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Aims To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M-III and M-IV with impaired renal function and normal renal function. Methods In a phase-I, open-label, parallel-group study, six healthy subjects with normal renal function (creatinine clearance > 80 ml min -1 ), nine patients with moderate renal impairment (creatinine clearance 30-60 ml min -1 ) and 12 patients with severe renal impairment (creatinine clearance < 30 ml min -1 ) received single and multiple oral doses of pioglitazone 45 mg. The serum pharmacokinetic profiles of pioglitazone and its metabolites M-III and M-IV were assessed for the first and last dose administered (day 1 and day 12, respectively). Results Pharmacokinetic data revealed no significant accumulation of pioglitazone or its metabolites M-III and M-IV in patients with renal impairment. There was no significant difference in the pharmacokinetic profile of pioglitazone in subjects with normal and with moderately impaired renal function. After single oral doses, mean area under the concentration-time curve (AUC) values were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (13 476 vs 17 387, P = 0.371; -23%; confidence interval (CI) -57, 38), M-III metabolite (13 394 vs 15 071, P = 0.841; -11%; 194) and M-IV metabolite (27 991 vs 49 856, P = 0.006; -44%; CI -62, -17). After repeated oral doses of pioglitazone, mean AUC values ( m g.h l -1 ) were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (8744 vs 14,565, P = 0.004; -40%; CI -57, -16), M-III (3991 vs 7,289, P = 0.0009; -45%; CI -60, -25) and M-IV (21 080 vs 25 706, P = 0.181; -18%; CI 39, 10). The tolerability and safety profile of pioglitazone was comparable between groups. Conclusions Pioglitazone was well tolerated in patients with varying degrees of renal impairment. Although mean serum concentrations of pioglitazone and its metabolites are increased in patients with severe renal impairment, adjustment of starting and maintenance doses in these patients is probably unwarranted.

The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

Background The prevalence of chronic pain among the elderly is high (estimated at 25–85%) and may adversely affect their everyday functioning, although it is often unrecognized. Material/Methods The aim of this study was to assess the prevalence of chronic pain, especially with the neuropathic component, and its effect on overall functioning of elderly patients. We enrolled 145 subjects older than 60 years (nursing home residents, or patients of outpatient geriatric clinic). Information on co-morbidities, functional and mental status, and medications was obtained using a questionnaire. Chronic pain was defined as lasting >3 months and the presence of neuropathic component was detected using the DN4 Questionnaire (Douleur Neuropathique en Questions). Results The mean age of patients was 76±9.68 years. Chronic pain was reported by 78% of participants and 32% reported neuropathic pain with neuropathic component (DN4 score ≥4 points). Patients complaining of chronic pain significantly more often presented mood disorders and lower satisfaction with life (particularly those with the highest pain intensity), with no difference in functional status according to the ADL (Activities of Daily Living) tool. Participants with chronic pain were treated with paracetamol (45%), non-steroidal anti-inflammatory drugs (25%), and opioids (24%). Conclusions The prevalence of chronic pain, particularly with neuropathic component, in the elderly population seems to be higher than expected based on previous reports, and its treatment appears to be ineffective. This problem requires further research and dissemination of knowledge on the diagnosis and treatment of chronic pain among health care workers caring for elderly patients on a daily basis.