Oral Probenecid for Nonhospitalized Adults with Symptomatic Mild-to-Moderate COVID-19.

Probenecid is an orally bioavailable, uricosuric agent that was first approved in 1951 for the treatment of gout, but was later found to have potent, broad-spectrum antiviral activity against several respiratory viruses including SARS-CoV-2. We conducted a phase 2 randomized, placebo-controlled, single-blind, dose-range finding study in non-hospitalized patients with symptomatic, mild-to-moderate COVID-19. Patients were randomly assigned in a 1:1:1 ratio to receive either 500 mg of probenecid, 1000 mg of probenecid, or a matching placebo every 12 h for five days. The patients' COVID-19 viral load hospitalization, or death from any cause through day 28, as well as safety, were evaluated. COVID-19-related symptoms were assessed at baseline, and on days 3, 5, 10, 15, and 28. The primary endpoints of the study were time to first negative SARS-CoV-2 viral test (or viral clearance) and the proportion of patients that were symptom-free at day 5. A total of 75 patients were randomized, with 25 patients in each group. All of the patients completed the study as planned with no hospitalizations or deaths being reported. The median time to viral clearance was significantly shorter for the probenecid 1000 mg group than for placebo (7 days vs. 11 days, respectively; p < 0.0001), and for the probenecid 500 mg group versus placebo (9 days vs. 11 days, respectively; p < 0.0001). In addition, the median time to viral clearance was significantly shorter for the probenecid 1000 mg group than for the probenecid 500 mg group (7 days vs. 9 days, respectively; p < 0.0001). All patients reported at least one COVID-19-related symptom on days 3 and 5; however, on day 10, a significantly greater proportion of patients receiving probenecid 1000 mg reported the complete resolution of symptoms versus placebo (68% vs. 20%, respectively; p = 0.0006), as well as for those receiving probenecid 500 mg versus placebo (56% vs. 20%, respectively, p = 0.0087). The incidence of adverse events during treatment was similar across all groups for any adverse event, and was 12%. All events were mild with no serious adverse events reported and no discontinuations due to an adverse event. The treatment of patients with symptomatic, mild-to-moderate COVID-19 with probenecid resulted in a significant, dose-dependent decrease in the time to viral clearance and a significantly higher proportion of patients reporting complete symptom resolution by day 10. (Supported by TrippBio; ClinicalTrials.gov number, NCT05442983 and Clinical Trials Registry India number CTRI/2022/07/043726).

Probenecid ameliorates testosterone-induced benign prostatic hyperplasia: Implications of PGE-2 on ADAM-17/EGFR/ERK1/2 signaling cascade.

Benign prostatic hyperplasia (BPH) is one of the most prevalent clinical disorders in the elderly. Probenecid (Prob) is a well-known FDA-approved therapy for gout owing to its uricosuric effect. The present study evaluated the use of Prob for BPH as a COX-2 inhibitor. Prob (100 and 200 mg/kg) was intraperitoneally injected into male Wistar rats daily for 3 weeks. In the second week, testosterone (3 mg/kg) was subcutaneously injected to induce BPH. Compared with BPH-induced rats, Prob treatment reduced prostate weight and index and improved histopathological architecture. The protease activity of ADAM-17/TACE and its ligands (TGF-α and TNF-α) were regulated by prob, which in turn abolished EGFR phosphorylation, and several inflammatory mediators (COX-2, PGE2, NF-κB (p65), and IL-6) were suppressed. By reducing the nuclear import of extracellular regulated kinase protein 1/2 (ERK1/2), Prob helped re-establish the usual equilibrium between antiapoptotic proteins like Bcl-2 and cyclin D1 and proapoptotic proteins like Bax. All of these data point to Prob as a promising treatment for BPH because of its ability to inhibit COX-2-syntheiszed PGE2 and control the ADAM-17/TGF-α-induced EGFR/ERK1/2 signaling cascade. These findings might help to repurpose Prob for the treatment of BPH.

Combination of Amoxicillin 3000 mg and Probenecid Versus 1500 mg Amoxicillin Monotherapy for Treating Syphilis in Patients With Human Immunodeficiency Virus: An Open-Label, Randomized, Controlled, Non-Inferiority Trial.

