Add-on Drug Research Articles

OS10.8.A The effectiveness of antiepileptic drug duotherapies in glioma patients: a multicenter observational cohort study

Abstract BACKGROUND About 30% of glioma patients need an add-on antiepileptic drug (AED) due to uncontrolled seizures on AED monotherapy. This study aimed to determine whether levetiracetam combined with valproic acid (LEV+VPA), a commonly prescribed duotherapy, is more effective than other duotherapy combinations including either LEV or VPA in glioma patients. MATERIAL AND METHODS In this multicenter retrospective observational cohort study, treatment failure (i.e. replacement by or addition of a new AED, or withdrawal of an AED) for any reason was the primary outcome. Secondary outcomes included: 1) treatment failure due to uncontrolled seizures; and 2) treatment failure due to adverse effects. Time to treatment failure was defined as the time from the start of AED duotherapy until the time of treatment failure. Multivariable Cox proportional hazard models were estimated to study the association between risk factors and treatment failure. The maximum duration of follow-up was 36 months. RESULTS A total of 1435 patients were treated with first-line monotherapy LEV or VPA, of which 355 patients received AED duotherapy after they had treatment failure due to uncontrolled seizures on monotherapy. LEV+VPA was prescribed in 66% (236/355) and other AED duotherapy combinations including LEV or VPA in 34% (119/355) of patients. Patients using other duotherapy versus LEV+VPA had higher risk of treatment failure for any reason (cause-specific hazard ratio [csHR]=1.50 [95%CI=1.07–2.12], p=0.020), treatment failure due to uncontrolled seizures (csHR=1.73 [95%CI=1.10–2.73], p=0.018). There were no differences in failure due to adverse effects (csHR=0.88 [95%CI=0.47–1.67]), p=0.703) between the two groups. CONCLUSION This observational cohort study suggests that LEV+VPA has better efficacy than other AED combinations. Similar toxicities were experienced in the two groups.

Type 1 diabetes glycemic management: Insulin therapy, glucose monitoring, and automation.

Despite innovations in insulin therapy since its discovery, most patients living with type 1 diabetes do not achieve sufficient glycemic control to prevent complications, and they experience hypoglycemia, weight gain, and major self-care burden. Promising pharmacological advances in insulin therapy include the refinement of extremely rapid insulin analogs, alternate insulin-delivery routes, liver-selective insulins, add-on drugs that enhance insulin effect, and glucose-responsive insulin molecules. The greatest future impact will come from combining these pharmacological solutions with existing automated insulin delivery methods that integrate insulin pumps and glucose sensors. These systems will use algorithms enhanced by machine learning, supplemented by technologies that include activity monitors and sensors for other key metabolites such as ketones. The future challenges facing clinicians and researchers will be those of access and broad clinical implementation.

Ripasudil Endgame: Role of Rho-Kinase Inhibitor as a Last-Ditch-Stand Towards Maximally Tolerated Medical Therapy to a Patient of Advanced Glaucoma.

PurposeTo elucidate the use of Ripasudil in patients of advanced glaucoma on maximally tolerated medical therapy who could not be offered the option of surgery due to the global pandemic lockdown.Materials and MethodsOnly patients with primary open angle glaucoma (POAG), who had a cup-disc ratio (CDR) of 0.9 or a near total cupping on maximum tolerated medical therapy for at least 4 weeks and yet could not meet the target IOP were included. Target IOP was defined as ≤12 mm Hg. A total of 30 patients were enrolled. All patients in study cohort were started on E/D Ripasudil BD. Patients were followed up at 1 week, 2 weeks, 4 weeks and then monthly for 6 months for their best corrected visual acuity (BCVA), intraocular pressure (IOP), disc changes (slit lamp biomicroscopy), perimetry, and retinal nerve fibre layer analysis using optical coherence tomography (OCT-RNFL).ResultsMean pre-treatment IOP on five drugs was 18.3 ± 2.1 mm Hg (range 14 to 22mmHg) on maximally tolerated medical therapy. At 1 week follow-up, mean post-treatment IOP was 15.1 ± 1.7 mm Hg (range 12 to 18mmHg) and at 2 week follow-up, mean post-treatment IOP was 12.5 ± 1.9 mmHg (range 10 to 16mmHg). Thus, target IOP ≤12mmHg was attained in 28 patients at 2 weeks. This target IOP was maintained throughout the 6 months of follow-up period. Of the 2 patients who could not meet target IOP, 1 patient needed rearrangement of their fixed-drug-combinations to achieve target IOP at 4 weeks. The second patient required unfixing of all fixed-drug-combinations to achieve target IOP at maximally tolerated medical therapy at 6 weeks.ConclusionRipasudil not only provides a better IOP control but also has a high safety profile even when started as an add-on drug to already-existing yet inadequate maximally tolerated medical therapy.

