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Precision dosing aims to optimize and customize pharmacological treatment at the individual level. The integration of pharmacometric models with Reinforcement Learning (RL) algorithms is currently under investigation to support the personalization of adaptive dosing therapies. In this study, this hybrid technique is applied to the real multiobjective precision dosing problem of givinostat treatment in polycythemia vera (PV) patients. PV is a chronic myeloproliferative disease with an overproduction of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). The therapeutic goal is to simultaneously normalize the levels of these efficacy/safety biomarkers, thus inducing a complete hematological response (CHR). An RL algorithm, Q‐Learning (QL), was integrated with a PK‐PD model describing the givinostat effect on PLT, WBC, and HCT to derive both an adaptive dosing protocol (QLpop‐agent) for the whole population and personalized dosing strategies by coupling a specific QL‐agent to each patient (QLind‐agents). QLpop‐agent learned a general adaptive dosing protocol that achieved a similar CHR rate (77% vs. 83%) when compared to the actual givinostat clinical protocol on 10 simulated populations. Treatment efficacy and safety increased with a deeper dosing personalization by QLind‐agents. These QL‐based patient‐specific adaptive dosing rules outperformed both the clinical protocol and QLpop‐agent by reaching the CHR in 93% of the test patients and completely avoided severe toxicities during the whole treatment period. These results confirm that RL and PK‐PD models can be valid tools for supporting adaptive dosing strategies as interesting performances were achieved in both learning a general set of rules and in customizing treatment for each patient.

•Low target trough attainment following a vancomycin loading dose in hemodialysis.•Vancomycin dosing interval affects therapeutic target attainment.•Vancomycin maintenance dose adjustment should consider previous dose and interval.•A weight-based loading dose is more likely to achieve a therapeutic trough. To determine the incidence of therapeutic target attainment using a three-times per week protocol for vancomycin therapy given during the last hour of intermittent hemodialysis (HD). A single-center retrospective cohort study was conducted of patient medical records in a remote dialysis center from January 2017 to July 2023. Adult patients with chronic kidney disease stage 5 on ≥3 months of intermittent HD who had received a course of vancomycin therapy with ≥1 serum vancomycin concentration recorded were included. Demographic and dosing data were collected. Clinician adherence with the dosing protocol and attainment of the therapeutic target (trough concentration within 15–20 mg/L) following the loading and maintenance doses were assessed. Factors associated with target nonattainment following the loading dose were analyzed, and the 48- and 72-h maintenance dosing intervals were analyzed for target nonattainment. A total of 98 vancomycin courses (67 patients) were available for analysis. Only 38% of the loading doses were prescribed as per protocol. Following the loading dose, 25% of trough concentrations achieved the therapeutic target concentration (15–20 mg/L), 25% returned a supra-therapeutic concentration (>20 mg/L) and 50% were sub-therapeutic (<15 mg/L). When compared with those achieving target, sub-therapeutic concentrations were associated with a lower loading dose (median 16.6 vs 20.0 mg/kg, P < 0.002), and supra-therapeutic concentrations had a shorter dosing interval between the loading dose and first maintenance dose (median 31.5 vs 39.0 h, P = 0.06). Of the 201 maintenance trough concentrations collected, 65% were therapeutic, 21% were sub-therapeutic and 14% were supra-therapeutic, with an overall median trough concentration of 17.3 mg/L. As the treatment duration increased, an increase was seen in the number of dose adjustments required to achieve the target trough concentration. The 48-h dosing interval was associated with more supra-therapeutic concentrations and the 72-h interval was associated with more sub-therapeutic concentrations (df = 2, P = 0.022). We have identified a high rate of target nonattainment for HD patients on a three times a week vancomycin dosing regimen. We recommend a loading dose of 20 to 25 mg/kg irrespective of the indication and a better-defined dosing interval after the loading dose. A higher maintenance dose should be prescribed when the time to next dialysis session is 72 h. Further pharmacokinetic studies are needed to assess factors influencing target concentration attainment following the maintenance doses and to determine an optimal dosing regimen. [Display omitted]

