Coronary artery disease (CAD) remains the leading cause of mortality among cardiovascular diseases, responsible for 16% of the world’s total deaths. According to a statistical report published in 2020, the global prevalence of CAD was estimated at 1655 per 100,000 people and is predicted to exceed 1845 by 2030. Annually, in the United States, CAD accounts for approximately 610,000 deaths and costs more than 200 billion dollars for healthcare services. Most patients with CAD need to be treated over long periods with a combination of drugs. Therefore, the inappropriate use of drugs, or drug-related problems (DRPs), can lead to many consequences that affect these patients’ health, including decreased quality of life, increased hospitalization rates, prolonged hospital stays, increased overall health care costs, and even increased risk of morbidity and mortality. DRPs are common in CAD patients, with a prevalence of over 60%. DRPs must therefore be noticed and recognized by healthcare professionals. This chapter describes common types and determinants of DRPs in CAD patients and recommends interventions to limit their prevalence.
This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδ expression. Gö6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCδ inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCδ knockout (–/–) mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKCδ (–/–) mice. Consistent with this, MA-induced apoptosis (i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKCδ (–/–) mice. Our results suggest that PKCδ gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCδ may be a useful target for protection against MA-induced neurotoxicity.
The present study was designed to evaluate the specific role of protein kinase C (PKC) δ in methamphetamine (MA)-induced dopaminergic toxicity. A multiple-dose administration regimen of MA significantly increases PKCδ expression, while rottlerin, a PKCδ inhibitor, significantly attenuates MA-induced hyperthermia and behavioural deficits. These behavioural effects were not significantly observed in PKCδ antisense oligonucleotide (ASO)-treated- or PKCδ knockout (−/−)-mice. There were no MA-induced significant decreases of dopamine (DA) content or tyrosine hydroxylase (TH) expression in the striatum in rottlerin-treated-, ASO-treated- or PKCδ (−/−)-mice. The administration of MA also results in a significant decrease of TH phosphorylation at ser 40, but not ser 31, while the inhibition of PKCδ consistently and significantly attenuates MA-induced reduction in the phosphorylation of TH at ser 40. Therefore, these results suggest that the MA-induced enhancement of PKCδ expression is a critical factor in the impairment of TH phosphorylation at ser 40 and that pharmacological or genetic inhibition of PKCδ may be protective against MA-induced dopaminergic neurotoxicity in vivo.
Pneumonia is one of the most common infectious diseases and the fourth leading cause of death globally. According to US statistics in 2019, pneumonia is the most common cause of sepsis and septic shock. In the US, inpatient pneumonia hospitalizations account for the top 10 highest medical costs, totaling $9.5 billion for 960,000 hospital stays. The emergence of antibiotic resistance in the treatment of infectious diseases, including the treatment of pneumonia, is a globally alarming problem. Antibiotic resistance increases the risk of death and re-hospitalization, prolongs hospital stays, and increases treatment costs, and is one of the greatest threats in modern medicine. Drug-related problems (DRPs) in pneumonia - such as suboptimal antibiotic indications, prolonged treatment duration, and drug interactions - increase the rate of antibiotic resistance and adverse effects, thereby leading to an increased burden in treatment. In a context in which novel and effective antibiotics are scarce, mitigating DRPs in order to reduce antibiotic resistance is currently a prime concern. A variety of interventions proven useful in reducing DRPs are antibiotic stewardship programs, the use of biomarkers, computerized physician order entries and clinical decision support systems, and community-acquired pneumonia scores.
Recently, we proposed that inhibition of protein kinase (PK) Cδ may be a useful target for protection against methamphetamine (MA)-induced dopaminergic toxicity. We demonstrated that treatment with MA resulted in a significant decrease in phosphorylation of tyrosine hydroxylase (TH) at Ser(40) in the striatum, but not in the phosphorylation of TH at Ser(31) . In the present study, treatment with rottlerin (1.5 or 3.0 μg, i.c.v, once a day for 5 days), a PKCδ inhibitor, or a PKCδ antisense oligonucleotide (ASO; 2.5 μg/μl, i.c.v., 3 times) significantly attenuated MA-induced reductions in the phosphorylation of TH at Ser(40) and in the expression of PKA in the striatum of mice. This attenuation was significantly counteracted by H89 (10 or 30 ng, i.c.v., 1 h after the last MA administration), a PKA inhibitor. Treatment with rottlerin or ASO significantly attenuated the MA-induced increase in protein phosphatase (PP) 2A activity. FTY720 (1 or 5 mg/kg, i.p., 1 h after the last MA administration), a PP2A activator, significantly reversed the recovery in TH phosphorylation mediated by inhibition of PKCδ after MA treatment. Both H89 and FTY720 counteracted the recovery of MA-induced behavioural impairments induced by PKCδ inhibition. The effects, mediated by rottlerin or ASO in MA-treated wild-type mice were comparable with those in MA-treated PKCδ(-/-) mice. However, neither inhibition of the mitogen-activated protein kinase subfamily (extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38) nor inhibition of calcium calmodulin kinase II significantly altered PKCδ inhibition-mediated attenuation of MA-induced impairment of TH phosphorylation. The results suggest that genetic or pharmacological inhibition of PKCδ requires modulation of PKA expression and/or PP2A activity to attenuate the impairment of TH phosphorylation at Ser(40) and behavioural activity induced by MA.
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