Efficacy and Safety of Intravenous Labetalol in Acute Hypertensive Crisis in Children

To determine the efficacy and safety of intravenous (IV) labetalol in the management of hypertensive crisis in children. A retrospective chart review of 56 consecutive children (age > 1 mo to ≤12 y) with hypertensive crisis admitted to a pediatric intensive care unit (PICU) from July 2009 to 2019. The proportion of children attaining the primary endpoint (target 95th percentile in >12 to ≤48h) was significantly more in the group receiving labetalol as first-line or add-on (n = 23) as compared to those not receiving labetalol (n = 33) (62% vs. 30.3%, p = 0.03). Higher proportion of neurological recovery was seen in the labetalol group (56.2% vs. 18.7%, p = 0.02). The proportion of children with hypotension before 12h was similar in both treatment groups (13% vs. 15%, p = 0.82). The practice variations between two periods of 5y each (2009-2013 and 2014-2019) showed significantly more use of labetalol in the latter cohort (53% for 2014-2019 vs. 25% for 2009-2013, p = 0.03). Labetalol, when used alone or as an add-on drug, was more efficacious than IV nitroprusside/nitroglycerine in attaining the primary endpoint in children up to ≤12 y of age with hypertensive crisis. Labetalol was safe and associated with higher neurological recovery.

The challenge of value-based pricing in combination therapy: the case of trastuzumab and pertuzumab in HER2+ metastatic breast cancer

ABSTRACT Background Under current reimbursement (CR) practice even though an add-on drug in a combination therapy may produce marginal value in terms of health gain, the original therapy may also share in the reward for this additional value. We examine an alternative ‘marginal value-based reimbursement’ (MVBR) model in which an original therapy would not share in the marginal value. Methods In a case study for treatment of HER2+ metastatic breast cancer, we computed the incremental cost-effectiveness ratios (ICERs) of adding pertuzumab to trastuzumab and docetaxel (PHT) vs. trastuzumab and docetaxel (HT) under the CR and the MVBR models, respectively. We further estimated the revised cost of pertuzumab under three alternative willingness-to-pay thresholds based on (a) using the current ICER of PHT vs. HT, (b) the historical ICER of HT vs. docetaxel, and (c) applying the oft-used $150,000/quality-adjusted life year (QALY) gained. Results If reimbursement were changed from CR to MVBR, at the current price of pertuzumab, the ICER would decline from $409,213 to $323,236/QALY gained. If the price were adjusted under the three thresholds, the payment for pertuzumab would be increased by between 32% and 93%. Conclusion The proposed MVBR model would provide a stronger economic incentive to develop add-on drugs.

Gabapentin add-on treatment for drug-resistant focal epilepsy.

