Effects of the phosphodiesterase 2 inhibitor BI 474121 on central nervous system cyclic guanosine monophosphate concentrations: Translational studies.

AIMS: Phosphodiesterase 2 (PDE2) regulates intracellular cyclic adenosine monophosphate and guanosine monophosphate (cAMP/cGMP) levels, which contribute to processes crucial for learning and memory. BI 474121, a potent and selective PDE2 inhibitor, is in development for treating cognitive impairment associated with schizophrenia. METHODS: The effects of BI 474121 on cGMP concentrations were first assessed in rat cerebrospinal fluid (CSF) to demonstrate central nervous system (CNS) and functional target engagement. Next, a Phase I study in healthy participants assessed the pharmacokinetics of BI 474121 in CSF vs. plasma, the pharmacodynamics of BI 474121 by measuring cGMP concentrations in the CSF, and the safety of BI 474121. RESULTS: In rats, BI 474121 was associated with a dose-dependent increase (71% at the highest dose tested [3.0 mg kg-1]) in cGMP levels in the CSF relative to vehicle (P < 0.001). In healthy participants, the maximum-measured concentration CSF-to-plasma ratio for BI 474121 exposure was similar following single oral doses of BI 474121 2.5, 10, 20 and 40 mg (dose-adjusted geometric mean: 8.96% overall). BI 474121 2.5-40 mg administration in healthy participants also increased cGMP levels in CSF (maximum exposure-related change from baseline ratio, BI 474121: 1.44-2.20 vs. placebo: 1.26). The most common treatment-emergent adverse event (AE) was mild-to-moderate post-lumbar puncture syndrome, which resolved with standard treatment. No AEs of special interest were observed. CONCLUSIONS: BI 474121 crosses the blood-brain barrier to inhibit PDE2, supporting cGMP as a translational marker to monitor CNS target engagement. These findings promote further clinical development of BI 474121. CLINICALTRIALS: gov number (NCT04672954).

E2027 Cardiac Safety Evaluation With Concentration-Response Modeling of ECG Data to Inform Dose Selection in Studies in Patients With Dementia With Lewy Bodies.

BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase 9 in development for dementia with Lewy bodies. Cardiac safety assessments for emerging agents are essential to avoid drug-induced QT interval prolongation, which may predispose individuals to potentially fatal ventricular arrhythmias. To evaluate the cardiac safety of E2027 and to inform dose selection for the phase 2 study of E2027 in dementia with Lewy bodies, we evaluated concentration-response modeling of pooled electrocardiogram data. PATIENTS AND METHODS: A post hoc concentration-QTc analysis evaluated potential QT effects using data from 2 randomized, double-blind studies in healthy subjects: a single ascending dose (SAD) study and a multiple ascending dose (MAD) study. Daily E2027 doses ranged from 5 to 1200 mg. RESULTS: A linear mixed-effects model was used to establish the relationship between plasma concentrations of E2027 and change from the baseline of QTcF (ΔQTcF). A significant but shallow relationship was observed in the estimated slope of the concentration-ΔQTcF: 0.002 ms/ng/mL (90% confidence interval: 0.0007-0.0031) with a small, nonsignificant treatment effect-specific intercept of -0.6 ms. Based on this pooled concentration-QTc analysis, an effect on the QTcF interval >10 ms can be excluded up to E2027 plasma concentrations of ∼3579 ng/mL, corresponding to a dose at least 4-fold larger than the 50 mg phase 2 dose. CONCLUSION: This pooled post hoc analysis evaluating cardiac safety of E2027 demonstrated that clinically concerning QTcF prolongation and related cardiac complications are highly unlikely with proposed E2027 doses planned for phase 2.

Do commonly used prostate medications alter prostate MRI and fusion biopsy performance?

