6343189
Mechanisms of angiotensin converting enzyme inhibitor-induced IOP reduction in normotensive rats.
Angiotensin converting enzyme inhibitors (ACEIs) have been shown to lower intraocular pressure (IOP). Since, the ACEIs cause increased tissue prostaglandin levels, we hypothesized that the mechanisms of ACEI-induced IOP reduction have similarity with those of prostaglandin analogs. The present study investigated the involvement of matrix metalloproteinases (MMPs) and cytokine activity modulation as the underlying mechanisms of ACEI-induced ocular hypotension. The IOP lowering effect of single drop of enalaprilat dehydrate 1% was evaluated in rats pretreated with a broad spectrum MMP inhibitor or a cytokine inhibitor. Effect of angiotensin receptor blocker, losartan potassium 2%, was also studied to evaluate involvement of angiotensin II receptor type 1 (AT1) in IOP lowering effect of ACEI. Topical treatment with single drop of enalaprilat resulted in significant IOP reduction in treated eye with mean peak reduction 20.3% at 3h post-instillation. Treatment with losartan resulted in a peak IOP reduction of 13.3%, which was significantly lower than enalaprilat, indicating involvement of mechanisms in addition to AT1 blockade. Pretreatment with a broad spectrum MMP inhibitor or a cytokine inhibitor significantly attenuated the enalprilat-induced IOP reduction with mean peak IOP reduction of 11.2% and 13.6% respectively. The IOP-lowering effect of enalaprilat seems to be attributed to reduced angiotensin II type 1 receptor stimulation and modulation of MMP and cytokines activities.
22333721
Current concepts in the pathophysiology of glaucoma
Glaucoma, the second leading cause of blindness, is characterized by changes in the optic disc and visual field defects. The elevated intraocular pressure was considered the prime factor responsible for the glaucomatous optic neuropathy involving death of retinal ganglion cells and their axons. Extensive investigations into the pathophysiology of glaucoma now reveal the role of multiple factors in the development of retinal ganglion cell death. A better understanding of the pathophysiological mechanisms involved in the onset and progression of glaucomatous optic neuropathy is crucial in the development of better therapeutic options. This review is an effort to summarize the current concepts in the pathophysiology of glaucoma so that newer therapeutic targets can be recognized. The literature available in the National Medical Library and online Pubmed search engine was used for literature review.
23113580
Future Target Molecules in Antiglaucoma Therapy: TGF-β May Have a Role to Play
Glaucoma, a leading cause of irreversible blindness, is often associated with increased resistance to aqueous outflow in trabecular tissue. Increased outflow resistance has been attributed to increased extracellular matrix (ECM) deposition in trabecular tissue. A critical balance between the synthesis and breakdown of the components of extracellular tissue is important in keeping the intraocular pressure within the normal range. Multiple mechanisms have been shown to affect ECM turnover in trabecular tissue. In this review, we examine the related literature to understand the role of TGF-β in ECM turnover, in the development and progression of glaucoma, and in possible therapeutic strategies that can be devised by targeting the TGF-β signaling pathways.
5792982
Therapeutic potential of Curcuma longa, the golden spice of India, in drug discovery for ophthalmic diseases
Background: Curcuma longa is among the most commonly used spices in India and other Asian countries. The herb has also been used in Ayurveda and other traditional systems of medicine for the prevention and treatment of a variety of ailments. Curcuminoids are the major chemical constituents of C. longa that are of medicinal importance. Today, a large body of scientific evidence exists to indicate potential therapeutic benefits of C. longa. Several preclinical and clinical studies have investigated the pharmacological properties of C. longa and results indicate strong therapeutic potential for anti-inflammatory, antioxidant, antibacterial, anticancer and many other properties. Objective: This review summarizes the scientific evidences showing possible benefits of C. longa in a variety of ophthalmic diseases. Conclusion: Although the putative mechanism(s), molecular targets and range of therapeutic applications have been researched widely, further investigations are needed to explore the true therapeutic potential and future of curcuminoids as novel drug molecules in ophthalmic diseases.
18999099
Pathogenetic role of magnesium deficiency in ophthalmic diseases
Magnesium is one of the most important regulatory cation involved in several biological processes. It is important for maintaining the structural and functional integrity of several vital ocular tissues such as cornea, lens and retina. The magnesium content of lens, especially in its peripheral part, is higher than that in aqueous and vitreous humor. Magnesium has also been shown to play critically important role in retinal functions. Magnesium plays significant role as a cofactor for more than 350 enzymes in the body and regulates neuroexcitability and several ion channels. Membrane associated ATPase functions that are crucial in regulating the intracellular ionic environment, are magnesium-dependent. Moreover, the enzymes involved in ATP production and hydrolysis are also magnesium-dependent. Magnesium deficiency by interfering with ATPase functions causes increased intracellular calcium and sodium and decreases intracellular potassium concentration. Such ionic imbalances in turn alter the other cellular enzymatic reactions and form the basis of the association of magnesium deficiency with ophthalmic diseases such as cataract. In presence of magnesium deficiency, an imbalance between mediators of vasoconstriction and vasorelaxation may underlie the vasospasm, which is one of the pathogenic factors in primary open angle glaucoma. Furthermore, magnesium deficiency is also a contributing factor in increased oxidative stress and inducible NOS stimulation that can further contribute in the initiation and progression of ocular pathologies such as cataract, glaucoma and diabetic retinopathy. In this paper we review the association of disturbances of magnesium homeostasis with several ophthalmic diseases.
