RESUMO
Intracavernosal injections of botulinum toxin A (BTX/A ic) may be effective for difficult-to-treat erectile dysfunction (ED). This is a retrospective case series study of the effectiveness of repeated off-label BTX/A ic (onabotulinumtoxinA 100U, incobotulinumtoxinA 100U or abobotulinumtoxinA 500U) in men with ED and insufficient response to phosphodiesterase type 5 inhibitors (PDE5-Is) or prostaglandinE1 intracavernosal injections (PGE1 ICIs), defined as an International Index of Erectile Function-Erectile Function domain score (IIEF-EF) < 26 on treatment. Further injections were performed on patients' requests, and the files of men who underwent at least two injections were reviewed. The response to BTX/A ic was defined as the achievement of the minimally clinically important difference in IIEF-EF adjusted to the severity of ED on treatment at baseline. Out of 216 men treated with BTX/A ic and PDE5-Is or PGE1-ICIs, 92 (42.6%) requested at least a second injection. The median time since the preceding injection was 8.7 months. In total, 85, 44 and 23 men received, respectively, two, three and four BTX/A ic. The overall response rate was 77.5%: 85.7% in men with mild ED, 79% for moderate ED and 64.3% for severe ED on treatment. The response increased with repeated injections: 67.5%, 87.5% and 94.7%, respectively, after the second, third and fourth injections. Post-injection changes in IIEF-EF were similar across injections. The time from injection to request for a further injection varied little. Four men reported penile pain at the time of injection (1.5% of all injections), and one experienced a burn at the penile crus. Repeated BTX/A injections combined with PDE5-Is or PGE1-ICIs produced an effective and durable response, with acceptable safety.
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Toxinas Botulínicas Tipo A , Disfunção Erétil , Masculino , Humanos , Disfunção Erétil/tratamento farmacológico , Ereção Peniana , Alprostadil/efeitos adversos , Estudos Retrospectivos , Toxinas Botulínicas Tipo A/efeitos adversos , Inibidores da Fosfodiesterase 5/efeitos adversos , Resultado do TratamentoRESUMO
Ejaculation is often impaired in men with spinal cord injury (SCI). The aim of this prospective study was to assess sequence of sphincteric events and ejaculation dyssynergia during penile vibratory stimulation (PVS) in SCI men. Simultaneous recordings of bladder, bladder neck, prostate and external urethral sphincter pressures were performed using a microtip catheter with 5 pressure transducers. Between 2017 and 2019, ten men participated in the study for a total of 17 procedures. Antegrade ejaculation was found in three men with upper motor neuron (UMN) lesion. Ejaculation was preceded by a progressive increase in all urethral pressures, reaching sustained (plateau) or intermittent peaks above 220 cm H20. Antegrade ejaculation occurred after intermittent decreases in pressure at the external urethral sphincter level down to 100 cm H20, while the pressure at the bladder neck remained high (up to or above 220 cm H20). PVS was ineffective in eliciting ejaculation in seven men. In the five patients with UMN lesions, PVS elicited an increase in the external urethral sphincter pressure (mean 51 cm H20), while there was no pressure change in the two patients with lower motor neuron lesions. Due to lack of enough retrograde retrieval attempts, the hypothesis of ejaculatory dyssynergia could not be verified.