AIMS: To determine whether phosphodiesterase inhibitors (PDEi) or α-antagonists (AA) were associated with differences in region of interest (ROI) characteristics or prostate cancer detection on fusion biopsy (FB). MATERIALS AND METHODS: Records from 847 consecutive patients undergoing FB at three separate institutions over a period of 2 years were retrospectively reviewed. Associations between medication use, Prostate Imaging Reporting & Data System (PIRADS) scores, and ROI locations were assessed with ordinal logistic regression. Associations with lesion size and International Society of Urologic Pathology (ISUP) grade group (GG) on biopsy were tested using multivariate regression. RESULTS: Medication use included PDEi in 14.2% and AA in 23.0%. PDEi use was associated with 19.3% smaller lesion diameter (-2.8 mm; CI from -4.8 to -0.7; p < 0.01) and lower PIRADS scores on MRI (OR 0.60; CI 0.40 - 1.00; p = 0.05). AA use was associated with higher PIRADS scores (OR 1.43; CI 0.97 - 2.11; p = 0.06), fewer positive fusion-directed biopsy cores (-28.6%, CI from -57.9 to 0.01%, p = 0.05), and downgrading on final pathology (-19%; CI from -40 to 2%; p = 0.06). CONCLUSION: For PIRADS scores ≥ 3, PDEi use is associated with smaller ROI and lower PIRADS scores, while AA use is associated with higher PIRADS scores. Neither medication was associated with differences in biopsy GG. Prospective studies are needed to investigate the discordance between multi-parametric magnetic resonance imaging (mpMRI) results and oncologic outcomes associated with PDEi and AA use.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Translational Development Strategies for TAK-063, a Phosphodiesterase 10A Inhibitor.

BACKGROUND: TAK-063 is an inhibitor of phosphodiesterase 10A (PDE10A), an enzyme highly expressed in medium spiny neurons of the striatum. PDE10A hydrolyzes both cyclic adenosine monophosphate and cyclic guanosine monophosphate and modulates dopamine signaling downstream of receptor activation in both direct and indirect pathways of the striatum. TAK-063 exhibited antipsychotic-like effects in animal models; however, the translatability of these models to the clinical manifestations of schizophrenia and the meaningfulness for new targets such as PDE10A has not been established. METHODS: The TAK-063 phase 1 program included a comprehensive translational development strategy with the main objective of determining whether the antipsychotic-like pharmacodynamic effects seen in nonclinical models would translate to human subjects. To evaluate this objective, we conducted a single-rising dose study (84 healthy subjects), a positron emission tomography (PET) study (12 healthy subjects), a functional magnetic resonance imaging blood oxygen level-dependent (BOLD) study (27 healthy subjects), and a multiple-rising dose study that included people with schizophrenia (30 healthy Japanese subjects and 47 subjects with stable schizophrenia). In addition, assessments of cognition and electroencephalography (27 healthy subjects and 47 subjects with stable schizophrenia) were included. RESULTS: PDE10A engagement by TAK-063 was verified with a novel PET radiotracer for use in primates and humans. TAK-063 showed favorable pharmacokinetic and safety profiles in humans, and TAK-063 reduced ketamine-induced changes in electroencephalography and BOLD signaling in animal models and healthy human subjects. In addition, analogous effects on cognition were observed in animal models and human subjects. CONCLUSIONS: Overall, the phase 1 results showed some consistent evidence of antipsychotic activity. This translational strategy may be valuable for the future development of novel therapeutic approaches, even when relevant nonclinical models are not available.

The immunomodulatory role of PDEs inhibitors in immune cells: therapeutic implication in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory synovitis and progressive joint. Although the etiology is extremely complex, overwhelming evidence suggests that dysregulation or imbalance of the immune system plays a central role in disease pathogenesis. The bone loss and joint destruction are immunological insults mediated by infiltration and abnormal activation of various immune cells. Since pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which degrade cyclic AMP and cyclic GMP, can regulate the activity of multiple immune cells, which are considered as a potential strategy for treating RA. Therefore, this review attempted to summarize the modulating effects of PDEs on immune cells and described the molecular underpinnings and potential clinical application of PDEs inhibitors for RA.