This is an updated version of the Cochrane Review previously published in 2018. Epilepsy is a common neurological disorder characterised by recurrent seizures. Most people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially people with focal seizures. In this review, we summarised the evidence from randomised controlled trials (RCTs) of gabapentin, when used as an add-on treatment for drug-resistant focal epilepsy. To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant focal epilepsy. For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) on 11 August 2020. CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups including Epilepsy. We imposed no language restrictions. Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant focal epilepsy. We also included trials using an active drug control group or comparing different doses of gabapentin. Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: seizure frequency, seizure freedom, treatment withdrawal (any reason) and adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best-case and worst-case analyses. We estimated summary risk ratios (RR) for each outcome and evaluated dose-response in regression models. We identified no new studies for this update, therefore, the results and conclusions are unchanged. In the previous update of this review, we combined data from six trials in meta-analyses of 1206 randomised participants. The overall risk ratio (RR) for reduction in seizure frequency of 50% or more compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55; 6 studies, 1206 participants; moderate-certainty evidence). Dose regression analysis (for trials in adults) showed increasing efficacy with increasing dose, with 25.3% (95% CI 19.3 to 32.3) of people responding to gabapentin 1800 mg compared to 9.7% on placebo, a 15.5% increase in response rate (95% CI 8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49; 6 trials, 1206 participants; moderate-certainty evidence). Adverse effects were significantly associated with gabapentin compared to placebo. RRs were as follows: ataxia 2.01 (99% CI 0.98 to 4.11; 3 studies, 787 participants; low-certainty evidence), dizziness 2.43 (99% CI 1.44 to 4.12; 6 studies, 1206 participants; moderate-certainty evidence), fatigue 1.95 (99% CI 0.99 to 3.82; 5 studies, 1161 participants; low-certainty evidence) and somnolence 1.93 (99% CI 1.22 to 3.06; 6 studies, 1206 participants; moderate-certainty evidence). There was no evidence of a difference for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35; 6 studies, 1206 participants; moderate-certainty evidence) or nausea (RR 0.95, 99% CI 0.52 to 1.73; 4 trials, 1034 participants; moderate-certainty evidence). Overall, the studies were at low to unclear risk of bias due to information on each risk of bias domain not being available. We judged the overall certainty of the evidence (using the GRADE approach) as low to moderate due to potential attrition bias resulting from missing outcome data and imprecise results with wide CIs. Gabapentin has efficacy as an add-on treatment in people with drug-resistant focal epilepsy, and seems to be fairly well-tolerated. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types. Further trials are needed to assess the long-term effects of gabapentin, and to compare gabapentin with other add-on drugs.

Experience with Low-Dose Sodium Valproate in Idiopathic Generalized Epilepsy Patients: A Long-Term Follow-Up Study on Selective Cohort from North India.

Background Idiopathic generalized epilepsy (IGE) is found in 20 to 30% of all patients presenting with seizures. Most of the patients require lifelong drug treatment. Efficacy and tolerability are important issues while selecting the most appropriate drug for a person with IGE. Objective The aim of this study was to look for usefulness of small dose valproate (<1,000 mg/day) in long-term treatment of IGE patients. Methods Diagnosis of IGE made with standard criteria among all patients presenting with seizures. Patients put on full doses of valproate (>1,000 mg/day) in first year, then reduction started in next year in patients with full seizure remission, and finally maintained on lowest possible dose of valproate. Lowest dose was defined as the minimum dose without seizures (between 200 and 900 mg/day). Patients, who were refractory on monotherapy, were put on add-on drug and followed for remission and reduction in doses of valproate at minimum possible dose. Results IGE was diagnosed in 21% of all patients presenting with seizures. Among 420 patients of IGE 368 (87.5%) were started on high-dose valproate monotherapy, 155 (42.1%) were responsive to single drug while 213 (57.9%) had been given add-on drug either lamotrigine or clonazepam or both. After minimum 3-year follow-up, 298 (81%) could be managed on low-dose valproate (<1,000 mg) without any relapse during 12 to 80 months follow-up. Conclusion Significant number of patients with IGE can be managed on low-dose valproate with good seizure control and less side effects.

