNTX bromide injection. In a multiple doses study, another 12 subjects subcutaneously received 0.15 mg/kg of MNTX bromide injection every 48 h, in total five administrations. The concentrations of MNTX in plasma were quantified by LC-MS/MS. 3. After single s.c. administrations of 0.075, 0.15, and 0.3 mg/kg of MNTX bromide, Cmax values of MNTX were 93.5 ± 28.6, 191 ± 37, and 364 ± 54 ng/mL, respectively, and AUC0-∞ were 88.8 ± 8.8, 181 ± 16, and 357 ± 34 ng⋅h/mL, respectively. The t1/2 of MNTX was about 7.7 h. After multiple doses administration, the Cmax, Cav, AUCss, and MRT0-∞ values were 191 ± 50, 3.79 ± 0.40 ng/mL, 182 ± 19 ng⋅h/mL, and 3.56 ± 1.17 h, respectively. 4. Methylnaltrexone bromide displayed dose-proportional pharmacokinetics in the dose range of 0.075-0.3 mg/kg. After multiple doses administration, t1/2 was slightly prolonged, with the cumulative factor of 1.02. This study provides a pharmacokinetic reference after a single dose and multiple doses of MNTX bromide in Chinese subjects.

Pharmacokinetics of doxycycline after oral administration of single and multiple dose in broiler chickens.

As a semisynthetic tetracycline derivative, doxycycline (α-6-deoxy-5-hydroxytetracycline) is a time-dependent bacteriostatic agent. It is being widely used in the broiler husbandry in China. In this study, doxycycline was orally administered by gavage to 10 healthy broiler chickens at the dose of 20 mg/kg body weight every 24 hr for five total treatments. Plasma samples were collected from each animal at 5, 10, 20, and 30 min and 1, 2, 4, 6, 8, and 12 hr after the first dose, at 0.25, 0.5, 0.45, 1, 2, 3, 4, 6, 7, 13.5, 24, 36, 48, 60, and 72 hr after the last dose. Additional plasma samples were collected at a 24-hr interval during the dosing period (immediately prior to each oral administration). The doxycycline concentrations were determined by high-performance liquid chromatography with an ultraviolet detector and subjected to noncompartmental analysis. Then, the pharmacokinetics profiles were compared after the first and last oral doses. After the first dosing, the elimination half-life, area under the concentration-time curve from 0 hr to ∞, peak concentration, time to reach peak concentration, and volume of distribution per fraction absorbed were determined as 7.78 hr, 94.19 µg·hr/ml, 5.65 µg/ml, 3.50 hr, and 2,502.65 ml/kg, respectively, while the corresponding values of these parameters after the last dose were 19.90 hr, 121.08 µg·hr/ml, 5.71 µg/ml, 7.25 hr, and 5,285.28 ml/kg, respectively. After multiple oral doses, the absorption and elimination both became slower, while the distribution was more extensive than that following a single dose. However, after multiple oral doses, accumulation of doxycycline in plasma was not observed with an average accumulation factor of 1.11.

[USE OF MULTIPLE DOSES OF ADRENALINE FOR FOOD-INDUCED ANAPHYLAXIS].

BACKGROUND: The aim of this study was to determine the rate, characteristics, and risk factors in patients who required multiple doses of adrenaline for treatment of anaphylaxis. METHODS: We retrospectively reviewed the positive oral food challenges (OFCs) with anaphylaxis in pediatric patients at Saitama City Hospital between January 2013 and November 2014, analyzing age, sex, comorbid allergic disease, specific IgE level, food, symptoms, and treatment. RESULT: There were 42 positive challenges with anaphylaxis, and the median age of the patients was 4 years old. Eighteen patients were treated with adrenaline, 5 of whom (11.9% of anaphylaxis cases) were administered multiple doses of adrenaline. Among the 5 patients, 3 were treated with infusion. We compared patients who were not administered adrenaline or were administered a single dose of adrenaline with those who were administered multiple doses of adrenaline. No significant differences were found among the groups in relation to age, sex, comorbid allergic disease, and the aim of OFCs. The number of patients who received multiple doses of adrenaline treatment was more in the milk OFCs than the other foods OFCs. Cardiovascular and neurological symptoms were more severe in patients who received multiple doses of adrenaline. CONCLUSION: Information that multiple doses of adrenaline may be required at the time of anaphylaxis should be widely disseminated.

