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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., (© 2022. The Author(s).)

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.

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.

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., (© 2022 American College of Veterinary Ophthalmologists.)

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., (Copyright © 2022 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

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%., Competing Interests: Competing interests: PH has received consultant honoraria from Bausch Health, Canada. CR is an employee of PeriPharm Inc. AXC, MB and KJ-G are employees of Bausch Health, Canada. KM is an employee of PeriPharm and Université de Montréal. JL and CB have received research funds from Bausch Health, Canada to conduct this study., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

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 β-amyloid protein (oAβ) 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 Aβ. More importantly, long-term administration of PGA1 remarkably decreased the formation of Aβ monomers, oligomers, and fibrils. The actions of PGA1 on the production and deposition of Aβ ultimately improved the cognitive decline of the amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The effect of a novel prostaglandin A1 derivative, TEI-3313, with the chemical structure 5-[(Z,2E)-4,7-dihydroxy-2-heptenyridene]-4-hydroxy- 2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone, on bone mineral content was investigated. Seven-week-old Sprague-Dawley rats in which the right hindlimbs were immobilized by sciatic nerve dissection received 1, 10, 100 or 500 micrograms of TEI-3313/kg/day, i.p., for 6 weeks. Control animals were operated on but received vehicle only. Bone mineral content of the femur was measured by single-photon absorptiometry, and biochemical parameters were analyzed. Histomorphometric observations were performed on the proximal metaphysial sections of the tibiae. The administration of up to 500 micrograms/kg of TEI-3313 to rats had no effect on body weight or on serum calcium, inorganic phosphorus and 1 alpha,25 dihydroxy vitamin D3 levels. Immobilization decreased the ash content, calcium content and total bone mineral content of the femur compared with nonimmobilization (unoperated femur). With TEI-3313 administration, changes in these parameters in the immobilized femur were prevented almost to the levels of the nonimmobilized femur, in a dose-dependent manner. The enhancement of bone mineral content was remarkable in the midshaft of the femur. TEI-3313 enhanced ash and calcium content and total bone mineral content in nonimmobilized femurs. Microradiograms showed that TEI-3313, unlike pamidronate and 17 beta-estradiol, had little inhibitory effect on trabecular bone resorption in the proximal portion of the tibia. TEI-3313 not only prevented the bone loss induced by immobilization but also increased bone mass in the nonimmobilized femurs without affecting the levels of 1 alpha,25 dihydroxy vitamin D3.(ABSTRACT TRUNCATED AT 250 WORDS)

An oligomeric ester of prostaglandin B2 (OC-5186) was found to reverse chloroquine resistance in the murine malarial parasite Plasmodium berghei. When mice were infected with either chloroquine-sensitive or -resistant P. berghei on day 0 (by intraperitoneal injection of 1 x 10(6) parasitized erythrocytes), they died before day 23. When treated with 15 mg/kg/day of chloroquine for the first four days of infection, all mice infected with the sensitive-strain survived, while all those infected with the resistant strain died before day 23. When OC-5186 (3-12 mg/kg/day) was administered in combination with chloroquine for the first four days, 60% of the animals infected with the resistant strain survived. The differences in the survival rate between the group treated with chloroquine only and the group treated with a combination of drugs (chloroquine plus 3-12 mg/kg/day of OC-5186) were significant. There was also a significant inhibition of parasitemia in the group treated with the combination of drugs. The combinations of chloroquine and a monomer ester of prostaglandin B2 (OC-5181) had some antimalarial activity, but the differences between the chloroquine-treated group and the combination treatment group were not significant in terms of both the parasitemia and the survival rate. Another oligomeric ester of prostaglandin E1 (MR-356) as well as unesterified monomer prostaglandins (PGA2 and PGB2) were ineffective by themselves and in combination with chloroquine.