Assuntos
Ejaculação , Traumatismos da Medula Espinal , Masculino , Humanos , Ejaculação/fisiologia , Estudos Prospectivos , Traumatismos da Medula Espinal/complicações , Pênis , UretraRESUMO
Capsaicin acts on sensory nerves via vanilloid receptors. TRPV1 has been extensively studied with respect to functional lower urinary tract (LUT) conditions in rodents and humans. We aimed to (1) provide background information on capsaicin and TRPV1 and its mechanisms of action and basis for clinical use, (2) review the use of acute intravesical capsaicin instillation (AICI) in rodents to mimic various LUT disorders in which capsaicin sensitive C-fibers are involved and (3) discuss future innovative treatments. A comprehensive search of the major literature databases until June 2022 was conducted. Both capsaicin-sensitive and resistant unmyelinated bladder afferent C-fibers are involved in non-neurogenic overactive bladder/detrusor overactivity (OAB/DO). AICI is a suitable model to study afferent hyperactivity mimicking human OAB. Capsaicin-sensitive C-fibers are also involved in neurogenic DO (NDO) and potential targets for NDO treatment. AICI has been successfully tested for NDO treatment in humans. Capsaicin-sensitive bladder afferents are targets for NDO treatment. TRPV1-immunoreactive nerve fibers are involved in the pathogenesis of interstitial cystitis/painful bladder syndrome (IC/PBS). The AICI experimental model appears relevant for the preclinical study of treatments targeting bladder afferents for refractory IC/BPS. The activity of capsaicin-sensitive bladder afferents is increased in experimental bladder outlet obstruction (BOO). The AICI model may also be relevant for bladder disorders resulting from C-fiber hyperexcitabilities related to BOO. In conclusion, there is a rationale for the selective blockade of TRPV1 channels for various bladder disorders. The AICI model is clinically relevant for the investigation of pathophysiological conditions in which bladder C-fiber afferents are overexcited and for assessing innovative treatments for bladder disorders based on their pathophysiology.
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Cistite Intersticial , Bexiga Urinária , Capsaicina/uso terapêutico , Cistite Intersticial/tratamento farmacológico , Cistite Intersticial/patologia , Humanos , Fibras Nervosas Amielínicas , Canais de Cátion TRPV , Bexiga Urinária/inervação , Bexiga Urinária/patologiaRESUMO
BACKGROUND: Neurogenic detrusor overactivity (NDO) is a severe pathological condition characterized by involuntary detrusor contractions leading to urine leakage. This condition is frequent after spinal cord injury (SCI). Gene therapy for NDO requires the development of vectors that express therapeutic transgenes driven by sensory neuron-specific promoters. The aim of this study was to develop and assess tools for the characterization of sensory neuron-specific promoters in dorsal root ganglia (DRG) neurons after transduction with herpes simplex virus type 1 (HSV-1)-based amplicon defective vectors. METHODS: The HSV-1 vector genome encoded two independent transcription cassettes: one expressed firefly luciferase (FLuc) driven by different promoters' candidates (rTRPV1, rASIC3, rCGRP, or hCGRP), and the other expressed a reporter gene driven by an invariable promoter. The strength and selectivity of promoters was assessed in organotypic cultures of explanted adult DRG, or sympathetic and parasympathetic ganglia from control and SCI rats. RESULTS: The rCGRP promoter induced selective expression in the DRG of normal rats. The rTRPV-1 promoter, which did not display selective activity in control rats, induced selective expression in DRG explanted from SCI rats. CONCLUSIONS: This study provides a methodology to assess sensory neuron-specific promoters, opening new perspectives for future gene therapy for NDO.
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Herpes Simples , Herpesvirus Humano 1 , Traumatismos da Medula Espinal , Bexiga Urinária Hiperativa , Animais , Gânglios Espinais/metabolismo , Terapia Genética/métodos , Vetores Genéticos/genética , Herpesvirus Humano 1/genética , Ratos , Células Receptoras Sensoriais/metabolismo , Traumatismos da Medula Espinal/metabolismo , Bexiga Urinária Hiperativa/terapiaRESUMO
