This study was conducted to define a safe, effective dose regimen for metformin in moderate and severe chronic kidney disease (CKD; stages 3A/3B and 4, respectively), after the lifting of ...restrictions on metformin use in patients with diabetes with moderate-to-severe CKD in the absence of prospective safety and efficacy studies.
Three complementary studies were performed:
) a dose-finding study in CKD stages 1-5, in which blood metformin concentrations were evaluated during a 1-week period after each dose increase;
) a 4-month metformin treatment study for validating the optimal metformin dose as a function of the CKD stage (3A, 3B, and 4), with blood metformin, lactate, and HbA
concentrations monitored monthly; and
) an assessment of pharmacokinetic parameters after the administration of a single dose of metformin in steady-state CKD stages 3A, 3B, and 4.
First, in the dose-finding study, the appropriate daily dosing schedules were 1,500 mg (0.5 g in the morning qam +1 g in the evening qpm) in CKD stage 3A, 1,000 mg (0.5 g qam + 0.5 g qpm) in CKD stage 3B, and 500 mg (qam) in CKD stage 4. Second, after 4 months on these regimens, patients displayed stable metformin concentrations that never exceeded the generally accepted safe upper limit of 5.0 mg/L. Hyperlactatemia (>5 mmol/L) was absent (except in a patient with myocardial infarction), and HbA
levels did not change. Third, there were no significant differences in pharmacokinetic parameters among the CKD stage groups.
Provided that the dose is adjusted for renal function, metformin treatment appears to be safe and still pharmacologically efficacious in moderate-to-severe CKD.
It is not known whether the adverse events (AEs) associated with the administration of lopinavir and ritonavir (LPV/r) in the treatment of COVID‐19 are concentration‐dependent. In a retrospective ...study of 65 patients treated with LPV/r and therapeutic drug monitoring (TDM) for severe forms of COVID‐19 (median age: 67; males: 41 63.1%), 33 (50.8%) displayed a grade ≥2 increase in plasma levels of hepatobiliary markers, lipase and/or triglycerides. A causal relationship between LPV/r and the AE was suspected in 9 of the 65 patients (13.8%). At 400 mg b.i.d., the plasma trough concentrations of LPV/r were high and showed marked interindividual variability (median interquartile range: 16,600 11,430–20,842 ng/ml for lopinavir and 501 247–891 ng/ml for ritonavir). The trough lopinavir concentration was negatively correlated with body mass index, while the trough ritonavir concentration was positively correlated with age and negatively correlated with prothrombin activity. However, the occurrence of abnormal laboratory values was not associated with higher trough plasma concentrations of LPV/r. Further studies will be needed to determine the value of TDM in LPV/r‐treated patients with COVID‐19.
Whereas the immediate-release (IR) formulation of metformin has to be taken two or three times a day, the extended-release (XR) formulation enables once-daily administration and so might help to ...improve patient adherence, particularly in patients with polypharmacy.Several studies have assessed metformin XR's efficacy, safety, and pharmacokinetics (PK) in healthy people and those with type 2 diabetes (T2D).1-4 Many factors affect metformin absorption, disposition and elimination in patients with chronic kidney disease (CKD), leading to metformin accumulation. Although dose adjustment has been simulated using data from metformin XR-treated patients with various levels of kidney function,5 the pharmacodynamics (PD) and PK of metformin XR in patients with T2D and a defined CKD stage have not previously been studied. We therefore decided to comprehensively assess the efficacy, steady-state PK, and safety of three dose levels of metformin XR in people with T2D and CKD stage 3B.
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.
What is already known about the subject?•Several drugs are known to induce osteoporosis and/or increase the fracture risk.•Pharmacovigilance studies are crucial for the safety assessment of marketed drugs.
What this study adds?•New signals with a pharmacologically plausible mechanism in bone fragility were found.
This retrospective cohort study included 53 patients admitted to the intensive care unit (ICU), with an average age of 69 years, without neurologic disorder before initiation of a continuous ...piperacillin infusion at the standard dose and who underwent piperacillin serum concentration monitoring. Among them, 23 developed a neurologic disorder for which the piperacillin causality was chronologically and semiologically suggestive. A concentration threshold of 157.2 mg/liter independently predicted neurotoxicity with 96.7% specificity and 52.2% sensitivity and may constitute a limitation when targeting less susceptible pathogens.
Abstract
Background
Therapeutic drug monitoring (TDM) contributes to optimizing exposure to β-lactam antibiotics. However, how excessive exposure to β-lactams can increase the burden of care of ...critically ill patients is unclear.