Variability and singularity arising from poor compliance in a pharmacokinetic model II: the multi-oral case.

We propose a stochastic model for the drug concentration in the case of multiple oral doses and in a situation of poor patient adherence. Our model is able to take into account an irregular drug intake schedule. This article is the second in a series of three. It presents a multi-oral version of the results given in Lévy-Véhel and Lévy-Véhel (J Pharmacokinet Pharmacodyn 40(1):15-39, 2013), that dealt with the multi-IV bolus case. Under the assumption that the irregular dosing schedule follows a Poisson law, we study features of the drug concentration that have practical implications, such as its variability and the regularity of its cumulative probability distribution, which describes its predictive power with respect to the mean behaviour. We consider four variants: continuous-time, with either deterministic or random doses, and discrete-time, also with either deterministic or random doses. Our computations allow one to assess in a precise way the effect of various significant parameters such as the mean rate of intake, the elimination rate, the absorption rate and the mean dose. They quantify how much poor adherence will affect the efficacy of therapy. To appreciate this impact, we provide detailed comparisons with the variability of concentration in two reference situations: a fully adherent patient and a population of fully adherent patients with log-normally distributed pharmacokinetic parameters. Besides, the discrete-time versions of our models reveal unexpected links with objects which have been studied in the mathematical literature under the name of infinite Bernoulli convolutions (Erdós, Am J Math 61:974-975, 1939). This allows us to quantify the fact that, when the random dosing schedule is too sparse, the concentration behaves in a very erratic way. Our results complement the ones in Lévy-Véhel and Lévy-Véhel (J Pharmacokinet Pharmacodyn 40(1):15-39, 2013) and help understanding the consequences of poor adherence. They may have practical outcomes in terms of drug dosing and scheduling.

Quantitative evaluation of local pulmonary distribution of TiO2 in rats following single or multiple intratracheal administrations of TiO2 nanoparticles using X-ray fluorescence microscopy.

Uneven pulmonary nanoparticle (NP) distribution has been described when using single-dose intratracheal administration tests. Multiple-dose intratracheal administrations with small quantities of NPs are expected to improve the unevenness of each dose. The differences in local pulmonary NP distribution (called microdistribution) between single- and multiple-dose administrations may cause differential pulmonary responses; however, this has not been evaluated. Here, we quantitatively evaluated the pulmonary microdistribution (per mesh: 100 µm × 100 µm) of TiO2 in lung sections from rats following one, two, three, or four doses of TiO2 NPs at a same total dosage of 10 mg kg(-1) using X-ray fluorescence microscopy. The results indicate that: (i) multiple-dose administrations show lower variations in TiO2 content (ng mesh(-1) ) for sections of each lobe; (ii) TiO2 appears to be deposited more in the right caudal and accessory lobes located downstream of the administration direction of NP suspensions, and less so in the right middle lobes, irrespective of the number of doses; (iii) there are not prominent differences in the pattern of pulmonary TiO2 microdistribution between rats following single and multiple doses of TiO2 NPs. Additionally, the estimation of pulmonary TiO2 deposition for multiple-dose administrations imply that every dose of TiO2 would be randomly deposited only in part of the fixed 30-50% of lung areas. The evidence suggests that multiple-dose administrations do not offer remarkable advantages over single-dose administration on the pulmonary NP microdistribution, although multiple-dose administrations may reduce variations in the TiO2 content for each lung lobe. Copyright © 2016 John Wiley & Sons, Ltd.

