Previous trials have suggested that vasopressin and methylprednisolone administered during in-hospital cardiac arrest might improve outcomes.
To determine whether the combination of vasopressin and ...methylprednisolone administered during in-hospital cardiac arrest improves return of spontaneous circulation.
Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark. A total of 512 adult patients with in-hospital cardiac arrest were included between October 15, 2018, and January 21, 2021. The last 90-day follow-up was on April 21, 2021.
Patients were randomized to receive a combination of vasopressin and methylprednisolone (n = 245) or placebo (n = 267). The first dose of vasopressin (20 IU) and methylprednisolone (40 mg), or corresponding placebo, was administered after the first dose of epinephrine. Additional doses of vasopressin or corresponding placebo were administered after each additional dose of epinephrine for a maximum of 4 doses.
The primary outcome was return of spontaneous circulation. Secondary outcomes included survival and favorable neurologic outcome at 30 days (Cerebral Performance Category score of 1 or 2).
Among 512 patients who were randomized, 501 met all inclusion and no exclusion criteria and were included in the analysis (mean SD age, 71 13 years; 322 men 64%). One hundred of 237 patients (42%) in the vasopressin and methylprednisolone group and 86 of 264 patients (33%) in the placebo group achieved return of spontaneous circulation (risk ratio, 1.30 95% CI, 1.03-1.63; risk difference, 9.6% 95% CI, 1.1%-18.0%; P = .03). At 30 days, 23 patients (9.7%) in the intervention group and 31 patients (12%) in the placebo group were alive (risk ratio, 0.83 95% CI, 0.50-1.37; risk difference: -2.0% 95% CI, -7.5% to 3.5%; P = .48). A favorable neurologic outcome was observed in 18 patients (7.6%) in the intervention group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 95% CI, 0.55-1.83; risk difference, 0.0% 95% CI, -4.7% to 4.9%; P > .99). In patients with return of spontaneous circulation, hyperglycemia occurred in 77 (77%) in the intervention group and 63 (73%) in the placebo group. Hypernatremia occurred in 28 (28%) and 27 (31%), in the intervention and placebo groups, respectively.
Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival.
ClinicalTrials.gov Identifier: NCT03640949.
Therapeutic drug monitoring is standard practice for the immunosuppressant tacrolimus (Tac). Venous blood sampling at outpatient clinics is time-consuming and impractical with regard to obtaining ...trough concentrations on clinical visit days. Home-based blood sampling may be patient friendly and pave the way for limited sampling strategies for the prediction of total drug exposure. The aim was to establish a Tac assay for dried capillary microsamples, ensuring reliable measurements during the full dose interval in renal transplant recipients.
An assay based on volumetric absorptive microsampling and liquid chromatography tandem mass spectrometry was validated. The agreement between capillary microsamples and liquid venous samples was investigated in stable renal recipients on twice-daily Tac dosing. Sampling throughout the 12-hour dose interval was examined at 2 separate days, at least 1 week apart, for each participant. Two sets of samples were obtained at each time point, one delivered directly to the laboratory and one sent through mail.
Twenty-seven renal transplant recipients were included, of whom 26 were investigated twice. Tac was efficiently extracted from the dried microsamples (mean recovery 94%-103%). The between-series mean accuracy was 88%-98% with coefficients of variation ≤5.0% (≤11% at the lower limit of quantification), measurement range 0.70-60 mcg/L. The mean difference between parallel microsamples was 5%-7%. Overall, the mean differences between dried microsamples and liquid samples were -3.1% when mailed (n = 679) and -4.2% when directly delivered (n = 682). Less than 8% were outside ±20%. The microsamples were stable for 1 month at ambient temperature.
The microsample method demonstrated acceptable performance. Tac concentrations can be reliably quantified throughout the dose interval by using volumetric absorptive microsampling in renal transplant recipients, and the results are not influenced by postal shipment.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• High dose methotrexate (HD MTX) is generally well tolerated, although unpredictable acute toxicities occur frequently.
• Low overall toxicity in paediatric ...patients and increased liver toxicity in adults has been reported, but there are no reports addressing the relationship between acute liver toxicity and gender in patients treated with HD MTX.