Background Higher doses of vancomycin are currently prescribed due to the emergence of bacterial tolerance and resistance. This study aimed to evaluate the efficacy and safety of the currently adopted vancomycin dosing guide in pediatric cardiology. Methods This was a single-center prospective cohort study with pediatric cardiac patients, younger than 14 years, from June 2020 to March 2021. The patients received intravenous vancomycin (40 mg/kg/day divided every 6–8 h) according to the department’s vancomycin medication administration guide (MAG) for at least three days. Results In total, 88 cardiac patients were included, with a median age of 0.82 years (IQR: 0.25–2.9), and 51 (58%) received cardiopulmonary bypass surgery (CPB). The majority (71.6%, n  = 61) achieved a serum vancomycin level within the therapeutic range (7–20 mg/L). Infants, young children, and children exposed to CPB surgery had an increased incidence of subtherapeutic vancomycin levels, [7 (29.2%); P  = 0.033], [13 (54.2%); P  = 0.01], and [21 (87.5%); P  = 0.009] respectively. After the treatment, 8 (10%) patients had an elevated Serum creatinine (SCr) and 2 (2.5%) developed acute kidney injury (AKI). However, no significant difference was found between the patients developing AKI or an elevated SCr and the group who did not, in terms of clinical, therapeutic, and demographic characteristics, except for the decreased incidence of SCr elevation in patients receiving an ACE inhibitor, [4 (36.4%); P  = 0.036]. Conclusion Our institution followed MAG recommendations; however, subtherapeutic serum concentrations were evident in infants, young children, and CPB patients. Strategies to prevent AKI should be investigated, as the possible causes have not been identified in this study.

Background: Pirfenidone and nintedanib are considered as the standard of care in idiopathic pulmonary fibrosis (IPF), but there is no consensus as to which of these two agents should be regarded as first-line treatment. Objective: To provide real-world data on therapeutic decisions of pulmonary specialists, particularly the choice of the antifibrotic drug in patients with IPF. Methods: This was a multicenter, prospective survey collecting clinical data of patients with IPF considered as candidates for antifibrotic treatment between September 2019 and December 2020. Clinical characteristics and information on the therapeutic approach were retrieved. Statistical evaluation included multiple logistic regression analysis with stepwise model selection. Results: Data on 188 patients [74.5% male, median age 73 (interquartile range, 68–78) years] considered for antifibrotic therapy were collected. Treatment was initiated in 138 patients, while 50 patients did not receive an antifibrotic, mainly due to the lack of consent for treatment and IPF severity. Seventy-two patients received pirfenidone and 66 received nintedanib. Dosing protocol (p < 0.01) and patient preference (p = 0.049) were more frequently associated with the choice of nintedanib, while comorbidity profile (p = 0.0003) and concomitant medication use (p = 0.03) were more frequently associated with the choice of pirfenidone. Age (p = 0.002), lung transfer factor for carbon monoxide (TLCO) (p = 0.001), and gastrointestinal bleeding (p = 0.03) were significantly associated with the qualification for the antifibrotic treatment. Conclusion: This real-world prospective study showed that dose protocol and patient preference were more frequently associated with the choice of nintedanib, while the comorbidity profile and concomitant medication use were more frequently associated with the choice of pirfenidone. Age, TLCO, and history of gastrointestinal bleeding were significant factors influencing the decision to initiate antifibrotic therapy.