Safety, tolerability, and pharmacokinetics of aildenafil citrate tablets, a novel oral PDE5 inhibitor, in healthy Chinese volunteers after multiple-dose administration.

Background: Aildenafil citrate is a potent and selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, developed for the treatment of erectile dysfunction (ED). Aim: This study aimed to assess the pharmacokinetics, safety, and tolerability of aildenafil citrate tablets after multiple doses in healthy Chinese males. Methods: Twenty participants were divided into 2 groups, 10 participants each. Participants were administered multiple doses of aildenafil citrate tablets at 30 and 60 mg. Outcomes: The safety evaluation was based on clinical symptoms and adverse events. Concentrations of aildenafil and its key metabolites (M1, M5, and M12) in human serum were measured by liquid chromatography-tandem mass spectrometry. Results: Pharmacokinetic analysis showed rapid absorption and elimination of aildenafil, with a median time to maximum serum concentration of 1 hour and mean terminal half-lives of 2.75 and 3.26 hours in the respective dose groups. The mean maximum concentration was proportional to the aildenafil dose in the range of 30 to 60 mg, although the area under the curve was not proportional for serum concentration vs time 0 to the last measurable time point (24 hours). Multiple doses of aildenafil were well tolerated, with 60.0% of men experiencing treatment-emergent adverse events, notably myalgia and fatigue, particularly in the 60-mg group. Clinical Implications: Aildenafil citrate tablets demonstrated favorable tolerability with once-daily administration over the clinical dose range. The occurrence of myalgia and fatigue was more prevalent in the 60-mg group. From a pharmacokinetic perspective, optimal administration of aildenafil citrate tablets appears to be 1 hour before sexual intercourse in men with ED. Strengths and Limitations: This study presents robust safety and pharmacokinetic data at expected therapeutic doses, unaffected by clinical factors. The efficacy of aildenafil citrate tablets warrants further validation in individuals with ED. Conclusion: Aildenafil citrate tablets exhibited good tolerability in healthy Chinese males following multiple doses at 30 and 60 mg. The 60-mg group showed an increased incidence of myalgia and fatigue, suggesting the need for heightened clinical vigilance. The mean maximum concentration, but not the area under the curve, displayed dose proportionality within the 30- to 60-mg dose range, and no significant drug accumulation was observed with repeated daily administration. Clinical Trial Registration: CTR20192473 (http://www.chinadrugtrials.org.cn).

A Mathematical Treatment of Multiple Intermittent Intravenous Infusions in a One-Compartment Model.

BACKGROUND AND OBJECTIVE: Compartment models in pharmacokinetics are generally described for a single dose and can only simulate drug concentration as a function of the first dosing interval. Our objective was to create a one-compartment model for constant rate repetitive intravenous intermittent infusions where drug concentration can be simulated as a function of real time. METHODS: The analytical solutions to differential equations that were set for the time periods of drug infusion and elimination after an intermittent intravenous infusion were used to derive sequences patterns and determine the partial sums of mathematical series for multiple intermittent infusion doses. RESULTS: The model's original theory was supplemented with explicit solutions to the concentration and AUC, at non steady state conditions, with and without a loading dose, for both the infusion and elimination time periods after repetitive intermittent intravenous infusions. The validity and accuracy of these formulas in calculating drug concentration and AUC was verified by mathematical proofs, numerical methods and the principle of superposition. CONCLUSIONS: Drug concentration and AUC can be simulated using the newly described one-compartment pharmacokinetic model in the entire time-domain of therapy after multiple and repetitive intermittent intravenous infusions and not just within the first dosing interval.

