The risk of uveitis due to prostaglandin analogs in pediatric glaucoma.

PURPOSE: To examine the incidence of uveitis in children prescribed prostaglandin analogs (PGAs) for glaucoma. METHODS: In this dual-center cohort study, the medical records of consecutive patients <18 years old treated with a PGA between January 1, 2012, and December 31, 2018, were reviewed retrospectively. Patients with all forms of glaucoma, including those with a prior history of uveitis, were included. Patients who had been on a PGA prior to their first recorded visit were excluded. Patient charts were reviewed for new or recurrent uveitis during the first year of PGA therapy. RESULTS: A total of 103 children (147 eyes) were included, with a total PGA exposure of 1,352 child-months. Ninety-eight children (142 eyes) tolerated the PGA without an episode of uveitis. Five patients with a documented prior history of uveitis experienced a unilateral episode of uveitis. A review of their medical records identified prescribed or unscheduled decrease in topical steroids or immunosuppressive medication as the most likely cause of uveitis recurrence. CONCLUSIONS: This study provides further evidence that PGAs are unlikely to induce uveitis in children being treated for glaucoma and suggests that this may also be true in those with a history of uveitis. We are unable to evaluate whether PGAs make recurrence more likely or the tapering of steroids more difficult.

A comparison of country-level data from the VISIONARY study examining treatment outcomes with preservative-free tafluprost/timolol fixed-dose combination therapy.

OBJECTIVE: Analysis and comparison of country-level data from the VISIONARY study, examining treatment outcomes with the topical fixed-dose combination of preservative-free tafluprost (0.0015%) and timolol (0.5%) (PF tafluprost/timolol FC) in adults with open-angle glaucoma (OAG) and ocular hypertension (OHT) who were insufficiently treated with or unable to tolerate either beta-blocker or prostaglandin analogue (PGA) topical monotherapy. METHODS: A European, prospective, observational study was conducted in 11 countries. Adults with OAG/OHT were switched to the PF tafluprost/timolol FC from either PGA or beta-blocker topical monotherapy. Statistical analysis examined changes in mean standard deviation (SD) intraocular pressure (IOP) from baseline at Week 4, Week 12 and Month 6. Data were documented for each eye separately at baseline and during follow up visits, with the eye reported to have the higher IOP (mmHg), as measured using Goldmann applanation tonometry, being selected for analysis (study eye). Country-level subanalysis examined outcomes by prior monotherapy, diagnosis and timing of dosing for those countries recruiting ≥20 patients (Country-level Subanalysis Population). Two-sided paired t-test was used to assess significance regarding mean IOP reduction from baseline and a compound symmetry covariance model was used in cross-country comparisons regarding variation in IOP change from baseline. Treatment-related adverse events (AEs) were evaluated. RESULTS: Mean (SD) age among patients recruited to the VISIONARY study ranged between 63.9 (11.8) and 72.4 (10.6) years across all countries. The majority of participants (>50%) were female in each country. The Country-level Subanalysis Population included 551 eyes. Mean (SD) IOP was significantly reduced from baseline in each country at Week 4, Week 12 and Month 6 (p < .0001). Mean IOP reduction at Month 6 ranged from 5.0 mmHg (22.6%, Hungary) to 7.8 mmHg (31.8%, Latvia) and varied significantly between countries (p < .001). The greatest reductions were in Latvia and Russia, where baseline IOP was highest. Country-level IOP reductions were significant irrespective of prior monotherapy, diagnosis or dosing time (p < .0001). Most treatment-related AEs occurred in the UK (26 events, 73% mild). One serious AE was reported (Russia, status asthmaticus). Tolerability with PF tafluprost/timolol FC therapy was rated as good/very good by most patients (85.7-100%) in all countries. CONCLUSION: Subanalysis of VISIONARY study data revealed significant IOP reductions following a switch to the PF tafluprost/timolol FC from either PGA or beta-blocker topical monotherapy. Cross-country variation was likely due to baseline IOP differences. Within country, outcomes were consistent regardless of diagnosis, dosing or prior monotherapy. Treatment was generally well tolerated.

