The nonsteroidal anti-inflammatory drugs and acetaminophen

Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (N-acetyl-p-aminophenol (APAP; paracetamol)) are the commonest analgesic drugs used in childhood. Though both drugs act through inhibition of prostaglandin H2 synthetase, acetaminophen lacks the anti-inflammatory effects of the NSAIDs. Neonatal acetaminophen hepatic clearance is reduced in premature neonates (5–10% adult rates) and increases to 30% adult rates in neonates born at term; adult rates (approximately 16–20 l/h/70 kg) are reached within the first year of life. NSAID clearance maturation, mostly through cytochrome P450 mixed oxidases, is more rapid. Concentration–response relationships suggest a maximum pain reduction of 5 or 6 on a 10-point scale for both drugs. Combination therapy does not increase this maximum effect but does prolong duration of analgesia. Whilst both drugs have good safety profiles, dosing of both drug groups is tempered by concerns about toxicity. Acetaminophen hepatotoxicity is associated with single doses (>250 mg/kg in preschool children, >150 mg/kg in adults) and therapy duration longer than 3–5 days (>90 mg/kg/day).The most common minor adverse events in NSAID recipients are nausea, dizziness, and headache. More concerning is the potential of NSAIDs to cause gastrointestinal irritation, blood clotting disorders, renal impairment, neutrophil dysfunction, and bronchoconstriction. These adverse effects are uncommon provided care is taken with drug dose, duration of therapy, and recognition of contraindications.

Cellular mechanism underlying oxytocin-stimulated Cl− secretion in rat cauda epididymal epithelium

The neurohypophyseal hormone oxytocin (OT) plays critical roles in lactation and parturition, while its function in male reproduction system is largely unknown. This study aims to investigate the effect of OT on regulating transepithelial ion transport in rat cauda epididymal epithelium. With the use of RT-PCR, Western blot, and immunohistochemical analysis, we found that OT receptor (OTR) was expressed and localized at the basal membrane of rat cauda epididymal epithelium. The short-circuit current ( Isc) measurement showed that basolateral application of OT to the primary cultured rat cauda epididymal epithelial cells elicited an increase in Isc, which was abrogated by pretreating the epithelial cells with CFTRinh-172, a blocker of cystic fibrosis transmembrane conductance regulator (CFTR). Pretreatment with the prostaglandin H synthase inhibitors indomethacin and piroxicam, or the nonselective antagonists of prostaglandin E2 (PGE2) receptor EP2 or EP4, AH-6809, and AH-23848, significantly attenuated OT-stimulated Isc response. Furthermore, the generation of PGE2 was measured using enzyme-linked immunosorbent assay, demonstrating that OT induced a substantial increase in PGE2 release from primary cultured rat cauda epididymal epithelial cells. In conclusion, activation of OTR by OT triggered PGE2 release, resulting in CFTR-dependent Cl− secretion through paracrine/autocrine pathways in rat cauda epididymal epithelium.

Cycle Network Model of Prostaglandin H Synthase-1

The kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was developed to investigate its complex network kinetics and non-steroidal anti-inflammatory drugs (NSAIDs) efficacy in different in vitro and in vivo conditions. To correctly describe the complex mechanism of PGHS-1 catalysis, we developed a microscopic approach to modelling of intricate network dynamics of 35 intraenzyme reactions among 24 intermediate states of the enzyme. The developed model quantitatively describes interconnection between cyclooxygenase and peroxidase enzyme activities; substrate (arachidonic acid, AA) and reducing cosubstrate competitive consumption; enzyme self-inactivation; autocatalytic role of AA; enzyme activation threshold; and synthesis of intermediate prostaglandin G2 (PGG2) and final prostaglandin H2 (PGH2) products under wide experimental conditions. In the paper, we provide a detailed description of the enzyme catalytic cycle, model calibration based on a series of in vitro kinetic data, and model validation using experimental data on the regulatory properties of PGHS-1. The validated model of PGHS-1 with a unified set of kinetic parameters is applicable for in silico screening and prediction of the inhibition effects of NSAIDs and their combination on the balance of pro-thrombotic (thromboxane) and anti-thrombotic (prostacyclin) prostaglandin biosynthesis in platelets and endothelial cells expressing PGHS-1.