Effect of leukotriene receptor antagonist therapy in bronchial asthma — A prospective, preliminary, hospital-based, randomized study in rural Konaseema, Andhra Pradesh

BACKGROUND: The role of leukotriene receptor antagonist is well documented in the management of chronic asthma. However, the efficacy in acute asthma is not yet established. AIM AND OBJECTIVES: This study was designed to evaluate the clinical efficacy of oral montelukast as an add-on drug to the standard therapy of the acute attack of bronchial asthma. MATERIALS AND METHODS: A prospective, institutional-based, single-blinded, randomized control study was done. A total of 100 (aged between 18 and 60 years) participants diagnosed with acute exacerbations due to bronchial asthma were enrolled in the study. They were divided into study and control groups randomly. The study group patients were treated with 10 mg of montelukast once in a day for 4 weeks as an add-on drug, whereas the control group received only standard medication of acute bronchial asthma (as per Global Initiative for Asthma guidelines). All the participants were monitored at baseline to every week for a month. RESULTS: All the 100 participants were assessed finally without any dropouts. The baseline characteristics were noted similarly in both groups. The mean age was 35.46 + 13.17 years in the control and 37.86 + 14.43 years in the study group. Majority were males in both the groups. At the end of the 4 weeks of oral montelukast administration, there was improvement in forced expiratory volume in 1 s (FEV1) and peak expiratory flow rate at 2 weeks and 1 month. On many occasions, there was a strong improvement in FEV1 and other clinical parameters after continuous treatment with beta-2 agonists and parenteral corticosteroids for patients with acute asthma. Even though there was no improvement in FEV1/forced vital capacity ratio among both the groups at 2 weeks and 4 weeks, statistically significant improvement was seen between 2 weeks to 1 month on baseline parameters. CONCLUSION: Administration of oral montelukast 10 mg as an add-on drug to standard therapy may help in quick recovery from acute bronchial asthma and relapse.

Cariprazine for late-life psychiatric illness: A review on therapeutic potential and challenges

Clinicians often face many challenges in the pharmacological treatment of late-life psychiatric illness especially while choosing an antipsychotic drug. The choice of antipsychotic is mostly guided by the extension of evidence from the adult population and tolerability. In India, based on evidence commonly prescribed antipsychotic drugs for older adults are quetiapine (QTP) followed by olanzapine (OLZN) and risperidone. Cariprazine is a newer antipsychotic that was recently launched in India. It is a novel mechanism of action at D3 receptors is known to have antidepressant and procognitive action in addition to the antipsychotic effects which is desirable in geriatric population. It can be a potential option as an add-on drug in late-life depression in addition to the existing aripiprazole and OLZN. The treatment of late-life mania and very late-onset schizophrenia is limited by the paucity of studies, with randomized control studies done only on QTP and amisulpride, respectively. Cariprazine can be considered in late-life psychotic disorders with the evidence available from its efficacy studies in adult patients. Merits of cariprazine are favorable metabolic profile, cardiac safety, and procognitive action. Demerits include extrapyramidal symptoms and fluctuations in blood pressure. Slower titration and monitoring for akathisia are recommended. There is a need for controlled studies in older adults with cariprazine to get better informed about its efficacy and safety.

Effects of Discontinuation of Drugs Used for Augmentation Therapy on Treatment Outcomes in Depression: A Systematic Review and Meta-analysis.

There has been no consensus on whether and how long add-on drugs for augmentation therapy should be continued in the treatment of depression. Double-blind randomized controlled trials that examined the effects of discontinuation of drugs used for augmentation on treatment outcomes in patients with depression were identified. Meta-analyses were performed to compare rates of study withdrawal due to any reason, study-defined relapse, and adverse events between patients who continued augmentation therapy and those who discontinued it. Seven studies were included (n=841 for continuing augmentation therapy; n=831 for discontinuing augmentation therapy). The rate of study withdrawal due to any reason was not significantly different between the 2 groups (risk ratio [RR]=0.86, 95% confidence interval [CI]=0.69-1.08, p=0.20). Study withdrawal due to relapse was less frequent in the continuation group than in the discontinuation group (RR=0.61, 95% CI=0.40-0.92, p=0.02); however, this statistical significance disappeared when one study using esketamine as augmentation was excluded. Analysis of the data from 5 studies that included a stabilization period before randomization found less frequent relapse in the continuation group than in the discontinuation group (RR=0.47, 95% CI=0.36-0.60, p<0.01). This finding was repeated when the esketamine study was excluded. No firm conclusions could be drawn in light of the small number of studies included. Currently available evidence suggests that add-on drugs, other than esketamine, used for augmentation therapy for depression may be discontinued. This may not be the case for patients who are maintained with augmentation therapy after remission.