Switching to Preservative-Free Tafluprost/Timolol Fixed-Dose Combination in the Treatment of Open-Angle Glaucoma or Ocular Hypertension: Subanalysis of Data from the VISIONARY Study According to Baseline Monotherapy Treatment.

INTRODUCTION: The VISIONARY study demonstrated statistically significant intraocular pressure (IOP) reductions with the preservative-free fixed-dose combination of tafluprost 0.0015% and timolol 0.5% (PF tafluprost/timolol FC) in open-angle glaucoma (OAG) or ocular hypertension (OHT) patients, sub-optimally controlled with topical prostaglandin analogue (PGA) or beta-blocker monotherapy. Current subanalyses have examined these data according to the baseline monotherapy. METHODS: A European, prospective, observational study included adults (aged ≥ 18 years) with OAG or OHT, who were switched to the PF tafluprost/timolol FC from PGA or beta-blocker monotherapy. Treatment outcomes were reported according to prior monotherapy subgroup: beta-blocker, preserved latanoprost, PF-latanoprost, bimatoprost, tafluprost, and travoprost. Endpoints included the mean change from baseline regarding IOP, conjunctival hyperemia, and corneal fluorescein staining (CFS) at Week 4 and Week 12, and at Month 6. RESULTS: The subanalysis included 577 patients. All prior monotherapy subgroups demonstrated statistically significant IOP reductions from baseline at Week 4, that were maintained through Month 6 (p < 0.001). Mean (SD) IOP change at Month 6 was 6.6 (4.16), 6.3 (4.39), 5.6 (3.67), 4.9 (2.97), 4.6 (4.39), and 4.7  (3.64) mmHg for prior beta-blocker, preserved latanoprost, PF-latanoprost, tafluprost, bimatoprost, and travoprost subgroups, respectively. The largest IOP change was observed in the preserved latanoprost subgroup for each of the ≥ 20%, ≥ 25%, ≥ 30%, and ≥ 35% IOP reduction categories at Month 6, demonstrating respective reductions of 8.06, 9.20, 10.64, and 11.55 mmHg. CFS was significantly reduced at Month 6 in the prior bimatoprost subgroup (p = 0.0013). Conjunctival hyperemia severity was significantly reduced at each study visit for prior preserved latanoprost users (p < 0.001). CONCLUSION: PF tafluprost/timolol FC therapy provided statistically and clinically significant IOP reductions from Week 4 over the total 6-month period, in patients with OAG/OHT, regardless of the type of prior PGA or beta-blocker monotherapy used. Conjunctival hyperemia severity and CFS decreased significantly in prior bimatoprost and preserved latanoprost users, respectively. CLINICAL STUDY NUMBER: European Union electronic Register of Post-Authorization Studies (EU PAS) register number: EUPAS22204.

Relationships of dermatologic symptoms and quality of life in patients with psoriatic arthritis: analysis of two tofacitinib phase III studies.

OBJECTIVES: Evaluate relationships between changes in dermatologic assessments and quality of life (QoL) measures; quantify dermatologic symptom severity impacts on QoL in patients with psoriatic arthritis (PsA) treated with tofacitinib. METHODS: Data were from two phase III studies; patients received tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg every other week, or placebo advancing to tofacitinib 5 or 10 mg BID at Month 3. Repeated measures longitudinal models assessed relationships between dermatologic assessments (predictors) Itch Severity Item (ISI), Physician's Global Assessment of Psoriasis (PGA-PsO), and Patient's Global Joint and Skin Assessment-Visual Analog Scale-Psoriasis question (PGJS-VAS-PsO), and QoL measures (outcomes) Dermatology Life Quality Index (DLQI) and Short Form-36 Health Survey Version 2 (SF-36v2). Models included one predictor and one outcome. RESULTS: Direct, approximately linear relationships existed between predictors and outcomes. ISI/PGA-PsO/PGJS-VAS-PsO improvements from baseline of ≥3/≥2/≥40-mm VAS corresponded with clinically meaningful DLQI improvements; improvements from baseline of ≥4/≥3/≥40-mm VAS generally corresponded with clinically meaningful improvements across component scores and all SF-36v2 domains. CONCLUSIONS: Substantial links exist between dermatologic symptoms and QoL in patients with PsA, potentially informing patient-centered care and research. Rheumatologists should be aware of dermatologic manifestations and QoL impacts in patients with PsA. CLINICALTRIALS.GOV: NCT01877668; NCT01882439.

