Lipoapoptosis of cardiomyocytes may underlie diabetic cardiomyopathy. Numerous forms of cardiomyopathies share a common end-pathway in which apoptotic loss of cardiomyocytes is mediated by p38alpha ...mitogen activated protein kinase (MAPK). Although we have previously shown that palmitic acid (PA), a saturated fatty acid (SFA) elevated in plasma of type 2 diabetes mellitus and morbid obesity, induces apoptosis in cardiomyocytes via p38alpha MAPK-dependent signaling, the downstream cascade events that cause cell death remain unknown. The objective of this study was to investigate mechanisms involved in palmitic acid-induced cardiomyocyte apoptosis. Human adult ventricular cardiomyocyte line (AC16 cells) exposed to high physiological levels of PA for 16 h showed enhanced transcription and phosphorylation of c-fos and c-jun subunits of AP-1 and transcription of caspase 8. When AC16 cells were transfected with small interfering RNA specific against p38alpha MAPK (si-p38alpha) for 24 or 48 h, the amplified phosphorylation of c-fos was dose-dependently attenuated, and procaspase 8 was dose-dependently reduced. With translational knockdown of c-fos, PA-induced apoptosis was diminished. Inhibition of caspase 8 for 24 h reduced apoptosis in PA-treated cardiomyocytes. These findings provide evidence for induction of apoptosis in cardiomyocytes exposed to high SFA by a novel pathway requiring activation of c-fos/AP-1 and caspase 8. These results demonstrate how elevated plasma SFA may lead to continual and cumulative loss of cardiomyocytes and potentially contribute to the development of diabetic cardiomyopathy.
Lipoapoptosis of cardiomyocytes may underlie diabetic cardiomyopathy. Numerous forms of cardiomyopathies share a common end-pathway in which apoptotic loss of cardiomyocytes is mediated by p38α ...mitogen activated protein kinase (MAPK). Although we have previously shown that palmitic acid (PA), a saturated fatty acid (SFA) elevated in plasma of type 2 diabetes mellitus and morbid obesity, induces apoptosis in cardiomyocytes via p38α MAPK-dependent signaling, the downstream cascade events that cause cell death remain unknown. The objective of this study was to investigate mechanisms involved in palmitic acid-induced cardiomyocyte apoptosis. Human adult ventricular cardiomyocyte line (AC16 cells) exposed to high physiological levels of PA for 16 h showed enhanced transcription and phosphorylation of c-fos and c-jun subunits of AP-1 and transcription of caspase 8. When AC16 cells were transfected with small interfering RNA specific against p38α MAPK (si-p38α) for 24 or 48 h, the amplified phosphorylation of c-fos was dose-dependently attenuated, and procaspase 8 was dose-dependently reduced. With translational knockdown of c-fos, PA-induced apoptosis was diminished. Inhibition of caspase 8 for 24 h reduced apoptosis in PA-treated cardiomyocytes. These findings provide evidence for induction of apoptosis in cardiomyocytes exposed to high SFA by a novel pathway requiring activation of c-fos/AP-1 and caspase 8. These results demonstrate how elevated plasma SFA may lead to continual and cumulative loss of cardiomyocytes and potentially contribute to the development of diabetic cardiomyopathy.
