Use Of Maximal Dosage Renin-Angiotensin-Aldosterone System Inhibitors In A Real Life Population Of Complicated Type 2 Diabetes – Contraindications And Opportunities

Objective Pharmacological inhibition of the renin-angiotensin-aldosterone-system (RAASi) is the cornerstone of hypertension treatment, renoprotection and secondary prevention of cardiovascular disease in patients with type 2 diabetes. Although there is a dose-dependent effect of RAASi with optimum protection when using maximal dose, little is known on actual use of maximal dosage RAASi in clinical practice. Here we investigate prevalence of maximal dosage RAASi, and contraindications for, optimizing RAASi dosage, in patients with complicated type 2 diabetes in a real-life clinical setting.Research Design and MethodsWe performed a retrospective analysis in 668 patients included in the DIAbetes and LifEstyle Cohort Twente (DIALECT). We grouped patients according to no RAASi, submaximal RAASi and maximal RAASi use. All potassium and creatinine measurements between January 1st 2000 and date of inclusion in DIALECT were extracted from patients files. We identified determinants of maximal RAASi use vs submaximal RAASi use with multivariate logistic regression analysis. ResultsMean age was 64 ± 10 years and 61% were men. In total, 460 patients (69%) used RAASi, and 30% used maximal RAASi. Maximal RAASi use was not statistically different between different indications for RAASi (i.e. hypertension, diabetic kidney disease, coronary heart disease and cerebrovascular disease; P>0.05). Per patient, 2 [1-4] measurements of potassium and 20 [13-31] measurements of creatinine were retrieved, retrospective follow-up time was -3.0 [-1.4 to -5.7] years. Pre-baseline hyperkalemia >5.0 mmol/l and acute kidney injury were found in 151 (23%) patients and 119 patients (18%), respectively. Determinants of maximal RAASi were prior acute kidney injury (OR 0.51 (0.30-0.87)), increased albuminuria (OR 1.89 (1.17-3.08)) and total number of used antihypertensives (OR 1.66 (1.33-2.06)).ConclusionsMaximal dose RAASi is used in almost one third of complicated type 2 diabetes patients in a real-life setting. The prevalence of contraindications is considerable, but relative in nature, suggesting that it is worthwhile to explore strategies aimed at maximizing RAASi while circumventing the alleged contraindications.

Efficacy and Tolerability of Methotrexate in the Treatment of Severe Paediatric Alopecia Areata

<b><i>Introduction:</i></b> Alopecia areata (AA) is a chronic, autoimmune condition affecting hair follicles, and its occurrence in the paediatric population is associated with poorer prognosis and limited treatment options compared to adults. Treatment with oral methotrexate (MTX) has been documented in adults, but there is a paucity of data for its use in the paediatric population. We aimed to study the efficacy and tolerability of MTX in severe paediatric AA. <b><i>Methods:</i></b> We performed a retrospective review on paediatric patients with severe AA who were treated with MTX in our centre from January 2019 to December 2020. <b><i>Results:</i></b> Thirteen patients were included (6 boys and 7 girls) aged between 4 and 16 years at the initiation of MTX (mean age of 8.8 years). The interval from diagnosis of AA to commencement of MTX was between 8 months and 9 years (mean duration of 3.3 years). Oral MTX was administered once weekly with a mean maximal dose of 0.4 mg/kg/dose. Out of 12 assessable patients, 5 were considered treatment success as they had more than 50% regrowth, while the other 7 were treatment failures. No serious side effects were reported. <b><i>Conclusion:</i></b> MTX was shown to have variable efficacy for the treatment of paediatric AA with overall good tolerability. MTX can be considered in the treatment of severe refractory AA for children.

Safety and Tolerability, Dose-Escalating, Double-Blind Trial of Oral Mannitol in Parkinson's Disease

Mannitol, a natural alcoholic-sugar, was recently suggested as a potential disease-modifying agent in Parkinson's disease. In animal models of the disease, mannitol interferes with the formation of α-synuclein fibrils, inhibits the formation of α-synuclein oligomers and leads to phenotypic recovery of impaired motor functions. Parkinson's patients who consume mannitol report improvements of both motor and non-motor symptoms. Safety of long-term use of oral mannitol, tolerable dose and possible benefit, however, were never clinically studied. We studied the safety of oral mannitol in Parkinson's disease and assessed the maximal tolerable oral dose by conducting a phase IIa, randomized, double-blind, placebo-controlled, single-center, dose-escalating study (ClinicalTrials.gov Identifier: NCT03823638). The study lasted 36 weeks and included four dose escalations of oral mannitol or dextrose to a maximal dose of 18 g per day. The primary outcome was the safety of oral mannitol, as assessed by the number of adverse events and abnormal laboratory results. Clinical and biochemical efficacy measures were collected but were not statistically-powered. Fourteen patients receiving mannitol completed the trial (in addition to eight patients on placebo). Mannitol-related severe adverse events were not observed. Gastrointestinal symptoms limited dose escalation in 6/14 participants on mannitol. None of the clinical or biochemical efficacy secondary outcome measures significantly differed between groups. We concluded that long-term use of 18 g per day of oral mannitol is safe in Parkinson's disease patients but only two third of patients tolerate this maximal dose. These findings should be considered in the design of future efficacy trials.