Comparative effects of latanoprost and latanoprostene bunod on intraocular pressure and pupil size in ophthalmologically normal Beagle dogs.

OBJECTIVE: To compare effects of latanoprost, a topical prostaglandin analogue (PGA) commonly used to treat glaucoma and lens instability in dogs, and latanoprostene bunod, a novel PGA with a nitric oxide-donating moiety, on intraocular pressure (IOP) and pupil diameter (PD). ANIMALS STUDIED: Ten ophthalmologically normal Beagle dogs. PROCEDURES: Dogs were treated twice a day for 5 days in a randomly selected eye with either latanoprost or latanoprostene bunod. After a 6-week washout period, dogs were treated with the opposite drug. IOP and PD were measured at treatment times, at midday on days 1 and 5, and for 6 days post-treatment. RESULTS: Both drugs significantly decreased IOP and PD. At midday on day 5 of treatment, mean IOP in eyes treated with latanoprost was 4.5 mmHg lower than the fellow eye and 3.0 mmHg lower than the same eye at baseline, while mean IOP in eyes treated with latanoprostene bunod was 5.5 mmHg lower than the fellow eye and 3.6 mmHg lower than baseline. Mean PD was 0.94 mm in eyes treated with latanoprost and 0.76 mmHg in eyes treated with latanoprostene bunod. There was no significant difference between the two drugs for either parameter at that time point (p = .372 and .619, respectively, for IOP relative to control and to baseline; p = .076 for PD) or when analyzed longitudinally. Significant diurnal variation in PD was noted and may have implications for treatment of lens' instability. CONCLUSIONS: Latanoprost and latanoprostene bunod produce similar IOP reduction and miosis in normal canine eyes.

Treatment of Open-Angle Glaucoma and Ocular Hypertension with Preservative-Free Tafluprost/Timolol Fixed-Dose Combination Therapy: Results from the VISIONARY Study Population in Spain.

Purpose: Data are presented from ophthalmology clinics in Spain participating in the VISIONARY study, examining the effectiveness, tolerability, and safety of the preservative-free tafluprost (0.0015%) and timolol (0.5%) fixed-dose combination (PF tafluprost/timolol FC) in the treatment of OAG and OHT. Methods: An observational, multicenter prospective study examined treatment outcomes following a switch to PF tafluprost/timolol FC in adult OAG/OHT patients demonstrating insufficient response to beta-blocker or prostaglandin analog (PGA) monotherapy. Primary end point was mean change in intraocular pressure (IOP) from baseline at month 6. Changes in the severity of ocular signs and symptoms were also assessed. Results: Overall, 92 patients (51.1% female) were included. Mean (standard deviation) age was 68.3 (12.1) years. Mean IOP was reduced from 21.9 mmHg at baseline to 16.7 mmHg at month 6 (22.3% decrease; P < 0.0001). Significant IOP reductions were observed at weeks 4 and 12 (P < 0.0001). Baseline PGA and beta-blocker users demonstrated mean month 6 IOP reductions of 5.5 mmHg (23.5%; P < 0.001) and 3.5 mmHg (14.6%; P = 0.029), respectively. Severity of conjunctival hyperemia, dry eye, irritation, itching, foreign body sensation, and eye pain was significantly reduced. Three treatment-related adverse events were reported, all were nonserious and mild/moderate in severity. Conclusion: In real-world clinical practice, PF tafluprost/timolol FC treatment provided significant IOP reductions over 6 months and was well tolerated among OAG/OHT patients showing poor response to PGA or beta-blocker monotherapy. IOP-lowering efficacy and improvements in ocular signs and symptoms were evident from week 4 and maintained over the 6-month study period. Trial Registration: European Union electronic Register of Post-Authorisation Studies (EU PAS) register number EUPAS22204.

Short-term efficacy of latanoprostene bunod for the treatment of open-angle glaucoma and ocular hypertension: a systematic literature review and a network meta-analysis.