Treatments targeting inotropy.

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.

Phosphodiesterase 10A Inhibitor Monotherapy Is Not an Effective Treatment of Acute Schizophrenia.

BACKGROUND: Current treatments for psychotic symptoms associated with schizophrenia often provide inadequate efficacy with unacceptable adverse effects. Improved therapeutics have long been a goal of research. Preclinical testing suggests that phosphodiesterase 10A (PDE10A) inhibitors may provide a novel approach to treating psychosis associated with schizophrenia. METHODS: The efficacy and safety of a highly selective PDE10A inhibitor, PF-02545920, was evaluated in a phase 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Eligible patients (18-65 years) with an acute exacerbation of schizophrenia were randomized 2:2:1:2 to PF-02545920 (5 or 15 mg every 12 hours [Q12H] titrated), risperidone (3 mg Q12H), or placebo for 28 days (n = 74:74:37:74). The primary objectives were to evaluate the efficacy of PF-02545920 using the Positive and Negative Syndrome Scale (PANNS) and safety/tolerability. RESULTS: At day 28, PF-02545920 (either dose) was not significantly different from placebo for mean change from baseline in the PANNS total score (primary end point) or most other end points. Pharmacokinetics exposures seemed adequate for binding/inhibiting PDE10A enzyme. Risperidone was statistically different from placebo for the PANNS total score, demonstrating study sensitivity. Incidence rates for adverse events were similar among the groups. Both doses of PF-02545920 were generally well tolerated. Dystonia occurred in 1, 6, 0, and 3 patients in the PF-02545920 5 mg Q12H, PF-02545920 15 mg Q12H, risperidone, and placebo groups, respectively. CONCLUSIONS: Neither dose of PF-02545920 was superior to placebo for the primary and most secondary end points. This indicates that PDE10A inhibition does not produce an antipsychotic effect in patients with acute exacerbation of schizophrenia.

The Potential Role of Arginine Supplements on Erectile Dysfunction: A Systemic Review and Meta-Analysis.

INTRODUCTION: The efficacy and safety of arginine supplements in erectile dysfunction (ED) remain debatable. AIM: To assess the potential role of arginine supplements on ED as alternatives to phosphodiesterase inhibitors. METHODS: Studies published up to April 2018 that evaluated the efficacy of arginine supplements were identified from multiple databases (Google Scholar, PubMed, Medline, Embase, Kiss, DBpia, and Cochrane databases). Studies comparing arginine supplements with placebo or no treatment; focusing only on patients with mild to moderate severity of ED; and presenting outcomes such as improvement rate, International Index of Erectile Function (IIEF) score, and adverse effects were included. Subgroup analysis for arginine alone and arginine in combination with other substances was further conducted to increase interpretability. MAIN OUTCOME MEASURE: The strength of the association between arginine supplements and ED was assessed using relative odds ratios and weighted mean differences with 95% CI. RESULTS: In total, 10 randomized controlled trials met the inclusion criteria, reporting the outcomes of 540 patients with ED. The analysis demonstrated that arginine supplements with dosage ranging from 1,500 to 5,000 mg significantly improved ED compared with placebo or no treatment (odds ratios, 3.37 [1.29, 8.77], P = .01, I2 = 44). Arginine supplements also caused significant improvements in the IIEF subdomain scores of overall satisfaction, intercourse satisfaction, orgasmic function, and erectile function, whereas the IIEF sexual desire score remain unchanged. The adverse effect rate in the arginine-treated group was 8.3%, and that in the placebo group was 2.3%, none of which were severe. CLINICAL IMPLICATIONS: Arginine supplements can be recommended to patients with mild to moderate ED. STRENGTH & LIMITATIONS: The strength of this study is that it is the first meta-analysis to assess the potential role of arginine supplements in ED compared with placebo or no treatment. A limitation is that the treatment dosage and duration varied among studies, which may have contributed to study heterogeneity. CONCLUSION: The results of our systematic review and meta-analysis provide evidence on the effectiveness of arginine supplements for mild to moderate ED. Rhim HC, Kim MS, Park Y-J, et al. The Potential Role of Arginine Supplements on Erectile Dysfunction: A Systemic Review and Meta-Analysis. J Sex Med 2019;16:223-234.