• Previous studies in animals suggested involvement of the 7‐hydroxy‐methotrexate metabolite in acute liver toxicity, but this has not been investigated in humans and the aetiology of acute liver toxicity remains unclear.
WHAT THIS STUDY ADDS
• Survival has increased dramatically over the past decades for patients with malignancies such as osteosarcoma and since these patients are frequently children or adolescents at the time of high dose methotrexate, identification of risk factors for toxicity increases the possibility for tailoring treatment.
• Our study presents a detailed analysis of acute toxicity, folate concentrations and pharmacokinetics of both methotrexate and its major extracellular metabolite 7‐hydroxy‐methotrexate and identifies several factors that are highly correlated with acute liver toxicity.
AIMS
To investigate the relationships between pretreatment folate concentrations, MTX pharmacokinetics and acute toxicities following high dose methotrexate (HD MTX) therapy.
METHODS
MTX and its major extracellular metabolite 7‐OH‐MTX were measured in eight serum samples per HD MTX cycle in 65 consecutive osteosarcoma patients (288 cycles) and AUC (area under the blood concentration–time curve) was calculated. Pretreatment concentrations of folate in serum (S) and erythrocytes (ER) were determined. Hepatic, renal and haematological toxicities, assessed by routine laboratory parameters, as well as mucositis were graded according to National Cancer Institute Common Terminology Criteria for adverse events (CTCAE v.3.0). Dermatitis and pleuritis were reported as occurred or not.
RESULTS
S‐ and ER‐folate pretreatment concentrations increased significantly with increasing number of HD MTX cycles (P < 0.001). ER‐folate pretreatment concentrations were higher among males (median 610 nmol l−1, 95% CI 550, 680) compared with females (median 465 nmol l−1, 95% CI 430, 520, P < 0.001), but showed no correlation with MTX or 7‐OH‐MTX pharmacokinetics. We found correlations between alanine aminotransferase peak concentration (ALATmax) and clearance of MTX (P < 0.001), gender (P < 0.001), age (P < 0.001) and 7‐OH‐MTX concentrations (P < 0.001), the latter being the main factor influencing ALATmax.
CONCLUSION
Our results suggest that 7‐OH‐MTX is involved in the development of HD MTX hepatic toxicity and that young female patients are most affected.
Postactivation potentiation refers to an acute enhancement of contractile properties following muscle activity. Previously, the effects of prior muscle activation on eccentric force at tetanic ...activation frequencies have only been sparsely reported. This paper aimed to study acute activity-induced effects on eccentric force of slow and fast-twitch muscles and characterize them in relation to postactivation potentiation. We elicited eccentric contractions in isolated rat extensor digitorum longus and soleus muscles by actively lengthening muscles at a constant velocity. We assessed contractile properties by measuring force over shortly interspaced, identical eccentric, and isometric contractions. We then analyzed stretch force, isometric peak force, rate of force development, and relaxation times. Finally, we compared the time courses for the development and cessation of changes in stretch force to known features of postactivation potentiation. In extensor digitorum longus, muscles stretch force consistently increased in a contraction-to-contraction manner by up to 49% 95% confidence interval (CI): 35-64% whereas isometric peak force simultaneously showed minor declines (8%, 95% CI: 5-10%). The development and cessation of eccentric force potentiation coincided with the development of twitch potentiation and increases in rate of force development. In soleus muscles we found no consistent eccentric potentiation. Characterization of the increase in eccentric force revealed that force only increased in the very beginning of an active stretch. Eccentric force at tetanic activation frequencies potentiates substantially in extensor digitorum longus muscles over consecutive contractions with a time course coinciding with postactivation potentiation. Such eccentric potentiation may be important in sport performance.
Force during eccentric contractions can increase to a magnitude that may have profound consequences for our understanding of skeletal muscle locomotion. This increase in eccentric force occurs over consecutive, shortly interspaced, tetanic contractions in rat extensor digitorum longus muscles-not in rat soleus muscles-and coincides with well-known traits of postactivation potentiation. Eccentric force potentiation may significantly enhance muscle performance in activities involving stretch-shortening cycles.