HTLV-I (Human T-cell leukemia virus type I) has been the first human retrovirus identified and then associated with a definite pathological entity, a leukemic syndrome that specifically affects mature T-lymphocytes (ATL, adult T-cell leukemia), expressing CD3+, CD4+, CD8-, CD11- phenotype. This form of leukemia/lymphoma is endemic in southwestern islands of Japan, although at present the number of HTLV-I seropositive individuals has greatly increased, with a worldwide diffusion, following the expansion wave of the AIDS-associated HIV retrovirus. In fact, double seropositivity for both HIV and HTLV is frequently found among intravenous drug users. Although ATL leukemia or lymphoma occurs with a low frequency among HTLV-I seropositive individuals, it is likely that the evolution from a latent phase of infection to acute leukemia could be favoured by depression of immunosurveillance levels in the host. Therefore, special attention is required to prevent the diffusion of this retrovirus in adults, taking into consideration that newborn babies from seropositive mothers have to be considered at high risk for development of HTLV-I associated disease, on the basis of their immature immunocompetence.

Prostaglandin A1 is a potent hypotensive, peripheral vasodilator, a weak oxytocic, antiplatelet aggregator. It improves the renal hemodynamics. Its effect on placental circulation was evaluated (expressed as systolic/diastolic ratio and umbilical artery resistance index) in 20 women with severe pre-eclampsia and 10 normotensive pregnant women, by using the Doppler technique. Moreover, another 10 women with severe pre-eclampsia received dextrose 5% as a placebo for comparative purposes. Significant improvements in both parameters studied were observed in the women with severe pre-eclampsia. The beneficial changes differed significantly from the recorded values when using dextrose in pre-eclampsia or prostaglandin A1 in normotensive subjects. Such promising data add another important perspective to prostaglandin A1 in severe pre-eclampsia and may open up new avenues for its use in other situations with compromised placental flow.

The effect of prostaglandin (PG) F2 alpha-isopropyl ester (IE), PGA2, or PGA2-IE on intraocular pressure (IOP) was tested in eight cynomolgus monkey eyes with argon laser-induced glaucoma. Dose-response testing and baseline IOP measurements were done. For multiple dose testing, 5 micrograms in 25 microliters (0.02%) of each PG was topically applied twice daily for 5 days. The IOP was measured at 30- or 60-minute intervals for 6 hours after the morning dose each day. A significant (P less than 0.05) reduction of IOP peaked at 5-9 mm Hg below baseline values on the 5th day of treatment for each PG. The ocular hypotensive effect of these PGs progressively became more pronounced during the course of twice-daily dosing, with a significant reduction maintained at least 17 hours after some doses. No more than trace aqueous flare and no cells were observed in any eye during the course of treatment. These findings demonstrate that PGs other than F2 alpha are potent ocular hypotensive agents in primates.

The effects of tumor necrosis factor (TNF) and cyclopentenone prostaglandins (PGA2 and delta 12-PGJ2), singly and in combination, against proliferation in three human gynecologic tumor cell lines (HeLa S3, HHUA, and CAOV-3) were examined in vitro. The HeLa S3 and CAOV-3 cells were unresponsive to TNF, and the HHUA cells exhibited a minimal degree of responsiveness to TNF. The HeLa S3 and HHUA cells were responsive dose-dependently to PGA2, and the CAOV-3 cells were slightly responsive to PGA2. All three cell lines were highly responsive to delta 12-PGJ2. The synergistic antiproliferative effect of TNF and delta 12-PGJ2 appeared in all three cell lines. Pretreatment with delta 12-PGJ2 enhanced the effectiveness of TNF in these cell lines, but not vice versa. A synergistic interaction between TNF and PGA2 was absent in these three cell lines. These results suggest that a combined treatment with TNF and delta 12-PGJ2 could provide a new approach to obtaining increased responses in clinical trials.

It has been shown that prostaglandin A2 (PGA2) is a more potent ocular hypotensive agent in cats than other PG free acids. We report here that significant IOP reduction can be achieved in normotensive cat eyes with the use of even lower doses of PGA2-1-isopropyl ester (PGA2-IE) than with PGA2, PGF2 alpha-1-isopropyl ester (PGF2 alpha-IE), or any other known ocular hypotensive agent. Furthermore, single applications of 0.5 microgram of PGA2-IE maintain significant IOP reductions for at least 24 hr. This hypotensive effect is enhanced during the first 3-5 days of daily treatment. Significant IOP reductions were maintained for several months as long as PGA2-IE was applied daily or at least once every 48 hr. None of the cats manifested signs of discomfort in response to treatment with doses ranging from 0.10 to 1.25 micrograms of PGA2-IE. Moreover, the extent of anterior chamber flare was less than that typically observed after the topical application of hypotensive doses of PGE2, PGD2, PGF2 alpha, or the esters or tromethamine salt of PGF2 alpha. Although it is possible that the human eye would respond differently to PGs of the A type, the results of these studies suggests that PGA2-IE or other esters of derived PGs of the A type, and probably the B type, may offer significant therapeutic advantages over the PGF2 alpha tromethamine salt and PGF2 alpha-IE, which have been shown to exert significant hypotensive effects on normal and glaucomatous human eyes.