BACKGROUND: Botulinum toxin A (BTX-A) has a variety of uses in medicine. Some evidence suggests that intracavernosal (ic) BTX-A injection administered in addition to phosphodiesterase type 5 inhibitors (PDE5-Is) could effectively treat erectile dysfunction (ED) in insufficient responders to PDE5-Is. AIM: To provide experimental pharmacological evidence for the use of onabotulinumtoxinA ic alone or in combination with PDE5-Is for difficult-to-treat ED. We thus compared the effects of BTX-A ic alone and BTX-A ic combined with PDE5-I iv, and a placebo treatment ic or iv. METHODS: Erectile function was evaluated following cavernous nerve electrical stimulation (6 V, 1-millisecond pulse, 45-second duration) at different frequencies (0, 2, 3, 4, 5, 7.5, and 10 Hz) in 4 groups (n = 8 / group) of anesthetized, spontaneously hypertensive rats, a robust animal model of ED of vascular origin. Rats were treated by onabotulinumtoxinA 10U or saline ic 1 week prior to erectile function testing and sildenafil (0.3 mg/kg) or saline iv 4 minutes prior to testing. Frequency-response curves were compared with a 2 way ANOVA. OUTCOMES: Both onabotulinumtoxinA ic, and sildenafil iv significantly improved erectile responses in spontaneously hypertensive rats, however the effect was greatly amplified when the treatments were combined. RESULTS: Intracavernosal pressure and/or mean arterial pressure ratios were significantly increased by sildenafil and onabotulinumtoxinA ic versus the control condition. OnabotulinumtoxinA 10U ic combined with sildenafil iv significantly potentiated erectile responses. Area under the curve and/or mean arterial pressure ratio increased by 19% with sildenafil iv, by 15% with onabotulinumtoxinA ic and by 58% with the combined treatment following cavernous nerve electrical stimulation at 6V, 1 ms, 10 Hz: these stimulation parameters elicited the maximal erectile response. CLINICAL TRANSLATION: These data provide a pharmacological rationale for the combined administration of onabotulinumtoxinA ic and sildenafil iv since the effects of both treatments were potentiated when their administration was combined. STRENGTHS & LIMITATIONS: First evidence of a synergistic pro-erectile effect of BTX-A combined with PDE5-I, however the mechanism behind the pro-erectile effect of BTX-A ic remains hypothetical. CONCLUSIONS: These results support further studies into the mechanisms behind the pro-erectile effect of BTX-A ic, as well as multicenter randomized control trials to evaluate the safety and efficacy of BTX-A ic combined with sildenafil for difficult-to-treat ED. Giuliano F., Joussain C., Denys P., et al. Intracavernosal OnabotulinumtoxinA Exerts a Synergistic Pro-Erectile Effect When Combined With Sildenafil in Spontaneously Hypertensive Rats. J Sex Med 2022;19:899-906.
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Toxinas Botulínicas Tipo A , Disfunção Erétil , Animais , Toxinas Botulínicas Tipo A/farmacologia , Disfunção Erétil/tratamento farmacológico , Masculino , Ereção Peniana , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Ratos , Ratos Endogâmicos SHR , Citrato de Sildenafila/farmacologia , Citrato de Sildenafila/uso terapêuticoRESUMO
Registered pharmacological treatments are insufficiently effective for erectile dysfunction (ED) in around 30% of affected men. Intracavernosal injection (ICI) of ona- and abobotulinumtoxinA can reduce ED in insufficient responders. We aimed to assess the safety and effectiveness of incobotulinumtoxinA ICI as an add-on therapy to phosphodiesterase-type 5 inhibitors (PDE5-Is) or prostaglandinE1 ICIs (PGE1 ICIs) to treat ED that did not respond sufficiently to this treatment alone. We retrospectively analyzed data from 66 men with difficult to treat ED treated with single or repeated incobotulinumtoxinA 100U ICI as an add-on therapy. Response rate (increase in International Index of Erectile Function-Erectile Function domain score ≥ the minimum clinically important difference) was 52% (median (1st-3rd quartile) 43.5 (34-71) days post-incobotulinumtoxinA ICI). ED etiology (except spinal cord injury) and severity did not influence effectiveness. Only a clinically significant response to the 1st injection predicted a request for a 2nd injection (OR = 5.6, 95%, CI 1.6-19.4). Three men reported mild penile pain during the injection. These results provide preliminary evidence for the effectiveness and safety of incobotulinumtoxinA ICI as an add-on therapy to treat ED that is insufficiently responsive to standard care and provides support for the multicenter randomized clinical trial NCT05196308.