Self‐perceived statin‐associated muscle symptoms (SAMS) are prevalent, but only a minority is drug‐dependent. Diagnostic biomarkers are not yet identified. The local statin exposure in skeletal ...muscle tissue may correlate to the adverse effects. We aimed to determine whether atorvastatin metabolites in blood reflect the corresponding metabolite levels in skeletal muscle, and whether genetic variants of statin transporters modulate this relationship. We also addressed atorvastatin metabolites as potential objective biomarkers of SAMS. Muscle symptoms were examined in patients with coronary disease and self‐perceived SAMS during 7 weeks of double‐blinded treatment with atorvastatin 40 mg/day and placebo in randomized order. A subset of 12 patients individually identified with more muscle symptoms on atorvastatin than placebo (confirmed SAMS) and 15 patients with no difference in muscle symptom intensity (non‐SAMS) attended the present follow‐up study. All received 7 weeks of treatment with atorvastatin 40 mg/day followed by 8 weeks without statins. Biopsies from the quadriceps muscle and blood plasma were collected after each treatment period. Strong correlations (rho > 0.7) between muscle and blood plasma concentrations were found for most atorvastatin metabolites. The impact of the SLCO1B1 c.521T>C (rs4149056) gene variant on atorvastatin's systemic pharmacokinetics was translated into muscle tissue. The SLCO2B1 c.395G>A (rs12422149) variant did not modulate the accumulation of atorvastatin metabolites in muscle tissue. Atorvastatin pharmacokinetics in patients with confirmed SAMS were not different from patients with non‐SAMS. In conclusion, atorvastatin metabolite levels in skeletal muscle and plasma are strongly correlated, implying that plasma measurements are suitable proxies of atorvastatin exposure in muscle tissue. The relationship between atorvastatin metabolites in plasma and SAMS deserves further investigation.
The primary results from the Vasopressin and Methylprednisolone for In-Hospital Cardiac Arrest (VAM-IHCA) trial have previously been reported. The objective of the current manuscript is to report ...long-term outcomes.
The VAM-IHCA trial was a multicenter, randomized, double-blind, placebo-controlled trial conducted at ten hospitals in Denmark. Adult patients (age ≥ 18 years) were eligible for the trial if they had an in-hospital cardiac arrest and received at least one dose of epinephrine during resuscitation. The trial drugs consisted of 40 mg methylprednisolone (Solu-Medrol®, Pfizer) and 20 IU of vasopressin (Empressin®, Amomed Pharma GmbH) given as soon as possible after the first dose of epinephrine. This manuscript report outcomes at 6 months and 1 year including survival, survival with favorable neurological outcome, and health-related quality of life.
501 patients were included in the analysis. At 1 year, 15 patients (6.3%) in the intervention group and 22 patients (8.3%) in the placebo group were alive corresponding to a risk ratio of 0.76 (95% CI, 0.41–1.41). A favorable neurologic outcome at 1 year, based on the Cerebral Performance Category score, was observed in 14 patients (5.9%) in the intervention group and 20 patients (7.6%) in the placebo group (risk ratio, 0.78 95% CI, 0.41–1.49. No differences existed between groups for favorable neurological outcome and health-related quality of life at either 6 months or 1 year.
Administration of vasopressin and methylprednisolone, compared with placebo, in patients with in-hospital cardiac arrest did not improve long-term outcomes in this trial.
Because several steroid hormones are metabolized to their respective 6β‐hydroxy forms by CYP3A4 and CYP3A5, these isoenzymes have been assumed to metabolize the immunosuppressive drug prednisolone, ...with conflicting results in the literature with respect to their relative importance. A direct study of the metabolism of prednisolone by microsomal CYP3A4 and CYP3A5 is missing. The aim of this in vitro study was to investigate the relative importance of recombinant CYP3A4 and recombinant CYP3A5 in the metabolism of prednisolone and to compare the extent of formation of 6β‐OH‐prednisolone by the two enzymes. Through in vitro incubations using rCYP3A4 and rCYP3A5 enzymes, intrinsic clearance (CLint) of prednisolone was determined by the substrate depletion approach. Formation of the metabolite 6β‐OH‐prednisolone by rCYP3A4 and rCYP3A5, respectively, was compared. Prednisolone concentrations were measured, and its metabolite 6β‐OH‐prednisolone was identified using a HPLC‐MS/MS in‐house method. CLint for prednisolone by rCYP3A5 was less than 26% relative to rCYP3A4. Formation of 6β‐OH‐prednisolone by rCYP3A5 was less than 11% relative to rCYP3A4. The study indicates that 6β‐hydroxylation of prednisolone assessed in vitro in recombinant CYP enzymes depends on rCYP3A4 rather than rCYP3A5 and that CYP3A5 may be responsible for the formation of other prednisolone metabolite(s) in addition to 6β‐OH‐prednisolone.