In an attempt to alter the natural course of glycerol and uranyl nitrate induced acute ranal failure in the rat, the vasodilator, prostaglandin A1 was adminstered systemically at varying times during the induction phase of renal failure. According to the method used, no significant beneficial effect could be demonstrated in either experimental model.

Endotoxin shock was produced in healthy, adult mongrel dogs by the intravenous injection of 1.5 mg/kg of E. coli endotoxin. The 24 hour survival of untreated animals was 34% and was not enhanced by volume replacement with low molecular weight dextran. Treatment with dextran and prostaglandin A1 or E1, although effecting significant hemodynamic improvements, did not increase survival.

It has recently been shown that derived prostaglandins (PGs) of the A and B types are much more potent ocular hypotensive agents than primary PGs of the E, F, or D type. The purpose of this study was to determine whether two representatives of these structurally different PGs, namely PGA2 and PGF2 alpha-1-isopropyl ester (PGF2 alpha IE), reduce intraocular pressure (IOP) of the feline eye by similar or dissimilar mechanisms. Aqueous humor flow rate was determined by a fluorophotometric technique, Schiotz electronic tonography was used to measure outflow facility and venomanometry was done to measure episcleral venous pressure. Although at the doses used, both PGF2 alpha IE (2.5 micrograms/eye) and PGA2 (5.0 micrograms/eye) caused significant IOP reduction within 2.5 hr after their topical application, neither caused a significant decrease in aqueous humor flow rate, a significant increase in outflow facility or a change in episcleral venous pressure. It was concluded, therefore, that both of these PGs reduce IOP by an apparently similar mechanism, presumably by increasing uveoscleral outflow.

Male Wistar rats were fed a lithium diet for 2--3 months producing marked polyuria (greater than 75 ml/100 g in 24 h) and a plasma Li concentration of 0.7 mmol/l. In acute experiments animals were anaesthetized with 5-ethyl-5-(1-methylpropyl)-2-thiobarbituric acid and infused with hypotonic glucose-saline (15 ml/h). Addition of prostaglandin A2 (PGA2; 0.2 ng/min) for 180 min to the infusate did not restore the impaired antidiuretic response to arginine-vasopressin (AVP) whether this agent was infused continuously (150 micromicron./min) or given as bolus injections (2500 micromicron.). In long-term experiments animals were kept in metabolism cages and Alzet osmotic minipumps were implanted for intravenous infusion of drugs at 1 microliter/h. Again, PGA2 infusion at 0.2 ng/min failed to restore the impaired antidiuretic response to AVP (150 micromicron./min). It was therefore concluded that in rats with severe polyuria induced by long-term administration of lithium, infusion of PGA2 at 0.2 ng/min cannot restore the impaired response to antidiuretic hormone as has been reported by others.

Dopamine and prostaglandin A1 were infused intravenously in 4 patients with the hepatorenal syndrome, in 1 patient with acute tubular necrosis, and 1 patient with cortical necrosis. Large doses of prostaglandin A1 decreased arterial blood pressure preventing increase in dosage; in contrast, high doses of dopamine elevated blood pressure. When the two drugs were administered conjointly, much larger doses of each agent could be administered without change in arterial blood pressure. Significant improvement of renal function was not observed in any of these critically ill patients during or within 24 hours after dopamine and prostaglandin A1 administration. This study demonstrated that extremely large doses of these vasodilating agents can be safely administered conjointly.

