Enhanced understanding of the relationship between erection and satisfaction in ED treatment: application of a longitudinal mediation model.

To apportion the direct effect and the indirect effect (through erections) that sildenafil (vs placebo) has on individual satisfaction and couple satisfaction over time, longitudinal mediation modeling was applied to outcomes on the Sexual Experience Questionnaire. The model included data from weeks 4 and 10 (double-blind phase) and week 16 (open-label phase) of a controlled study. Data from 167 patients with erectile dysfunction (ED) were available for analysis. Estimation of statistical significance was based on bootstrap simulations, which allowed inferences at and between time points. Percentages (and corresponding 95% confidence intervals) for direct and indirect effects of treatment were calculated using the model. For the individual satisfaction and couple satisfaction domains, direct treatment effects were negligible (not statistically significant) whereas indirect treatment effects via the erection domain represented >90% of the treatment effects (statistically significant). Week 4 vs week 10 percentages of direct and indirect effects were not statistically different, indicating that the mediation effects are longitudinally invariant. As there was no placebo arm in the open-label phase, mediation effects at week 16 were not estimable. In conclusion, erection has a crucial role as a mediator in restoring individual satisfaction and couple satisfaction in men with ED treated with sildenafil.

Erectile function, erection hardness and tolerability in men treated with sildenafil 100 mg vs. 50 mg for erectile dysfunction.

AIM: To compare efficacy and tolerability between 100-mg and 50-mg sildenafil doses in five double-blind, placebo-controlled (DBPC) fixed-dose studies. METHODS: Doses were compared for the change (baseline to end of 8-12 weeks of DBPC treatment) in score on the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF; from five fixed-dose studies, > 1500 men); the per-patient estimated percentage of occasions that a specified Erection Hardness Score (EHS; from two of the five fixed-dose studies, > 500 men) was achieved, computed from logistic regression; the odds ratio (OR) of achieving EHS3 (hard enough for penetration, but not completely hard) and EHS4 (fully hard and completely rigid); and the adverse event incidence by treatment (from all five fixed-dose studies). RESULTS: For the 100-mg vs. 50-mg dose, IIEF-EF score improvement was consistently greater across the five studies and was statistically significant when data from two studies with similar design were pooled (10.7 ± 0.64 vs. 8.9 ± 0.83, p = 0.0287); and during the first 2 weeks of treatment, the odds of achieving EHS4 erections were almost doubled in one study (OR = 1.77, p = 0.0398). Sildenafil was generally well tolerated at either dose. CONCLUSION: Men with erectile dysfunction treated with 100-mg compared with 50-mg sildenafil may be more likely to achieve a greater improvement in erectile function and, within the first 2 weeks, completely hard and fully rigid erections, with little or no greater risk to tolerability.

Hardness, function, emotional well-being, satisfaction and the overall sexual experience in men using 100-mg fixed-dose or flexible-dose sildenafil citrate.

The prescribing information for sildenafil citrate (VIAGRA, Pfizer, New York, NY, USA) recommends flexible dosing (50 mg initially, adjusted to 100 or 25 mg based on effectiveness and tolerability) in most men with erectile dysfunction (ED). In many men, however, 100 mg may be the most appropriate initial dose because it would reduce the need for titration and could prevent discouragement and treatment abandonment should 50 mg be insufficient. Results of two previously published double-blind, placebo-controlled sildenafil trials of similar design except for a fixed-dose vs flexible-dose regimen were analyzed. Relative to the flexible-dose, approximately one-third more men were satisfied with an initial and fixed dose of 100 mg. In addition, tolerability was similar, and improvements from baseline in outcomes on validated, ED-specific, patient-reported questionnaires were either similar (erectile function and the percentage of completely hard and fully rigid erections) or greater (emotional well-being and the overall sexual experience). The similarity in outcomes is not surprising given that almost 90% of the men in the flexible-dose trial titrated to 100 mg after 2 weeks. These data suggest prescription of an initial dose of 100 mg for men with ED, except in those for whom it is inappropriate.