A case of a hemodialysis patient with secondary hyperparathyroidism who was resistant to etelcalcetide treatment but not to cinacalcet hydrochloride

Although both cinacalcet and etelcalcetide are calcimimetics that directly inhibit parathyroid hormone (PTH) secretion by activating the calcium (Ca)-sensing receptor (CaSR), their binding sites are different. We report a first case of a hemodialysis (HD) patient with secondary hyperparathyroidism (SHPT), in whom cinacalcet, but not etelcalcetide, could reduce serum intact PTH (i-PTH) levels. A HD patient received total parathyroidectomy (PTx) with auto-transplantation 16 years earlier. Due to SHPT relapse, cinacalcet was started at 7 years after PTx. His i-PTH levels had been controlled with both 75–100 mg of cinacalcet and 4.5 μg/week of calcitriol for a year before switching from cinacalcet to etelcalcetide. At 1 month following the switch, his serum i-PTH level increased to 716 pg/mL. The dose of etelcalcetide was gradually increased and finally reached the maximal dose of 45 mg/week. Because even the maximal dose of etelcalcetide for > 4 months did not reduce his serum i-PTH levels to < 700 pg/mL, etelcalcetide was switched to 50 mg/day of cinacalcet, which reduced the levels to 208 pg/mL at 2 months after the switch. Genomic sequencing test using whole blood revealed no mutation in the portion including Cys 482 of CaSR gene. The patient was resistant to etelcalcetide treatment but not to cinacalcet, suggesting the possibility that the enlarged parathyroid gland has some change in the portion including Cys 482 in the CaSR gene. Therefore, considering the possibility of etelcalcetide resistance during SHPT treatment should be kept in mind.

Seizures in palliative medicine: brivaracetam

Seizures occur in around 13% of patients with cancer and can be distressing for family members to witness. In those unable to manage regular antiepileptic medications, midazolam can be administered subcutaneously using a syringe driver, but this may cause sedation. Brivaracetam is a newer drug licensed as an adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation and for restricted use in those with refractory epilepsy. It is associated with fewer behavioural or psychiatric side effects than levetiracetam, has a very low incidence of drug interactions and the maximal dose can be accommodated in a single syringe driver. We present three cases from 2019 to 2020 where subcutaneous brivaracetam has been successfully used in a Specialist Inpatient Palliative Care setting to manage seizures. Brivaracetam dosing is 1:1 conversion from oral:subcutaneous, with syringe driver doses ranging from 150 mg to 300 mg/24 hours being successfully used, with no adverse effects observed.

Investigations on the Ulcer protection ability of various extracts of Crossandra benoistii L.

The Benoistii Crossandra L. A widely distributed plant in India and Africa belongs to the Acanthaceae family. The forests of India have traditionally been used by several tribal people. This plant is home to many forests in India and is rich in Southern India. In this study, methanol and ethanol leaf extracts were tested for antiulcer activity following the folklore reports of antimicrobial activity. Methanolic and aqueous extracts were studied and proven to be equally effective in prevention and cure of ulcers for synthetic medicines. The CBME and CBEE inhibits were at 400 mg/kg higher than normal and the lower doses of 200 mg/kg still appeared to be the same operation as the standard one. The higher dose of the extracts was supposed to lead to greater activity. With the maximal dose of 2000mg/kg, the UD50 is raised, and the above limits contribute to an even greater dose than the one seen in the process. Given the side effects of prescription medications, it is strongly recommended to use natural medicines for the ulcer. Much phytochemical study has been carried out on the plant and the same number of feedings has so far been isolated. It demands that the latest medicine provision be implemented in order to include plant extracts to cure all diseases.

Hyperinflammation in COVID-19 Obese Patients Treated With Tocilizumab: A Successful Case Series

The cytokine storm syndrome has been suggested as a mechanism in the pathophysiology of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2; COVID-19 [coronavirus disease 2019]) infection. Drugs such as tocilizumab, an interleukin-6 antagonist, have shown good results in other scenarios of hyperinflammatory state and might also be effective in COVID-19 disease. However, the best dosing regimen and the timing of infusion is currently unknown, specifically in obese patients. We report the first cases of tocilizumab administration in obese patients during the first days of COVID-19 worsening hypoxemia. This infusion was not adjusted by weight, following the manufacturer maximal dose limit. We kept a strict monitoring for possible infections, prior and during the treatment. All patients showed good improvements on chest-computed tomography images and oxygenation and were discharged from hospital shortly after, without complications or intubation. This case series highlights that tocilizumab seems to be effective to treat hyperinflammation of critical COVID-19 obese patients, even when the infusion of the ideal dose is not feasible to be administered. It also shows the importance of early timing in the decision to treat and the relevance of infections exclusion prior to the induction of immunosuppression by tocilizumab.