Prostaglandins of the A series have been reported to inhibit tumor cell growth and induce tumor cell differentiation by a yet unknown mechanism. We propose that these effects are due to the presence of a reactive alpha, beta-unsaturated carbonyl group (delta 10,11) in the cyclopentane ring of the PGA molecule. PGA was effective whereas PGB (sterically hindered alpha, beta-unsaturated carbonyl at delta 8, 12) and PGA conjugated to glutathione were ineffective. 15-Epi-PGA2 was as effective as PGA2 suggesting that the S absolute configuration of the 15-hydroxyl group is not essential. There was no correlation between generation of cAMP and inhibition of cell proliferation or induction of differentiation by various prostaglandins. The data suggest that PGA's and PGA-like compounds inhibit tumor cell growth and induce differentation because of the chemical reactivity of the alpha, beta-unsaturated carbonyl rather than hormonal activity of the prostanoid nucleus.

Acute renal failure induced in Charles River rats by right nephrectomy and left renal artery clamping for 70 min, constantly produced high blood urea and serum creatinine levels 24 h following the experimental procedure. The intravascular administration of propranolol in different doses persistently alleviated the severity of uremia seen on the following day. The optimum dose in this experimental set-up was 1 mg/kg/h. The mean blood urea level was 237 +/- 15.5 (SEM) mg% in the saline-treated controls and 116 +/- 16 mg% in the group treated with propranolol 1 mg/kg/h. P113 alone and prostaglandin A1 alone were not effective in alleviating the ARF. The combination of P113 and propranolol produced the same amount of alleviation in uremia as propranolol alone. The PRA was low in the propranolol-treated rats and high in the group which received both P113 and propranolol, even though alleivation of ARF was produced in both of these groups. The mechanism by which the beta-adrenergic blockade produced by propranolol alleviates the anoxic type of acute renal failure is unknown. However, it does not seem to act through the suppression of renin release from the kidney.

The prostaglandins A1, E1, A2, E2 and F2a were comparatively studied for their antiarrhythmic action using the model of strophanthin arrhythmia of narcotized cats. Infusions of prostaglandins A1, E2 and F2a in doses of 1-5 mug/kg/min for 5 min improved the arrhythmias in 63%, 83% and 81% of the animals, respectively, whereas prostaglandin A2 was effective in 44%, and prostaglandin E1 in only 10% of the cats. Prostaglandins A1 and E2 transiently established a sinus rhythm in 54 and 50%, and prostaglandin F2a in 18% of the animals. The injection of 12 mu9/kg prostaglandin F2a brought about improvement of arrhythmia in 70% of the animals, producing a transient sinus rhythm in 40%. With ajmaline as the standard substance in doses of 0.3 mg/kg/min for 5 min produced an antiarrhythmic effect in 50% of the animals, while injection of 1 mg/kg was effective in 60% of the animals. Effects on the vegetative nervous system are discussed as the possible action mechanism of the prostaglandins.

The present study compares the effects of PGE1 and PGA1 on ventricular arrhythmias following coronary artery occlusion. The left anterior descending coronary artery (LAD) was occluded abruptly in 55 cats anesthetized with alpha-chloralose. Lead II of the ECG along with arterial blood pressure were monitored for one hour after occlusion. Either vehicle or prostaglandin was infused into the left atrium (LA) or femoral vein (IV) 15 min prior to and for 1 hour after LAD occlusion at a rate of 0.15 ml/min. Prostaglandin was infused at either a high dose (1.0 microgram/kg/min) or a low dose (0.1 microgram/kg/min). Infusion of either PGE1 or PGA1 produced a marked fall in blood pressure and heart rate which returned toward control before occlusion. Abrupt occlusion of the LAD produced ventricular arrhythmia in all cats ranging from ventricular premature beats to ventricular fibrillation (VF). The control animals had a 38% incidence of VF. VF occurred in 75% of the animals in which PGE1 was administered into the LA at either the high or low dose while the occurrence in those administered PGA1 was 67% and 50%, respectively. Intravenous administration of the high dose of PGE1 or PGA1 resulted in VF in 13% and 67% of the animals after LAD occlusion, respectively. These data indicate that the IV administration of PGE1 may protect the heart from VF while the infusion of PGE1 or PGA1 into the LA may enhance VF after LAD occlusion.