Counterfeit phosphodiesterase type 5 inhibitors pose significant safety risks.

Counterfeit drugs are inherently dangerous and a growing problem; counterfeiters are becoming increasingly sophisticated. Growth of the counterfeit medication market is attributable in part to phosphodiesterase type 5 inhibitor (PDE5i) medications for erectile dysfunction (ED). Millions of counterfeit PDE5is are seized yearly and account for the bulk of all counterfeit pharmaceutical product seizures. It has been estimated that up to 2.5 million men in Europe are exposed to illicit sildenafil, suggesting that there may be as many illegal as legal users of sildenafil. Analysis of the contents of counterfeit PDE5is shows inconsistent doses of active pharmaceutical ingredients (from 0% to > 200% of labelled dose), contaminants (including talcum powder, commercial paint and printer ink) and alternative ingredients that are potentially hazardous. In one analysis, only 10.1% of samples were within 10% of the labelled tablet strength. Estimates place the proportion of counterfeit medications sold over the Internet from 44% to 90%. Of men who purchase prescription-only medication for ED without a prescription, 67% do so using the Internet. Counterfeit PDE5is pose direct and indirect risks to health, including circumvention of the healthcare system. More than 30% of men reported no healthcare interaction when purchasing ED medications. Because > 65% actually had ED, these men missed an opportunity for evaluation of comorbidities (e.g. diabetes and hypertension). Globally, increased obstacles for counterfeiters are necessary to combat pharmaceutical counterfeiting, including fines and penalties. The worldwide nature of the counterfeit problem requires proper coordination between countries to ensure adequate enforcement. Locally, physicians who treat ED need to inform patients of the dangers of ordering PDE5is via the Internet.

Clinically meaningful improvement on the quality of erection questionnaire in men with erectile dysfunction.

Defining the minimal clinically meaningful improvement (MCMI) is crucial to understanding the treatment effects on health-status measures. We estimated the MCMI on the quality of erection questionnaire (QEQ), a validated measure specific to assess erectile quality during sexual intercourse. Data were from two controlled trials of an investigational phosphodiesterase type 5 inhibitor. Improvement on the Erectile Function domain of the International Index of Erectile Function was used as the anchor. For men who improved by exactly 1 erectile dysfunction severity category (anchor group (n=95)), clinically meaningful improvement (CMI, estimated with mean QEQ total change score from baseline to end of treatment) and MCMI (estimated with the lower limit of the 95% confidence interval of the mean) were 22.4 (s.d., 2.2) and 18.0 points, respectively. For the difference between the anchor group and men with no change in severity category (n=116), CMI and MCMI were 17.7 (s.d., 2.9) and 12 points, respectively. Distribution-based analyses (baseline s.e. of measurement (s.e.m.)=7.99, end-of-treatment s.e.m.=8.22 and s.e. of difference=11.46) supported a proposed MCMI of 12 points. Convergence of anchor-based and distribution-based criteria supports at least a 12-point difference in QEQ scores between treatments as clinically important.

Self-esteem, confidence and relationship satisfaction in men with erectile dysfunction: a randomized, parallel-group, double-blind, placebo-controlled study of sildenafil in Mexico.

Erectile dysfunction (ED) negatively impacts self-esteem and relationship satisfaction. The Self-Esteem and Relationship (SEAR) questionnaire is a validated, ED-specific, patient-reported instrument that specifically addresses self-esteem and relationship issues within the context of ED. Effective ED treatment with sildenafil in a double-blind, placebo-controlled clinical trial conducted in Brazil, Mexico, Australia and Japan showed pooled cross-cultural improvements in self-esteem, confidence and relationship satisfaction. This report focuses on the results from the subgroup of men from nine Mexican centers who participated in the multinational study. A total of 95 men aged >or=18 years with clinically diagnosed ED and currently in a stable relationship were randomized to placebo (n=47) or sildenafil (n=48). The SEAR results for Mexican men showed that sildenafil treatment led to significant improvements in self-esteem, confidence and relationship satisfaction. These data support an earlier study showing that Latin American men taking sildenafil have similar safety and efficacy profiles compared to non-Latin counterparts.