BACKGROUND/AIMS: To assess the comparative efficacy of latanoprostene bunod (LBN), a novel prostaglandin analogue (PGA), to other medications for open-angle glaucoma and ocular hypertension on lowering intraocular pressure (IOP). METHODS: A systematic literature review adapted from the Li et al (Ophthalmology, 2016) study was conducted. Medline, Embase and PubMed were searched for randomised controlled trials published between 1 January 2014 and 19 March 2020. Studies had to report IOP reduction after 3 months for at least two different treatments among placebo, PGAs (bimatoprost 0.01%, bimatoprost 0.03%, latanoprost, LBN, tafluprost, unoprostone) or apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide, levobunolol, timolol, travoprost. A Bayesian network meta-analysis was performed to provide the relative effect in terms of mean difference (95% credible interval) of IOP reduction and ranking probabilities. Surface under the cumulative ranking curve (SUCRA) was generated. RESULTS: A total of 106 trials were included with data for 18 523 participants. LBN was significantly more effective than unoprostone (-3.45 (-4.77 to -2.12)). Although relative effect was not significative, compared with other PGAs, LBN numerically outperformed latanoprost (-0.70 (-1.83 to 0.43)) and tafluoprost (-0.41 (-1.87 to 1.07)), was similar to bimatoprost 0.01% (-0.02(-1.59 to 1.55)) and was slightly disadvantaged by bimatoprost 0.03% (-0.17 (-1.42 to 1.07)). LBN was significantly more efficient than the beta-blockers apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide and timolol. According to SUCRA, LBN was ranked second after bimatoprost 0.03%, followed by bimatoprost 0.01%. CONCLUSION: LBN was significantly more effective than the PGA unoprostone and most of the beta-blockers. Compared with the most widely used PGAs, LBN numerically outperformed latanoprost and travoprost and was similar to bimatoprost 0.01%.

Prostaglandin A1 Inhibits the Cognitive Decline of APP/PS1 Transgenic Mice via PPARγ/ABCA1-dependent Cholesterol Efflux Mechanisms.

Prostaglandins (PGs) are early and key contributors to chronic neurodegenerative diseases. As one important member of classical PGs, PGA1 has been reported to exert potential neuroprotective effects. However, the mechanisms remain unknown. To this end, we are prompted to investigate whether PGA1 is a useful neurological treatment for Alzheimer's disease (AD) or not. Using high-throughput sequencing, we found that PGA1 potentially regulates cholesterol metabolism and lipid transport. Interestingly, we further found that short-term administration of PGA1 decreased the levels of the monomeric and oligomeric ß-amyloid protein (oAß) in a cholesterol-dependent manner. In detail, PGA1 activated the peroxisome proliferator-activated receptor-gamma (PPARγ) and ATP-binding cassette subfamily A member 1 (ABCA1) signalling pathways, promoting the efflux of cholesterol and decreasing the intracellular cholesterol levels. Through PPARγ/ABCA1/cholesterol-dependent pathway, PGA1 decreased the expression of presenilin enhancer protein 2 (PEN-2), which is responsible for the production of Aß. More importantly, long-term administration of PGA1 remarkably decreased the formation of Aß monomers, oligomers, and fibrils. The actions of PGA1 on the production and deposition of Aß ultimately improved the cognitive decline of the amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice.

[An example of oscillatory (cyclic) reaction for prostaglandin chemistry].

It is shown an ability of prostaglandin A1 to the oscillatory reaction which has significance both the theoretical and practical if prostaglandins are used for therapy.

LipoCardium: endothelium-directed cyclopentenone prostaglandin-based liposome formulation that completely reverses atherosclerotic lesions.