Prednisolone or pentoxifylline for alcoholic hepatitis.

BACKGROUND: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: There is evidence for an association between major depressive disorder (MDD) and both inflammatory and phosphodiesterase (PDE) pathways. This study aimed to evaluate the adjunct role of the PDE inhibitor pentoxifylline (PTX), a compound with anti-inflammatory properties, in the treatment of adult patients with MDD. METHODS: This was a prospective, 12-week, double-blind study of parallel groups. Eighty adult outpatients who met the DSM-IV criteria for MDD participated in the trial. Patients were required to have a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 18. Patients were allocated randomly: 40 received escitalopram 20 mg/day plus placebo while the other 40 received escitalopram 20 mg/day plus PTX (400 mg b.i.d.). Patients were assessed by a psychiatrist at baseline, and 4, 8, and 12 weeks after the medication had been started. The serum levels of TNF-α, IL-6, IL-10, BDNF, 8-OHdG, and serotonin were measured at baseline and after therapy. RESULTS: After 8 and 12 weeks, the PTX group showed a statistically significantly greater improvement in HAM-D score compared to the control group (least squares mean difference [LSMD] -3.29, p = 0.000 and LSMD -3.49, p = 0.000, respectively). Moreover, the PTX group showed a statistically significantly greater reduction in the serum levels of TNF-α, IL-6, IL-10, and 8-OHdG along with a statistically significant increase in the levels of BDNF and serotonin in comparison with the control group after the treatment. CONCLUSION: The findings of this study suggest that PTX could be a promising adjunct to antidepressants in the treatment of MDD patients.

Phosphodiesterase inhibitors for lower urinary tract symptoms consistent with benign prostatic hyperplasia.