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Disfunção Erétil , Toxinas Botulínicas Tipo A , Disfunção Erétil/tratamento farmacológico , Feminino , Humanos , Masculino , Ereção Peniana , Inibidores da Fosfodiesterase 5/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Spinal cord injury often results in erectile dysfunction and an ejaculation along with impaired semen parameters. Fertility is a major concern in spinal cord injury adult males and some fear that the delay post-spinal cord injury may negatively affect sperm quality. OBJECTIVES: We aimed to (i) assess semen parameters over time in SCI patients according to age at spinal cord injury, time post-spinal cord injury, and the spinal cord injury level and completeness and (ii) measure markers in semen for inflammation and marker of oxidative stress to investigate their impact on sperm parameters. MATERIALS AND METHODS: The study is a prospective, longitudinal, pilot study over 18 months. Thirty-five men with spinal cord injury from 18 to 60 years of age were enrolled. Their mean age was 29.4 ± 6.4 years. Semen retrieval was scheduled every 6 months, allowing analysis of four ejaculates, in association with measurement of granulocyte and seminal plasma elastase concentrations to assess markers in semen for inflammation and spermatozoa DNA fragmentation to assess oxidative stress. RESULTS: Based on reference limits, a normal total sperm number, decreased motility and vitality of the spermatozoa, and increased morphological abnormalities were found. Mean round cell and granulocyte concentrations were elevated in the semen. Markers in semen for inflammation and marker of oxidative stress were elevated in several semen samples, compared to reference limits. However, neither the presence of markers in semen for inflammation or oxidative stress, the completeness or the level of the spinal cord lesion, the age or the time post-spinal cord injury had a negative impact on the semen quality over time. DISCUSSION: There was no significant decline in semen quality in spinal cord injury patients over time within the limitations of this pilot study. Moreover, a chronic genital inflammatory status was not associated with impairment of semen quality. CONCLUSION: The present findings are reassuring for men with spinal cord injury and could guide the management of their reproductive ability. According to these preliminary data, not all spinal cord injury patients who are able to ejaculate require systematic freezing of their spermatozoa.
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Infertilidade Masculina/epidemiologia , Análise do Sêmen/estatística & dados numéricos , Traumatismos da Medula Espinal/fisiopatologia , Adolescente , Adulto , Humanos , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/etiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Recuperação Espermática , Traumatismos da Medula Espinal/complicações , Adulto JovemRESUMO
BACKGROUND: Some evidence suggests that intracavernosal botulinum toxin A (BTX-A IC) injections administered in addition to phosphodiesterase type 5 inhibitors (PDE5-Is) or prostaglandin E1 intracavernosal injections (PGE1 ICI) could effectively treat erectile dysfunction (ED) in non-responders, or insufficient responders to these pharmacologic treatments. AIM: To determine the long-term effectiveness and safety of combined treatment involving a single injection of BTX-A IC as an add on therapy to PDE5-Is or PGE1-ICI for the treatment of ED of different etiologies. METHODS: A retrospective, uncontrolled, single center study was conducted. Data from 123 consecutive patients with ED who were insufficient responders to PDE5-Is or PGE1-ICI and who received onabotulinumtoxinA 100 U, abobotulinumtoxinA 250 U or 500 U IC as an add on to their current pharmacologic treatment were analyzed. All analyses were exploratory. Qualitative data were compared using the Fisher's exact test. Univariate and multivariate analysis were performed using logistic regression with Odds Ratios (OR). Only variables with P < .05 in the univariate analysis were selected for multivariate analysis. RESULTS: The minimally clinically important difference (relative to baseline severity of ED) in the International Index of Erectile Function-Erectile function domain (IIEF-EF) score was achieved in 50% of patients at 34 (27-42) days and in 41% at 5.9 (3.9 - 8.1) months following BTX-A IC in combination with PDE5-Is or PGE1 ICI. The severity of ED influenced response to BTX-A IC according to the multivariate analysis (ORâ¯=â¯0.3, IC(95%])â¯=â¯(0.16 - 0.56). Neither being post prostatectomy nor the type of BTX-A affected the response. Effectiveness tended to decrease more over time with abobotulinumtoxinA 250 U than 500 U. The only side-effects were mild penile pain on injection (nâ¯=â¯1) and mild penile pain for 3 days following injection (nâ¯=â¯1); no systemic effects were reported. CLINICAL IMPLICATIONS: BTX-A IC (all types) administered as an add on to registered pharmacologic treatments improved erectile function for at least 6 months in 41% of patients with ED of varying etiologies, and was safe. STRENGTHS & LIMITATIONS: A relatively large cohort of patients with ED was included, with a long follow-up period, however the study was retrospective, and uncontrolled. CONCLUSION: This study provides preliminary evidence that BTX-A IC administered as an add-on therapy for ED that is insufficiently responsive to standard therapy is effective for at least 6 months, and is safe. Randomized clinical trials are now needed to fully confirm these results. Giuliano F, Joussain C, Denys P, Long Term Effectiveness and Safety of Intracavernosal Botulinum Toxin A as an Add-on Therapy to Phosphosdiesterase Type 5 Inhibitors or Prostaglandin E1 Injections for Erectile Dysfunction. J Sex Med 2022;19:83-89.