Effectiveness, safety and cost analysis of add-on pidotimod in maintenance therapy for exacerbation of chronic obstructive pulmonary disease in adults

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the sudden worsening in airway function and respiratory symptoms in patients with COPD which range from self-limited diseases to episodes of florid respiratory failure requiring mechanical ventilation. An average patient with COPD might experience 2 episodes of AECOPD per year and 10% of these episodes require hospitalization. Pidotimod, an immunostimulant, has shown promising results in conditions with underlying cause of suppressed cell-mediated immunity like chronic bronchitis and recurrent respiratory tract infection (RRTI). The current study evaluated the safety, efficacy and cost effectiveness of Pidotimod in adult Indian patients with COPD as an add-on drug in maintenance therapy of acute exacerbations. In this prospective, open label, single arm, single centre study, Pidotimod was administered as an add-on therapy for 2 months in 114 patients (? 18 years and ? 55years; mean age: 59.51± 8.66 years) with COPD having experienced two or more exacerbation that required antibiotics. The study comprised of screening visit, enrolment and 3 follow-up visits (at the end of 2, 6 and 12 months). Of the 111 patients at baseline, only one patient had an AECB episode at 2 and 6 months. At the end of 12 months, none of the patient had an AECB. Only one subject was prescribed with antibiotic treatment at the end of 2 and 6 months. No episodes of either exacerbations or antibiotic prescription at the end of 12 months were reported. A significant reduction (p Keywords: Immunostimulant, Pidotimod, Acute exacerbations of chronic bronchitis (AECB), Cost-analysis, Respiratory infections.

Preference and practice of Indian physicians towards the use of vasodilator di-hydralazine in the management of resistant hypertension

Background: The treatment modalities of resistant hypertension (RH) remain a clinical challenge, often requiring secondary/add-on drugs with first-line therapy to control blood pressure (BP). This study was conducted to explore and understand the preferences and practices of Indian physicians towards the use of vasodilator (especially di-hydralazine) in the management of RH.Methods: This was a cross-sectional, observational, web-based physician survey. The study included cardiologist, nephrologist and consultant physicians from different geographical regions of India. A web-based physician survey questionnaire (PSQ) was created in google forms and the link was circulated to the physicians. Responses obtained were analysed.Results: A total of 457 physicians participated in this survey. In majority of the physicians, vasodilators were the treatment choice as secondary or add-on drugs with first line therapy to control BP in RH; especially hydralazine/di-hydralazine preferred the most. Majority of the physicians preferred to combine vasodilator with beta blocker and diuretic in patients with uncontrolled and RH. Cardiac failure, followed by chronic kidney disease (CKD), diabetes, dyslipidaemia, hypertensive emergency and angina were the common patient profile in RH in which majority physicians prescribed vasodilator (di-hydralazine). Majority of the physicians rated vasodilator di-hydralazine as “good-very good” in terms of efficacy, safety, tolerability, patient compliance and patient satisfaction in RH.Conclusions: Overall, vasodilators (hydrazinophthalazine derivatives) are preferred as add-on drugs along with first-line drugs in RH. Physician’s opinion towards the use of di-hydralazine was positive. Di-hydralazine may be preferred as an add-on therapeutic option to control BP in RH, however randomized clinical trials are needed for recommendation in cardio-renal medicine.

The Effects of Resveratrol on Telomeres and Post Myocardial Infarction Remodeling.