An assessment of patient-reported outcomes for men with erectile dysfunction: Pfizer's perspective.

Patient-reported outcomes (PROs) for men with erectile dysfunction (ED) have blossomed in the published literature and at professional conferences. These outcomes have been central to study the science of ED itself and to evaluate efficacy of treatment for men with ED. In this review article we highlight and distinguish among seven key PROs: the International Index of Erectile Function, for sexual function including erectile function; the Sexual Health Inventory for Men (SHIM), for diagnosis of ED; the Quality of Erection Questionnaire, for satisfaction with quality of erections; the Erectile Dysfunction Inventory of Treatment Satisfaction, for personal evaluation of treatment received; the Self-Esteem And Relationship questionnaire, for emotional well-being; the Erection Hardness Score (EHS), for targeting erection hardness and the Sexual Experience Questionnaire, for erection (both function and quality), individual satisfaction and couples satisfaction. Depending on the purpose of the investigation, all seven PROs have merit for use in clinical trials and at least deserve consideration in clinical practice. The SHIM and the EHS, given their aims and brevity, deserve special consideration in clinical practice. As a unit these seven PROs complement and supplement each other. Which ones to choose in a particular undertaking depends on the objective or purpose of a given study. These PROs acknowledge that sexual dysfunction and its treatment have multiple dimensions. Each of these instruments represents a significant contribution to sexual medicine research and, when used judiciously and appropriately, can help to provide optimal patient care and management.

Correlations between increased erection hardness and improvements in emotional well-being and satisfaction outcomes in men treated with sildenafil citrate for erectile dysfunction.

To explore relationships between erection hardness and other outcomes in men with erectile dysfunction (ED). Pooled analyses were conducted on 27 randomized, double-blind, placebo-controlled trials and six open-label trials from the worldwide sildenafil database. Outcomes included erection hardness graded subjectively, hardness and sexual satisfaction questions from the International Index of Erectile Function, general and sexually-specific emotional well-being from the self-esteem and relationship questionnaire, and the erectile dysfunction inventory of treatment satisfaction. Hardness outcomes improved (with a possible dose-response relationship for the achievement of fully hard and rigid erections) and correlated positively with the other outcomes. Sildenafil 100 mg produced optimal erection hardness (fully hard and rigid erections) in a substantial proportion of men with ED. Because optimal erection hardness correlated positively with some emotional well-being and satisfaction outcomes, sildenafil 100 mg may be the most appropriate dosage for treatment of ED for most men.

A double blind, randomised study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis.

OBJECTIVE: Identifying and effectively treating erectile dysfunction (ED) can result in an improvement of the quality of life (QoL) in men with multiple sclerosis (MS). METHODS: This randomised, double blind (DB), placebo controlled, flexible dose study with an open label extension (OLE) assessed efficacy, QoL, and safety of sildenafil citrate in men with MS and ED. Overall, 217 men received sildenafil (25-100 mg; n = 104) or placebo (n = 113) for 12 weeks. Efficacy was assessed by the International Index of Erectile Function (IIEF) questionnaire that includes questions on achieving (Q3) and maintaining (Q4) an erection as well as a global efficacy question (GEQ). QoL was also assessed. RESULTS: After 12 weeks, patients receiving sildenafil had higher mean scores for IIEF Q3 and Q4 compared with those receiving placebo (p<0.0001), and 89% (92/103) reported improved erections compared with 24% (27/112) of patients receiving placebo (p<0.0001). At the end of the OLE phase, 95% of men reported improved erections. Patients receiving placebo during the DB phase showed a nearly fourfold increase in improved erections (97% v 26%). Men receiving sildenafil also showed improvements in five of the eight general QoL questions compared with men receiving placebo (p<0.05). The total mean score for the QoL questionnaire improved by 43% for the sildenafil group versus 13% for the placebo group (p<0.0001). Treatment related AEs were predominantly mild in nature, and no patient discontinued due to an AE. CONCLUSION: Sildenafil treatment for ED in men with MS was effective and well tolerated, and resulted in significant improvements in both general and disease specific QoL variables.