BACKGROUND: Amoxicillin plus probenecid is an alternative to intramuscular benzathine penicillin G for treating syphilis in the United Kingdom. Low-dose amoxicillin is an alternative treatment option used in Japan. METHODS: We conducted an open-label, randomized, controlled, non-inferiority trial between 31 August 2018, and 3 February 2022, to compare 1500 mg low-dose amoxicillin monotherapy with the combination of 3000 mg amoxicillin and probenecid (non-inferiority margin 10%). Patients with human immunodeficiency virus (HIV) infection and syphilis were eligible. The primary outcome was the cumulative serological cure rate within 12 months post-treatment, measured using the manual rapid plasma reagin card test. Secondary outcomes included safety assessment. RESULTS: A total of 112 participants were randomized into 2 groups. Serological cure rates within 12 months were 90.6% and 94.4% with the low-dose amoxicillin and combination regimens, respectively. Serological cure rates for early syphilis within 12 months were 93.5% and 97.9% with the low-dose amoxicillin and combination regimens, respectively. Non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid overall and for early syphilis was not confirmed. No significant side effects were detected. CONCLUSIONS: This is the first randomized controlled trial to demonstrate a high efficacy of amoxicillin-based regimens for treating syphilis in patients with HIV infection, and the non-inferiority of low-dose amoxicillin compared with amoxicillin plus probenecid was not seen. Therefore, amoxicillin monotherapy could be a good alternative to intramuscular benzathine penicillin G with fewer side effects. However, further studies comparing with benzathine penicillin G in different populations and with larger sample sizes are needed. TRIALS REGISTRATION: (UMIN000033986).

Addition of probenecid to oral ß-lactam antibiotics: a systematic review and meta-analysis.

OBJECTIVES: To explore the literature comparing the pharmacokinetic and clinical outcomes from adding probenecid to oral ß-lactams. METHODS: Medline and EMBASE were searched from inception to December 2021 for all English language studies comparing the addition of probenecid (intervention) with an oral ß-lactam [flucloxacillin, penicillin V, amoxicillin (±â€Šclavulanate), cefalexin, cefuroxime axetil] alone (comparator). ROBINS-I and ROB-2 tools were used. Data on antibiotic therapy, infection diagnosis, primary and secondary outcomes relating to pharmacokinetics and clinical outcomes, plus adverse events were extracted and reported descriptively. For a subset of studies comparing treatment failure between probenecid and control groups, meta-analysis was performed. RESULTS: Overall, 18/295 (6%) screened abstracts were included. Populations, methodology and outcome data were heterogeneous. Common populations included healthy volunteers (9/18; 50%) and those with gonococcal infection (6/18; 33%). Most studies were crossover trials (11/18; 61%) or parallel-arm randomized trials (4/18; 22%). Where pharmacokinetic analyses were performed, addition of probenecid to oral ß-lactams increased total AUC (7/7; 100%), Cmax (5/8; 63%) and serum t½ (6/8; 75%). Probenecid improved PTA (2/2; 100%). Meta-analysis of 3105 (2258 intervention, 847 control) patients treated for gonococcal disease demonstrated a relative risk of treatment failure in the random-effects model of 0.33 (95% CI 0.20-0.55; I2 = 7%), favouring probenecid. CONCLUSIONS: Probenecid-boosted ß-lactam therapy is associated with improved outcomes in gonococcal disease. Pharmacokinetic data suggest that probenecid-boosted oral ß-lactam therapy may have a broader application, but appropriately powered mechanistic and efficacy studies are required.

Repurposing Probenecid for the Treatment of Heart Failure (Re-Prosper-HF): a study protocol for a randomized placebo-controlled clinical trial.