Post myocardial infarction (MI) remodeling is the term used to define the changes in cardiac musculature after sustaining an ischemic injury. These changes decrease myocardial function and ultimately lead to heart failure. We review the contributing factors to post-MI remodeling, its association with telomere biology, as well as a myriad of other factors affecting aging and telomere length in relation to cardiovascular health. The main focus is on the effects of resveratrol in the cardiovascular system and its potential for therapeutic use in preventing long-term cardiovascular morbidity and mortality. We tried to answer important questions regarding the potential for resveratrol as a therapeutic drug to prevent adverse post-MI remodeling. In our search, we gathered 62 studies and narrowed our data down to 44 studies. The database used was PubMed, and the keywords used are "Resveratrol", "Telomere", "Post Myocardial Infarction". All the studies were carefully screened for relevant articles regarding our topic manually, Articles related to a positive association between resveratrol and its anti-aging, cardioprotective effects have been included in our study, as we could not find any articles in our search which showed a negative correlation. Our review concluded that resveratrol had pro-telomerase effects which could counter the development of adverse post-MI remodeling. Therefore resveratrol could be a useful therapeutic add-on drug to prevent cardiovascular disease. It is essential that further research including observational and large-scale clinical trials should be conducted to increase our understanding of the efficacy and viability of these novel therapeutic interventions.

Indole Propionic Acid, an Unusual Antibiotic Produced by the Gut Microbiota, With Anti-inflammatory and Antioxidant Properties.

Most antibiotics are produced by soil microbes and typically interfere with macromolecular synthesis processes as their antibacterial mechanism of action. These natural products are often large and suffer from poor chemical tractability. Here, we discuss discovery, mechanism of action, and the therapeutic potentials of an unusual antibiotic, indole propionic acid (IPA). IPA is produced by the human gut microbiota. The molecule is small, chemically tractable, and targets amino acid biosynthesis. IPA is active against a broad spectrum of mycobacteria, including drug resistant Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM). Interestingly, the microbiota-produced metabolite is detectable in the serum of healthy individuals, tuberculosis (TB) patients, and several animal models. Thus, the microbiota in our gut may influence susceptibility to mycobacterial diseases. If a gut-lung microbiome axis can be demonstrated, IPA may have potential as a biomarker of disease progression, and development of microbiota-based therapies could be explored. In addition to its antimycobacterial activity, the molecule displays anti-inflammatory and antioxidant properties. This raises the possibility that IPA has therapeutic potential as both antibiotic and add-on host-directed drug for the treatment of TB in patient populations where disease morbidity and mortality is driven by excessive inflammation and tissue damage, such as TB-associated immune reconstitution inflammatory syndrome, TB-meningitis, and TB-diabetes.

Regression of the Left Ventricular Hypertrophy in Patients with Essential Hypertension on Standard Drug Therapy.

PURPOSE: The American College of Cardiology/ American Heart Association 2017 and European Society of Cardiology/European Society of Hypertension 2018 guidelines were a paradigm shift in hypertension management in contemporary medicine. Lowering of blood pressure to less than 130 (systolic) and 80 (diastolic) mm of Hg irrespective of cardiovascular risk is recommended. While intensive blood pressure control is commonly achievable with rational pharmacotherapy, the magnitude of left ventricular hypertrophy regression is an independent factor in improvement in cardiovascular health. The regression of left ventricular hypertrophy has been adjudged as a clinically useful surrogate marker that reflects the efficacy of hypertension treatment. Though angiotensin converting enzyme inhibitors/ angiotensin receptor blockers (ACEI/ARB) are the preferred initial drug for greater regression of left ventricular mass, the choice of add-on therapy, if required, is still debatable. Therefore, in our observational study, we sought to compare the reduction in left ventricular mass index in hypertensives with left ventricular hypertrophy on standard ACEI/ARB based drug therapy. MATERIALS AND METHODS: The cohort (n=217) comprised of patients with uncontrolled hypertension (blood pressure>140/90 mm of Hg) and left ventricular hypertrophy (left ventricular mass index>115 and 95 gram/square meter in males and females respectively). The add-on drug in ACEI/ARB therapy was either thiazide diuretics (TD) or calcium channel blockers (CCB). Four sub-cohorts were constituted: mono-therapy - group A (n=70, ACEI/ARB), dual-therapy - group B (n=48, ACEI/ARB+TD) and group C (n=51, ACEI/ ARB+CCB), triple therapy - group D (n=48, ACEI/ ARB+TD+CCB). Left ventricular mass index was determined using echocardiography at baseline and after 24 weeks of therapy. RESULTS: There was no significant difference in baseline clinical or demographic variables between group B and group C. Baseline blood pressure and duration of hypertension was greater in group D compared to group A (P<0.001). The reduction in left ventricular mass index (mean ±SD) in the four groups (A to D) was 16.7±18.7, 21.0±20.8, 20.5±15.5 and 29.1±21.5 g/m2 respectively (D>A, P=0.011, B versus C, P=1.00). The corresponding change in blood pressure (systolic/diastolic) was 18.5±13.6/8.9±11.2, 27.5±19.2/12.2±9.3, 23.4±16.7/ 5.4±10.1, 26.6±19.5/10.7±12.8 mm of Hg respectively (systolic, B>A, P=0.027, D>A, P=0.048) (diastolic, B>C, P=0.013). CONCLUSION: Anti-hypertensive treatment with angiotensin converting enzyme inhibitors/angiotensin receptor blockers-based therapy produced graded regression of left ventricular hypertrophy with monotherapy, dual therapy and triple therapy. In dual therapy, add-on of either thiazide diuretics or calcium channel blockers to angiotensin converting enzyme inhibitors/angiotensin receptor blockers showed equal efficacy in regression of left ventricular hypertrophy independent of blood pressure reduction.