Patients and methods
In a prospective cohort study, we examined whether excessive β-lactam serum concentrations contribute to neurological deterioration and the associated complications of adult septic patients without recent history of neurological disease treated with β-lactams in a medical ICU. Excessive β-lactam concentrations were defined as serum concentrations that exceeded the upper limit of the therapeutic range recommended by the French Societies of Pharmacology and Therapeutics (SFPT) and Anesthesia and Intensive Care Medicine (SFAR). Neurological deterioration was defined as an increase in the neurological Sequential Organ Failure Assessment score (nSOFA) of ≥1 between the day of starting treatment at admission and the day of TDM performed 2 days after treatment initiation.
Results
We included 119 patients median age: 65 years; males: 78 (65.5%) admitted for acute respiratory distress 59 (49.6%) or septic shock 25 (21%). In adjusted logistic regression analysis, an excessive β-lactam serum concentration was associated with neurological deterioration OR (95% CI): 10.38 (3.23–33.35), P < 0.0001. Furthermore, in adjusted linear regression analysis, an excessive β-lactam serum concentration was associated with longer time to discharge alive (β=0.346, P = 0.0007) and, among mechanically ventilated patients discharged alive, with longer time to extubation following the withdrawal of sedation (β=0.248, P = 0.0030).
Conclusions
These results suggest that excessive exposure to β-lactams could complicate the management of septic patients in the ICU and confirm the clinical relevance of the upper concentration limits recommended for dose reduction.
Nicotinamide (NAM) has been proposed as an alternative treatment to phosphate binders for hyperphosphataemia in chronic kidney disease.
The NICOREN multicentre, open-label and randomized study was ...designed to examine non-inferiority and safety of NAM when compared with sevelamer (SEV) in chronic haemodialysis patients. One hundred patients were randomized to either NAM or SEV treatment for 24 weeks. Serum biochemistry and NAM's main metabolite, N -methyl-2-pyridone-5-carboxamide (2PY), were measured to assess compliance, efficacy and safety.
After 24 weeks, we observed a comparable decrease in serum phosphorus in the NAM and SEV treatment arms, from 2.1 ± 0.4 to 1.8 ± 0.5 and 2.3 ± 0.5 to 1.7 ± 0.5 mM (P = not significant), respectively. The criterion for non-inferiority was, however, not met due to a more limited number of patients being included than planned. Treatment discontinuation due to adverse events was 1.6 times higher in the NAM than in the SEV group with only 55% of study completers in the NAM arm versus 90% in the SEV arm. Thrombocytopenia was observed in four NAM-treated patients. Serum 2PY levels were comparable at baseline, but increased markedly in the NAM group, but not in the SEV group, at 24 weeks (P < 0.0001).
Thus, both drugs are equally effective in lowering serum phosphorus, but patients' tolerance of NAM was largely inferior to that of SEV. Extremely high 2PY levels may contribute to NAM's side effects.
It is difficult to carry out toxicological investigations in biological samples collected from extensively decomposed bodies and to interpret obtained results as several pitfalls should be ...considered: redistribution phenomena, degradation of xenobiotics during the
postmortem
period, contamination by putrefaction fluids, and external contamination. This work aims to present two cases in order to illustrate and discuss these difficulties in this tricky situation. Case#1: the body of a 30-year-old woman was found in a wooded area (1 month after she has been reported missing by her family): hair and a femur section were sampled. Case#2: the decomposed corpse of a 52-year-old man was found in a ditch: hair and nails were sampled. After decontamination steps, toxicological investigations were performed using liquid chromatography with high-resolution mass spectrometry and tandem mass spectrometry detection methods. In case#1, the same drugs or metabolites (benzodiazepines, propranolol, tramadol, acetaminophen, paroxetine, and oxetorone) were detected in hair and in bone specimens. This result combination strongly suggests intakes close to the time of death for three of them (oxazepam, lormetazepam, and propranolol). In case#2, results of toxicological investigations in hair and nails (hair/nail concentration in ng/mg) nordiazepam (1.12/1.06), oxazepam (0.113/0.042), zolpidem (0.211/< 0.01), hydroxyzine (0.362/< 0.01), and cetirizine (0.872/1.110) were both consistent with several drug intakes but were not contributory to cause of death determination. In case of positive toxicological results in biological samples collected from extensively decomposed bodies (such as hair, bones, or nails), it is challenging to determine the time, and even more, the level of the dose of exposure(s).
Ceftobiprole is a fifth-generation cephalosporin approved for the treatment of pneumonia, with a broad antibacterial spectrum, including potent activity against methicillin-resistant
As for the other ...cephalosporins, high pharmacokinetic variability and concentration-dependent neurotoxicity are expected. We describe here the first simple and rapid analytical method intended for ceftobiprole serum concentration monitoring. We report the data of 5 patients treated with ceftobiprole, among who 2 developed reversible neurological disorders with high ceftobiprole serum concentration.
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