BACKGROUND: Improving contractility in heart failure with reduced ejection fraction (HFrEF) has resurfaced as a potential treatment goal. Inotropic therapy is now better understood through its underlying mechanism as opposed to the observed effect of increasing contractility. Calcitropes are a subgroup of inotropes that largely depend on the stimulation of adenylyl cyclase to transform ATP into cyclic adenosine monophosphate (cAMP). At least two clinically relevant calcitropes-istaroxime and probenecid-improve contractility through an increase in systolic intracellular calcium without activating cAMP production. Probenecid, which has been safely used clinically for decades in non-cardiac conditions, has recently been identified as an agonist of the transient receptor potential vanilloid 2 channel. Translational studies have shown that it improves calcium cycling and contractility without activating noxious pathways associated with cAMP-dependent calcitropes and can improve cardiac function in patients with HFrEF. METHODS: The Re-Prosper-HF study (Repurposing Probenecid for the Treatment of Heart Failure with Reduced Ejection Fraction) is a three-site double-blinded randomized-controlled trial that will test the hypothesis that probenecid can improve cardiac function in patients with HFrEF. Up to 120 patients will be randomized in this double-blind, placebo-controlled study that will assess whether oral probenecid administered at 1 g orally twice per day for 180 days in patients with NYHA II-III HFrEF improves systolic function (aim 1), functional status (aim 2), and self-reported health status (aim 3). DISCUSSION: Findings from this study will provide data informing its use for improving symptomatology in patients with HFrEF as well as exploratory data for outcomes such as hospital admission rates. TRIAL TEGISTRATION: The Re-Prosper HF Study (Re-Prosper HF) is registered on ClinicalTrials.gov with the identifier as NCT04551222. Registered on 9 September 2020.

Clinical efficacy and tolerability of 1.5 g/day oral amoxicillin therapy without probenecid for the treatment of syphilis.

OBJECTIVES: Intramuscular benzathine penicillin G is not available in certain countries. In a previous report, 3 g/day amoxicillin with probenecid was shown to be effective in treating syphilis in patients with HIV; however, 7.3% of patients changed their therapy owing to adverse events. The objective of this study was to assess the clinical efficacy and tolerability of 1.5 g/day amoxicillin without probenecid for the treatment of syphilis. METHODS: The routine clinical records of patients diagnosed with syphilis and treated with 1.5 g/day amoxicillin at a tertiary care hospital between 2006 and 2018 were retrospectively analysed. Syphilis was diagnosed if serum rapid plasma reagin (RPR) titres were ≥8 RU and the Treponema pallidum latex-agglutination test was positive. Serological cure was defined as a ≥fourfold decrease in the RPR titre within 12 months in symptomatic early syphilis and within 24 months in latent syphilis. RESULTS: Overall, 138 patients (112 with HIV) were analysed. The percentages of primary, secondary, early latent, late latent and latent syphilis of unknown duration were 8.0%, 50.0%, 25.4%, 5.8% and 10.9%, respectively. The median treatment duration was 4.5 weeks (IQR 4-8 weeks), which was not related to the stage of syphilis. Two patients (1.5%) changed treatment due to skin rash. The rate of serological cure was 94.9% (131/138; 95% CI 89.8% to 97.9%) overall; 93.8% (105/112; 95% CI 87.5% to 97.5%) in patients with HIV and 100% (26/26; 95% CI 86.8% to 100%) in patients without HIV. Treatment duration was not related to the treatment efficacy. CONCLUSION: The regimen of 1.5 g/day amoxicillin without probenecid is highly effective with a low switch rate in patients with and without HIV.

Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro.

BACKGROUND: Transient receptor potential vanilloid 2 is a calcium channel activated by probenecid. Probenecid is a Food and Drug Administration-approved uricosuric drug that has recently been shown to induce positive lusitropic and inotropic effects in animal models through cardiomyocyte transient receptor potential vanilloid 2 activation. The aim of this study was to test the hypothesis that oral probenecid can improve cardiac function and symptomatology in patients with heart failure with reduced ejection fraction and to further elucidate its calcium-dependent effects on myocyte contractility. METHODS AND RESULTS: The clinical trial recruited stable outpatients with heart failure with reduced ejection fraction randomized in a single-center, double-blind, crossover design. Clinical data were collected including a dyspnea assessment, physical examination, ECG, echocardiogram to assess systolic and diastolic function, a 6-minute walk test, and laboratory studies. In vitro force generation studies were performed on cardiomyocytes isolated from murine tissue exposed to probenecid or control treatments. The clinical trial recruited 20 subjects (mean age 57 years, mean baseline fractional shortening of 13.6±1.0%). Probenecid therapy increased fractional shortening by 2.1±1.0% compared with placebo -1.7±1.0% (P=0.007). Additionally, probenecid improved diastolic function compared with placebo by decreasing the E/E' by -2.95±1.21 versus 1.32±1.21 in comparison to placebo (P=0.03). In vitro probenecid increased myofilament force generation (92.36 versus 80.82 mN/mm2, P<0.05) and calcium sensitivity (pCa 5.67 versus 5.60, P<0.01) compared with control. CONCLUSIONS: Probenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with heart failure with reduced ejection fraction and increases force development and calcium sensitivity at the cardiomyocyte level. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01814319.