Assuntos
Toxinas Botulínicas Tipo A , Disfunção Erétil , Alprostadil/efeitos adversos , Toxinas Botulínicas Tipo A/efeitos adversos , Disfunção Erétil/etiologia , Humanos , Masculino , Ereção Peniana , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The retrotrapezoid nucleus (RTN) is a hub for respiratory chemoregulation in the mammal brainstem that integrates chemosensory information from peripheral sites and central relays. Chemosensitive neurons of the RTN express specific genetic and molecular determinants, which have been used to identify RTN precise location within the brainstem of rodents and nonhuman primates. Based on a comparative approach, we hypothesized that among mammals, neurons exhibiting the same specific molecular and genetic signature would have the same function. The co-expression of preprogalanin (PPGAL) and SLC17A6 (VGluT2) mRNAs with duplex in situ hybridization has been studied in formalin fixed paraffin-embedded postmortem human brainstems. Two specimens were processed and analyzed in line with RTN descriptions in adult rats and macaques. Double-labeled PPGAL+/SLC17A6+ neurons were only identified in the parafacial region of the brainstem. These neurons were found surrounding the nucleus of the facial nerve, located ventrally to the nucleus VII on caudal sections, and slightly more dorsally on rostral sections. The expression of neuromedin B (NMB) mRNA as a single marker of chemosensitive RTN neurons has not been confirmed in humans. The location of the RTN in human adults is provided. This should help to develop investigation tools combining anatomic high-resolution imaging and respiratory functional investigations to explore the pathogenic role of the RTN in congenital or acquired neurodegenerative diseases.
Assuntos
Tronco Encefálico/metabolismo , Tronco Encefálico/patologia , Galanina/biossíntese , Neurônios/metabolismo , Neurônios/patologia , Proteína Vesicular 2 de Transporte de Glutamato/biossíntese , Biomarcadores/metabolismo , Núcleo do Nervo Facial/metabolismo , Núcleo do Nervo Facial/patologia , Galanina/genética , Expressão Gênica , Humanos , Corpo Trapezoide/metabolismo , Corpo Trapezoide/patologia , Proteína Vesicular 2 de Transporte de Glutamato/genéticaRESUMO
BACKGROUND: The main purpose of this study is to investigate the effect of silodosin on the urodynamic consequences in a previously established model of lower urinary tract symptoms associated with benign prostate hyperplasia, the spontaneously hypertensive rats (SHR) supplemented with testosterone. METHODS: Three groups of animals (8-week-old; n = 10/group) were considered: Wistar Kyoto (control) rats (WKY), SHR supplemented with testosterone at 3 mg/kg/day and treated with either vehicle (SHR-T, n = 10) or silodosin at 0.1 mg/kg/day (SHR-T + silodosin, n = 10) by oral gavage for 6 weeks. Cystometry experiments were performed. The bladder was harvested, weighed and paraffin-embedded for morphometric analysis. The prostate was also harvested and weighed. RESULTS: The number of animals included in the analysis were n = 10/10 for WKY and n = 7-8/10 for each SHR rats supplemented with testosterone group. SHR-T displayed a significant decrease in the intercontraction interval, infused volume and mean flow rate whereas the frequency of non-voiding contractions was increased. Silodosin improved the voiding behavior of SHR-T by significantly increasing the intercontraction interval, the infused volume and the mean flow rate and decreasing the number of non-voiding contractions. SHR-T displayed a significant increase in prostate and bladder weights and a 15% increase in the detrusor wall area compared to WKY. CONCLUSIONS: Chronic silodosin treatment relieved storage symptoms in SHR supplemented with testosterone and decreased the frequency of non-voiding detrusor contractions during the filling phase.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Indóis/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Testosterona/uso terapêutico , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , Animais , Masculino , Estudo de Prova de Conceito , Hiperplasia Prostática/complicações , Distribuição Aleatória , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Resultado do Tratamento , Obstrução do Colo da Bexiga Urinária/etiologiaRESUMO