BACKGROUND: Benign prostatic hyperplasia (BPH) refers to non-malignant enlargement of the prostate gland that may cause bothersome lower urinary tract symptoms (LUTS). Alpha-blockers (ABs) and 5-alpha reductase inhibitors (5-ARIs) are the mainstay of medical treatment. Recently, phosphodiesterase inhibitors (PDEIs) that so far have been used mainly to treat erectile dysfunction were introduced to treat male LUTS. OBJECTIVES: To assess the effects of PDEIs compared to placebo and other standard of care drugs (ABs and 5-ARIs) in men with LUTS consistent with BPH. SEARCH METHODS: We conducted a systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, and clinical trials registries of the World Health Organization (WHO) and the National Institutes of Health (NIH) (updated 2 August 2018). We performed citation tracking and handsearching of abstracts and conference proceedings. We also contacted study authors to ask for additional information. SELECTION CRITERIA: We considered for inclusion in this systematic review randomised controlled trials (RCTs) comparing PDEIs versus placebo, ABs, or 5-ARIs for at least four weeks in men with BPH-LUTS. DATA COLLECTION AND ANALYSIS: Three review authors independently screened the literature and extracted data. Primary outcomes were effects on urinary symptoms as assessed by the International Prostate Symptom Score (IPSS-total; score ranging from 0 to 35, with higher values reflecting more symptoms), urinary bother as assessed by the Benign Prostatic Hyperplasia Impact Index (BPHII; score ranging from 0 to 13, with higher values reflecting more bother), and adverse events (AEs). We used GRADE to rate the quality of evidence. We considered short-term (up to 12 weeks) and long-term (12 weeks or longer) results separately. MAIN RESULTS: We included a total of 16 randomised trials in this review. The results for primary outcomes are as follows.PDEI versus placebo: PDEIs may result in a small improvement in IPSS-total score (mean difference (MD) 1.89 lower, 95% confidence interval (CI) 2.27 lower to 1.50 lower; n = 4293; low-quality evidence) compared to placebo, and may reduce the BPHII score slightly (MD 0.52 lower, 95% CI 0.71 lower to 0.33 lower; n = 3646; low-quality evidence). Rates of AEs may be increased (risk ratio (RR) 1.42, 95% CI 1.21 to 1.67; n = 4386; low-quality evidence). This corresponds to 95 more AEs per 1000 participants (95% CI 47 more to 151 more per 1000). Study results were limited to a treatment duration of six to 12 weeks.PDEI versus AB: PDEIs and ABs probably provide similar improvement in IPSS-total score (MD 0.22 higher, 95% CI 0.49 lower to 0.93 higher; n = 933; moderate-quality evidence) and may have a similar effect on BPHII score (MD 0.03 higher, 95% CI 1.10 lower to 1.16 higher; n = 550; low-quality evidence) and AEs (RR 1.35, 95% CI 0.80 to 2.30; n = 936; low-quality evidence). This corresponds to 71 more AEs per 1000 participants (95% CI 41 fewer to 264 more per 1000). Study results were limited to a treatment duration of six to 12 weeks.PDEI and AB versus AB alone: the combination of PDEI and AB may provide a small improvement in IPSS-total score (MD 2.56 lower, 95% CI 3.92 lower to 1.19 lower; n = 193; low-quality evidence) compared to AB alone. We found no evidence for BPHII scores. AEs may be increased (RR 2.81, 95% CI 1.53 to 5.17; n = 194; moderate-quality evidence). This corresponds to 235 more AEs per 1000 participants (95% CI 69 more to 542 more per 1000). Study results were limited to treatment duration of four to 12 weeks.PDEI and AB versus PDEI alone: the combination of PDEI and AB may provide a small improvement in IPSS-total (MD 2.4 lower, 95% CI 6.47 lower to 1.67 higher; n = 40; low-quality evidence) compared to PDEI alone. We found no data on BPHII or AEs. Study results were limited to a treatment duration of four weeks.PDEI and 5-ARI versus 5-ARI alone: in the short term (up to 12 weeks), the combination of PDEI and 5-ARI probably results in a small improvement in IPSS-total score (MD 1.40 lower, 95% CI 2.24 lower to 0.56 lower; n = 695; moderate-quality evidence) compared to 5-ARI alone. We found no evidence on BPHII scores or AEs. In the long term (13 to 26 weeks), the combination of PDEI and 5-ARI likely results in a small reduction in IPSS-total score (MD 1.00 less, 95% CI 1.83 lower to 0.17 lower; n = 695; moderate-quality evidence). We found no evidence about effects on BPHII scores. There may be no difference in rates of AEs (RR 1.07, 95% CI 0.84 to 1.36; n = 695; low-quality evidence). This corresponds to 19 more AEs per 1000 participants (95% CI 43 fewer to 98 more per 1000).We found no trials comparing other combinations of treatments or comparing different PDEI agents. AUTHORS' CONCLUSIONS: Compared to placebo, PDEI likely leads to a small reduction in IPSS-total and BPHII sores, with a possible increase in AEs. There may be no differences between PDEI and AB with regards to improvement in IPSS-total, BPHII, and incidence of AEs. There appears to be no added benefit of PDEI combined with AB compared to PDEI or AB alone or PDEI combined with 5-ARI compared to ARI alone with regards to urinary symptoms. Most evidence was limited to short-term treatment up to 12 weeks and of moderate or low certainty.

Pentoxifylline Treatment of Very Low Birth Weight Neonates with Nosocomial Sepsis.