Possible mechanisms of action of clarithromycin and its clinical application as a repurposing drug for treating multiple myeloma.

Clarithromycin (CAM), a semisynthetic macrolide antibiotic, is a widely used antibacterial drug. Recently, the efficacy of CAM as an add-on drug for treating multiple myeloma (MM) has been noted. Its effect on treating MM has been confirmed in combination chemotherapies that include CAM. However, a single treatment of CAM has no efficacy for treating MM. Many myeloma growth factors (MGFs) including interleukin (IL)-6 are known to be closely involved in the development of MM. CAM has been shown to suppress many MGFs, particularly IL-6. The possible mechanisms of action of CAM in treating MM have been suggested to include its immunomodulatory effect, autophagy inhibition, reversibility of drug resistance, steroid-sparing/enhancing effect and suppression of MGFs. In addition, MM is characterised by uncontrolled cell growth of monoclonal immunoglobulin (Ig)-producing neoplastic plasma cells. Large quantities of unfolded or misfolded Ig production may trigger considerable endoplasmic reticulum stress. Thus, MM is originally a fragile neoplasm particularly susceptible to autophagy-, proteasome- and histone deacetylase 6-inhibitors. Taken together, CAM plays an important role in MM treatments through its synergistic mechanisms.In addition, CAM with its pleiotropic effects on cytokines including IL-6 and indirect antiviral effects might be worth a try for treating COVID-19.

Cognitive function and adaptive skills after a one-year trial of cannabidiol (CBD) in a pediatric sample with treatment-resistant epilepsy

ObjectiveCannabidiol (CBD) is a nonpsychoactive derivative of cannabis. Studies indicate that it is safe and effective in treating certain types of epilepsy. The present study examined the presence of adverse or beneficial cognitive or functional adaptive effects associated with CBD in the treatment of children, adolescents, and teenagers with treatment-resistant epilepsy (TRE) as part of an ongoing prospective, open-label safety study. MethodsParticipants (N = 38) between the age of 3 and 19 years with TRE were enrolled in an open-label study of a pharmaceutical formulation of CBD (Epidiolex®; GW Research Ltd.) as an add-on treatment. In addition to baseline physical, neurological, and laboratory testing, cognitive assessment was completed prior to initiating CBD and after one year, both using the NIH Toolbox Cognition Battery (NIHTB-CB). Many participants were unable to complete the NIHTB-CB because of the magnitude of their cognitive impairment (n = 24), and in these cases, the participant's caregiver was asked to complete the Adaptive Behavior Assessment System – Second Edition (ABAS-II) as a measure of functional adaptive skills. ResultsThere were no statistically significant changes in cognitive function, as measured by the NIHTB-CB, in those participants who were able to complete such testing, but there was a nonsignificant trend toward improvement in some cognitive domains. For participants who were unable to complete formal standardized cognitive testing because of the magnitude of their cognitive impairment, their functional adaptive skills, as measured by the ABAS-II, were unchanged after a one-year trial of CBD. SignificanceOur findings suggest that CBD, as an add-on drug for TRE in a pediatric sample, does not appear to cause adverse effects (AEs) involving cognition or adaptive function over one year of treatment.