Minimal time to successful intercourse after sildenafil citrate: results of a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To determine the minimal time to successful intercourse after taking sildenafil citrate for erectile dysfunction (ED). METHODS: Male patients with ED (mean age 60 years; mean ED duration 7.0 years) who were successfully treated with sildenafil (100 mg) for 2 months or longer were randomized to sildenafil (n = 115) or placebo (n = 113) for 4 weeks of double-blind treatment. Using a stopwatch, patients recorded the time needed to obtain an erection hard enough for sexual intercourse after taking the study drug at least 2 hours after eating. RESULTS: Within 14 and 20 minutes of sildenafil dosing, 35% and 51% of sildenafil-treated patients, respectively, versus 22% and 30% of placebo-treated patients, respectively, had an erection that led to successful intercourse (P <0.05 for both). The median time to erection leading to successful intercourse after sildenafil dosing was 36 minutes compared with 141 minutes for placebo. CONCLUSIONS: In this study, slightly more than one half of a population of prior sildenafil responders achieved an erection that led to successful sexual intercourse within 20 minutes of sildenafil administration, suggesting that the onset of action of sildenafil can be less than 30 minutes in men with ED.

Patient and partner satisfaction with Viagra (sildenafil citrate) treatment as determined by the Erectile Dysfunction Inventory of Treatment Satisfaction Questionnaire.

OBJECTIVES: To assess the efficacy and safety of Viagra (sildenafil citrate) in male outpatients with erectile dysfunction and patient and partner satisfaction with treatment using the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). METHODS: A total of 247 patients with erectile dysfunction of broad-spectrum etiology were treated in a randomized, double-blind, parallel-group, multicenter study conducted at outpatient clinics. Patients receiving oral sildenafil (25, 50, and 100 mg) were compared with patients receiving placebo during a 12-week period. The principal efficacy measures were responses to question 3 (ability to achieve an erection) and question 4 (ability to maintain an erection) on the International Index of Erectile Function and three global efficacy questions. Patient and partner satisfaction with treatment were assessed, for the first time, using the EDITS questionnaire. RESULTS: Efficacy scores for the International Index of Erectile Function questions and the global efficacy questions were significantly higher for patients receiving sildenafil than for those receiving placebo (P <0.001). Both patients and partners receiving sildenafil also had significantly higher EDITS scores than those receiving placebo (P <0.001). Adverse events were chiefly mild or moderate. Two patients receiving sildenafil and none receiving placebo discontinued treatment because of adverse events. CONCLUSIONS: Sildenafil was an effective, well-tolerated treatment for erectile dysfunction in an outpatient setting. Partner evaluations corroborated patient assessments. The results from the EDITS questionnaire indicated that after 12 weeks of receiving sildenafil both patients and partners reported higher levels of treatment satisfaction relative to placebo.

Inhibition of HIV-1 replication by hydroxychloroquine: mechanism of action and comparison with zidovudine.