Objective The objective of this study was to assess the result of intravenous pentoxifylline as an adjunct to antibiotic therapy on mortality and morbidity in very low birth weight (VLBW) preterm neonates with nosocomial sepsis. Methods For the 18 VLBW preterm neonates, as an adjunct therapy to antibiotics regimens, pentoxifylline (5 mg/kg/h for 6 hours) was administered to premature infants with sepsis on 3 successive days. Clinical and laboratory parameters were recorded before and after treatment. Results Following pentoxifylline therapy, the immature-to-total neutrophil ratio and C-reactive protein (CRP) levels were significantly decreased, while the blood pH and base excess were significantly increased (p < 0.05). The axillary temperature, noninvasive blood pressure, hemoglobin, leukocyte, and thrombocyte values did not significantly differ after treatment (p > 0.05). Coagulase-negative staphylococci (CoNS) (32%), Streptococcus hominis (7.3%), Pseudomonas aeruginosa (5.3%), and Candida parapsilosis (3.1%) were identified in the blood cultures. There were no short-term morbidities (intraventricular hemorrhages, necrotizing enterocolitis, periventricular leukomalacia, and patent ductus arteriosus), no adverse effects, and no mortalities during or after the pentoxifylline therapy in the preterm neonate participants. Conclusion The CRP levels and heart rate both decreased, while the pH and base excess parameters of the blood gas analysis changed positively after pentoxifylline treatment in VLBW preterm neonates with nosocomial sepsis.

Pentoxifylline and Pentaglobin adjuvant therapies for neonatal nosocomial sepsis in neonates less than 1500g weight.

OBJECTIVE: To compare different support therapies in very low birth-weight preterm neonates with nosocomial sepsis. METHODS: This clinical pilot study was conducted at the Bagcilar Research and Training Hospital, Istanbul, Turkey, from September 2015 to November 2016. Preterm infants appropriately sized for a gestational age of < 32 weeks and < 1,500g were included in the study. Pentaglobin was initiated on the day of diagnosis of nosocomial sepsis to very low birth-weight preterm neonates as a support therapy in addition to antibiotics: 5 ml/kg per day of pentaglobin was infused over a four-hour period on three consecutive days. Pentoxifylline (5 mg/kg every 6 hours) was administered to premature infants with sepsis on three successive days. RESULTS: Of the 41 neonates, 19(46.3%) were girls and 22(53.7%) were boys. Vital signs, haematologic tables, peripheral blood smear left shift ratio, and blood-gas parameters did not differ significantly between the groups (p>0.05), but the C-reactive protein (mg/dl) values significantly decreased after pentoxifylline treatment (p<0.05). Coagulase-negative staphylococci were the most frequently isolated bacteria in the two groups (n=4; 19% vs. n=4; 20%). There was no difference in isolated microorganisms. There was no significant difference in intraventricular haemorrhage, necrotising enterocolitis, periventricular leukomalacia or symptomatic patent ductus arteriosus in the neonates when comparing the two groups and no systemic reactions were observed during adjuvant therapy in the preterm neonates (p>0.05). The total duration of hospitalisation was 49.46±13.52 days for the pentaglobin group and 44.21±11.1 days for the pentoxifylline group neonates. CONCLUSIONS: Pentoxifylline treatment for nosocomial sepsis decreased C-reactive protein levels and heart rate more than pentaglobin therapy.

Peyronie's disease - Watch out for the bend.

BACKGROUND: Peyronie's disease is a relatively common condition in urological practice, but is still poorly identified and understood in the wider medical community and by most of the public. Identifying the condition and appropriate referral for expert opinion can significantly lessen the physical and psychological effect on patients. OBJECTIVE: The objective of this article is to provide general practitioners with a concise and updated review of Peyronie's disease, with the aim of helping them to provide appropriate advice to their patients. DISCUSSION: Peyronie's disease is an aberrant wound healing process culminating in excess scar formation in the penis, which may cause penile pain, shortening and curvature. It is often accompanied by erectile dysfunction, and can result in progressive and severe impairment of penetrative intercourse. The course of the disorder is divided into active inflammatory and chronic stable phases. Oral therapy is usually of limited efficacy, while penile traction may only be beneficial in motivated patients. Intralesional injections of collagenase were recently introduced as a non-surgical measure to decrease penile curvature. Surgery remains the most effective treatment for Peyronie's disease and is considered the gold standard.