Oral probenecid improves sperm motility in men with spinal cord injury.

STUDY DESIGN: Prospective cohort study (twenty men with spinal cord injury [SCI]). OBJECTIVE: Determine if administration of oral probenecid results in improved sperm motility in men with SCI. SETTING: Major university medical center. METHODS: Twenty men with SCI were administered probenecid for 4 weeks (250 mg twice a day for 1 week, followed by 500 mg twice a day for 3 weeks). Semen quality was assessed at three time points: pre-treatment, post-treatment (immediately after the 4-week treatment), and follow-up (4 weeks after the last pill was ingested). RESULT(S): Probenecid was well-tolerated by all subjects. Sperm motility improved in each subject after 4 weeks of oral probenecid. The mean percent of sperm with progressive motility increased from 19% to 26% (P < 0.05). A more striking increase was seen in the mean percent of sperm with rapid linear motility, from 5% to 17%, (P <0.001). This improvement continued into the four week follow up period. Similar improvements were seen in the total motile sperm count (15 million, 28 million, and 27 million at pre-treatment, post-treatment, and follow-up, respectively). Sperm concentration was not significantly different at pre-treatment, post-treatment, and follow-up, (52 million, 53 million and 53 million, respectively). CONCLUSION: This study showed that administration of an oral agent (probenecid) known to interfere with the pannexin-1 cellular membrane channel, can improve sperm motility in men with spinal cord injury. It is the first study to report improved sperm motility after oral medication in men with SCI.

Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. RESULTS: Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m2) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group (P=0.83), -4 (-16 to 9) in the allopurinol group (P=0.32), and 1 (-21 to 17) in the placebo group (P=0.96), with no significant treatment effect (P=0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was -1.6±10.1 with probenecid (P=0.43), -0.4±6.1 with allopurinol (P=0.76), and 0.5±6.0 with placebo (P=0.65); there was no significant treatment effect (P=0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively. CONCLUSIONS: In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney-specific or systemic RAS activity after 8 weeks or on mean systolic BP. These data do not support the hypothesis that higher levels of uric acid are a reversible risk factor for increased BP.

Achieving serum urate targets in gout: an audit in a gout-oriented rheumatology practice.

AIM: To assess the proportion of patients with gout who achieve target serum urate levels, the drug regime required and the reasons for failing to do so. METHODS: We reviewed the files of all patients with gout who presented to a gout-oriented rheumatology practice between January 2010 and September 2014. RESULTS: Two hundred and thirty patients agreed to commence urate lowering therapy (ULT); 73% achieved their urate target, including 74% with non-tophaceous gout (target ≤ 0.36 mmol/L) and 71% with tophi (target ≤ 0.30 mmol/L). Of the 62 who failed to reach target, in 61 it was due to non-adherence and in one due to inefficacy. CONCLUSION: Adherence remains the major challenge to successful long-term gout management.

Therapeutic effects of paeonol on methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-induced Parkinson's disease in mice.