Cyclopentenone prostaglandins (PGs) such as prostaglandin A1 (PGA1) and prostaglandin J2 (PGJ2) significantly increased the life span of Ehrlich ascites tumor-bearing mice. In order to obtain PG derivatives which have more potent antitumor activity than PGA1 and PGJ2, we synthesized a number of alkylidenecyclopentenone PGs and studied the antitumor activity of these compounds in vitro and in vivo. delta 7-PGA1, 12-epi-delta 7-PGA1, and delta 12,14-PGJ2 showed 50% inhibitory concentrations of 0.3 microgram/ml against the growth of L1210 culture cells. These compounds are several times more cytotoxic than parent compounds. From a structure-activity relationship analysis, we concluded that, as for PGA derivatives: (a) a double bond in C7-8 potentiates the cytotoxicity; (b) a 15-hydroxy group is not essential for cytotoxicity; (c) the stereochemistry of R2 chain is not essential, while 12-epi derivatives also have full activity; (d) a double bond in C12-13 seems to be essential for full activity, and for PGJ derivatives a double bond in C12-13 and C14-15 potentiates the cytotoxicity. These compounds showed marked antitumor activity against Ehrlich ascites tumor in vivo. At doses of 20-30 mg/kg/day three or five consecutive i.p. treatments with these compounds resulted in a 66 to 111% increase in life span with long-term survivors. A single i.p. injection with 12-epi-delta 7-PGA1 (100 mg/kg) resulted in 73% increase in life span with 33% of long-term survivors, indicating an activity comparable to that of cyclophosphamide (200 mg/kg). However, delta 7-PGA1 and 12-epi-delta 7-PGA1 were marginally effective against P388 leukemia. Treatment with delta 7-PGA1 (10 mg/kg/day i.p.) and 12-epi-delta 7-PGA1 (20 mg/kg/day i.p.) on Days 1-9 resulted in 25.8 and 29.6% increases in life span, respectively. delta 7-PGA1 and delta 12-PGJ2 derivatives may be a potential new class of antitumor agents.

The classic primary prostaglandins (PGs), as well as some of their analogs and derivatives, are potent ocular hypotensive agents. The present studies show that A and B PGs, which are derived from PGs of the E type by dehydration and isomerization, have a much greater ocular hypotensive potency than the primary PGs of the E, F or D type. A single application of 5 micrograms of PGA2 to the cat eye in a 25-microliters volume of aqueous vehicle solution yielded a greater and more prolonged ocular hypotensive effect than as much as 100 micrograms of topically applied PGF2 alpha. As little as 1 microgram of PGA2 had a significant ocular hypotensive effect that was enhanced by three or more consecutive daily applications of the same dose. This IOP reduction, which remained significant for several days after the last of 10 daily treatments, was not associated with biomicroscopically detectable flare or invasion of the anterior chamber by cells. Although PGF2 alpha and, to a much lesser extent, PGE2 have a miotic effect in cats, PGs of the A and B type did not cause significant miosis even at doses 50- to 100-fold greater than the minimum dose required to yield significant ocular hypotension. PGA2 retained its ocular hypotensive potency when stored in an aqueous solution at room temperature for four months. The conjunctival hyperemia caused by 5 micrograms or 10 micrograms of A or B type PGs on rabbit eyes was milder and shorter in duration than that caused by the same doses of PGE2 or PGF2 alpha. These findings suggest that derived PGs, especially PGs of the A type, may have a therapeutic advantage over primary PGs for the treatment of ocular hypertension and glaucoma.

Experimental studies on BaCl2 induced arrhythmias in unanaesthetized rabbits showed an antiarrhythmic effect of prostaglandins A1, A2, E1, E2 and F2a by infusions of 0,1 to 6,0 mug/kg/min over 3 min. There was a maximum antiarrhythmic effect between 50% and 80%. Ajmaline was similarly effective when given in doses 100-1000 times higher. PGA1 and PGE2 were most effective in this model; the ED50-values of the other PGs were 2-3 times higher. The mode of action of PGs is unknown; the following factors are discussed: the influence on the ionic movements, the negative feedback mechanism on the release of adrenergic transmitter and central nervous effects.