Paralytic shellfish poisoning is a worldwide problem induced by shellfish contaminated with paralytic shellfish toxins. To protect human health, a regulatory limit for these toxins in shellfish flesh has been adopted by many countries. In a recent study, mice were dosed with saxitoxin and tetrodotoxin mixtures daily for 28 days showing toxicity at low concentrations, which appeared to be at odds with other work. To further investigate this reported toxicity, we dosed groups of mice with saxitoxin and tetrodotoxin mixtures daily for 21 days. In contrast to the previous study, no effects on mouse bodyweight, food consumption, heart rate, blood pressure, grip strength, blood chemistry or hematology were observed. Furthermore, no histological findings were associated with dosing in this trial. The dose rates in this study were 2.6, 3.8 and 4.9 times greater, respectively, than the highest dose of the previous study. As rapid mortality in three out of five mice was observed in the previous study, the deaths are likely to be due to the methodology used rather than the shellfish toxins. To convert animal data to that used in a human risk assessment, a 100-fold safety factor is required. After applying this safety factor, the dose rates used in the current study were 3.5, 5.0 and 6.5 times greater, respectively, than the acute reference dose for each toxin type set by the European Union. Furthermore, it has previously been proposed that tetrodotoxin be included in the paralytic shellfish poisoning suite of toxins. If this were done, the highest dose rate used in this study would be 13 times the acute reference dose. This study suggests that the previous 28-day trial was flawed and that the current paralytic shellfish toxin regulatory limit is fit for purpose. An additional study, feeding mice a diet laced with the test compounds at higher concentrations than those of the current experiment, would be required to comment on whether the current paralytic shellfish toxin regulatory limit should be modified.

We examined the effects of dose and dosing protocol on the pharmacodynamics of in vivo nitroglycerin (NTG) tolerance in conscious rats. Mechanism-based pharmcokinetic/pharmacodynamic (PK/PD) models were tested for their ability to describe the observed data. Rats were infused with 1, 3, or 10 microg/min of NTG or vehicle for 10 h. Peak mean arterial pressure (MAP) response to an hourly 30 microg i.v. NTG challenge dose (CD) was measured before, during, and at 12 and 24 h after infusion. In separate experiments, the MAP effects of repeated bolus doses of NTG were compared to those after a continuous infusion, both at a total dose of 510 microg NTG. NTG tolerance was indicated by a decrease in peak MAP response to the CD, relative to the preinfusion peak MAP response. Tolerance toward the MAP effects of bolus CD was observed within 1 h of 10 microg/min of NTG infusion (26.8 +/- 2.8% vs. 10.6 +/- 0.4% for 0 and 1 h, respectively, p < 0.001), and the rate and extent of tolerance development increased with the infusion dose. No apparent MAP tolerance was observed when NTG was given as multiple bolus doses whereas significant MAP tolerance was observed when this dose was infused continuously. PK/PD modeling indicated that a cofactor/enzyme depletion mechanism could adequately describe the composite data. Our data showed that in vivo nitrate tolerance was dose- and dosing protocol-dependent. The pharmacodynamics of tolerance development are consistent with depletion of either critical enzymes or cofactors that are necessary to induce vasodilation.

The objectives of this study were to determine if a standardized gentamicin dosing protocol would improve clinical effectiveness, yield higher peak serum concentrations, and improve the success rate of attaining peaks in the desired range when compared with empiric dosing practices used by prescribers. The study was conducted as a before-after program effectiveness evaluation in non-critically ill patients, aged 16-65 y with stable renal function, who were prescribed gentamicin. A standardized dose of 2 mg/kg (ideal or adjusted weight) was administered intravenously every 12 h in the intervention phase. Response to therapy (time to defervescence, white cell count, reinstitution of antibiotic therapy), serum concentrations (peaks > 10 mumol/L (5.6 mg/L) and troughs < 4 mumol/L (2.2 mg/L)), and toxicity were monitored in both groups. Thirty-four consecutive patients were enrolled into the control phase and an equal number into the intervention phase. Surgical patients comprised the majority of the study population. Desired peak concentrations were attained in 97% of intervention vs. 59% of control patients (p < 0.001). Mean peak serum concentrations were higher in the intervention phase than in the control phase, 16.1 mumol/L vs. 11.2 mumol/L (p < 0.001), respectively. Median time to become afebrile trended toward a statistical decrease in the intervention as compared to the control group, 3 vs. 5 d (p = 0.076), respectively. There was no significant difference in clinical effectiveness nor in the occurrence of nephro- or ototoxicity. Continued evaluation of this dosing protocol is warranted.