Atherosclerosis is a multifactorial inflammatory disease of blood vessels which decimates one in every three people in industrialized world. Despite the important newest clinical approaches, currently available strategies (e.g. nutritional, pharmacological and surgical) may only restrain the worsening of vascular disease. Since antiproliferative cyclopentenone prostaglandins (CP-PGs) are powerful anti-inflammatory agents, we developed a negatively charged liposome-based pharmaceutical formulation (LipoCardium) that specifically direct CP-PGs towards the injured arterial wall cells of atherosclerotic mice. In the blood stream, LipoCardium delivers its CP-PG contents only into activated arterial wall lining cells due to the presence of antibodies raised against vascular cell adhesion molecule-1 (VCAM-1), which is strongly expressed upon inflammation by endothelial cells and macrophage-foam cells as well. After 4 months in a high-lipid diet, all low-density lipoprotein receptor-deficient adult control mice died from myocardium infarction or stroke in less than 2 weeks, whereas LipoCardium-treated (2 weeks) animals (still under high-lipid diet) completely recovered from vascular injuries. In vitro studies using macrophage-foam cells suggested a tetravalent pattern for LipoCardium action: anti-inflammatory, antiproliferative (and pro-apoptotic only to foam cells), antilipogenic and cytoprotector (via heat-shock protein induction). These astonishing cellular effects were accompanied by a marked reduction in arterial wall thickness, neointimal hyperplasia and lipid accumulation, while guaranteed lifespan to be extended to the elderly age. Our findings suggest that LipoCardium may be safely tested in humans in a near future and may have conceptual implications in atherosclerosis therapy.

Enhancement of neuroprotection and heat shock protein induction by combined prostaglandin A1 and lithium in rodent models of focal ischemia.

Both prostaglandin A(1) (PGA(1)) and lithium have been reported to protect neurons against excitotoxic and ischemic injury. The present study was undertaken to examine the effects of lithium and PGA1 on heat shock proteins (HSP) and the growth arrest and DNA-damage-inducible gene (GADD153) and to evaluate if lithium could potentiate PGA(1)'s neuroprotective effects against cerebral ischemia. Rats were pretreated with a subcutaneous injection of lithium for 2 days and a single intracerebral ventricle administration of PGA(1) 15 min before ischemic insult. Brain ischemia was induced by a permanent middle cerebral artery occlusion. The infarct volume, motor behavior deficits and brain edema were analyzed 24 h after ischemic insult. The result showed that PGA(1) significantly reduced infarct volume, neurological deficits and brain edema. Except for neurological deficit, lithium enhanced PGA(1)'s neuroprotection. The neuroprotective effects of PGA(1) were associated with an up-regulation of cytoprotective heat shock proteins HSP70 and GRP78 in the ischemic brain hemisphere as determined by immunoblotting and immunofluorescence. The induction of HSP70 and GRP78 was enhanced by lithium. However, although the expression of GADD153 was enhanced significantly after pMCAO, it was not influenced by either PGA(1) or lithium or their combination. These studies suggest that lithium can potentiate PGA(1)'s neuroprotective effects and thus may have potential clinical value for the treatment of stroke in combination with other neuroprotective agents.

[Ten years' experience in continuous intravenous epoprostenol therapy in severe pulmonary arterial hypertension]. / Experiencia de 10 años en el tratamiento con epoprostenol en perfusión intravenosa continua en hipertensión pulmonar arterial grave.

INTRODUCTION: Primary pulmonary hypertension and its associated forms is a progressive and often fatal disease, the course of which has been favourably modified by prostacyclin therapy in the last decade. OBJECTIVE: The aim of this study is to analize retrospectively the efficacy of continuous intravenous epoprostenol (synthetic prostacyclin) therapy in pulmonary arterial hypertension, and to compare it with conventional therapy (anticoagulants, digoxin and diuretics). METHODS: Between 1990-2000, 31 patients with severe precapillary pulmonary hypertension in functional class III or IV went on continuous intravenous epoprostenol therapy, administered by a portable infusion pump through a Hickman catheter. We compared their survival with a group of 16 patients treated with conventional therapy alone. RESULTS: Time of follow-up was 33.25 months in the prostacyclin group and 20 months in the conventional group. The one- three- and five- year survival rates were 86%, 50% and 38% respectively for patients treated with epoprostenol compared with 40%, 40% and 8% survival rates at idetical periods for patients treated conventionally (p = 0,02). Functional class and the mean distance walked in the 6 minutes test were improved in patients treated with prostacyclin (p < 0,01). Serious complications attributable to the delivery system included 3 deaths, mainly due to infection. CONCLUSION: Continuous intravenous epoprostenol therapy improves survival and exercise capacity in patients with severe pulmonary arterial hypertension despite potentially serious complications attributable to the delivery system.

The role of some prostaglandin analogues in experimental intoxication produced by carbon tetrachloride in rats.