AIM: To assess the impact of baseline characteristics on Men's Sexual Health Questionnaire (MSHQ) total scores and to evaluate the clinical relevance of MSHQ changes and their association with spontaneously reported sexual adverse events (SexAEs) in patients with benign prostatic hyperplasia. METHODS: This was a post hoc analysis of the Phase 4 FDC116115 study, in which patients aged ≥50 years were randomised 1:1 to receive a fixed-dose combination of dutasteride 0.5 mg and tamsulosin 0.4 mg (DUT-TAM FDC), or placebo. End-points included: change in MSHQ total scores by baseline characteristics and SexAEs; cumulative distribution function for change from baseline to month 12 in MSHQ total score and the ejaculation, erection, satisfaction and sexual desire (libido) domain scores; and relationship between changes in MSHQ scores and SexAEs. RESULTS: The intent-to-treat population comprised 489 patients (DUT-TAM FDC, n = 243; placebo, n = 246). The mean reduction in total MSHQ score was greater in patients with SexAEs across both groups, compared with patients without SexAEs. Most patients reporting any SexAE (86% DUT-TAM FDC, 67% placebo) had a worsening of the MSHQ total score at month 12 compared with baseline. Specifically, 90% (DUT-TAM FDC) and 75% (placebo) of patients reporting an ejaculation SexAE and 73% (DUT-TAM FDC) and 87% (placebo) of patients reporting an erection SexAE had a worsening of MSHQ ejaculation and erection domain scores, respectively, at month 12. A threshold effect for incident SexAE was observed; patients showing a decrease of approximately 6-10 points in the total MSHQ score were more likely to report SexAEs. CONCLUSION: Findings support the clinical utility of the MSHQ tool in assessing the impact of DUT-TAM on sexual function by linking numerical changes in MSHQ scores to spontaneously reported SexAEs for the first time. The threshold effect for incidence of SexAEs warrants further investigation to determine its clinical relevance.
Assuntos
Dutasterida/efeitos adversos , Sintomas do Trato Urinário Inferior/tratamento farmacológico , Hiperplasia Prostática/tratamento farmacológico , Saúde Sexual , Tansulosina/efeitos adversos , Idoso , Método Duplo-Cego , Dutasterida/uso terapêutico , Ejaculação/efeitos dos fármacos , Humanos , Libido/efeitos dos fármacos , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Saúde do Homem , Pessoa de Meia-Idade , Ereção Peniana , Estudos Prospectivos , Hiperplasia Prostática/complicações , Comportamento Sexual , Inquéritos e Questionários , Tansulosina/uso terapêuticoRESUMO
The physiopathology of digestive disorders in patients with spinal cord injury (SCI) remains largely unknown, particularly the involvement of the enteric nervous system (ENS). We aimed in a rat model of chronic thoracic SCI to characterize (1) changes in the neurochemical coding of enteric neurons and their putative consequences upon neuromuscular response, and (2) the inflammatory response of the colon. Ex vivo motility of proximal and distal colon segments of SCI and control (CT) rats were studied in an organ chamber in response to electrical field stimulation (EFS) and bethanechol. Immunohistochemical analysis of proximal and distal segments was performed using antibodies again Hu, neuronal nitric oxide synthase, (nNOS), and choline acetyltransferase. Colonic content of acetylcholine and acetylcholinesterase was measured; messenger RNA (mRNA) expression of inflammatory cytokines was measured using reverse transcription quantitative polymerase chain reaction (RT-qPCR) approaches. Compared with the CT rats, the contractile response to bethanechol was significantly decreased in the proximal colon of SCI rats but not in the distal colon. The proportion of nNOS immunoreactive (IR) neurons was significantly reduced in the proximal but not distal colon of SCI rats. No change in proportion of choline acetyltransferase (ChAT)-IR was reported; the tissue concentration of acetylcholine was significantly decreased in the proximal colon of SCI rats. The expression of tumor necrosis factor alpha (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) was significantly reduced in the proximal and distal colon of SCI rats. This study demonstrates that functional motor and enteric neuroplastic changes affect preferentially the proximal colon compared with the distal colon. The underlying mechanisms and factors responsible for these changes remain to be discovered.