Repeated infusion of mesenchymal stem cells maintain the condition to inhibit deteriorated motor function, leading to an extended lifespan in the SOD1G93A rat model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disorder in which motor neurons within the brain and spinal cord degenerate. A single infusion of mesenchymal stem cells (MSCs) delays disease progression by protecting motor neurons and restoring the blood-spinal cord barrier in the SOD1G93A transgenic ALS rat model. However, the therapeutic effect of a single infusion of MSCs is transient and does not block disease progression. In this study, we demonstrated that repeated administration of MSCs (weekly, four times) increased the survival period, protected motor functions, and reduced deterioration of locomotor activity compared to a single infusion and vehicle infusion, after which rats displayed progressive deterioration of hind limb function. We also compared the days until gait ability was lost in rats and found that the repeated-infused group maintained gait ability compared to the single-infusion and vehicle-infusion groups. These results suggest that repeated administration of MSCs may prevent the deterioration of motor function and extend the lifespan in ALS.

Comparison of One and Three Intraventricular Injections of Cardiac Progenitor Cells in a Murine Model of Chronic Ischemic Cardiomyopathy.

Repeated doses of c-kit+ cardiac progenitor cells (CPCs) are superior to a single dose in improving LV function in rats with old myocardial infarction (MI). However, this concept needs testing in different species to determine whether it is generalizable. We used a new murine model of chronic ischemic cardiomyopathy whose unique feature is that cell therapy was started late (3 months) after MI. Mice received three echo-guided intraventricular infusions, 5 weeks apart, of vehicle, CPCs × 1, or CPCs × 3. Echocardiography demonstrated that the single-dose group exhibited improved LV ejection fraction (EF) after the 1st infusion (CPCs), but not after the 2nd and 3rd (vehicle). In contrast, in the multiple-dose group LVEF continued to improve, so that the final value was greater than in vehicle or single-dose groups (P < 0.05). Hemodynamic studies showed that compared with vehicle, both preload-dependent and preload-independent functional parameters were significantly increased in the multiple-dose group but not in the single-dose group. Thus, two independent methods of functional assessment (echocardiography and hemodynamic studies) consistently demonstrated the superiority of three doses of CPCs vs. one dose. Compared with the single-dose group, the multiple-dose group exhibited less LV hypertrophy, as evidenced by a greater reduction in LV/body weight ratio and cardiomyocyte cross-sectional area. Furthermore, unlike the single dose, three CPC doses reduced myocardial inflammatory cells in the risk region. This is the first study of echo-guided intraventricular infusion of CPCs in mice with chronic ischemic cardiomyopathy. The results demonstrate that the beneficial effects of three CPC doses are greater than those of one dose, supporting the concept that multiple treatments are necessary to properly evaluate cell therapy. Our findings indicate that this concept applies not only to rat models but also to murine models. The generalizability of this strategy greatly enhances its importance and provides a rationale for large animal studies. Graphical abstract.

Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression.

INTRODUCTION AND OBJECTIVES: The impact of multiple subcutaneous (s.c.) esketamine injections on the blood pressure (BP) and heart rate (HR) of patients with unipolar and bipolar treatment-resistant depression (TRD) is poorly understood. This study aimed to assess the cardiovascular safety of multiple s.c. doses of esketamine in patients with TRD. METHODS: Seventy TRD patients received 394 weekly s.c. esketamine injections in conjunction with oral antidepressant therapy for up to six weeks. Weekly esketamine doses were 0.5, 0.75 or 1.0 mg/kg according to each patient's response to treatment. Participants were monitored before each treatment and every 15 minutes thereafter for 120 minutes. We assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR measurements for the entire treatment course. RESULTS: BP increased after the first s.c. esketamine injection, reaching maximum mean SBP/DBP levels of 4.87/5.54 mmHg within 30-45 minutes. At the end of monitoring, 120 minutes post dose, vital signs returned to pretreatment levels. We did not detect significant differences in BP between doses of 0.5, 0.75, and 1 mg/kg esketamine. Mean HR did not differ significantly between doses or before and after s.c. esketamine injection. CONCLUSIONS: The BP changes observed with repeated s.c. esketamine injections were mild and well tolerated for doses up to 1 mg/kg. The s.c. route is a simple and safe method of esketamine administration, even for patients with clinical comorbidities, including obesity, hypertension, diabetes, and dyslipidemia. However, 14/70 patients experienced treatment-emergent transient hypertension (SBP >180 mmHg and/or a DBP >110 mmHg). Therefore, we strongly recommend monitoring BP for 90 minutes after esketamine dosing. Since s.c. esketamine is cheap, requires less frequent dosing (once a week), and is a simpler procedure compared to intravenous infusions, it might have an impact on public health.