Abstract Objectives: The primary objective of this study was to assess the efficacy and tolerability of tapentadol immediate release (IR) in patients who were candidates for joint replacement surgery ...due to end-stage joint disease. A secondary objective was to compare tapentadol IR with oxycodone HCl IR with respect to efficacy and prespecified tolerability end points. Methods: This 10-day, Phase III, randomized, double-blind, active- and placebo-controlled study compared the efficacy and tolerability of tapentadol IR, oxycodone HCl IR, and placebo in patients with uncontrolled osteoarthritis pain who were candidates for primary replacement of the hip or knee as a result of end-stage degenerative joint disease. Patients received tapentadol IR 50 mg, tapentadol IR 75 mg, oxycodone HCl IR 10 mg, or placebo every 4 to 6 hours during waking hours. The primary end point was the sum of pain intensity difference (SPID) over 5 days. Secondary efficacy end points included 2- and 10-day SPID; 2-, 5-, and 10-day total pain relief (TOTPAR); and the sum of total pain relief and pain intensity difference (SPRID). Prespecified noninferiority comparisons with oxycodone HCl IR were performed with respect to efficacy (based on 5-day SPID) and tolerability (based on incidence of the reported adverse events (AEs) of nausea and/or vomiting and constipation). Results: Of 666 patients originally enrolled, 659 were included in the efficacy analysis (51% male; 91% white; mean age, 61.2 years; mean weight, 97 kg). Five-day SPID was significantly lower in those treated with tapentadol IR (tapentadol IR 50 mg: least squares mean difference LSMD = 101.2 95% CI, 54.58- 147.89; tapentadol IR 75 mg: LSMD = 97.5 95% CI, 51.81-143.26) or oxycodone HCl IR (LSMD = 111.9 95% CI, 66.49-157.38) (all, P < 0.001). Tapentadol IR 50 and 75 mg and oxycodone HCl IR 10 mg were associated with significant reductions in pain intensity compared with placebo, based on 2- and 10-day SPID and 2-, 5-, and 10-day TOTPAR and SPRID (all, P < 0.001). The efficacy of tapentadol IR 50 and 75 mg was noninferior to that of oxycodone HCl IR 10 mg; however, the incidence of selected gastrointestinal AEs (nausea, vomiting, and constipation) was significantly lower for both doses of tapentadol IR compared with oxycodone HCl IR 10 mg (nominal P < 0.001). The odds ratios for nausea and/or vomiting for tapentadol IR 50 and 75 mg relative to oxycodone HCl IR 10 mg were 0.21 (95% CI, 0.128-0.339) and 0.32 (95% CI, 0.204-0.501), respectively; for constipation, the corresponding odds ratios were 0.13 (95% CI, 0.057-0.302) and 0.20 (95% CI, 0.098-0.398). Rates of treatment discontinuation were 18% (28/157) in the tapentadol IR 50-mg group, 26% (43/168) in the tapentadol IR 75-mg group, 35% (60/172) in the oxycodone HCl IR 10-mg group, and 10% (17/169) in the placebo group. In a post hoc analysis, tapentadol IR 50 mg was associated with a significantly lower incidence of treatment discontinuation than was oxycodone HCl IR 10 mg ( P < 0.001). Conclusions: In these patients with uncontrolled osteoarthritis pain who were awaiting joint replacement surgery, tapentadol IR 50 and 75 mg were associated with analgesia that was noninferior to that provided by oxycodone HCl IR 10 mg. Tapentadol treatment was associated with improved gastrointestinal tolerability. ClinicalTrials.gov Identifier: NCT00361582.
To evaluate treatment responder rate using the Attention-Deficit/Hyperactivity Disorder Rating Scale-5 (ADHD-RS-5) score based on optimized dose level of serdexmethylphenidate/dexmethylphenidate ...(SDX/d-MPH) and changes in ADHD severity in children (aged 6-12 years) with ADHD.
During a 21-day dose-optimization phase, 155 patients initiated treatment with 39.2/7.8 mg SDX/d-MPH in the first week and then were titrated to an optimum dose; 5 patients were downtitrated to 26.1/5.2 mg, 76 were uptitrated to 52.3/10.4 mg, and 69 remained at 39.2/7.8 mg during the following 2 weeks. Responder threshold values were 30% and 50% based on the percent change from baseline (day 0) to days 7, 14, and 21 in the ADHD-RS-5 score. The Conners 3rd Edition-Parent score was used to assess weekly changes in ADHD severity during the dose-optimization and treatment phases.
Of the 5 subjects whose dose was optimized at 26.1/5.2 mg, ≥80% across all days had ≥50% responder rate. Of the 69 subjects whose dose was optimized at 39.2/7.8 mg, 81.2% had ≥50% responder rate by day 21. Of the 76 subjects whose dose was optimized to 52.3/10.4 mg, 72.4% had ≥50% responder rate by day 21. Changes in ADHD severity, based on mean Conners 3rd Edition-Parent scores, improved from baseline at each visit during dose optimization for each subscale. At the dose-optimization phase, Conners 3rd Edition-Parent scores improved from baseline for SDX/d-MPH in all subscales.
A high percentage of subjects were responders upon reaching their final optimized dose. SDX/d-MPH demonstrated significant reductions in ADHD severity in children based on the Conners 3rd Edition-Parent scores. Determining the optimal dosage of SDX/d-MPH and its effect on ADHD severity could enable the development of a more clinically relevant treatment regimen in children with ADHD.
•Saturated fatty acids, including palmitate, are elevated in obesity and type 2 diabetes.•High palmitate level dose-dependently activates p38α MAPK in human cardiomyocytes.•High palmitate level ...induces dose-dependent apoptosis in human cardiomyocytes.•Blocking p38α MAPK activation attenuates palmitate-induced cardiomyocyte apoptosis.
