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Insulin receptors are distributed in the whole brain, including different parts of the reward circuit that modulate dopamine as the primary neurotransmitter implicated in addiction. The goal of the current study was to illuminate the role of insulin in the extinction period and reinstatement of morphine-induced conditioned place preference (CPP) in the naïve and diabetic rats. One hundred and twelve male rats were randomly divided into two naïve and diabetic groups. Diabetes was induced by one dose administration of streptozotocin (STZ; 60 mg/kg; IP) ten days before the conditioning procedure. To evaluate the insulin's role in the duration of extinction period of morphine-CPP, naïve and diabetic rats received insulin (10 U/kg; IP) before each morphine injection (5 mg/kg; sc) during the 3-day conditioning phase. All rats that passed the conditioning phase and then underwent the extinction period. Morphine priming-induced reinstatement was determined in both naïve and diabetic rats by injection of different ineffective doses of morphine (0.5 and 1 mg/kg; sc) in extinguished rats. In the following experiments, three groups of diabetic rats received insulin during the conditioning, expression, or reinstatement phase to illustrate insulin's effect on the morphine-induced reinstatement and the duration of the extinction period (insulin was only treated during the acquisition phase). The results showed that the extinction period and reinstatement of morphine were potentiated in the STZ-induced diabetic rats. The obtained findings also revealed that insulin replacement shortened the extinction period of morphine-induced CPP in STZ-diabetic rats. However, insulin replacements in conditioning, expression, and reinstatement phases did not affect morphine priming-induced reinstatement in diabetic animals.

Aims. Augmented renal clearance (ARC), which is commonly defined as increased renal clearance above 130 ml/min/1.73 m2, is a common phenomenon among critically ill patients. The increased elimination rate of drugs through the kidneys in patients with ARC can increase the risk of treatment failure due to the exposure to subtherapeutic serum concentrations of medications and affect the optimal management of infections, length of hospital stay, and outcomes. The main goal of this review article is to summarize the recommendations for appropriate dosing of antibiotics in patients with ARC. Methods. This article is a narrative review of the articles that evaluated different dosing regimens of antibiotics in patients with ARC. The keywords “Augmented Renal Clearance,” “Critically ill patients,” “Drug dosing,” “Serum concentration,” “Beta-lactams,” “Meropenem,” “Imipenem,” “Glycopeptide,” “Vancomycin,” “Teicoplanin,” “Linezolid,” “Colistin,” “Aminoglycosides,” “Amikacin,” “Gentamycin,” “Fluoroquinolones,” “Ciprofloxacin,” and “Levofloxacin” were searched in Scopus, Medline, PubMed, and Google Scholar databases, and pediatric, nonhuman, and non-English studies were excluded. Results. PK properties of antibiotics including lipophilicity or hydrophilicity, protein binding, the volume of distribution, and elimination rate that affect drug concentration should be considered along with PD parameters for drug dosing in critically ill patients with ARC. Conclusion. This review recommends a dosing protocol for some antibiotics to help the appropriate dosing of antibiotics in ARC and decrease the risk of subtherapeutic exposure that may be observed while receiving conventional dosing regimens in critically ill patients with ARC.

Purpose Limited number of medications are available for the post-exposure prophylaxis of COVID-19 infection. Whether bromhexine can prevent or mitigate symptomatic infection after virus exposure is undetermined. Methods A multi-center randomized; double-blind, placebo-controlled clinical trial was conducted. The 372 adults (≥ 18 years) who had close contact within 4 days with a household member with confirmed COVID-19 were randomly assigned to receive bromhexine (n = 187) or placebo (n = 185) three times a day for two weeks. The primary outcome was the incidence of symptomatic COVID-19. Secondary outcomes included the incidence of hospitalization or death, the incidence of confirmed COVID-19 detection by PCR in symptomatic patients and presence of adverse drug reactions. Results The incidence of symptomatic COVID-19 was significantly lower in individuals who received bromhexine than in those who received the placebo (16 [8.6%] vs 34 [18.4%], relative risk = 0.47, p = 0.005). PCR-confirmation was reported in 13 (7.0%) and 26 (14.1%) of the individuals in the bromhexine and placebo groups, respectively (p = 0.025), with a relative risk reduction of 50%. The hospitalization rate, death and medication side effects did not vary significantly between the bromhexine or placebo arms. Conclusion Bromhexine is an effective, non-invasive, and affordable agent with a low side-effect profile to prevent symptomatic COVID-19. Early use of bromhexine potentially provides another layer of protection and hence it can play a prominent role in ending the pandemic especially given the emergence of new variants and the vaccination challenges faced by developing countries.

