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Nathan Goodyear

Potent Inhibition of Human Phosphodiesterase-5 by Icariin Derivatives - Journal of Natu... - 0 views

pubs.acs.org/...np800049y

phosphodiesterase 5 inhibitors ED Icariin natural horny goat weed PDE5 phosphodiesterase inhibitors

shared by Nathan Goodyear on 12 Jun 13 - No Cached
  • Nathan Goodyear on 12 Jun 13
     
    A natural phosphodiesterase 5 inhibitor would be nice.  This study looked at a lot of traditional herbal remedies to block phosphodiesterase 5 activity.  Only Epimedii herb with the active ingredient icariin worked.  Other preparations were shown to work, but via different mechanisms.  This is a review of studies looking at these herbal preparations.
Nathan Goodyear

Phosphodiesterase-5 inhibitors in the management of cancer - 0 views

cAMP PDE5 inhibitors phosphodiesterase inhibitors PDE chemotherapy phosphodiesterase 5 inhibitors cancer cyclic AMP

shared by Nathan Goodyear on 16 Feb 21 - No Cached
  • Nathan Goodyear on 16 Feb 21
     
    Phosphodiesterase 5 inhibitors shown to have numerous effects against cancer, including restoring treatment sensitivity to chemotherapy.
Nathan Goodyear

Phosphodiesterase 5 Inhibitors Enhance Chemotherapy Killing in Gastrointestinal/Genitou... - 0 views

www.ncbi.nlm.nih.gov/...PMC3935155

chemotherapy phosphodiesterase 5 inhibitors repurposed drugs PDE inhibitors PDE5I phosphodiesterase inhibitors cancer PDE5 inhibitors

shared by Nathan Goodyear on 08 Mar 21 - No Cached
  • Nathan Goodyear on 08 Mar 21
     
    PDE inhibitors repurposed to augment chemotherapy in treatment of cancer.
Nathan Goodyear

International Journal of Impotence Research - PDE5 inhibitors beyond erectile dysfunction - 0 views

www.nature.com/...3901577a.html

ED phosphodiesterase 5 inhibitors impotence PDE5

shared by Nathan Goodyear on 12 Jun 13 - No Cached
  • Nathan Goodyear on 12 Jun 13
     
    Good review on phosphodiesterase 5 inhibitors.
Nathan Goodyear

Salivary 8-OHdG: a useful biomarker for predicting severe ED and hypogonadism. - PubMed... - 0 views

www.ncbi.nlm.nih.gov/...18422497

oxidative stress 8-OHdG 8-hydroxy-2-deoxyguanosine hormones Testosterone phosphodiesterase 5 inhibitors

shared by Nathan Goodyear on 15 Jun 15 - No Cached
  • Nathan Goodyear on 15 Jun 15
     
    Study finds salivary 8-OHdG is associated with increased severity of ED in men.  The study found that phosphodiesterase 5 inhibitor therapy increased total and free Testosterone as well as decreased 8-OHdG.
Nathan Goodyear

Inhibition of breast cancer cell migration by activation of cAMP signaling - PubMed - 0 views

pubmed.ncbi.nlm.nih.gov/26022351

phosphodiesterase inhibitors breast cancer phosphodiesterase 5 inhibitors cyclic AMP PDE5 inhibitors cAMP

shared by Nathan Goodyear on 08 Mar 21 - No Cached
  • Nathan Goodyear on 08 Mar 21
     
    Increase in cAMP found to inhibit breast cancer motility and migration. Here, they used cAMP analogs, forskolin and PDE inhibitors.
Nathan Goodyear

Phosphodiesterase-5 inhibitors use and risk for mortality and metastases among male pat... - 0 views

www.ncbi.nlm.nih.gov/...PMC7314744

phosphodiesterase inhibitors PDE5 cAMP cancer

shared by Nathan Goodyear on 15 Feb 21 - No Cached
  • Nathan Goodyear on 15 Feb 21
     