Paeonol is a major phenolic compound of the Chinese herb, Cortex Moutan, and is known for its antioxidant, anti-inflammatory and antitumor properties. The present study was designed to investigate the therapeutic potential and underlying mechanisms of paeonol on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p)-induced mouse model of Parkinson's disease (PD). MPTP (25 mg/kg), followed by probenecid (250 mg/kg), was administered via i.p. injection for five consecutive days to induce the mouse model of PD. Paeonol (20 mg/kg) was administrated orally for 21 days. Behavior was assessed using the rotarod performance and open­field tests. Additionally, the levels of tyrosine hydroxylase (TH), microglia, interleukin­1ß (IL­1ß), and brain­derived neurotrophic factor (BDNF) in the substantia nigra pars compacta (SNpc) were evaluated by immunohistochemical staining. MPTP/p­induced motor deficits were observed to be significantly improved following long­term treatment with paeonol. Paeonol treatment decreased MPTP/p­induced oxidative stress, as determined by evaluating the activity levels of superoxide dismutase, catalase and glutathione. Additionally, MPTP/p­induced neuroinflammation was assessed by examining the levels of microglia and IL­1ß, which were significantly decreased following paeonol treatment. Paeonol treatment improved the MPTP/p­induced dopaminergic neurodegeneration, as measured by observing the increased TH level in the SNpc. Furthermore, the BDNF level was significantly elevated in the paeonol treatment group compared with mice treated with MPTP/p only. In conclusion, paeonol exerted therapeutic effects in the MPTP/p­induced mouse model of PD, possibly by decreasing the damage from oxidative stress and neuroinflammation, and by enhancing the neurotrophic effect on dopaminergic neurons. The results demonstrate paeonol as a potential novel treatment for PD.

Penicillin Encephalopathy: An Unlikely Adversary in the Treatment of Neurosyphilis--Case Report and Review of the Literature.

UNLABELLED: Penicillin encephalopathy is a rare, potentially reversible phenomenon of drug-induced neurotoxicity. CASE: A 65-year-old female with a history of HIV was admitted with a three-day history of worsening headache, confusion, and lethargy. On examination she was awake but confused. Cerebrospinal fluid (CSF) and serum venereal disease research laboratory (VDRL) test returned positive and the patient was started on intravenous penicillin G with probenecid. On the second day of therapy, she developed myoclonic jerking, consistent with penicillin neurotoxicity. Repeat labs also showed new onset renal failure. Penicillin and probenecid therapy were stopped with a resolution of symptoms. Subsequently, therapy without probenecid was reinstituted uneventfully. DISCUSSION: Herein, we describe a female who developed penicillin neurotoxicity after initiation of intravenous penicillin therapy with probenecid for neurosyphilis. It is important that penicillin-induced toxicity be considered if characteristic myoclonic movements accompany encephalopathy. The presence of coexistent renal compromise should heighten the vigilance of clinicians.

High-dose oral amoxicillin plus probenecid is highly effective for syphilis in patients with HIV infection.

BACKGROUND: Intramuscular benzathine penicillin G (BPG) is widely used for the treatment of syphilis. However, BPG is not available in some countries. This study examined the effectiveness and safety of high-dose oral amoxicillin plus probenecid for the treatment of syphilis in patients with human immunodeficiency virus type 1 (HIV-1). METHODS: This retrospective observational study included 286 HIV-infected male patients with syphilis (median age, 36 years; median CD4 count, 389 cells/µL) who were treated with oral amoxicillin 3 g plus probenecid. Syphilis was diagnosed by both serum rapid plasma reagin (RPR) titers ≥8 and positive Treponema pallidum hemagglutination test. Patients with neurosyphilis diagnosed by cerebrospinal fluid examination were excluded. Successful treatment was defined as a at least 4-fold decrement in RPR titer. RESULTS: The overall treatment efficacy was 95.5% (95% confidence interval [CI], 92.4%-97.7%; 273/286 patients), and efficacy for primary, secondary, early latent, late latent, and unknown duration syphilis was 93.8% (95% CI, 68.1%-99.8%; 15/16), 97.3% (95% CI, 92.9%-99.2%; 142/146), 100% (95% CI, 90.5%-100%; 37/37), 85.7% (95% CI, 58.6%-96.4%; 18/21), and 92.4% (95% CI, 81.9%-97.3%; 61/66), respectively. Treatment duration was mostly 14-16 days (49.7%) or 28-30 days (34.3%), with efficacy of 94.4% (134/142) and 95.9% (94/98), respectively; 96.3% of successfully treated patients achieved a ≥4-fold decrement in RPR titer within 12 months. Adverse events were noted in 28 (9.8%) patients, and 25 of these (89.3%) were successfully treated. Only 6% of patients underwent lumbar puncture. CONCLUSIONS: The combination of oral amoxicillin 3 g plus probenecid was highly effective and tolerable for the treatment of syphilis in patients with HIV-1 infection.

Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.

OBJECTIVE: Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. METHODS: Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4-12); study 2: canagliflozin 300 mg (days 1-17), probenecid 500 mg twice daily (days 15-17); and study 3: canagliflozin 300 mg (days 1-8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at prespecified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2-8 (study 3). RESULTS: Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. CONCLUSION: Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.

Intestinal absorption of raltitrexed and evaluation of the effects of absorption enhancers.

Raltitrexed (RTX) has shown clinical activity in a variety of advanced solid tumours. Its oral bioavailability is low and its intestinal absorption mechanism is not clear. In the present study, the absorption mechanism of RTX in the small intestine was investigated, and the effects of absorption enhancers and efflux transporter inhibitors were evaluated by in vitro transport studies using the Caco-2 cell model and in situ perfusion experiments in rats. Oral bioavailability of RTX in rats in the presence or absence of enhancers were also investigated. The results of in vitro and in situ experiments indicated that the kinetic model of combined mechanism (active and passive transport) fitted the concentration-time data of RTX best with the highest R2 and lowest SSE (Sum of Squares for Error). The apparent or effective permeability coefficient (P(app) or P(eff)) of RTX remained statistically constant in a certain concentration range, then decreased when the concentration increased. But the decrease trend did not continue with further increase in concentration. And folic acid could competitively inhibit RTX absorption. These results suggested that a combined absorption mechanism for RTX existed. Furthermore, within certain concentration ranges, Carbomer 934P and sodium caprate (Cap-Na) exhibited significant absorption enhancement effects with low toxicity, whereas the enhancement effects of sodium deoxycholate (Deo-Na) were accompanied with acute toxicities. Moreover, probenecid and pantoprazole obviously enhanced RTX absorption, demonstrating that RTX is a substrate of the multidrug resistance protein (MRP) and breast cancer resistance protein (BCRP). A secretion experiment indicated that RTX could be effluxed into the intestines both with bile and by active efflux action. Oral bioavailability of RTX was significantly improved by the investigated absorption enhancers and transporter inhibitors, which is consistent with the in vitro and in situ experiments.

Probenecid: an emerging tool for neuroprotection.

Probenecid (PROB) has been widely used for long time for different clinical purposes, from gout treatment to designs as a coadjutant for antibiotic agents. Among its many properties, the ability of PROB to preserve high concentrations of several metabolites and other agents in the CNS, together with its relative lack of side-effects, have made this drug a valuable pharmacological tool for clinical and basic research. Nowadays, biomedical research offers evidence about new targets for PROB that may help to explain its many beneficial actions. In this regard, despite most of its protective actions in the brain have been largely related to its capacity to accumulate the inhibitory metabolite kynurenic acid to further inhibit the glutamate-related excitotoxicity in different animal models of neurological disorders, in this review we describe the basic aspects of PROB's pharmacokinetics and mechanisms of action and discuss other alternative targets recently described for this drug that may complement its pattern of activity in the CNS, including its role as anti-inflammatory and anti-nociceptive agent when targeting different key proteins.

Efficacy and tolerability of probenecid as urate-lowering therapy in gout; clinical experience in high-prevalence population.

OBJECTIVE: Probenecid is recommended as urate-lowering therapy (ULT) in patients with gout where xanthine oxidase inhibitors are ineffective, not tolerated, or contraindicated. The aim of our study was to determine the efficacy of probenecid to achieve serum urate (SU) targets (< 0.36 mmol/l) in clinical practice. METHODS: We identified 57 patients prescribed with probenecid from a database of 521 rheumatology clinic attenders with gout. Demographic characteristics, indications for probenecid, probenecid doses, side effects, and laboratory data including estimated glomerular filtration rate (eGFR) and SU were recorded. RESULTS: There were 30/57 (53%) patients treated with probenecid as monotherapy and 27/57 (47%) patients treated with probenecid in combination with allopurinol. Target SU concentrations (< 0.36 mmol/l) were achieved in 10/30 (33%) of the probenecid monotherapy group and 10/27 (37%) of the combination treatment group. Baseline SU concentrations, but not eGFR or probenecid dose, independently predicted achievement of target SU. Target SU was achieved in 5/15 (33%) patients with eGFR < 50 ml/min/1.73 m(2). There was no difference in the percentage of patients achieving SU target in those with eGFR < 50 ml/min/1.73 m(2) compared with those with eGFR ≥ 50 ml/min/1.73 m(2). Adverse events attributed to probenecid were observed in 8/42 (19%) patients with eGFR ≥ 50 ml/min/1.73 m(2) and in 2/15 (13%) patients with eGFR < 50 ml/min/1.73 m(2). CONCLUSION: Probenecid has moderate efficacy as ULT in clinical management of patients with complex gout who have a lack of efficacy or intolerance to allopurinol. Patients with chronic kidney disease may respond to probenecid with similar rates of adverse events.