In response to ischaemic or vasoconstrictor stimuli the kidney reacts by synthesising prostaglandins (PG) which modify local vascular tone. They induce a compensatory vasodilatation and direct the blood flow towards the internal cortex. It is thus not necessary to attribute a systemic role to PG in order to understand their haemodynamic action. This explains the natriuresis following the injection of PG both in the animal and in man. Nevertheless the direct effet of PG upon the tubular reabsorption of sodium remains controversial since very different experimental models lead to contradictory conclusions. Despite these disparate data, it is probable that PG are intimately involved in the pathogenesis of hypertension. A lack of PG or a deficiency in their metabolism may be responsible in essential hypertension.

The renal prostaglandins PGS2 and PGE2 possess potent antihypertensive and vasodepressor activity. The mechanism of blood pressure lowering effect is through peripheral arteriolar dilation with a fall in total peripheral resistance. PGA unlike PGE escape degradation by the lung and thus could circulate as antihypertensive hormones. Since plasma PGA levels rise in humans on a low sodium intake, it has been postulated that the beneficial effects of a low sodium diet in some hypertensives may be the result of an increase in peripheral vasodilating PGA. Support that plasma PGA may be a regulator of systemic blood pressure is also derived from the fact a PGA-secreting renal tumor was associated with a fall in blood pressure and a rise in plasma PGA in a previously hypertensive woman. The removal of the tumor resulted in a return of blood pressure to elevated levels and a concomitant fall in PGA. Recently, a number of human patients with essential hypertension have been infused with PGA1 and PGA2. It was observed that there was an initial increase in renal blood flow, sodium and water excretion which was associated with no change in the elevated blood pressure. When blood pressure ultimately fell, there was a return of renal blood flow, sodium and water excretion to preinfusion levels. It would appear that PGA compounds act as 'ideal' antihypertensive agents since they favorably effect renal resistance, sodium and water homeostasis, plasma volume, total peripheral resistance, blood pressure and indirectly cardiac output through baroreceptor stimulation, all factors known to be important in etiology in human hypertension.

The vasodepressor prostaglandin A1 appeared to offer a major clinical potential solution in cases of severe pregnancy-induced hypertension. Thirty pregnant women with severe pregnancy-induced hypertension and a low Bishop score were studied in three equal groups. Group 1 received prostaglandin A1 infusions alone (0.5 microgram/kg/min for a maximum of 24 hours). Group 2 had received initial priming by prostaglandin E2 vaginal gel 6 hours before the onset of the prostaglandin A1 infusion, and group 3 was treated by conventional therapy and oxytocin induction. In the first two groups blood pressure was reduced to normotensive values, and labor was induced satisfactorily in 15 of the 20 cases, but four patients in group 1 were delivered within 24 hours after infusion. Group 2 offered the most favorable results because 80% were delivered during the infusion; thus the postinfusion rebound rise in blood pressure was avoided. Group 3 presented the least acceptable results, with the highest failure rate and an increased number of operative deliveries.

In addition to its well known prohypertensive role in various states of experimental and human hypertension, the kidney has also been shown to exert an antihypertensive "endocrine" function. According to this hypothesis, certain forms of experimental and human hypertension might not solely be the result of an excess in the activity of such renal pressor systems as the renin-angiotensin system and the sympathetic nervous system, but might also result from an absolute or relative deficiency of intra-renal vasodilator antihypertensive factors which might allow pressor systems to act unopposed to produce peripheral arteriolar vasoconstriction and sustained hypertension. At least four factors have been characterized in the kidney of various animal species and man which might be responsible for such an antihypertensive function. These are (1) the renomedullary prostaglandins (PGs), (2) the renomedullary antihypertensive neutral lipid, (3) antirenin phospholipid and (4) the renal kinins. This review is restricted to an examination of the possibility that the vasodepressor renomedullary prostaglandins (PGA and/or PGE) may, at least in part, mediate the so-called antihypertensive function of the kidney and participate in the regulation of renal blood flow and natriuresis by physiologic antagonism of various renal vasoconstrictor stimuli such as the renal renin-angiotensin and the sympathetic nervous systems.

This study evaluated the effects of PGA1 on B 16 melanoma bearing mice. PGA1 was observed to inhibit the rate of melanoma growth, both as delay in the rate of appearance and decrease in tumor volume. Furthermore PGA1 stimulated humoral but not cellular immune response in melanoma bearing mice, while it was ineffective in normal mice.