Purpose No study has been evaluated pharmacokinetic (PK) and pharmacodynamic (PD) properties of β-lactam antibiotics in patients with acute kidney injury (AKI), not requiring renal replacement therapy (RRT). We evaluated the time that plasma concentrations remain above four times the MIC (ft > 4MIC) and PK parameters of meropenem in this population. Methods In this prospective, randomized clinical trial (RCT), all patients received standard dose (3 g daily) of meropenem for 48 h, then randomly allocated in standard or adjusted groups. The standard group received meropenem without dose adjustment. In the adjusted group, the meropenem dose was adjusted based on the Cockcroft-Gault(C-G) equation. Meropenem concentrations were measured at the peak and trough times on the 2nd and 5th days of the study. Results On the 2nd day of the study, 3 out of 10 (30%) of patients attained the PD target (≥ 80%ft > 4MIC). In the 5th day of the study, the PD target was attained in 2 out of 10 (20%) and 1 out of 5 (20%) of patients who received standard and adjusted doses of meropenem, respectively (p = 1). In all samples, increased volume of distribution (Vd) (median; IQR) (46.04; 23.06–103.18 L), terminal half-life (T1/2) (4.51; 2.67–8.88 h) and decreased clearance (6.52; 4.43–10.16 L/h) have been shown. Conclusion In critically ill patients with AKI, who not receive RRT, standard doses, and adjusted according to renal function of meropenem failed to achieve PD target of ≥ 80%ft > 4MIC. Higher doses are required for this target. Retrospectively registered The study protocol with registered retrospectively and approved on January 19, 2019, with the number of IRCT20160412027346N5. Supplementary Information The online version contains supplementary material available at 10.1007/s00228-020-03062-0.

Because of an increased prevalence of infections with resistant Gram-negative bacteria, finding optimal treatment regimens for these cases is one of the major healthcare concerns. Providencia is a Gram-negative bacteria belonging to the Enterobacteriaceae family. This article aims to describe an effective antibacterial regimen used for treating ventilator-associated pneumonia (VAP) with species of Providencia that are resistant to all antimicrobial classes. We present the case of a 74-year-old woman suffering from VAP caused by pandrug-resistant Providencia. The patient received high-dose intravenous meropenem (1 g every 12 h, infused over 4 h), intravenous amikacin (1,500 mg every 48 h) and nebulised amikacin (250 mg every 6 h). The dosages were calculated based on weight and renal function (GFR = 13.69 ml/min/1.73). After 23 days of treatment, following improvement in clinical signs (including fever), a drop in leucocytes counts, a higher than 80% reduction in procalcitonin levels (0.12), together with confirmed microbial eradication (negative sputum cultures), the antibacterial regimen was discontinued. In conclusion, when dealing with an infection with a pan-resistant microorganism, using combinations of antibiotics in high doses can be an option. These treatment regimens have the potential of overcoming in vitro resistance, leading to clinical improvement and microbial eradication.

Augmented Renal Clearance (ARC) reflects a measured creatinine clearance (CrCl) of more than 130 ml/min. Also, there are two scoring systems for the prediction of the ARC phenomenon i.e., the ARC score (ARCS) and the Augmented Renal Clearance in Trauma Intensive Care score (ARCTICs). The objectives of the current study were the evaluation the effect of using both scoring systems, on the chance of identifying this phenomenon and evaluating the accuracy of the three commonly used formulas for estimating glomerular filtration rate (eGFR) in ICU patients.In this prospective cross-sectional study, the CrCls of all patients admitted to the ICU were evaluated by using ARCS and ARCTICS, and for high-risk subjects based on scoring systems, a 12-hour urine sample was collected to measure CrCl. Besides, daily serum creatinine was recorded to estimate the daily eGFR.During the study period, 810 subjects were evaluated and 145 were categorized as high-risk using scoring systems. The ARC phenomenon was confirmed in 79 patients on the recruitment day and 81.01 and 18.98% of them were recruited by ARCS and ARCTICS, respectively. The ROC curves showed AUCs0.5 for CockcroftGault (C-G) and CKD-EPI with the cut-off of 100.48 and 107.05 mL/min/ 1.73m2, respectively; to detect the ARC phenomenon.We recommend using ARCS and ARCTICS simultaneously to assess critically ill patients regarding the possibility of the ARC phenomenon which should be confirmed by using urinary CrCl, as none of the formulas could accurately detect the ARC phenomenon, neither the 12-hour CrCl. DOI: 10.52547/ijkd.6695.

