Metabolic studies of the effects of methotrexate (2023)

Bone remodeling is a complex process, and many conditions (including drug exposure) lead to osteoporosis. Here, we sought to detect new disproportionality signals for drugs associated with osteoporosis.

We performed a disproportionality analysis of the World Health Organization's VigiBase® pharmacovigilance database through April 12, 2020. The frequency of reports on osteoporosis for all identified drug classes was compared with that for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)].

Of the 7,594,968 cases spontaneously recorded to VigiBase®, 4758 concerned osteoporosis. New disproportionality signals with a pharmacologically plausible mechanism were found for drugs used in neurology (levodopa (ROR [95%CI]: 10.18 [4.33–25.10]), selective serotonin agonists (4.22 [2.34–7.00]) and memantine (4.10 [1.56–8.93])), hematology (romiplostim (4.93 [1.15–21.10])), pulmonology (macitentan (3.02 [1.84–4.90])), ophthalmology (ranibizumab (3.31 [1.00–10.51])) and rheumatology (tofacitinib (3.65 [3.00–4.40])). The robustness of these new results is supported by the significant RORs for the vast majority of drugs already known to induce osteoporosis and/or increase the fracture risk, namely glucocorticoids, gonadotropin-releasing hormone analogs, anti-aromatases, androgen receptor blockers, thyroid hormones, proton pump inhibitors, thiazolidinediones, vitamin K antagonists, loop diuretics, protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, and enzyme-inducing antiepileptics including barbiturates and derivatives, hydantoin derivatives, carboxamide derivatives and fatty acid derivatives.

We established up a comprehensive list of drugs potentially associated with osteoporosis and highlighted those with pharmacologically plausible mechanisms leading to bone fragility. Our results might pave the way for additional exploration of these mechanisms.

African potato (Hypoxis obtusa) is commonly used in Sub-Saharan Africa as a complementary herbal remedy for HIV-infected patients. It is unknown whether or not co-administration of African potato alters the pharmacokinetics of protease inhibitor antiretrovirals. The objective of this study was to investigate the impact of the African potato on the steady-state pharmacokinetics of ritonavir-boosted lopinavir (LPV/r).

Sixteen adult volunteers were administered LPV/r 400/100mg twice a day for 14 days, followed by concomitant administration with African potato given once daily for 7 days. Lopinavir plasma exposure as estimated by the area under the concentration–time curve over the 12-h dosing interval (AUC_0–12h, AUCτ) was determined on day 14 and again on day 21. Lopinavir in plasma was analyzed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Steady-state AUCτ and the maximum concentration following dose administration (C_max) were determined using non-compartmental methods using WinNonlin Professional version 5.2.1. Statistical analyses were performed using Stata version 12.1.

Co-administration of African potato was not associated with any change in lopinavir AUCτ, C_max, or C_trough.

African potato when taken concomitantly with LPV/r is well-tolerated and not associated with clinically significant changes in lopinavir pharmacokinetics.

To investigate the effects of asymmetric dimethyl-arginine (ADMA), adiponectin (APN) and apelin in predicting macroangiopathy in impaired glucose regulation (IGR) patients.

A total of 210 patients undergoing oral glucose tolerance test were included in this study. They were classified to normal glucose tolerance (NGT, n=42), impaired fasting glucose (IFG, n=36), impaired glucose tolerance (IGT, n=92, including 44 IGT1 and 48 IGT2 patients) and IFG+IGT (n=40) groups. APN, apelin and ADMA levels, blood pressure, blood lipid, insulin, body mass index (BMI), and homeostasis model assessment of insulin resistance (HOMA-IR) were detected. The severity and extent of coronary atherosclerosis were determined by the Gensini score.

The prevalence of coronary heart disease and Gensini scores in IGT and IFG+IGT groups were similar but both were higher than NGT and IFG groups (all P<0.05). Lower APN, higher ADMA and apelin levels were witnessed in IGT and IGT+IFG groups compared with NGT and IFG groups (all P<0.05). IGT2 group had higher 2-h PG and apelin levels and Gensini scores but lower APN levels than IGT1 group (all P<0.05). Gensini score was positively correlated with apelin (r=0.669) and ADMA (r=0.764), but were negatively correlated with APN (r=–0.555, all P<0.001). ADMA and APN were the independent factors affecting Gensini score.

ADMA and APN levels could be predictive factors for macroangiopathy in IGR patients, especially in IGT cases.

Étudier le rôle de la diméthyl-arginine asymétrique (ADMA), de l’adiponectine (APN) et l’apeline dans la prédiction de macroangiopathie chez des patients souffrant de troubles de la glycémie.