Prostaglandins are synthesized ubiquitously in the body from unsaturated fatty acids and they act as paracrine messengers. We have studied the influence of a prostaglandin analogue on experimental induced hepatopathy. The tested compound is a synthetic isopropyl ester of PGF2 alpha (IPEF) and as hepato-toxic agent we used CCl4. We worked on four groups of 4 adult male rats each. Group I received no substance; Group II received CCl4 0.1 ml/bw/per os, single dose, for three days; Group III received CCl4 as series I and IPEF 15 micrograms/bw i.p., single dose daily, one hour before CCl4 administration; Group IV received CCl4 as series I and IPEF 50 micrograms/bw i.p., single dose daily. Twenty-four hours after the last administration, samples of blood were taken and ALT, AST, LDH as well as conjugate and unconjugate bilirubin were determined. We also determined MDH, GSH and glutathion peroxidase, in liver homogenate. Our data show that MDH levels are increased in Group I (20.81 +/- 3.15 microM/microgram protein) as compared with both Group III (8.44 +/- 1.32 microM/microgram protein) and IV (7.31 +/- 1.92 microM/microgram protein) which might suggest that prostaglandin analogue IPEF decreases the polyunsaturated fatty acids degradation, at both low and high level. ALAT levels for group that received CCl4 (782 +/- 20.8 U/L) are significantly higher than those for group III (264 +/- 15.4 U/L) and IV (227 +/- 8.4 U/L) which received IPEF at low, respectively high dose. Our data suggest that the synthetic prostaglandin analogue presents stabilizing membrane effects (plasmatic and membrane of some cellular organelles) and reduces peroxide radicals production.

Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size.

This study was designed to investigate the effects of various chemically distinct activators of PPAR-gamma and PPAR-alpha in a rat model of acute myocardial infarction. Using Northern blot analysis and RT-PCR in samples of rat heart, we document the expression of the mRNA for PPAR-gamma (isoform 1 but not isoform 2) as well as PPAR-beta and PPAR-alpha in freshly isolated cardiac myocytes and cardiac fibroblasts and in the left and right ventricles of the heart. Using a rat model of regional myocardial ischemia and reperfusion (in vivo), we have discovered that various chemically distinct ligands of PPAR-gamma (including the TZDs rosiglitazone, ciglitazone, and pioglitazone, as well as the cyclopentanone prostaglandins 15D-PGJ2 and PGA1) cause a substantial reduction of myocardial infarct size in the rat. We demonstrate that two distinct ligands of PPAR-alpha (including clofibrate and WY 14643) also cause a substantial reduction of myocardial infarct size in the rat. The most pronounced reduction in infarct size was observed with the endogenous PPAR-gamma ligand, 15-deoxyDelta12,14-prostagalndin J2 (15D-PGJ2). The mechanisms of the cardioprotective effects of 15D-PGJ2 may include 1) activation of PPAR-alpha, 2) activation of PPAR-gamma, 3) expression of HO-1, and 4) inhibition of the activation of NF-kappaB in the ischemic-reperfused heart. Inhibition by 15D-PGJ2 of the activation of NF-kappaB in turn results in a reduction of the 1) expression of inducible nitric oxide synthase and the nitration of proteins by peroxynitrite, 2) formation of the chemokine MCP-1, and 3) expression of the adhesion molecule ICAM-1. We speculate that ligands of PPAR-gamma and PPAR-alpha may be useful in the therapy of conditions associated with ischemia-reperfusion of the heart and other organs. Our findings also imply that TZDs and fibrates may help protect the heart against ischemia-reperfusion injury. This beneficial effect of 15D-PGJ2 was associated with a reduction in the expression of the 1) adhesion molecules ICAM-1 and P-selectin, 2) chemokine macrophage chemotactic protein 1, and 3) inducible isoform of nitric oxide synthase. 15D-PGJ2 reduced the nitration of proteins (immunohistological analysis of nitrotyrosine formation) caused by ischemia-reperfusion, likely due to the generation of peroxynitrite. Not all of the effects of 15D-PGJ2, however, are due to the activation of PPAR-gamma. For instance, exposure of rat cardiac myocytes to 15D-PGJ2, but not to rosiglitazone, results in an up-regulation of the expression of the mRNA for heme-oxygenase-1 (HO-1). Taken together, these results provide convincing evidence that several, chemically distinct ligands of PPAR-gamma reduce the tissue necrosis associated with acute myocardial infarction.