Pregnancy hypertension diagnosis and care in COVID-19 era and beyond.

Pregnancy hypertension diagnosis and care in COVID-19 era and beyond.

The Protective Effect of Safinamide in Ischemic Stroke Mice and a Brain Endothelial Cell Line.

Stroke is one of the leading causes of mortality in cardiovascular diseases. The disruption of the brain-blood barrier is the common feature of stroke-related complications. Safinamide is a newly approved add-on drug to treat Parkinson's disease, and previously studies suggest safinamide could have a potential role on neuroprotection. In this study, we investigated its preventive effect in both acutely induced stroke animals and brain endothelial cells. By the induction of middle cerebral artery occlusion (MCAO) in mice, we established a transit stroke model. Mice were administered 90mg/kg/day safinamide prior to MCAO and during ischemia and reperfusion. Results indicate that the administration of safinamide significantly ameliorated MCAO-caused cerebral infarction volume, neurological deficit, disruption of the brain-blood barrier (BBB), and impaired expression of tight junction protein occludin and ZO-1. In cultured brain endothelial cell line bEND.3, pre-treatment with safinamide alleviated oxygen and glucose deprivation/reperfusion (OGD/R) caused cytotoxicity and favored cell survival. Transwell assay showed safinamide prevented OGD/R-induced hyperpermeability and the reduction of occludin and ZO-1. Moreover, safinamide treatment suppressed OGD/R-caused induction of metalloproteinase 2 (MMP-2) and 9 (MMP-9). Collectively, our data conclude safinamide has a preventive neuroprotection in acute stroke animals. The protective effect of safinamide on brain endothelial cells suggests the drug may ameliorate BBB disruption and improve vascular integrity in ischemia stroke.

Efficacy and safety of metformin and sitagliptin‐based dual and triple therapy in elderly Chinese patients with type 2 diabetes: Subgroup analysis of STRATEGY study

Aims/IntroductionTo assess the efficacy and safety of metformin/sitagliptin‐based dual/triple therapy in elderly Chinese patients with type 2 diabetes mellitus.Materials and MethodsThis subgroup analysis included individuals aged ≥65 years from the STRATEGY study, a two‐stage study in which type 2 diabetes mellitus patients with unsatisfactory glycemic control on metformin were first treated with the dual combination of metformin and sitagliptin for 16 weeks (n = 681), and then, if glycemic control had not been achieved, were treated with a third add‐on oral antihyperglycemic drug for another 24 weeks (n = 291). The efficacy end‐point was change in glycated hemoglobin (HbA1c) in each stage, and the safety end‐point was adverse events with a focus on hypoglycemia.ResultsAt week 16, the change in HbA1c was −0.81% from baseline, and the percentages of patients who achieved HbA1c targets of <7% and <7.5% were 44.9 and 67.2%, respectively. After 24 weeks, a further average HbA1c reduction of −0.60% was observed with specific reductions of −0.70% with glimepiride, −0.63% with gliclazide, −0.51% with repaglinide and −0.45% with acarbose. The proportions of patients who achieved HbA1c targets of <7% and <7.5% were 65.4 and 81.3%, respectively, over the entire study. The rates of drug‐related adverse events and hypoglycemia were, respectively, 4.1 and 4.3% in the dual therapy stage, and 5.2% and 7.1% in the triple therapy stage, without occurrence of severe hypoglycemia.ConclusionsIn elderly Chinese type 2 diabetes mellitus patients, metformin/sitagliptin‐based dual and triple oral therapy can provide clinically meaningful glycemic control and is generally well tolerated with a low incidence of hypoglycemia.