We have previously described the inhibition of human immunodeficiency virus serotype 1 (HIV-1) using the antimalarial hydroxychloroquine (HCQ), a weak base that inhibits the posttranslational modification of glycoprotein 120 (gp 120) in T cells and monocytes. The mechanism of inhibition of gp 120 production was presumed to be the ability of HCQ to increase endosomal pH and therefore alter enzymes required for gp120 production. To further clarify this action, we have determined the effect of HCQ and its enantiomers on endosomal pH. Pretreatment of cells with HCQ and the levo- and dextro-enantiomers at concentrations demonstrated to suppress anti-HIV-1 activity increased endosomal pH to levels similar to increases seen with chloroquine and ammonium chloride, two other weak bases, and decreased gp 120 production. The dextro- and levo-enantiomers suppressed HIV-1 replication to a similar extent and were no more toxic than racemic HCQ. We next compared the anti-HIV-1 effect of HCQ with zidovudine (ZDV) in both newly and chronically HIV-1-infected T-cell and monocytic cell lines (63 and 63HIV). HCQ suppressed HIV-1 replication in a dose-dependent manner in both recently and chronically infected T-cell and monocytic cell lines. In contrast, ZDV pretreatment had potent anti-HIV-1 activity in the newly infected T and monocytic cells but not in chronically infected cells. An additive effect of HCQ with ZDV was observed in the newly infected T and monocytic cells but not in the chronically infected cells. Although the anti-HIV-1 effect of HCQ was less than that of ZDV, HCQ may still be potentially useful either as an alternative HIV-1 treatment or in combination with other anti-HIV-1 agents, especially in patients who have rheumatic manifestations of HIV-1 infection.

The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE.

Hydroxychloroquine has several less well-known actions that may have clinical relevance in treating systemic lupus erythematosus (SLE). (1) Hydroxychloroquine has a possible anti-thrombotic action. It is a platelet inhibitor and appears to decrease the risk of thromboembolism in patients with anticardiolipin antibodies. (2) Hydroxychloroquine is associated with lower serum cholesterol and low-density lipoprotein levels compared to those present in patients who are taking corticosteroids but not antimalarials for SLE. (3) It may also decrease abnormal levels of cytokines. Interleukin-6 (IL-6), soluble CD8 and soluble IL-2 receptors (sIL-2R) are lower in patients taking antimalarials compared to those on corticosteroids alone or on neither medication. Serum levels of CD8 and sIL-2R decrease after 6 weeks of hydroxychloroquine treatment. These findings may help explain the favorable response of SLE patients treated with antimalarials.

Inhibition of human immunodeficiency virus type 1 replication by hydroxychloroquine in T cells and monocytes.

Chloroquine and its analogue hydroxychloroquine (HCQ) have been shown to inhibit a variety of viral infections including influenza and adenovirus through blockade of viral entry via inhibition of endosomal acidification. We have extended these observations to human immunodeficiency virus type 1 (HIV-1) infection utilizing primary T cells and monocytes, a T cell line (CEM), and a monocytic cell line (U-937). HCQ inhibited HIV-1 replication (> 75%), as measured by reverse transcriptase activity, in the primary T cells and monocytes as well as the T cell and monocytic cell lines. HCQ itself had no anti-reverse transcriptase activity and was not toxic to the cells at concentrations inhibitory to viral replication. Intracytoplasmic staining with an anti-p24 antibody, 24 h after infection, revealed the presence of intracytoplasmic virus, suggesting that the drug does not block viral entry. The production of steady-state HIV-1 mRNA was not affected by HCQ in that comparable levels of HIV-1 mRNA could be detected by Northern blot analysis and by in situ hybridization in both the HCQ-treated and untreated cells. However, HCQ does appear to affect production of infectious HIV-1 virions because viral isolates from HCQ-treated cells could not infect target CEM cells. These data suggest that HCQ may be useful adjunctive therapy in the treatment of HIV-1 infection.

Cholesterol-lowering effect of hydroxychloroquine in patients with rheumatic disease: reversal of deleterious effects of steroids on lipids.

PURPOSE: The effects of hydroxychloroquine (HCQ) on serum levels of cholesterol, triglycerides, and high- (HDL) and low-density lipoprotein (LDL) were studied in patients with rheumatoid arthritis or systemic lupus erythematosus. PATIENTS AND METHODS: A total of 155 women were divided into the following treatment groups: Group A: patients taking HCQ and no steroids (n = 58); Group B: patients taking steroids and no HCQ (n = 35); Group C: patients receiving both HCQ and steroids (n = 18); and Group D: patients receiving neither HCQ nor steroids (n = 44). RESULTS: HCQ therapy had a high statistical association with low serum levels of cholesterol (181 mg/dL; p = 0.0006), triglycerides (106 mg/dL; p = 0.0459), and LDL (101 mg/dL; p = 0.0004), irrespective of concomitant steroid administration. The HCQ-treated group (A) had lower cholesterol (181 mg/dL; p = 0.0039) and LDL (101 mg/dL; p = 0.007) levels than those receiving neither HCQ nor steroids (205 mg/dL) and 128 mg/dL) (Group D). No HDL differences were observed. CONCLUSION: The effects of HCQ do not appear to be due to changes in diet or weight, and the drug was well tolerated. Although the mechanism of cholesterol lowering by HCQ is not known, this drug deserves further investigation for its lipid-lowering properties.