Induction of the heat-shock response by antiviral prostaglandins in human cells infected with human immunodeficiency virus type 1.

Cyclopentenone prostaglandins inhibit the replication of several DNA and RNA viruses, including retroviruses. The antiviral activity has been associated with the induction of a 70-kDa heat-shock protein (HSP70), via activation of the heat-shock transcription factor (HSF) in infected cells. In the present study we investigated the effect of prostaglandin A1 (PGA1) on the regulation of HSP70 gene expression as well as on viral RNA and protein synthesis in CEM-SS cells during acute infection with human immunodeficiency virus type 1 (HIV-1). We report that HIV-1 infection does not alter HSF activation by PGA1, whereas it causes an increase in intracellular HSP70 mRNA levels, as a result of enhanced HSP70 mRNA stability. We also show that, as reported in studies of different virus/host cell models, PGA1 inhibits HIV-1 replication by acting at multiple levels during HIV-1 infection. In addition to the previously reported block of HIV-1 mRNA transcription, PGA1 was also found to inhibit viral protein synthesis. These results, together with the fact that prostaglandins are used clinically in the treatment of several diseases, open new perspectives in the search for novel antiretroviral drugs.

Inhibition of Mayaro virus replication by prostaglandin A1 and B2 in Vero cells

The effect of prostaglandins (PGA1 and PGB2) on the replication of Mayaro virus was studied in Vero cells. PGA1 and PGB2 antiviral activity was found to be dose-dependent. However, while 10 µg/ml PGB2 inhibited virus yield by 60 percent, at the same dose PGA1 suppressed virus replication by more than 90 percent. SDS-PAGE analysis of [35S]-methionine-labelled proteins showed that PGA1 did not alter cellular protein synthesis. In infected cells, PGA1 slightly inhibited the synthesis of protein C, while drastically inhibiting the synthesis of glycoproteins E1 and E2

Inhibition of Mayaro virus replication by prostaglandin A1 and B2 in Vero cells.

The effect of prostaglandins (PGA1 and PGB2) on the replication of Mayaro virus was studied in Vero cells. PGA1 and PGB2 antiviral activity was found to be dose-dependent. However, while 10 micrograms/ml PGB2 inhibited virus yield by 60%, at the same dose PGA1 suppressed virus replication by more than 90%. SDS-PAGE analysis of [35S]-methionine-labelled proteins showed that PGA1 did not alter cellular protein synthesis. In infected cells, PGA1 slightly inhibited the synthesis of protein C, while drastically inhibiting the synthesis of glycoproteins E1 and E2.

Prostaglandin A1 inhibits replication of classical swine fever virus.

Prostaglandins (Pgs) have been shown to inhibit the replication of several DNA and RNA viruses. Here we report the effect of prostaglandin (PgA1) on the multiplication of a positive strand RNA virus, Classical Swine Fever Virus (CSFV) in PK15 cells. PgA1 was found to inhibit the multiplication of CSFV. At a concentration of 5 micrograms/ml, which was nontoxic to the cells, PgA1 inhibitis virus production in 99%. In PgA1 treated cells the size and number of characteristic Classical Swine Fever focus decreased in amount.

Transient blockage of proliferative signalling: a novel strategy for protective chemotherapy.

An intact proliferative signalling pathway is essential to the growth of all normal cells, but is often not required by tumor cells. This fact was used to devise a protective chemotherapeutic protocol potentially applicable to all tissues. Four treatments were chosen to temporarily disrupt proliferative signalling. They acted either upstream, at, or downstream of cellular ras activity. As expected, the cell cycle progression of normal cells was temporarily interrupted, while those cells transformed by tumor genes, or tumor cells themselves often were not affected. During these cell cycle blocking treatments the cells were exposed to the topoisomerase inhibitor m-AMSA. This anti-cancer drug is selectively toxic to cycling cells. In each case the tumor cells were selectively killed as judged either by their ability to incorporate labeled thymidine, replate, or grow. These studies suggest new ways to utilize current drugs or search for new ones.