Probenecid as a noninjurious positive inotrope in an ischemic heart disease murine model.

The current therapeutic options for acute decompensated heart failure are limited to afterload reducers and positive inotropes. The latter increases myocardial contractility through changes in myocyte calcium (Ca²âº) handling (mostly through stimulation of the ß-adrenergic pathways [ß-ADR]) and is associated with paradoxical effects of arrhythmias, cell death, and subsequently increased mortality. We have previously demonstrated that probenecid can increase cytosolic Ca²âº levels in the cardiomyocyte resulting in an improved inotropic response in vitro and in vivo without activating the ß-ADR system. We hypothesize that, in contrast to other commonly used inotropes, probenecid functions through a system separate from that of ß-ADR and hence will increase contractility and improve function without damaging the heart. Furthermore, our goal was to evaluate the effect of probenecid on cell death in vitro and its use in vivo as a positive inotrope in a mouse model of ischemic cardiomyopathy. Herein, we demonstrate that probenecid induced an influx of Ca²âº similar to isoproterenol, but does not induce cell death in vitro. Through a series of in vivo experiments we also demonstrate that probenecid can be used at various time points and with various methods of administration in vivo in mice with myocardial ischemia, resulting in improved contractility and no significant difference in infarct size. In conclusion, we provide novel data that probenecid, through its activity on cellular Ca²âº levels, induces an inotropic effect without causing or exacerbating injury. This discovery may be translatable if this mechanism is preserved in man.

Combination of probenecid-sulphadoxine-pyrimethamine for intermittent preventive treatment in pregnancy.

The antifolate sulphadoxine-pyrimethamine (SP) has been used in the intermittent prevention of malaria in pregnancy (IPTp). SP is an ideal choice for IPTp, however, as resistance of Plasmodium falciparum to SP increases, data are accumulating that SP may no longer provide benefit in areas of high-level resistance. Probenecid was initially used as an adjunctive therapy to increase the blood concentration of penicillin; it has since been used to augment concentrations of other drugs, including antifolates. The addition of probenecid has been shown to increase the treatment efficacy of SP against malaria, suggesting that the combination of probenecid plus SP may prolong the useful lifespan of SP as an effective agent for IPTp. Here, the literature on the pharmacokinetics, adverse reactions, interactions and available data on the use of these drugs in pregnancy is reviewed, and the possible utility of an SP-probenecid combination is discussed. This article concludes by calling for further research into this potentially useful combination.

[Gout - regardless of therapeutic options a "forgotten" disease]. / Gicht - die "vergessene" Erkrankung trotz vieler therapeutischer Optionen.

Compared to other chronic inflammatory diseases, gout appears to based on a rather "simple" pathophysiology and therefore the amount of teaching time in medical school and during internship is rather limited. On the other hand, several problems in short- and long-term management still need to be solved - combined with the problem of an increased incidence in elderly people. However, there is significant advance in the knowledge of its pathophysiology including the fact that gout is more than a pure "crystal arthopathy" but rather within the spectrum of chronic inflammatory immunologic diseases. This includes cytokines such as interleukin-1 and intracellular signaling via the inflammasome. For treatment, the novel and effective xanthine oxidase inhibitor febuxostat has been added to the therapeutic armamentarium. Guidelines of EULAR and BSR support the physician in the long-term management of the numerous gout patients.