N-Acetyl cysteine mitigates histopathological changes and inflammatory genes expressions in the liver of cadmium exposed rats

This study aimed to consider the expression of Nrf2, NLRP3 and caspase 1 genes, as well as oxidative stress, and the protective role of N-acetyl cysteine (NAC) in the liver of rats treated with cadmium (Cd). Male rats were randomly divided into five groups including G1 (control), G2 (single dose of Cd), G3 (continuous dose of Cd), G4 (single dose of Cd + NAC), and G5 (continuous dose of Cd + NAC). Levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured. Expression of Nrf2, NLRP3 and caspase 1 genes was considered using RT-PCR. NAC treatments significantly improved TAC, but decreased MDA values in rats that exposed to continuous dose of Cd (p<0.05). Exposure to continuous dose of Cd caused a significant decrease in Nrf2 expression by 2.46-fold (p<0.001), but enhanced expression of NLRP3 and Caspase 1 genes by 3.13-fold and 3.16-fold), respectively (p<0.001). Compared to rats that treated to continuous dose of Cd, NAC supplementation enhanced the expression of Nrf2 by 1.67-fold (p<0.001) and reduced the expression of NLRP3 and Caspase 1 genes by 1.39-fold (p<0.001) and 1.58-fold (p<0.001), respectively. Down-regulation of Nrf2 and overexpression of NLRP3 and caspase 1 seems to be one of the main mechanisms of Cd toxicity on liver tissue. NAC protects liver tissue against Cd-induced oxidative injuries via enhancement of Nrf2 expression and reduction of NLRP3 and caspase 1 genes.

Comparing Patient-Controlled Analgesia Versus Non-PCA Hydromorphone Titration for Severe Cancer Pain: A Randomized Phase III Trial

Background: Opioid titration is necessary to achieve rapid, safe pain relief. Medication can be administered via patient-controlled analgesia (PCA) or by a healthcare provider (non-PCA). We evaluated the efficacy of intravenous PCA versus non-PCA hydromorphone titration for severe cancer pain (≥7 at rest on the 11-point numeric rating scale [NRS]). Patients and Methods: Patients with severe cancer pain were randomized 1:1 to PCA or non-PCA titration, stratified by opioid-tolerant or opioid-naïve status. The PCA pump was set to no continuous dose, with a hydromorphone bolus dose 10% to 20% of the total previous 24-hour equianalgesic (for opioid-tolerant patients) or 0.5 mg (for opioid-naïve patients). For the non-PCA group, the initial hydromorphone bolus dose was identical to that in the PCA group, with the subsequent dose increased by 50% to 100% (for NRS unchanged or increased) or repeated at the current dose (for NRS 4–6). Hydromorphone delivery was initiated every 15 minutes (for NRS ≥4) or as needed (for NRS ≤3). The primary endpoint was time to successful titration (TST; time from first hydromorphone dose to first occurrence of NRS ≤3 in 2 consecutive 15-minute intervals). Results: Among 214 patients (PCA, n=106; non-PCA, n=108), median TSTs (95% CI) were 0.50 hours (0.25–0.50) and 0.79 hours (0.50–1.42) for the PCA and non-PCA groups, respectively (hazard ratio [HR], 1.64; 95% CI, 1.23–2.17; P=.001). TSTs in opioid-tolerant patients were 0.50 hours (0.25–0.75) and 1.00 hours (0.50–2.00) for the PCA and non-PCA groups, respectively (HR, 1.92; 95% CI, 1.32–2.78; P=.003); in opioid-naive patients, TST was not significantly different for the PCA versus non-PCA groups (HR, 1.35; 95% CI, 0.88–2.04; P=.162). Pain score (median NRS; interquartile range) over 24 hours was significantly lower in the PCA group (2.80; 2.15–3.22) than in the non-PCA group (3.00; 2.47–3.53; P=.020). PCA administration produces significantly higher patient satisfaction with pain control than non-PCA administration (P<.001). Conclusions: Intravenous hydromorphone titration for severe cancer pain was achieved more effectively with PCA than with non-PCA administration.