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BACKGROUND: Low-intensity extracorporeal shock wave therapy (Li-ESWT) has been reported to improve erectile function in patients with moderate-to-severe erectile dysfunction (ED) or even convert phosphodiesterase type 5 inhibitors nonresponders to responders. ED is highly prevalent in hypertensive patients. The effect of Li-ESWT on an animal model of hypertension-associated ED has not been reported. AIM: To investigate the effect of Li-ESWT on hypertension-associated ED and provide plausible mechanisms of action of Li-ESWT on local mechanisms of penile erection. METHODS: Spontaneously hypertensive rats (SHRs) in the active group (n = 13) received Li-ESWT at energy flux density 0.06 mJ/mm2 (Aries; Dornier MedTech, Wessling, Germany) twice weekly for 6 weeks. The emitter was set to zero for SHRs in the sham group (n = 12). Erectile function was assessed 4 weeks post-treatment by monitoring intracavernosal pressure (ICP) in response to electrical stimulation of cavernous nerve before and after single dose of 0.3 mg/kg intravenous sildenafil. Cavernosal tissue was then evaluated for collagen/smooth muscle content, neuronal nitric oxide synthase (nNOS), and vascular endothelial factor (CD31) expression. OUTCOMES: Erectile function was assessed with ICP, erectile tissue remodeling was studied by smooth muscle/collagen ratio, nNOS and CD31 were semiquantitatively evaluated on cavernosal sections. RESULTS: The improvement of ICP parameters was greater in Li-ESWT-treated rats compared with controls with and without sildenafil. Sildenafil led to 20% increase in area under the intracavernosal pressure curve measured during the entire response/mean arterial pressure at 10 Hz in ESWT_SHR + sildenafil compared with ESWT_SHR. The smooth muscle/collagen ratio increased 2.5-fold in Li-ESWT compared with sham. Expression of CD31 tended to be increased whereas nNOS was unchanged. CONCLUSIONS: Li-ESWT by Aries may represent an effective noninvasive therapeutic alternative and a relevant add-on therapy to phosphodiesterase type 5 inhibitors for ED in hypertensive patients, and it is suggested that it acts via remodeling of the penile tissue and promoting cavernosal vascularization. Assaly R, Giuliano F, Clement P, et al. Extracorporeal Shock Waves Therapy Delivered by Aries Improves Erectile Dysfunction in Spontaneously Hypertensive Rats Through Penile Tissue Remodeling and Neovascularization. Sex Med 2019;7:441-450.
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INTRODUCTION: Cligosiban is an orally administered oxytocin receptor antagonist being developed to treat premature ejaculation (PE). AIM: To determine the safety and efficacy of cligosiban capsules (dose range 400-800 mg) to improve intravaginal ejaculation latency time (IELT) and patient-reported outcomes in men with severe lifelong PE. METHODS: Patients recorded details of at least 4 sexual intercourse events during a 4-week run-in period, after which they underwent baseline assessments. Patients were eligible for the study if they rated their control of ejaculation as poor/very poor and their stopwatch-assessed IELT was ≤1 minute in ≥75% of intercourse attempts. Eligible patients were randomized to an 8-week treatment period with double-blind cligosiban or placebo (to be taken 1 to 6 hours prior to sexual activity). The starting dose was 400 mg (not more than 1 dose per day) which could be increased to 800 mg after 2 and/or 4 weeks of treatment. Assessments were conducted at 2, 4, and 8 weeks. MAIN OUTCOME MEASURE: Efficacy measures were comprised of IELT, self-rating of ejaculation control and ejaculation-related distress (recorded in an electronic diary after each intercourse attempt), premature ejaculation profile, and the Clinical Global Impression of Change. RESULTS: The mean ratio of fold change from baseline in IELT to the last 4 weeks of treatment (cligosiban/placebo) was 1.9 compared to a baseline of 1.0 (P = .0079). The mean increase in IELT from baseline to the last 4 weeks of treatment was 61.0 seconds for cligosiban, which was significantly different from (and 3.6-fold greater than) the mean increase of 16.4 seconds for placebo (P = .0086). Statistically significant improvements in ejaculation control and ejaculation-related personal distress scores were also observed for cligosiban compared to little or no change with placebo. Cligosiban was generally well tolerated, with no serious or severe adverse events or other safety parameters. CLINICAL IMPLICATIONS: This proof-of-concept study demonstrated the potential for cligosiban, an oxytocin antagonist, to successfully treat symptoms of severe lifelong PE. STRENGTHS AND LIMITATIONS: This was a Phase II, randomized, double-blind, placebo-controlled study that was adequately powered to detect a clinically meaningful difference in change in IELT between cligosiban and placebo. Larger studies will be needed to confirm these findings, determine the optimal dose of cligosiban and assess efficacy in men with acquired PE. CONCLUSIONS: Cligosiban was well tolerated, and resulted in significant benefits in both objective and subjective measures of ejaculatory control in men with lifelong PE and therefore offers significant potential as an on-demand, orally administered agent for the treatment of PE. McMahon C, Althof S, Rosen R, et al. The Oxytocin Antagonist Cligosiban Prolongs Intravaginal Ejaculatory Latency and Improves Patient-Reported Outcomes in Men with Lifelong Premature Ejaculation: Results of a Randomized, Double-Blind, Placebo-Controlled Proof-of-Concept Trial (PEPIX). J Sex Med 2019; 16:1178-1187.