We investigated whether stem cells remember past physical signals and whether these can be exploited to dose cells mechanically. We found that the activation of the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) as well as the pre-osteogenic transcription factor RUNX2 in human mesenchymal stem cells (hMSCs) cultured on soft poly(ethylene glycol) (PEG) hydrogels (Young’s modulus E ~ 2 kPa) depended on previous culture time on stiff tissue culture polystyrene (TCPS; E ~ 3 GPa). In addition, mechanical dosing of hMSCs cultured on initially stiff ( E ~ 10 kPa) and then soft ( E ~ 2 kPa) phototunable PEG hydrogels resulted in either reversible or—above a threshold mechanical dose—irreversible activation of YAP/TAZ and RUNX2. We also found that increased mechanical dosing on supraphysiologically stiff TCPS biases hMSCs towards osteogenic differentiation. We conclude that stem cells possess mechanical memory—with YAP/TAZ acting as an intracellular mechanical rheostat—that stores information from past physical environments and influences the cells’ fate. Mechanical cues from the local cellular microenvironment can direct cell fate. Now, experiments with human mesenchymal stem cells cultured on phototunable soft poly(ethylene glycol) hydrogels show that the cells remember past physical environments—with the transcriptional co-activators YAP and TAZ acting as a mechanical rheostat—and therefore that appropriate doses of mechanical cues can be used to manipulate the cells’ fate.

Summary Background : AT-101 is a BCL-2 Homolog domain 3 mimetic previously demonstrated to have tumoricidal effects in advanced solid organ malignancies. Given the evidence of activity in xenograft models, treatment with AT-101 in combination with docetaxel is a therapeutic doublet of interest in metastatic head and neck squamous cell carcinoma. Patients and Methods : Patients included in this trial had unresectable, recurrent, or distantly metastatic head and neck squamous cell carcinoma (R/M HNSCC) not amenable to curative radiation or surgery. This was an open label randomized, phase II trial in which patients were administered AT-101 in addition to docetaxel. The three treatment arms were docetaxel, docetaxel plus pulse dose AT-101, and docetaxel plus metronomic dose AT-101. The primary endpoint of this trial was overall response rate. Results : Thirty-five patients were registered and 32 were evaluable for treatment response. Doublet therapy with AT-101 and docetaxel was well tolerated with only 2 patients discontinuing therapy due to treatment related toxicities. The overall response rate was 11 % (4 partial responses) with a clinical benefit rate of 74 %. Median progression free survival was 4.3 months (range: 0.7–13.7) and overall survival was 5.5 months (range: 0.4–24). No significant differences were noted between dosing strategies. Conclusion : Although met with a favorable toxicity profile, the addition of AT-101 to docetaxel in R/M HNSCC does not appear to demonstrate evidence of efficacy.

PurposePrior to docetaxel chemotherapy, incomplete dosing of steroid premedication is common. The lack of standardized steroid replacement strategies can lead to variability in care and delays in starting docetaxel.MethodsThis randomized trial compared physician-directed with fixed-dose dexamethasone. Patients who had missed at least one dose of steroid premedication were randomized to physician-directed replacement (any choice of steroid, dose or route) or to dexamethasone 8 mg oral before starting docetaxel. The primary outcome was time from randomization to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin toxicity.ResultsOf 60 eligible patients, 30 (50%) and 30 (50%) were randomized to physician-directed and fixed-dose arms, respectively. Overall tumour types: breast (42 [70%]), gastrointestinal (7 [12%]), prostate (7 [12%]) and lung (3 [7%]). Dexamethasone was most commonly incompletely taken with cycles 1 (28 [48%]) and 2 (13 [22%]) of docetaxel. Seven different replacement strategies were used in the physician-choice arm. Patients in the fixed-dose arm received docetaxel a mean of 21.2 (95% CI for the difference is 2.1 to 44.6) minutes earlier than the physician-choice arm (p = 0.033 Wilcoxon rank sum test or p = 0.073 two-sample t test). Median time to docetaxel was 47.5 vs 61 min (mean 62.2 vs 83.4 min) by arm, respectively. No significant difference in toxicity rates was observed.ConclusionWhile not meeting our predefined criteria of improving the time from randomization to starting docetaxel by 30 min, the fixed-dose replacement strategy reduced both the time to starting docetaxel and treatment variability. Fixed dosing with oral dexamethasone 8 mg should be the preferred standard of care.Registrationwww.clinicaltrials.gov NCT02815319Registration DateJune 28, 2016