Cycle network model of Prostaglandin H Synthase-1

The kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was developed to investigate its complex network kinetics and non-steroidal anti-inflammatory drugs (NSAIDs) efficacy in different in vitro and in vivo conditions. To correctly describe the complex mechanism of PGHS-1 catalysis, we developed a microscopic approach to modelling of intricate network dynamics of 35 intraenzyme reactions among 24 intermediate states of the enzyme. The developed model quantitatively describes interconnection between cyclooxygenase and peroxidase enzyme activities; substrate (arachidonic acid, AA) and reducing cosubstrate competitive consumption; enzyme self-inactivation; autocatalytic role of AA; enzyme activation threshold, and synthesis of intermediate PGG2 and final PGH2 products under wide experimental conditions. In the paper we provided the detailed description of the enzyme catalytic cycle, model calibration based on a series of in vitro kinetic data and model validation using experimental data on the regulatory properties of PGHS-1.The validated model of PGHS-1 with a unified set of kinetic parameters is applicable for in silico screening and prediction of the inhibition effects of NSAIDs and their combination on the balance of pro-thrombotic (thromboxane) and anti-thrombotic (prostacyclin) prostaglandin biosynthesis in platelets and endothelial cells expressing PGHS-1.

Pathophysiology of Intracranial Aneurysms

Background and Purpose: The pathophysiology of development, growth, and rupture of intracranial aneurysms (IAs) is only partly understood. Cyclooxygenase 2 (COX-2) converts arachidonic acid to prostaglandin H 2 , which, in turn, is isomerized to prostaglandin E 2 . In the human body, COX-2 plays an essential role in inflammatory pathways. This explorative study aimed to investigate COX-2 expression in the wall of IAs and its correlation to image features in clinical (1.0T, 1.5T, and 3.0T) magnetic resonance imaging (MRI) and ultra-high-field 7T MRI. Methods: The study group comprised 40 patients with partly thrombosed saccular IAs. The cohort included 17 ruptured- and 24 unruptured IAs, which had all been treated microsurgically. Formaldehyde-fixed paraffin-embedded samples were immunohistochemically stained with a monoclonal antibody against COX-2 (Dako, Santa Clara, CA; Clone: CX-294). We correlated Perls Prussian blue staining, MRI, and clinical data with immunohistochemistry, analyzed using the Trainable Weka Segmentation algorithm. Results: Aneurysm dome size ranged between 2 and 67 mm. The proportion of COX-2 positive cells ranged between 3.54% to 85.09%. An upregulated COX-2 expression correlated with increasing IA dome size ( P =0.047). Furthermore, there was a tendency of higher COX-2 expression in most ruptured IAs ( P =0.064). At all field strengths, MRI shows wall hypointensities due to iron deposition correlating with COX-2 expression ( P =0.022). Conclusions: Iron deposition and COX-2 expression in IAs walls correlate with signal hypointensity in MRI, which might, therefore, serve as a biomarker for IA instability. Furthermore, as COX-2 was also expressed in small unruptured IAs, it could be a potential target for specific medical treatment.

Prostacyclin Promotes Degenerative Pathology in a Model of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies, while epidemiological and experimental evidence suggests that the use of anti-inflammatory agents may be neuroprotective. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression significantly worsened multiple measures associated with amyloid disease pathologies. Mice overexpressing both amyloid and PGI2 exhibited impaired learning and memory and increased anxiety-like behavior compared with non-transgenic and PGI2 control mice. PGI2 overexpression accelerated the development of amyloid accumulation in the brain and selectively increased the production of soluble amyloid-β 42. PGI2 damaged the microvasculature through alterations in vascular length and branching; amyloid expression exacerbated these effects. Our findings demonstrate that chronic prostacyclin expression plays a novel and unexpected role that hastens the development of the AD phenotype.