    PDE5 shown to prevent metastasis in cancer. The mechanism is through an increase in cAMP levels.
Nathan Goodyear

JAMA Network | JAMA Internal Medicine | Sildenafil Use and Increased Risk of ... - 0 views

archinte.jamanetwork.com/article.aspx

sildenafil viagra melanoma cancer skin men phosphodiesterase 5 inhibitors

shared by Nathan Goodyear on 14 Apr 14 - No Cached
  • Nathan Goodyear on 14 Apr 14
     
    Viagra associated with a 84% increased risk of melanoma.  The key word here is associated.  No cause and effect relationship is seen.  Anytime use was also associated with increased risk.  This study did not look at the other phopsphodiesterase 5 inhibitors, though the logic is there risk may be higher as they are longer acting.
Nathan Goodyear

Testosterone: a vascular hormone in health and disease - 0 views

joe.endocrinology-journals.org/...R47.full

testosterone hormone health disease hormones men male cardiovascular disease CVD

shared by Nathan Goodyear on 13 May 13 - No Cached
  • Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
  • In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure.
  • testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells
  • ...54 more annotations...
  • Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis
  • there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)
  • bidirectional effect between decreased testosterone concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular risk factors
  • Achieving a normal physiological testosterone concentration through the administration of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory profiles and vascular function
  • It is well known that impaired erectile function and CVD are closely related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5 years
  • no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.
  • free testosterone levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated brachial artery vasodilation in men with CAD
  • Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects when testosterone is replaced within normal physiological limits in humans
  • Endothelium-independent mechanisms of testosterone are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)
  • Testosterone shares the same molecular binding site as nifedipine
  • Testosterone increases the expression of endothelial nitric oxide synthase (eNOS) and enhances nitric oxide (NO) production
  • Testosterone also inhibited the Ca2+ influx response to PGF2α
  • one of the major actions of testosterone is on NO and its signalling pathways
  • In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger
  • the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult to delineate and may be dependent upon the stage of plaque development
  • Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate with serum testosterone
  • t long-term testosterone treatment reduced CIMT in men with low testosterone levels and angina
  • neither intracellular nor membrane-associated ARs are required for the rapid vasodilator effect
  • acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described, primarily in the context of vascular tone regulation via the modulation of gene transcription
  • Testosterone and DHT increased the expression of eNOS in HUVECs
  • oestrogens have been shown to activate eNOS and stimulate NO production in an ERα-dependent manner
  • Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase inhibition
  • non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle
  • increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated human umbilical vein endothelial cells
  • Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy
  • Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM and/or hypogonadism
  • patients with the highest IL1β concentrations had lower endogenous testosterone levels
  • TRT has been reported to significantly reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD
  • testosterone treatment to normalise levels in hypogonadal men with the MetS resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo
  • parenteral testosterone undecanoate, CRP decreased significantly in hypogonadal elderly men
  • Higher levels of serum adiponectin have been shown to lower cardiovascular risk
  • Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ (IFNG)) in endothelial cells, can be attenuated by treatment with testosterone
  • Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types including human endothelial cells
  • decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in human endothelial cells when treated with DHT
  • The key to unravelling the link between testosterone and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.
  • testosterone functions through the AR to modulate adhesion molecule expression
  • pre-treatment with DHT reduced the cytokine-stimulated inflammatory response
  • DHT inhibited NFκB activation
  • DHT could inhibit an LPS-induced upregulation of MCP1
  • Both NFκB and AR act at the transcriptional level and have been experimentally found to be antagonistic to each other
  • As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription
  • prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis may reduce or alter any potentially protective effects of testosterone
  • DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional level, suggesting that androgens down-regulate IFN-induced genes
  • (Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT 3β-derivative, 3β-Adiol
  • TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly reduced by a pre-incubation with 3β-Adiol in HUVECs
  • 3β-Adiol also reduced LPS-induced gene expression of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)
  • This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory effects that are mediated by ER activation.
  • The authors suggest that DHT differentially effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and via AR-dependent and -independent mechanisms influenced by the physiological state of the cell
  • There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated an increased risk of adverse cardiovascular events or mortality
  • The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm
  • trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase in either cardiovascular events or mortality in studies up to 12 months
  • Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors, there may possibly be a cardioprotective action
  • The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen and/or disease status.
  • the majority of studies suggest that testosterone may display both acute and chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via endothelium-dependent and -independent mechanisms
  • Nathan Goodyear on 13 May 13
     