11594402
Intraocular Pressure-Lowering Activity of Topical Application of Aegle Marmelos Fruit Extract in Experimental Animal Models
Aim: The present study was designed to evaluate the intraocular pressure (IOP)-lowering activity of topical application of the aqueous extract of Aegle marmelos fruit in experimental animal models. Materials and Methods: New Zealand white rabbits with normal and experimentally elevated IOP using water loading and steroid-induced models were included in this study. The IOP-lowering effect of A. marmelos fruit extract in rabbits with experimentally elevated IOP was also compared with that of timolol 0.25%. Results: In rabbits with normal IOP, the A. marmelos fruit extract at a concentration of 1% showed the maximum IOP-lowering effect with 22.81% reduction from baseline IOP. The maximum IOP reduction achieved in water loading and steroid-induced models with the same concentration of A. marmelos was 27.57 and 28.41% from baseline, respectively. The efficacy was comparable to that of timolol after 45 min of water loading in the water loading model, and during the first 2 h of treatment in the steroid-induced model. Conclusion: A. marmelos fruit extract showed significant IOP-lowering activity in experimental animal models.
1329844
Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-beta levels.
Progression of renal failure, despite renoprotection with angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuric nephropathies, may be caused by persistent renal production of transforming growth factor-beta1 (TGF-beta1) through the angiotensin II subtype 1 (AT1) receptors. We tested the hypothesis that AT1-receptor blocker therapy added to a background of chronic maximal ACE inhibitor therapy will result in a reduction in urinary TGF-beta1 levels in such patients. Sixteen patients completed a two-period, crossover, randomized, controlled trial, details of which have been previously reported. All patients were administered lisinopril, 40 mg/d, with either losartan, 50 mg/d, or placebo. Blood pressure (BP) was measured using a 24-hour ambulatory BP monitor. Overnight specimens of urine were analyzed for urine TGF-beta1, protein, and creatinine concentrations. Mean age of the study population was 53 +/- 9 (SD) years; body mass index, 38 +/- 5.7 kg/m2; seated BP, 156 +/- 18/88 +/- 12 mm Hg; and urine protein excretion, 3.6 +/- 0.71 g/g of creatinine. Twelve patients had diabetic nephropathy, and the remainder had chronic glomerulonephritis. At baseline, urinary TGF-beta1 levels were significantly increased in the study population compared with healthy controls (13.2 +/- 1.2 versus 1.7 +/- 1.1 ng/g creatinine; P < 0.001). There was a strong correlation between baseline urine protein excretion and urinary TGF-beta1 level (r2 = 0.53; P = 0.001), as well as systolic BP and urinary TGF-beta1 level (r2 = 0.57; P < 0.001). After 4 weeks of add-on losartan therapy, there was a 38% (95% confidence interval [CI], 16% to 55%) decline in urinary TGF-beta1 levels (13.3 [95% CI, 11.4 to 15.5] to 8.2 pg/mg creatinine [95% CI, 6.2 to 10.7]). The reduction in urinary TGF-beta1 levels occurred independent of changes in mean urinary protein excretion or BP. Thus, proteinuric patients with renal failure, despite maximal ACE inhibition, had increased urinary levels of TGF-beta1 that improved over 1 month of add-on therapy with losartan. We speculate that dual blockade with losartan and an ACE inhibitor may provide additional renoprotection by decreasing renal production of TGF-beta1.
5643940
Individualizing decision-making--resurrecting the doctor-patient relationship in the anemia debate.
Among patients with chronic kidney disease (CKD), erythropoiesis-stimulating agents (ESAs) are approved for avoiding transfusions, a risk that increases when hemoglobin (Hgb) falls to <10 g/dl. Transfusions increase sensitization, prolong the waiting time to and the likelihood of transplantation, and when transplantation is performed worsen graft survival. Accordingly, the risk of transfusion among those expecting transplantation is comparable to that of cardiovascular events. Nonetheless, targeting Hgb to >13 g/dl is associated with increased cardiovascular events. Paradoxically, if this level is achieved mortality is lower. The anemia paradox--higher cardiovascular events when targeting higher Hgb but lower events when patients achieve these targets--appears to be at least partially attributable to a hyporesponse to ESAs. Whether it is the ESAs or conditions that lead to the increased ESA dose that provokes morbidity cannot be answered definitively at present. The lowest ESA dose to achieve the desired level of anemia correction appears to be a safer strategy. In acute illnesses, reducing the dose of ESAs or stopping it altogether may aggravate anemia, but this may be permissible. The rate of rise in Hgb>1 g/dl in any 2-week period is associated with an increase in blood pressure (BP) and poor outcomes. Accordingly, while initiating and maintaining ESA therapy, monitoring BP at home twice daily is warranted. The clinical decision-making process in managing anemia should consider the risks of transfusion; kidney transplant potential; presence of cancer; and the risks of stroke, heart failure, and possibly death. Above all, clinical decision-making should incorporate patient preference.