The mechanisms underlying lipotoxic/diabetic cardiomyopathy remain poorly understood. Saturated fatty acid (SFA) levels, elevated in obesity and type 2 diabetes, induce apoptosis in many cell types including cardiomyocytes. Signaling pathways, including the p38α mitogen-activated kinase (MAPK)-dependent pathway, have been implicated in apoptosis due to a diverse range of insults.
We tested the hypothesis that SFA-induced cardiomyocyte apoptosis is dependent on p38α activation.
Human adult ventricular cardiomyocytes (AC16 cells) were exposed to high physiological levels of palmitate (PA), a SFA. The apoptotic response was measured using annexin-V by flow cytometry, and the p38α-dependent pathway was evaluated using a p38 inhibitor PD169316, and by p38α small interfering RNA (siRNA) knockdown. PA exposure for 16h dose-dependently increased apoptosis in AC16 cardiomyocytes (control: 2.6±0.6%, 150μM PA: 3.5±0.9%, 300μM PA: 11.5±1.6%, n=4, p<0.01). PA did not change total p38α protein levels, but increased p38α phosphorylation dose-dependently (n=5, p<0.01). PD169316 tended to reduce PA-induced apoptosis (n=4, p=0.05). Specific p38α siRNA markedly reduced the expression of p38α but not p38β (n=3, p<0.0001), and dose-dependently attenuated PA-induced apoptosis (control siRNA: 7.7±1.0%, 300μM PA: 34.4±5.0%, 300μM PA+30pmol siRNA: 23.7±4.4%, 300μM PA+60pmol siRNA: 19.7±2.6%, 300μM PA+120pmol siRNA: 17.3±2.8%, n=4, p<0.0001).
These results demonstrate that PA induces p38α activation, and reducing p38α expression attenuates PA-induced cardiomyocyte apoptosis. Our results support a potential mechanism by which high plasma SFA levels through p38α activation may lead to the development of lipotoxic/diabetic cardiomyopathy.
This is a plain language summary of an article published in the
. It describes an adhesive patch placed on the skin's surface, also referred to as a transdermal delivery system (or TDS), that ...delivers donepezil (called donepezil TDS going forward) through the skin of patients with mild, moderate, and severe dementia of the Alzheimer's type. This summary focuses on how fast and how much of the medication donepezil enters the body through the skin, and how it compares with taking a pill form of donepezil by mouth (oral donepezil). This summary also looks at how much donepezil is circulating through the body with the use of the once-a-week donepezil TDS versus the once-a-day donepezil pill. We show that the same amount of donepezil circulates through the body when donepezil TDS is used once a week as when a participant takes an oral donepezil pill once a day.
Dementia is a term used to describe a person's decreasing ability to remember, think, or make decisions necessary to successfully complete daily activities. Alzheimer's disease is a disorder that progresses slowly, with the symptoms of dementia getting worse over many years. When viewed under a microscope, the visible features of Alzheimer's disease within the brain are protein deposits called plaques between brain cells and protein strands within brain cells that appear as tangles. One of the many features that cannot be seen with the naked eye in the Alzheimer's brain is the low level of a chemical called acetylcholine that allows certain nerve cells in the brain involved with memory to communicate with one another. Donepezil, a drug that is widely used to treat dementia associated with Alzheimer's disease, increases the amount of acetylcholine in the brain. Donepezil is usually in pill form and taken by mouth. However, one problem with taking oral donepezil is that it can cause stomach or intestinal side effects like diarrhea, nausea, and vomiting. These side effects may be bad enough that people stop taking their medication. In 2022, for the first time, the United States Food and Drug Administration approved a donepezil TDS marketed under the name Adlarity. Donepezil TDS is for use in patients who have mild, moderate, and severe dementia caused by Alzheimer's disease. It is applied once a week to skin on the patient's back, upper buttocks, or thigh. Donepezil TDS allows the drug donepezil to be absorbed into the body directly through the skin, which means that the drug does not go through the digestive system. This means that many stomach and intestinal side effects (the undesirable effects of the drug) can potentially be reduced.
In healthy volunteers, we showed that donepezil TDS allows a similar amount of the drug into the body as the oral donepezil pill. This is done using a type of examination known as pharmacokinetics (how much, how fast, and how steadily donepezil is taken into the bloodstream). In healthy participants, donepezil TDS had overall fewer stomach and intestinal side effects (like constipation, diarrhea, nausea, and vomiting) than the oral donepezil pill, although more participants reported abdominal pain with donepezil TDS than with oral donepezil. Donepezil TDS also had fewer instances of nervous system side effects (like dizziness and sleepiness) than the oral donepezil pill. These findings support using donepezil TDS to treat patients with Alzheimer's disease.