The purpose of this study was evaluating the efficacy and safety of intravenous (IV) ampicillin–sulbactam plus nebulized colistin in the treatment of Ventilator-Associated Pneumonia (VAP) caused by MDR Acinetobacter (MDRA) in ICU patients as an alternative to IV plus nebulized colistin. In this single-blinded RCT, one group received IV colistin and another group IV ampicillin–sulbactam (16 and 12 patients from total 28 patients, respectively) for 14 days or since clinical response. Both groups received nebulized colistin by mesh nebulizer. There were no statistically significant differences between the 2 groups in baseline characteristics and previous antibiotic therapy. In follow up period, no significant difference was observed between 2 groups in rate of microbiological eradication, clinical signs of VAP improvement, survival rate and length of hospital as well as ICU stays. Although we have found no significant differences in Acute Kidney Injury (AKI) incidence between two groups, comparison of cumulative patient-days with stages 2 and 3 AKI with days with no or stage 1 AKI, according to AKIN criteria, revealed significant difference in IV colistin versus IV ampicillin–sulbactam group (p = 0.013). The results demonstrated that the high dose IV ampicillin–sulbactam plus nebulized colistin regimen has comparable efficacy with IV plus nebulized colistin in the treatment of VAP caused by MDRA, with sensitivity to colistin only, with probably lower incidence of kidney injury.

Aim: Augmented Renal Clearance (ARC) is a common phenomenon among critically ill patients and create sub-therapeutic concentrations of antibiotics, due to an increase in renal clearance of them. We evaluated the Pharmacokinetic and Pharmacodynamic (PK/PD) properties of recommended doses of meropenem in critically ill patients with ARC. Methods: Adult critically ill patients with confirmed ARC, based on 12-hour Creatinine Clearance (CrCl) (≥130 ml/min/1.73 m2), who received standard doses of meropenem enrolled. Two blood samples were gathered from each participant, at the steady-state time, to determination of peak and trough concentrations. Serum concentrations of meropenem were measured by High-Performance Liquid Chromatography (HPLC) with Ultra-Violet (UV) detector. Results: From eighteen paired samples (peak and trough concentrations) that were obtained from 16 critically ill patients, peak concentrations were significantly lower in group 1 (received meropenem 1g every 8 hours) than group 2 (received meropenem 2g every 8 hours) (mean ±SD, 5.95 ±3.39 µg/mL vs. 11.93± 4.18 µg/mL, respectively, p= 0.005). Trough concentration were sub-threshold ( MIC ≥ 50% was achieved in 83.3% of patients in both groups whereas 16.6% of patients of group 1 and 33.3% of patients of group 2 had ft> MIC= 100%. Conclusion: ARC is an essential cause of sub-therapeutic concentrations of meropenem in critically ill patients, and higher than the recommended doses of meropenem administered as an intermittent infusion may be necessary to achieve the PD targets and improve efficacy.

Diabetes mellitus is a chronic illness that has been associated with the decrease of insulin in type I diabetes. Insulin has an impact not only on the direct control of food intake and plasma glucose levels, but also on brain pathways associated with reward. It affects brain reward pathways through regulation of the dopamine (DA) transporter (DAT). Moreover, it has been found to affect the ability of drugs that target the DA system. In the present study, the effects of streptozotocin (STZ)-induced diabetes on the acquisition (development) and maintenance of morphine-induced conditioned place preference (CPP) were investigated in rats. Forty adult male Albino Wistar rats were used in these experiments. For induction of diabetes, STZ was administered at a dose of 60 mg/kg. After seven days, the CPP paradigm was done; conditioning score and locomotor activity were recorded by Ethovision software. The results showed that diabetes significantly increased the magnitude of conditioning scores, acquisition of morphine-induced CPP in compared to naive animals (P0.05). Moreover, in the diabetic group, there were significant differences among conditioning scores in the post-conditioning phase and the last four days (7th-10th), but these differences elongated up to 10 days after the CPP protocol while the extinction period was eight days in the naive group. Our findings indicated that the magnitude and maintenance of morphine rewarding properties have been changed in STZ-induced diabetic animals. It seems that a level of insulin and their receptors are involved in the development and maintenance of morphine-induced CPP in the rats.