Differential effects of anti-arthritic agents on subnormal plasma iron levels in adjuvant arthritic rats.

Nonsteroidal anti-inflammatory drugs (NSAID's) and other antirheumatic compounds such as disease modifying antirheumatic drugs (DMARD's), immunosuppressives and glucocorticoids were tested to determine if daily medication for two weeks could elevate subnormal levels of plasma iron in adjuvant-arthritic (AA) rats. Aspirin, indomethacin, ibuprofen and phenylbutazone were chosen as representative carboxylic acids and pyrazole NSAID's. Although NSAID's at all doses significantly reduced noninjected paw swelling, no NSAID significantly enhanced subnormal plasma iron levels in AA rats. In contrast, the standard DMARD's auranofin and gold sodium thiomalate, as well as the glucocorticoid, dexamethasone and the immunosuppressives, methotrexate and cyclosporin-A all significantly restored plasma iron levels 28 to 100 percent. Plasma iron depression, a parameter of the acute phase response probably under regulation by pro-inflammatory cytokines, is not reversed by NSAID treatment. This appears to be a useful method for distinguishing NSAID's from other anti-arthritic compounds.

Elevation of plasma fibronectin and serum amyloid P in autoimmune NZB, B/W, and MRL/1pr mice.

The acute-phase proteins, fibronectin (Fn) and serum amyloid P (SAP), are opsonins which by virtue of their adhesive properties may be involved in the glomerular nephritis associated with splenic lupus erythematosus (SLE). Because of their possible involvement in the pathophysiology of lupus, plasma Fn and SAP levels from three strains of autoimmune mice were measured over time to determine if Fn and SAP rose as the mice sickened and renal function degenerated. Baseline levels of Fn and SAP were measured when the mice were between 1.5 and 3 months of age. The characteristic rapid onset of autoimmune disease in MRL/1pr mice was accompanied by a two- to threefold increase in plasma Fn and SAP by Day 100. The B/W mice, which develop autoimmune disease more slowly, did not have a significant increase in plasma Fn and SAP until Day 240. The NZB mice, with the most delayed onset of disease, exhibited a modest but significant elevation of plasma Fn and SAP by Day 360. Histologic examination of the kidneys of B/W and NZB mice indicated that pathological abnormality of the glomeruli and tubules coincided with the elevation of plasma Fn and SAP levels. In contrast, blood samples taken over time from normal BALB/c mice did not possess abnormal levels of Fn or SAP. It appears that elevation of plasma Fn and SAP in the MRL/1 pr, B/W, and NZB mice is related to the onset and severity of autoimmune disease and the subsequent loss of renal function.

Lymphocyte activating factor (LAF) and the acute-phase response in adjuvant arthritic rats.