Un total de 210patients soumis à un test de tolérance au glucose oral ont été inclus dans cette étude. Ils ont été classés selon les groupes suivants: tolérance normale au glucose (NGT, n=42), altération de la glycémie à jeun (IFG, n=36), intolérance au glucose (IGT, n=92, y compris 44patients IGT1et 48patients IGT2) et IFG+IGT (n=40). Taux d’APN, d’apeline et d’ADMA, pression artérielle, lipides sanguins, insuline, indice de masse corporelle (IMC), et évaluation de modèle d’homéostasie de la résistance à l’insuline (HOMA-IR) ont été notés. La gravité et l’étendue de l’athérosclérose coronarienne ont été déterminées par le score Gensini.

La prévalence de la maladie coronarienne et les scores Gensini étaient similaires dans les groupes IGT et IFG+IGT mais étaient tous deux plus élevés dans les groupes NGT et IFG (p<0,05). Un taux abaissé d’apeline et élévé d’ADMA étaient relevés dans les groupes IGT et IGT+IFG comparé aux groupes NGT et IFG (p<0,05). Le groupe IGT2avait des taux de 2heures PG et d’apeline ainsi qu’un score Gensini supérieurs mais un taux d’APN inféreur au groupe IGT1 (p<0,05). Le score Gensini était positivement corrélé avec l’apeline (r=0,669) et l’ADMA (r=0,764), mais négativement avec l’apodinectine (r=–0,555, p<0,001). L’ADMA et l’APN étaient les facteurs indépendants affectant le score Gensini.

Les taux d’ADMA et d’APN pourraient être des facteurs prédictifs de macroangiopathie chez les patients IGR, en particulier dans les cas d’intolérance au glucose.

The Modification of Diet in Renal Disease (MDRD) equation is widely used to estimate glomerular filtration rate (eGFR) in kidney transplant (KT) patients. The novel Chronic Kidney Disease–Epidemiology Collaboration equation (CKD-EPI) could improve accuracy of GFR estimation. Our aim was to compare both equations for staging of CKD in KT patients.

In a cohort of KT patients, correlation of eGFR according to MDRD and CKD-EPI with 24-hour creatinine clearance (24h-CrCl) was evaluated. Concordance between both equations for CKD staging was performed. MDRD was used for initial CKD staging. The mean difference of GFR between 24h-CrCl and each equation was calculated and Bland-Altman analysis applied.

A cohort of 463KT patients were studied: 67% female, overall average age 46 ± 14 years, 41% living donor, mean time of transplantation 71 months (3–95), and mean serum creatinine 1.68 ± 1.03mg/dL. For the whole cohort (all CKD stages), eGFR by CKD-EPI was 5.33mL/min/1.73m² higher than by MDRD (P< .01). For CKD stages 1, 2, and 3A, the mean eGFR differences (CKD-EPI− MDRD) were 13.98 ± 3.27, 8.2 ± 1.98, and 5.34 ± 1.32mL/min/1,73 m², respectively. The percentage of patients with eGFR<60mL/min/1.73m² decreased from 63.8% according to MDRD to 53.9% with the use of CKD-EPI. In women and patients≤65 years old, eGFR by CKD-EPI was 5.98 and 5.81mL/min/1.73m² higher, respectively, than by MDRD (P< .01).

The novel CKD-EPI reduces the number of patients with eGFR<60mL/min/1.73m² and consequently assigns lower CKD stages to our KT population.

Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrations in the absence of analytical techniques that allow for direct quantification. The present study applied this modeling approach to determine active drug release from a nanoparticle prodrug formulation. A comparative pharmacokinetic study of a nanoscale micellar docetaxel (DTX) prodrug, Procet 8, and commercial DTX formulation, Taxotere, was conducted in bile duct cannulated rats. The nanoscale (~40nm) size of the Procet 8 formulation resulted in confinement within the plasma space and high prodrug plasma concentrations. Ex vivo prodrug hydrolysis during plasma sample preparation resulted in unacceptable error that precluded direct measurement of DTX concentrations. Pharmacokinetic modeling of Taxotere and Procet 8 plasma concentrations, and their associated biliary metabolites, allowed for prediction of the DTX concentration profile and DTX bioavailability, and thereby evaluation of Procet 8 metabolism.