A cautionary tale of multiple-dose drug products: Fluticasone and salmeterol combination inhaler waste.

RATIONALE: Some drugs can only be dispensed in multiple-dose containers. Multiple-dose packaging may pose a problem for hospitals in terms of drug wastage and cost. Oral inhalers, such as fluticasone propionate and salmeterol combination inhalers, are only available as multiple-dose formats in Canada. OBJECTIVES: The objectives of this study are to quantify the amount of fluticasone propionate and salmeterol combination inhaler waste and to assess possible factors that could be contributing to waste. METHODS: A retrospective chart review of 189 patients was conducted. Patients were included if they had received an order for fluticasone propionate and salmeterol combination inhaler at one of the 12 acute hospital sites of Fraser Health Authority. The primary outcome was the proportion of patients who were dispensed one or more inhalers unnecessarily. The number of inhalers dispensed was compared with the number of inhalers needed to complete a patient's order duration. The chart was also reviewed for possible factors that could have contributed to extra inhalers being dispensed unnecessarily. RESULTS: Thirty-seven patients (19.6%) had at least one inhaler dispensed unnecessarily and thus wasted. About 17.4% of the total amount of inhalers dispensed were dispensed unnecessarily, and 76.3% of doses dispensed were wasted. The cost of inhalers wasted for our sample was $5151.12 (CAD). The most common factors that contributed to inhaler waste appeared to be loss of medication during patient transfers and storage of inhalers as wardstock. CONCLUSIONS: The use of drugs that are only available in multiple-dose formats results in significant drug wastage and unnecessary health care expenditure. To minimize wastage of drug product, procedures could be implemented to ensure that drugs are properly transferred with the patient when a patient transfers locations in the hospital. As well, a review of wardstock inventory may minimize waste. Further assessment of multiple-dose drug product waste and evaluations of methods to mitigate waste are encouraged.

Influence of intranasal exposure of MPTP in multiple doses on liver functions and transition from non-motor to motor symptoms in a rat PD model.

Besides the effects on the striatum, the impairment of visceral organs including liver functions has been reported in Parkinson's disease (PD) patients. However, it is yet unclear if liver functions are affected in the early stage of the disease before the motor phase has appeared. The aim of our present study was thus to assess the effect of intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in different doses on striatum and liver functions. Deterioration of non-motor activities appeared on single exposure to MPTP along with rise in striatum oxidative stress and decline in antioxidant levels. Decreases in dopamine, noradrenaline, and GABA and increase in serotonin were detected in striatum. Motor coordination was impaired with a single dose of MPTP, and with repeated MPTP exposure, there was further significant impairment. Locomotor activity was affected from second exposure of MPTP, and the impairment increased with third MPTP exposure. Impairment of liver function through increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels was observed after first MPTP insult, and it worsened with second and third administrations. First administration of MPTP triggered systemic inflammation showing significant increase in inflammatory markers in the liver. Our data shows for the first time that an intranasal route of entry of MPTP affects liver from the non-motor phase of PD itself, occurring concomitantly with the reduction of striatal dopamine. It also suggests that a single dose is not enough to bring about progression of the disease from non-motor to locomotor deficiency, and a repeated dose is needed to establish the motor severity phase in the rat intranasal MPTP model.