Safety of Intravenous Methamphetamine Administration During Ibudilast Treatment.

BACKGROUND: Methamphetamine dependence is a significant public health concern without any approved medications for treatment. We evaluated ibudilast, a nonselective phosphodiesterase inhibitor, to assess the safety and tolerability during intravenous methamphetamine administration. We conducted a randomized, double-blind, placebo-controlled, within-subjects crossover clinical trial. METHODS: Participants received ibudilast (20 mg twice daily followed by 50 mg twice daily) and placebo, with order determined by randomization, and then underwent intravenous methamphetamine challenges (15 and 30 mg). We monitored cardiovascular effects, methamphetamine pharmacokinetics, and reported adverse events. RESULTS: Ibudilast treatment had similar rates of adverse events compared with placebo, and there was no significant augmentation of cardiovascular effects of methamphetamine. Pharmacokinetic analysis revealed no clinically significant change in maximum concentration or half-life of methamphetamine with ibudilast. CONCLUSIONS: Methamphetamine administration during ibudilast treatment was well tolerated without additive cardiovascular effects or serious adverse events, providing initial safety data to pursue ibudilast's effectiveness for the treatment of methamphetamine dependence.

First-in-human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males.

AIMS: The aim of the present study was to investigate the safety, tolerability, dose proportionality and relative bioavailability of tablet and oral solution formulations of BI 409306 in healthy male subjects, and to compare the safety and pharmacokinetics in subjects who were extensive metabolizers (EMs) or poor metabolizers (PMs) of cytochrome P450 (CYP)-2C19. METHODS: The present randomized, double-blind, placebo-controlled, single-centre study evaluated single rising doses of BI 409306 (0.5-500 mg) administered as a tablet or oral solution to EMs or PMs. RESULTS: Of 80 enrolled subjects (mean age 36.7 years), 79 (CYP2C19 EMs, 71; CYP2C19 PMs, eight) received treatment and completed the study. Adverse events (AEs) were mild to moderate in intensity. Overall, 17/71 (23.9%) EMs and 6/8 (75.0%) PMs experienced 28 and eight AEs, respectively, of which, 25 and seven AEs, respectively, were considered to be drug related. The most frequently reported AEs were nervous system and eye disorders; all occurred shortly (20-30 min) after administration and mostly resolved within 1-2 h. No serious AEs occurred. BI 409306 systemic absorption and elimination were rapid; peak plasma concentration (Cmax ) was reached <1 h after drug administration, and the half-life ranged from 0.99 h to 2.71 h. Both the tablet and oral solution resulted in similar exposures. In PMs, at dose levels of 10 mg and 100 mg, Cmax was 2.2-2.3-fold higher, and the area under the plasma concentration-time curve over the time interval 0 extrapolated to infinity was 4.1-5.0-fold higher compared with EMs. CONCLUSIONS: In healthy male subjects, BI 409306 was generally safe and well tolerated, with rapid absorption and elimination. Systemic exposure was higher in CYP2C19 PMs than EMs at the same dose level.

Phosphodiesterase-5 Inhibitor Use: An Under-Reported Cause of Profuse Nasal Bleeding.