Procet 8 plasma decay and in vitro plasma hydrolytic rates were identical, suggesting that systemic clearance of the prodrug was primarily metabolic. The Procet 8 and Taxotere plasma profiles, and associated docetaxel hydroxy-tert-butyl carbamate (HDTX) metabolite biliary excretion, were best fit by a two compartment model, with both linear and non-linear DTX clearance, and first order Procet 8 hydrolysis. The model estimated HDTX clearance rate agreed with in vitro literature values, supporting the predictability of the proposed model. Model simulation at the 10mg DTX equivalent/kg dose level predicted DTX formation rate-limited kinetics and a peak plasma DTX concentration of 39ng/mL at 4h for Procet 8, in comparison to 2826ng/mL for Taxotere. As a result of nonlinear DTX clearance, the DTX AUCinf for the Procet 8 formulation was predicted to be 2.6 times lower than Taxotere (775 vs. 2017h×ng/mL, respectively), resulting in an absolute bioavailability estimate of 38%. As DTX clearance in man is considered linear, this low bioavailability is likely species-dependent. These data support the use of pharmacokinetic modeling and simulation in cases of complex formulations, where analytical methods for direct measurement of free (released) drug concentrations are unavailable. Uses of such models may include interpretation of preclinical toxicology studies, selection of first in man dosing regimens, and PK/PD model development.

High sensitivity C-reactive protein (hsCRP) and advanced glycation end-products (AGEs) have been proposed as mediators in inflammation and atherosclerosis. Therefore, we studied the relation between AGE and hsCRP in patients with acute myocardial infarction (AMI).

Patients with AMI diagnosis and satisfying our inclusion criteria were included during 2009–2011 in an unicentre registry of AMI patients for a cross-sectional study. The final cohort was composed of 156 patients (46.2% STEMI and 27.6% with type-2 diabetes). AGE and hsCRP were measured in plasma.

Diabetic patients were older than non-diabetics (68.6±10.6 vs. 60.4±13.9years; p<0.05), presented more incidence of hypertension (62.8 vs. 36.3%; p<0.05) and were in a higher Killip class (p<0.05). The mean values of fluorescent AGE and hsCRP levels were 61.3±49.8 AU and 2.4±4.0mg/L, respectively, and there were no differences in these parameters between diabetic and non-diabetic patients. A direct association between AGE and hsCRP levels was observed, mainly in diabetic patients (r=0.258; p=0.018). Importantly, this association disappeared in patients who had been treated with statins before their AMI (r=−0.055; p=0.845), but it was maintained in non-diabetic patients naïve for statins treatment (r=0.634; p<0.001), independently of other treatments and confounding parameters.

This is the first evidence in humans of a feedback regulation mechanism between CRP and the AGE–RAGE axis modulated by statins.

Patients with anorectal malformations (ARMs) have a high incidence of genitourinary anomalies. Those with a recto-bladder neck fistula may represent a high-risk group, but their long-term urologic outcomes are poorly described.

To evaluate the clinical and urodynamic outcomes in a large cohort of patients with an ARM subtype of recto-bladder neck fistula.

A retrospective cohort study was performed of patients who had been treated for a recto-bladder neck fistula at the present institution since 2007. The primary outcomes were the ability to achieve urinary continence after 4 years of age, and development of a mildly decreased glomerular filtration rate (GFR) or worse (<89ml/min/1.73m²). Continence was defined as the ability to store urine for 3–4h during the day and 8h overnight without leakage.

Demographic and clinical data are provided in the Summary Table. The most recent urodynamic findings included the presence of detrusor overactivity in 30 (75%) patients, median leak point pressure of 56.0cmH₂O (range, 14–140), median functional cystometric capacity at 40cmH₂O of 125.5% age-expected capacity (range, 36–473%), and median maximum cystometric capacity of 131.0% age-expected capacity (range, 44–473%). A mildly decreased GFR or worse developed in 13 (24%) patients. Of the 52 (78%) patients who were followed by pediatric urology at the present institution with a median follow-up of 30.9 months (range, 0.0–86.8), 35 (67%) were at least 4 years of age and could be assessed for continence. Continence was achieved in five (14%) patients voiding spontaneously and 15 (43%) performing CIC. Recurrent urinary tract infections (UTI) (OR 0.70, P=0.006) were an independent predictor of incontinence, while urethral anomalies (OR 1.40, P=0.03) were an independent predictor of chronic kidney disease (CKD) on multiple logistic regression analysis.

The findings favorably compared with other studies, but were more robust due to the size of the cohort and breadth of urologic evaluation. Limitations included the retrospective design at a single institution. Incomplete clinical data and misclassification of continence may have lead to bias.

This large cohort of patients with an ARM subtype of recto-bladder neck fistula had a high incidence of genitourinary anomalies. They were rarely able to achieve continence with spontaneous voiding alone and were at risk of developing CKD, both of which were likely multifocal in origin. Long-term urologic follow-up is warranted for patients with a recto-bladder neck fistula.