Prednisolone (PL) is a standard component of most immunosuppressive protocols after solid organ transplantation (Tx). Adverse effects are frequent and well known. The aim of this study was to ...characterize the pharmacokinetics (PKs) of PL and prednisone (PN), including cortisol (CL) and cortisone (CN) profiles, after PL treatment in renal Tx recipients in the early post-Tx phase.
This single-center, prospective, observational study included stable renal Tx recipients, >18 years of age, and in the early postengraftment phase. Blood samples were obtained predose and during a 24-hour dose interval n = 26 samples per area under the curve (AUC0-24), within the first 8 weeks post-Tx. PL, PN, CL, and CN concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry.
In renal Tx recipients (n = 28), our results indicated a relatively high PL exposure median, range AUC0-24 = 3821 (2232-5382) mcg h/L, paralleled by strong suppression of endogenous CL profile, demonstrated by a low CL evening-to-morning ratio median, range 11 (3-47)%. A negative correlation (r = -0.83) between PL AUC0-24 and morning CL levels was observed. The best single PK variable to predict PL AUC0-24 was PL C6 (r2 = 0.82). An algorithm based on 3 PK sampling time points: trough, 2, and 4 hours after PL dosing, predicted PL AUC0-24 with a low percentage prediction error (PPE = 5.2 ± 1.5%) and a good correlation of determination (r2 = 0.91). PL AUC0-24 varied 3-fold among study participants, whereas CL AUC0-24 varied by 18-fold.
The large interindividual variability in both PL exposure and suppression of endogenous CL implies a possible role for therapeutic drug monitoring. An abbreviated profile within the first 4 hours after PL dosing provides a good prediction of PL exposure in renal Tx recipients. The strong negative correlation between PL AUC0-24 and morning CL levels suggests a possible surrogate marker for drug exposure for further evaluation.
Tacrolimus (TAC) is currently the cornerstone of immunosuppressive protocols for renal transplant recipients. Despite therapeutic whole blood monitoring, TAC is associated with nephrotoxicity, and it ...has been hypothesized that intrarenal accumulation of TAC and/or its metabolites are involved. As TAC is a substrate of P-glycoprotein (P-gp), the expression and activity of this efflux transporter could influence the levels of TAC in renal tissue. The primary aim of this study was to develop and validate a method for quantification of TAC in tissue homogenates from single human renal core biopsies. The secondary aim was to provide measures of P-gp expression and of the demethylated metabolites of TAC in the same renal biopsy.
Human renal tissue, with and without clinical TAC exposure, was used for method development and validation. Homogenates were prepared with bead-beating, and concentrations of TAC and its demethylated metabolites were analyzed with liquid chromatography tandem mass spectrometry after protein precipitation. A Western blot method was used for semiquantification of P-gp expression in the homogenates. The final methods were applied to renal core biopsies from 2 transplant patients.
The TAC assay showed within- and between-run mean accuracy between 99.7% and 107% and coefficients of variation ≤6.7%. Matrix effects were nonsignificant, and samples were stable for 3 months preanalytically when stored at -80°C. TAC concentrations in the renal core biopsies were 62.6 and 43.7 pg/mg tissue. The methods for measurement of desmethyl-TAC and P-gp expression were suitable for semiquantification in homogenates from renal core biopsies.
These methods may be valuable for the elucidation of the pharmacokinetic mechanisms behind TAC-induced nephrotoxicity in renal transplant recipients.
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