    Good deep look into the testosterone and CVD link.
Nathan Goodyear

Testosterone deficiency and cardiovascular mortality Morgentaler A, - Asian J Androl - 0 views

www.ajandrology.com/preprintarticle.asp

testosterone low t low Testosterone CVD cardiovascular mortality therapy

shared by Nathan Goodyear on 01 Dec 14 - No Cached
  • overall mortality and CV mortality were inversely associated with serum T concentrations.
  • men with low serum T, defined as < 8.7 nmol l−1 (250 ng dl−1 ), demonstrated significantly greater all-cause mortality than men with higher serum T (hazard ratio [HR]: 2.24; 95% CI: 1.41-3.57), as well as greater CV mortality
  • lower T levels were significantly associated with the presence of any CV disease
  • ...19 more annotations...
  • more than 30 years of studies suggesting that low levels of T represent an increased risk for CV and overall mortality,
  • lower serum T concentrations also are associated with CV disease, including incident coronary artery disease [17],[18],[19] and atherosclerosis,
  • the actual rate of adverse events was only half as great in the T group (123 events in 1223 men at risk = 10.1%) as in the untreated group (1587 events in 7486 men = 21.2%)
  • The study by Vigen et al. [7] has already undergone two published corrections,
  • 29 medical societies have called for retraction of the article, asserting "gross data mismanagement and contamination," that rendered the study "no longer credible
  • Mortality in T-treated men was reduced by approximately half in treated men compared with untreated men, at 10.3% versus 20.7%, respectively
  • The mortality rate for men who received TTh was 3.4 deaths per 100 person-years, and 5.7 deaths per 100 person-years in untreated men
  • HR of 0.61 (95%CI: 0.42-0.88; P = 0.008), indicating a significant reduction in mortality with TTh
  • men in the highest prognostic MI risk quartile, treatment with TTh was associated with reduced risk
  • tripling in T prescriptions in the US over the last decade
  • a majority of observational studies have found that low endogenous serum T levels are associated with increased mortality.
  • Men who received TTh were able to exercise significantly longer without ischemia compared with men who received placebo
  • In men with congestive heart failure, those who received T demonstrated greater walking distance and other functional endpoints compared with those who received placebo
  • TTh has been shown uniformly and repeatedly to improve several known CV risk factors, including reduced fat mass, body fat percent, and waist circumference, and increased lean mass
  • improved glycemic control
  • reductions in insulin resistance.
  • the evidence strongly points to improved CV status with normal serum T or treatment with TTh in men with TD
  • analysis of health insurance claims data that reported a 36% increased rate of nonfatal MI in the 90d following receipt of a T prescription compared with the 12 prior months.
  • Comparison with men who received a prescription for a phosphodiesterase type 5 inhibitor (PDE5i) revealed no increased rate of MI following the prescription
  • Nathan Goodyear on 01 Dec 14
     
    Great review by Morgentaler of Testosterone and CVD.  He highlights the significant flaws in the JAMA and the NEJM articles of Testosterone therapy risks.  Morgentaler highlights the significant evidence that points to low T and increased risk of CVD. On contention I have, is Morgantaler seems to flip aside the massive uptick of Testosterone use in the US as compared to other countries.  The evidence definitely points to Testosterone therapy as being safe in those with low T, but there is definitely a problem of significant Testosterone doping that is taking place as well.
Nathan Goodyear