ASPIRIN DOSIS RENDAH SEBAGAI USAHA PREVENTIF UNTUK IBU YANG BERISIKO TINGGI TERKENA PREEKLAMPSIA

ABSTRAK Pendahuluan: Preeklampsia merupakan salah satu penyebab utama kematian ibu hamil, janin, dan neonatus, terutama di negara-negara dengan pendapatan rendah dan sedang. Seorang ibu hamil dikatakan berisiko tinggi terkena preeklampsia apabila memiliki riwayat preeklampsia sebelumnya, hipertensi kronis, diabetes melitus, ataupun penyakit autoimun seperti systemic lupus erythematosus dan sindrom antifosfolipid. Komplikasi pada preeklampsia tentunya dapat meningkatkan angka mortalitas dan morbiditas ibu. Aspirin dosis rendah merupakan salah satu solusi untuk mencegah preeklampsia. Pembahasan: Aspirin bekerja dengan cara menginhibisi cycloocxygenase, yaitu suatu enzim yang bertanggung jawab untuk mengubah asam arakidonat menjadi prostaglandin. Enzim yang berperan dalam jalur cyclooxygenase yaitu COX-1 dan COX-2 (juga disebut prostaglandin H sintase) yang memediasi produksi prostaglandin, prostasiklin, dan tromboksan. Aspirin dapat menginhibisi COX-1 hanya dengan dosis rendah, sedangkan untuk COX-2 membutuhkan dosis yang lebih tinggi. COX-1 memediasi produksi TXA2 (tromboksan) yang meregulasi agragasi platelet dan vasokonstriksi sehingga dapat mencegah preeklampsia. Selain itu, pada kondisi hipoksia, aspirin juga dapat menginhibisi ekspresi sFlt-1 pada trofoblas sehingga menunjukan efek proangiogenik pada obat ini. Kesimpulan: Pemberian aspirin dapat menjadi usaha preventif terhadap kejadian preeklampsia dengan dosis 75-150 mg perhari, diberikan malam hari pada ibu dengan usia gestasi 16-20 minggu diberikan sampai usia gestasi 36 minggu bagi pasien risiko tinggi preeklampsia. Kata Kunci: aspirin, cyclooxygenase, preeklampsia, tromboksan ABSTRACT Introduction: Preeclampsia is one of the leading causes of death in pregnant women, fetuses, and neonates, especially in countries with low and moderate incomes. Pregnant woman with history of chronic hypertension, diabetes mellitus, or autoimmune diseases such as systemic lupus erythematosus and systemic antiphospholipids is a woman with high risk of preeclampsia. The complications that caused by preeclampsia of course can increase mother’s mortality and morbidity. Low-dose aspirin is one of the solutions for the prevention of preeclampsia. Discussion: Aspirin works by inhibiting cyclooxygenase, an enzyme that is responsible for converting arachidonic acid to prostaglandins. The enzymes involved in the cyclooxygenase pathway are COX-1 and COX-2 (also called prostaglandin H synthase) which mediate the production of prostaglandins, prostacyclin, and thromboxane. Aspirin can inhibit COX-1 only with a low dose, whereas for COX-2 requires a higher dose. COX1 mediates the production of TXA2 (thromboxane) which regulates platelet and vasoconstrictive aggression to prevent preeclampsia. Furthermore, in hypoxic conditions, aspirin can also inhibit the expression of sFlt-1 on the trophoblast, thus showing a proangiogenic effect on this drug. Conclusion: 75-150 mg per day of Aspirin can be a preventive effort for preeclampsia, given at night start from 16-20 weeks of gestation and stop until 36 weeks of gestation for patients with high risk of preeclampsia. Keywords: aspirin, cyclooxygenase, preeclampsia, thromboxane