19545652
What can we learn from null randomized controlled trials?
Cardiovascular disease is an important cause of mortality and morbidity in patients with CKD. Elevated serum phosphorus concentration is associated with an increased cardiovascular event rate. Recent data suggest that even in the normal range, serum phosphorus concentration is associated with an
27402652
Primary peritoneal carcinoma: a diagnostic dilemma
We read with deep interest the report by Bhuyan et al. [1] detailing diagnosis and management aspects of extra ovarian primary peritoneal carcinoma (EOPPC). Indeed the clinician is intrigued by the presentation of EOPPC and equally challenging is the management because of limited guidance available in literature with these tumours. We recently diagnosed EOPPC in a 62-year-old lady and would like to share the atypical presentation of the carcinoma. This patient had received six cycles of chemotherapy (paclitexal and cisplatin) for papillary adenocarcinoma. At prior exploratory laparotomy, there was an inoperable mass adherent to transverse colon serosa with liver metastasis. As no primary site of tumour was discernable, biopsies from peritoneum and peritoneal washings were taken revealing papillary adenocarcinoma. Post chemotherapy, computed tomography scan showed resolution of ascitis, normal-sized bilateral adnexa and uterus; however, omental thickening and liver metastasis still persisted. Serum CA125 level decreased from 200 to 17.5 IU/ml. At subsequent debulking laparotomy, there was no free Xuid in abdomen but a large desmoplastic transverse colon [2] was seen. The uterus with bilateral adnexa was normal in size and shape; however, multiple hard peritoneal deposits ranging 1–10 cm in size were present in the mesentery, inWltrating up to the wall of transverse colon. Panhysterectomy and resection of transverse colon mass was done. The second laparotomy again could not reveal the primary site of tumour. Repeated histopathology of colonic segment showed serous papillary adenocarcinoma with numerous psammoma bodies inWltrating serosa and reaching up to muscularis propria. Both ovaries showed superWcial cortical involvement by the same tumour (Figs. 1, 2). Serosal aspect of both fallopian tubes, mesentery and parametrium were also studded with the same tumour. Since the gynaecologic oncology group criteria were fulWlled in our case, a diagnosis of EOPPC was rendered [3]. In our case, positive immunostaining for pan-cytokeratin (CK) and estrogen receptor, and negative staining for calretinin further supported the
11453581
Proinflammatory effects of oxidative stress in chronic kidney disease: role of additional angiotensin II blockade.
Oxidative stress plays an important role in causing progressive chronic kidney disease (CKD). We examined the influence of add-on ANG II receptor blockade administered as losartan (50 mg/day for 1 mo) on oxidative stress and proinflammatory state of the kidney in patients with CKD. All subjects were taking an angiotensin-converting enzyme inhibitor plus other antihypertensive agents. Oxidative stress to lipids and proteins was measured by an HPLC assay for malondialdehyde (MDA) and carbonyl concentration, respectively. Urinary inflammation was measured by monocyte chemotactic protein-1 (MCP-1) excretion rate. The etiology of CKD was type 2 diabetes mellitus in 12 and glomerulonephritis in 4 patients. There was no change in proteinuria or 24-h ambulatory blood pressure (BP) with add-on ANG II receptor blockade with losartan therapy. Before losartan therapy, urinary protein and albumin oxidation were 99 and 71% higher, respectively, compared with in plasma (P < 0.05). There was a 35% reduction in urinary oxidized albumin with add-on losartan therapy (P = 0.036). Urinary and plasma MDA were elevated compared with age-matched controls. Urinary MDA was significantly reduced from 4.75 +/- 3.23 to 3.39 +/- 2.17 micromol/g creatinine with add-on losartan therapy. However, plasma MDA or oxidized proteins did not change in response to additional ANG II blockade. A good correlation was seen between the change in urinary oxidized albumin and MCP-1 levels (r = 0.61, P = 0.012). These data demonstrate that oxidative damage to urinary protein and lipids can be reduced with additional ANG II receptor blockade, independently of reductions in proteinuria or BP. Urinary measurements of markers of oxidative damage to lipids and proteins appear to be more sensitive than plasma measurements in patients with CKD. The significant association of the change in urinary MCP-1 with a reduction in oxidative stress supports the role of the redox state in the kidney with renal fibrosis and progressive kidney damage.