Hormonal Modulation in Aging Patients with Erectile Dysfunction and Metabolic Syndrome - 0 views

www.ncbi.nlm.nih.gov/...PMC3888699

low T Testosterone hypogonadism MetS metabolic syndrome men male hormone hormones

shared by Nathan Goodyear on 05 Feb 14 - No Cached
  • Hypogonadism and MetS are strongly associated [12, 13, 16], having even been demonstrated that with the increasing number of MetS parameters there is a proportional raise in the incidence of hypogonadism
  • increasing number of MetS components is inversely associated with T levels
  • the presence of MetS did not prove to be a significant determinant of hypogonadism, as it did not lead to a decline in T levels, in MetS patients with already established hypogonadism, the increasing number of MetS features was associated with further decline in T
  • ...15 more annotations...
  • In the setting of MetS, hypertriglyceridemia and increased WC have been reported as the most important determinants of hypogonadism
  • recent literature consistently associates obesity not only with higher risk of hypogonadism [4, 6, 27] but also with lower T levels
  • Visceral adiposity has been particularly related with reduction of T and SHBG levels (independent of other metabolic disorders)
  • WC was one of the MetS parameters with the greatest influence in T levels decrease, presenting itself as a strong risk factor for hypogonadism development
  • MetS-related T decline was not accompanied by an increase in pituitary LH levels, suggesting impairment in gonadotropin secretion
  • The molecules behind this smoothing compensatory effect of GnRH/LH are still unknown, but estrogens and insulin, as well as leptin, TNF-α, and other adipokines, were proposed candidates
  • fat stores undertake an increase aromatization of androgens, therefore raising estrogen levels [9, 15], which in turn decrease LH secretion
  • our data contradicts the concept that estradiol exerts a negative feedback on hypothalamic GnRH secretion
  • taking into account that high estradiol levels have already been described as the only abnormality in a subset of patients with ED, the hypothesis that the later might not only be caused by androgen deficiency is becoming increasingly evident
  • it has been reported that the chronic exposure to phosphodiesterase type 5 inhibitors (PDE5i), widely used for the treatment of ED, may influence serum estradiol levels
  • thyroid disorders (specially hyperthyroidism) have been related to ED and hypogonadism, and so must be considered in a sexual-dysfunction setting
  • It is clear from the current literature that collecting a more thorough hormonal panel might be a wise approach to further uncover hormonal relations
    • Nathan Goodyear
      Nathan Goodyear on 05 Feb 14
       
      outstanding point.  This hits to the point that Low T is the effect not the cause.
  • We concluded that in ED patients with hypogonadism and MetS, the attenuated response of HPG axis (normal or low LH levels) might not always be due to an underlying adiposity-dependent estrogen-raising effect.
  • our findings indicate that ED, aging, and estradiol might have a stronger connection than what is currently described in the literature.
  • this study underlines the importance of the collection of a full hormonal panel in ED men
  • Nathan Goodyear on 05 Feb 14
     
    low T strongly associated with metabolic syndrome in men.
Nathan Goodyear

Impact of Low Testosterone on Response to Treatment ... [Urology. 2014] - Pub... - 0 views

www.ncbi.nlm.nih.gov/...24726311

ED libido men male hormone hormones low Testosterone T PDE5I phosphodiesterase 5 inhibitors

shared by Nathan Goodyear on 16 Apr 14 - No Cached
  • Nathan Goodyear on 16 Apr 14
     
    Here is where science and particularly conclusions fail the public.  The authors conclusions are that tadalifl improves ED and sexual function irrespective of Testosterone levels.  However, the results say something different.  The group with normal Testosterone responded better versus the low Testosterone group.  This difference didn't reach statistical significance though.  This lack of statistical significance does not exclude the fact that there indeed was a difference.  The authors conlcusions take no part in reporting the whole truth, just that which supports their hypothesis. The diagnosis of low T in this study was < 300 ng/dl
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