BACKGROUND: Phosphodiesterase-5 (PDE-5) inhibitors enhance penile erection and have gained popularity not only for erectile dysfunction, but also in recreational settings. Nevertheless, adverse effects have been associated with their use, with nasal bleeding among them. PDE-5 inhibitor action is materialized through the inhibition of the cyclic guanosine monophosphate (cGMP) enzyme. cGMP is present at several sites of the human body in addition to the corpus cavernosum, leading to the adverse effects associated with its nonselective inhibition. CASE REPORTS: Two male patients with severe epistaxis who were taking PDE-5 inhibitors for erectile dysfunction or recreational purposes are discussed. Surgical intervention was required in both patients to control the nasal hemorrhage. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Nasal bleeding in patients who are taking PDE-5 inhibitors might represent an under-reported cause of epistaxis because of the unwillingness of most male patients to discuss issues pertaining their use without hesitation. Yet such episodes are rather profuse. This is especially true when the venous engorgement caused in the nasal mucosa by the smooth muscle relaxant effect of PDE-5 inhibitors is combined with a second event (e.g., specific drugs or blood dyscrasia). Emergency physicians should be also aware of the possibility that in the coming years the number of such cases might increase because of the increased use of these medications for erectile dysfunction or recreational purposes. It is likely that these patients could not be managed conservatively, but would rather require referral to an Ear, Nose, and Throat Department for surgical intervention.

A Novel Compound Analgesic Cream (Ketamine, Pentoxifylline, Clonidine, DMSO) for Complex Regional Pain Syndrome Patients.

BACKGROUND: Evidence suggests that complex regional pain syndrome (CRPS) is a manifestation of microvascular dysfunction. Topical combinations of α2-adrenergic receptor agonists or nitric oxide donors with phosphodiesterase or phosphatidic acid inhibitors formulated to treat microvascular dysfunction have been shown to reduce allodynia in a rat model of CRPS-I. Driven by these findings, we assessed the outcomes of CRPS patients treated with a compound analgesic cream (CAC) consisting of ketamine 10%, pentoxifylline 6%, clonidine 0.2%, and dimethyl sulfoxide 6% to 10%. METHODS: An audit was conducted on 13 CRPS patients who trialed the CAC. A detailed report was compiled for each patient which comprised baseline characteristics, including CRPS description, previous treatments, and pain scores (numerical pain rating scale; 0 to 10). Recorded outcomes consisted of pain scores, descriptive outcomes, and concurrent medications/treatments, for which basic analysis was performed to determine the effectiveness of the CAC. Case reports are presented for 3 patients with varying outcomes. RESULTS: Nine patients (69%) reported pain/symptom reduction (4.4 ± 2.1 vs. 6.3 ± 1.9) with use of the CAC. Six patients reported sustained benefits after 2 months of CAC use, and 2 patients reported complete resolution of pain/symptoms: one had early CRPS-I and the other received a partial CRPS diagnosis. An otherwise medication refractory and intolerant patient found partial benefit with the CAC. CONCLUSIONS: These results demonstrate promise for this topical combination as a useful treatment in multimodal therapy for patients with CRPS, with the potential to resolve pain/symptoms in early CRPS patients.

Molecular Simulations of Solved Co-crystallized X-Ray Structures Identify Action Mechanisms of PDEδ Inhibitors.

PDEδ is a small protein that binds and controls the trafficking of RAS subfamily proteins. Its inhibition protects initiation of RAS signaling, and it is one of the common targets considered for oncological drug development. In this study, we used solved x-ray structures of inhibitor-bound PDEδ targets to investigate mechanisms of action of six independent all-atom MD simulations. An analysis of atomic simulations combined with the molecular mechanic-Poisson-Boltzmann solvent accessible surface area/generalized Born solvent accessible surface area calculations led to the identification of action mechanisms for a panel of novel PDEδ inhibitors. To the best of our knowledge, this study is one of the first in silico investigations on co-crystallized PDEδ protein. A detailed atomic-scale understanding of the molecular mechanism of PDEδ inhibition may assist in the design of novel PDEδ inhibitors. One of the most common side effects for diverse small molecules/kinase inhibitors is their off-target interactions with cardiac ion channels and human-ether-a-go-go channel specifically. Thus, all of the studied PDEδ inhibitors are also screened in silico at the central cavities of hERG1 potassium channels.