Background
Oral donepezil, a reversible acetylcholinesterase inhibitor, is a widely prescribed treatment for dementia of the Alzheimer type. Dose escalation of oral donepezil can result in ...gastrointestinal distress, leading to treatment discontinuation, which emphasizes the need for a transdermal system (TDS). Donepezil TDS (Adlarity®) was recently approved for the treatment of mild, moderate, and severe dementia of the Alzheimer’s type.
Methods
An open‐label, randomized, crossover, 3‐period trial (NCT04617782) with healthy volunteers (aged 18‐55 years) was conducted to assess bioequivalence of once‐weekly 10‐mg/d and 5‐mg/d donepezil TDS with once‐daily 10‐mg oral donepezil. All participants received 5‐mg/d donepezil TDS during the 5‐week Period 1, followed by 10‐mg/d TDS or 10‐mg/d oral donepezil in the 5‐week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state in Week 5 of each treatment. Safety and tolerability were also evaluated.
Results
Of 60 participants enrolled, all received 5‐mg/d TDS, 55 received 10‐mg/d TDS, and 56 received oral donepezil. At steady state, adjusted geometric mean ratio (GMR; % 90% CI) of TDS to oral donepezil for maximum plasma concentration and area under the plasma concentration versus time curve (0‐168 h) were 88.7 (81.7‐96.2) and 108.6 (100.5‐117.4) for 10‐mg/d and 86.1 (79.8‐92.9) and 105.3 (97.6‐113.6) for 5‐mg/d TDS (dose normalized). The 90% CIs for the GMRs were generally within the accepted 80%–125% range for establishing bioequivalence. Adverse events (AEs) were reported in 80% of participants—53.3% for the 5‐mg/d TDS, 54.5% for the 10‐mg/d TDS, and 57.1% for oral donepezil. Except for abdominal pain (5.5% vs 1.8%), fewer gastrointestinal AEs were reported with 10‐mg/d TDS than oral donepezil (constipation, 5.5% vs 17.9%; nausea 1.8% vs 30.4%; diarrhea 3.6% vs 12.5%), respectively. There were also fewer AEs of dizziness (3.6% vs 19.6%) and no incidence of somnolence (0 vs 10.7%) reported with TDS. No serious AEs, AEs leading to treatment discontinuation, or deaths were reported.
Conclusion
Both donepezil TDS strengths were bioequivalent to oral donepezil on a milligram‐per‐day basis. The safety profile of donepezil TDS supports its use in treating dementia of the Alzheimer type.
Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States.
To compare steady-state pharmacokinetics of once-weekly ...10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil.
Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5.
All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% 90% CI) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively).
Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.
Serdexmethylphenidate/dexmethylphenidate (SDX/d-MPH) is approved for the treatment of patients aged ≥6 years with attention-deficit/hyperactivity disorder (ADHD). A 12-month, open-label safety study ...with SDX/d-MPH in children with ADHD showed that SDX/d-MPH was well tolerated and comparable with other methylphenidate products. In this
analysis of the 12-month study, the objective was to characterize the effect of SDX/d-MPH on growth in children with ADHD over 12 months.
This was a
analysis of a dose-optimized, open-label, phase 3 safety study of SDX/d-MPH in children aged 6-12 years with ADHD (NCT03460652). Weight and height
-score analyses were conducted.
-score change from baseline was calculated based on the baseline values for the subjects remaining in the study at the observation time point.
Subjects (
= 238) from the treatment-phase safety population included all enrolled subjects who received ≥1 dose of study drug and had ≥1 postdose safety assessment. During treatment, the mean weight and height
-scores decreased over time from their respective baselines. At the 12-month time point, mean (standard deviation SD)
-score changes from baseline for weight and height for the subjects remaining in the study were -0.20 (0.50) and -0.21 (0.39), respectively; however, these mean changes in Z-scores were not clinically significant (change <0.5 SD). Long-term treatment with SDX/d-MPH was associated with modest reductions in expected weight and lower-than-expected increases in height: effects that plateaued or diminished later in treatment.
The overall effects of SDX/d-MPH on growth velocity (the change in weight and height from one time point to the next) were minimal, and the range of changes was not considered clinically significant. ClinicalTrials.gov identifier: NCT03460652.