The purpose of the study was to determine the temporal relationship between lymphocyte activating factor (LAF) activity and the acute-phase response, as measured by plasma fibronectin (Fn), C-reactive protein (CRP), and albumin levels in adjuvant arthritic rats. LAF activity as measured in the thymocyte costimulator assay, and plasma Fn, CRP, and albumin levels were measured during the acute (Day 3), intermediate (Day 10), and systemic (Day 17) phases of arthritic disease. On Day 3, supernatants from whole spleen cells of adjuvant-injected rats did not exhibit abnormal LAF activity. By Day 10, LAF activity in splenic supernatants from arthritics was significantly (P less than or equal to 0.05) higher than normal, although the increase was no greater than 60%. On Day 17 the LAF activity from arthritic rats had increased an average 300% compared to normals. In contrast to the time course of IL-1 activity, Fn and CRP levels in the arthritic rat were significantly higher than normal at all three time points, although there was a transient fall in Fn and CRP concentrations on Day 10. Plasma albumin levels in arthritic rats were subnormal (P less than or equal to 0.01) on Days 3, 10, and 17, although the concentration of plasma albumin on Day 10 was significantly higher than that measured on Day 3. The acute, intermediate, and systemic phases of adjuvant arthritic paw inflammation paralleled the abnormal profile of Fn, CRP, and albumin concentrations over time. However, LAF activity from arthritic rat spleen cells increased gradually and more closely coincided with the systemic appearance of the disease. Since the appearance of abnormal plasma protein levels in arthritic rats preceded the appearance of increased splenic LAF activity, it appears that there is no causal relationship between enhanced splenic LAF activity and early alteration of plasma Fn, CRP, and albumin levels.

The effect of danazol in the MRL/lpr mouse model of autoimmune disease.

The purpose of the study was to determine if danazol was efficacious in the treatment of lupus MRL/MpJ (lpr) mice, as measured by longevity, proteinuria and serum amyloid protein (SAP) levels. Danazol, administered at an oral dose of 100 mg/kg, significantly prolonged survival of female MRL/MpJ (lpr) mice but had no effect on the mortality of their male counterparts. Medication with danazol began 40 days after birth of the mice and resulted in a significant decrease in proteinuria in female but not male lupus mice. The concentration of SAP, an acute phase reactant, was significantly decreased in danazol-treated female lupus mice at 80, 100, 120, 140 and 160 days of age when compared to vehicle-treated control mice. SAP levels in male lupus mice treated with danazol were significantly lower than normal control levels only at the 120 and 160 day time points. Measurements of mortality, proteinuria and SAP concentration indicate that danazol at 100 mg/kg is orally active in the treatment of MRL/MpJ (lpr) female, but not male mice.

Alteration of interleukin-1 activity and the acute phase response in adjuvant arthritic rats treated with disease modifying antirheumatic drugs.

Interleukin-1 (IL-1) activity and the acute phase response, as measured by plasma CRP and iron, were used to determine if the standard disease modifying antirheumatic drugs (DMARDs), gold, chloroquine and D-penicillamine had a common profile of activity in the adjuvant arthritic (AA) rat. All drugs were tested at a dose which significantly reduced noninjected paw swelling in AA rats. Inhibition of paw edema ranged from 37% for D-penicillamine (100 mg/kg) to 69% for auranofin (10 mg/kg). Two week medication of AA rats with gold sodium thiomalate (GST, 10 mg/kg, i.m.) or auranofin (10 mg/kg, p.o.) resulted in a significant decrease in splenic IL-1 activity, as measured in the standard lymphocyte activating factor (LAF) assay. The acute phase response, often associated with elevated IL-1 activity, was also significantly reduced following treatment of AA rats with 10 mg/kg of GST or auranofin (oral gold). Inhibition of the acute phase response by gold was determined by a significant reduction of plasma CRP levels (56-71% reduction) and enhancement of plasma iron levels (27-52% enhancement). In contrast to the effect of GST and auranofin on IL-1, CRP and iron, treatment with chloroquine (20, 30 and 35 mg/kg) and D-penicillamine (55 and 100 mg/kg) failed to reduce the acute phase response (as measured by plasma CRP and iron) or alter LAF activity from AA rat spleen cell supernatants. Based on its ability to reduce LAF activity in spleen cell supernatants and reduce the acute phase response, it is possible that the activity of gold in the AA rat may in part be due to its ability to inhibit IL-1 production in vivo. The inability of chloroquine and D-penicillamine to alter LAF activity and the acute phase response in AA rats does not preclude their possession of an immunoregulatory mechanism of action, but it does indicate that their mechanism of action in the AA rat probably differs from that of GST and auranofin.