Intrathecal baclofen pumps in the management of hypertonia in childhood: a UK and Ireland wide survey

BackgroundIntrathecal baclofen (ITB) is a useful treatment for hypertonia where non-invasive treatments have been ineffective or poorly tolerated. There is an absence of national guidance on selection criteria and a lack of literature regarding patient characteristics and treatment details for children and young people (CYP) receiving ITB therapy in the UK and Ireland. We aimed to gather patient and treatment characteristics for CYP receiving ITB in the UK and Ireland.MethodsAn electronic survey was sent to all paediatric ITB centres in the UK and Ireland. Anonymised data were returned between December 2019 and April 2020. CYP >16 years and those awaiting ITB pump removal were excluded from the dataset.Results176 CYP were identified as receiving ITB therapy across the UK and Ireland. The majority of CYP with ITB pumps were non-ambulant (93%) with a diagnosis of cerebral palsy (79%). Median age of ITB insertion was 9 years; median current age was 14 years. 79% of CYP had significant spasticity, 55% had significant dystonia. The most commonly used ITB dosing modes were continuous (73%) and flexible (23%).ConclusionsITB pumps were most frequently used for non-ambulant CYP with cerebral palsy and existence of spasticity and/or dystonia in the UK and Ireland. Most CYP were receiving a continuous dose of ITB. There is significant variation in the number of paediatric ITB pumps across UK and Ireland. There is a need for development of nationally accepted paediatric referral criteria and clinical standards for ITB use.

Effects of N-Acetyl Cysteine on the Expression of Matrix Metalloproteinases 2 and 9 in the Lung Tissue of Rats Exposed to Cadmium

Objectives: This study aimed to investigate the effect of cadmium (Cd) on the matrix metalloproteinases (MMPs) -2 and -9 expression in the lung, and the role of N-acetylcysteine (NAC) in preserving the lung cells against Cd toxicity. Methods: The rats were randomly divided into five groups of G1 (control), G2 (single dose of Cd), G3 (continuous dose of Cd), G4 (single dose of Cd+NAC), and G5 (continuous dose of Cd+NAC). The level of Cd in the blood and lung tissue was measured by atomic absorption spectroscopy. Moreover, the expression of MMP2 and MMP9 genes was considered using RT-PCR. Results: Single and continuous exposure to Cd caused a significant increase in serum and the lung tissue of Cd in G2 (0.23±0.04 mg/L and 0.35±0.047 μg/g tissue) and G3 (0.50±0.068 mg/L and 0.81±0.063 μg/g tissue) groups, compared to other groups (P<0.001). The NAC supplementation significantly decreased Cd levels in the serum and lung tissue samples of rats exposed to single or continuous Cd (P<0.001). Furthermore, exposure to a single and continuous dose of Cd caused a significant increase in the MMP2 expression by 3.24-fold (P=0.003) and 11.9-fold (P<0.001), respectively. Additionally, single and continuous dose treatment of Cd led to a significant increase in the MMP9 expression by 3.20-fold (P=0.004) and 7.54-fold (P<0.001), respectively. The NAC treatments decreased the expression of MMP2 and MMP9 in the lung of rats exposed to single or continuous Cd. Conclusion: The Cd exposure was strongly associated with the accumulation of Cd and overexpression of MMP2 and MMP9 in the lung tissue. Moreover, the NAC can protect the lungs against Cd toxicity by decreasing Cd and down-regulating MMPs.

Patient controlled analgesia (PCA) vs non-PCA intravenous hydromorphone titration for severe cancer pain: A multi-center, phase III trial, HMORCT09-1.

12078 Background: The titration of opioid dosage is necessary for adequate pain relief with acceptable side effects among individuals with cancer pain. The titration process can be achieved by non-patient administration or PCA pump. The aim of this study was to evaluate the efficacy of PCA versus non-PAC titration for severe cancer pain. Methods: Patients with severe cancer pain (NRS ≥ 7/10 at rest) were randomized into PCA or non-PCA titration and stratified by opioid tolerance or intolerance. For PCA, the pump was set as no continuous dose, hydromorphone bolus dose was 10%-20% of the total equianalgesic of past 24h for opioid tolerance, or 0.5 mg for opioid intolerance. The lockout time was 15 min. For non-PCA, initial hydromorphone bolus was the same with PCA. Reassess pain at 15 min. The dose of hydromorphone was increased by 50%-100% if pain unchanged or increased, or repeated if NRS was 4-6, or continue at current dose as needed if NRS≤3. The primary endpoint was the time to successful titration (TST) - time from start to the time of pain controlled at NRS ≤ 3 in two consecutive evaluation with 15-min intervals, which was tested by K-M curve. Results: A total of 214 patients were randomized (106 in PCA, 108 in non-PCA) in 17 study sites. The most common sites of primary cancer were lung (21.03%), stomach (15.89%), colorectal (14.49%) etc. Median TSTs were 0.50h in PCA, 0.79h in non-PCA, HR 1.64 (95% CI 1.23, 2.17, P = 0.00127). In opioid tolerance, 0.50h in PCA, 1.00h in non-PCA (HR 1.92, 95% CI 1.32, 2.78, P = 0.0025). while in opioid intolerance, 0.50h in PCA and 0.50 in non-PCA (HR 1.35, 95% CI 0.88, 2.04, P = 0.162). The median dosage of hydromorphone for TST was 1.00mg (P25, P75 0.50, 2.00) in PCA, 1.50mg (P25, P75 1.00, 2.50) in non-PCA (P = 0.086). In opioid tolerance, 1.00mg (P25, P75 1.00, 2.00) in PCA, 2.00mg (P25, P75 1.00, 4.00) in non-PCA (P = 0.009). In opioid intolerance, 1.00mg (P25, P75 0.50, 2.00) in PCA and 1.00 mg (P25, P75 0.50, 2.00) non-PCA (P = 0.793). Mean patient satisfaction assessed by ESAS score was significantly superior in PCA to non-PCA (0.62±0.67 vs 1.27±0.98 for ITT, 0.66±0.66 vs 1.39±1.00 for opioid tolerance, and 0.56±0.69 vs 1.13±0.95 for opioid intolerance). Adverse events were similar in both PCA/non-PCA groups. Conclusions: PCA IV hydromorphone titration provided quicker analgesic effect, higher patients satisfaction, and a similar tolerability as compared to non-PCA administration in patients with severe cancer pain. Clinical trial information: NCT03375515 .

Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial).

505 Background: Ribociclib (R) + letrozole (L) is superior to L in metastatic breast cancer (BC). Preoperative endocrine prognostic index (PEPI) score 0 after neoadjuvant endocrine therapy (NET) is associated with low risk of relapse without chemotherapy in ER+ BC. On-therapy change in Ki-67 predicts adjuvant recurrence. FELINE is a biomarker-based multicenter randomized trial comparing changes in Ki-67 and PEPI between L+ Placebo (P) & L+R. Methods: Postmenopausal women with >2 cm or node+ ER+ HER2- BC were randomized 1:1:1 between L+P, L+R 400 mg continuous dose (Rc) and L+R 600 mg, 3 weeks on/1 week off - intermittent dose (Ri). Treatment was continued for six 28-day cycles. Core biopsies, blood samples were obtained at baseline, Day 14 cycle 1 (D14C1), and surgery. Clinical measurement, mammogram and US were obtained at baseline, surgery; MRI at baseline, week 8. Primary endpoint was rate of PEPI score 0 between L+P and L+R (i+c combined). Other endpoints were change in centrally performed Ki-67, complete cell cycle arrest (CCCA): Ki-67 <2.7%, clinical/imaging response, and difference in response & toxicity between the two R (Rc and Ri) arms. Results: From 2/2016 to 8/2018, 120 women were enrolled at 9 US centers. Thirty-eight were randomized to L+P and 82 to L+R groups (41 in Ri and Rc). Treatment groups were balanced at baseline. PEPI score of 0 was equal (25%) in L+P & L+R groups. CCCA at D14C1 was observed in 52% vs. 92% in L+P, L+R respectively (p < 0.0001). CCCA at surgery was observed in 63.3% vs. 71.4% in L+P, L+R respectively (p = NS). A significant increase in Ki-67 was observed between D14C1 and surgery in 66% vs. 33% in L+R, L+P respectively (p = 0.006). There was no difference in clinical, mammographic, US or MRI response between L+P and L+R. CCCA at D14C1 and surgery was similar in Ri & Rc arms. Grade >3 AEs were observed in 4 (10%) patients in L+P, 23 (56%) in L+Ri, 19 (46%) in L+Rc arms. Conclusions: Addition of R to L as NET did not result in more women with a PEPI score of 0. At D14C1 twice as many women on L+R had CCCA compared to L+P (92% vs 52%). However, significantly more women on L+R had increased proliferation between D14C1 and surgery , resulting in similar CCCA at surgery. Correlative studies are being performed to determine mechanisms of on-therapy acquired resistance to ribociclib. Continuous and intermittent doses of R have similar efficacy, toxicity. Clinical trial information: NCT02712723 . [Table: see text]

Bivalirudin resistance in a patient on veno-venous extracorporeal membrane oxygenation with a therapeutic response to argatroban

A 48-year-old male patient requiring extracorporeal membrane oxygenation (ECMO) support for hypoxaemic respiratory failure failed to achieve therapeutic anticoagulation with bivalirudin after continuous dose escalations, and continued to have recurrent fibrin stranding in the circuit over a 6-day course of treatment. Suspecting bivalirudin resistance, the patient was transitioned to argatroban and achieved a therapeutic response in less than 24 hours. The case describes the challenges of anticoagulation in ECMO supported patients. The interplay between bivalirudin metabolism, renal replacement therapy, and immunological effects leading to a heparin-like-effect, inflammatory mediators, and thrombotic burdens may all impact the clinical effect during bivalirudin therapy. The structural biochemistry of thrombin and bivalirudin likely plays a role in the presented patient’s successful response to argatroban. Bivalirudin may fail at achieving therapeutic anticoagulation in patients with genetic thrombin mutations or structural defects that alter the binding pockets at the thrombin exosites.