Axillary nodal irradiation practice in the sentinel lymph node biopsy era: Comparison of the contemporary available 3D and IMRT techniques

Objective: Our study aimed to compare regional node coverage and doses to the organ at risk (OAR) using conventional technique (CT) vs “AMAROS” (AT) vs intensity-modulated radiation therapy (IMRT) techniques in patients receiving regional nodal irradiation (RNI) for breast cancer (BC). Methods: We included 30 consecutive patients with BC who received RNI including axillary nodes. Two independent and blinded dosimetric RNI plans were generated for all patients. For target volume coverage, we analyzed the V95%, the D95%, the mean and the minimal dose within the nodal station. For hotspots within nodal target volume, we used the V105%, the V108% and the maximal doses. For OAR, lung V20, mean lung and heart doses, the maximal dose to the brachial plexus and the axillary-lateral thoracic vessel junction region were compared between the three techniques. Results: Target volume coverage and hotspots: Mean V95% in stations I, II, III and IV were 35.8% and 75% respectively with CV, 22.59 and 59.9% respectively with AT technique and 45.58 and 99.6% respectively with IMRT with statistically significant differences (p < 0.001). Mean V105% (cc) in axillary and supraclavicular stations were 21.3 and 6.4 respectively with CV, 1.2 and 0.02 respectively with AT technique and 0.5 and 0.4 respectively with IMRT with statistically significant differences (p < 0.001).. OARs: The mean ipsilateral lung V20 was 16.9%, 16.4 and 13.3% with CT, AT and IMRT respectively. The mean heart dose (Gy) was 0.3, 0.2 and 0.2 with CT, AT and IMRT respectively. The maximal dose to the plexus brachial (Gy) was 50.3, 46.3 and 47.3 with CT, AT and IMRT respectively. The maximal dose to the axillary-lateral thoracic vessel junction (Gy) was 52.3, 47.3 and 47.6 with CT, AT and IMRT respectively. The differences were statistically significant for all OAR (p < 0.001). Conclusion: AT is a valuable technique for RNI including axilla in patients with limited sentinel lymph node biopsy involvement without additional axillary lymph node dissection since it decreases hotspots in the target volume and lowers the radiation exposure of the OAR. For more advanced tumors or patients who did not respond to primary systemic therapy, CT or IMRT should be considered because of their better coverage of the potentially residual nodal disease. IMRT combines several advantages of offering high conformal plans, limited hotspots and protection of main OAR. The clinical impact of these dosimetric differences need to be addressed. Advances in knowledge: This study is to our knowledge the first to compare conventional three-dimensional and IMRT techniques for regional nodal irradiation for each nodal station in breast cancer in a context of increasing utilization of axillary irradiation.

Reduced Sensitivity to Anesthetic Agents upon Lesioning the Mesopontine Tegmental Anesthesia Area in Rats Depends on Anesthetic Type

Background The brainstem mesopontine tegmental anesthesia area is a key node in circuitry responsible for anesthetic induction and maintenance. Microinjecting the γ-aminobutyric acid–mediated (GABAergic) anesthetic pentobarbital in this nucleus rapidly and reversibly induces general anesthesia, whereas lesioning it renders the animal relatively insensitive to pentobarbital administered systemically. This study investigated whether effects of lesioning the mesopontine tegmental anesthesia area generalize to other anesthetic agents. Methods Cell-selective lesions were made using ibotenic acid, and rats were later tested for changes in the dose–response relation to etomidate, propofol, alfaxalone/alfadolone, ketamine, and medetomidine delivered intravenously using a programmable infusion pump. Anesthetic induction for each agent was tracked using five behavioral endpoints: loss of righting reflex, criterion for anesthesia (score of 11 or higher), criterion for surgical anesthesia (score of 14 or higher), antinociception (loss of pinch response), and deep surgical anesthesia (score of 16). Results As reported previously for pentobarbital, on-target mesopontine tegmental anesthesia area lesions reduced sensitivity to the GABAergic anesthetics etomidate and propofol. The dose to achieve a score of 16 increased to 147 ± 50% of baseline in control animals ± SD (P = 0.0007; 7 lesioned rats and 18 controls) and 136 ± 58% of baseline (P = 0.010; 6 lesioned rats and 21 controls), respectively. In contrast, responsiveness to the neurosteroids alfaxalone and alfadolone remained unchanged compared with baseline (94 ± 24%; P = 0.519; 6 lesioned rats and 18 controls) and with ketamine increased slightly (90 ± 11%; P = 0.039; 6 lesioned rats and 19 controls). The non-GABAergic anesthetic medetomidine did not induce criterion anesthesia even at the maximal dose tested. The dose to reach the maximal anesthesia score actually obtained was unaffected by the lesion (112 ± 8%; P = 0.063; 5 lesioned rats and 18 controls). Conclusions Inability to induce anesthesia in lesioned animals using normally effective doses of etomidate, propofol, and pentobarbital suggests that the mesopontine tegmental anesthesia area is the effective target of these, but not necessarily all, GABAergic anesthetics upon systemic administration. Cortical and spinal functions are likely suppressed by recruitment of dedicated ascending and descending pathways rather than by direct, distributed drug action. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New