Assuntos
Ejaculação/efeitos dos fármacos , Ejaculação Precoce/tratamento farmacológico , Piridinas/administração & dosagem , Receptores de Ocitocina/antagonistas & inibidores , Triazóis/administração & dosagem , Adulto , Coito , Método Duplo-Cego , Antagonistas de Hormônios/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Comportamento SexualRESUMO
Erectile dysfunction (ED) is a highly prevalent condition with a variety of possible risk factors and/or etiologies. Despite significant advances regarding ED pharmacological management, there are still insufficient responders to existing pharmacological treatments e.g., approximately 30% of patients are insufficient responders to phosphodiesterase type 5 inhibitors (PDE5-Is). It has been recently proposed that botulinum toxin A intracavernosally (IC) delivered could be effective in these patients. Data from a retrospective uncontrolled single center study of 47 ED patients, consecutively recruited, insufficient responders to existing pharmacological treatments e.g., PDE5-Is or IC PGE1 injections treated with IC abobotulinumtoxinA 250 or 500 U as free combination with their existing treatment have been analyzed. Response rate, according to the International Index of Erectile Function-Erectile Function domain score, 6 weeks following IC abobotulinumtoxinA in combination with prior pharmacological treatment, was 54%. Two patients have reported mild penile pain on injection or during the 3 days following injection. Therapeutic efficacy did not seem to be influenced by the etiologies and/or risk factors for ED. Conversely, the less severe ED, the higher the response rate. Preliminary evidence for the therapeutical potential with acceptable safety of IC abobotulinumtoxinA as add-on therapy for ED not sufficiently responsive to standard therapy should be confirmed in randomized clinical trials.
Assuntos
Alprostadil/administração & dosagem , Toxinas Botulínicas Tipo A/administração & dosagem , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Adulto , Idoso de 80 Anos ou mais , Toxinas Botulínicas Tipo A/efeitos adversos , Quimioterapia Combinada , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Chemosensitivity is a key mechanism for the regulation of breathing in vertebrates. The retrotrapezoid nucleus is a crucial hub for respiratory chemoreception within the brainstem. It integrates chemosensory information that are both peripheral from the carotid bodies (via the nucleus of the solitary tract) and central through the direct sensing of extracellular protons. To date, the location of a genetically defined RTN has only been ascertained in rodents. We first demonstrated that Phox2b, a key determinant for the development of the visceral nervous system and branchiomotor nuclei in the brainstem including the RTN, had a similar distribution in the brainstem of adult macaques compared to adult rats. Second, based on previous description of a specific molecular signature for the RTN in rats, and on an innovative technique for duplex in situ hybridization, we identified parafacial neurons which coexpressed Phox2b and ppGal mRNAs. They were located ventrally to the nucleus of the facial nerve and extended from the caudal part of the nucleus of the superior olive to the rostral tip of the inferior olive. Using the previously described blockface technique, deformations were corrected to allow the proper alignment and stacking of digitized sections, hence providing for the first time a 3D reconstruction of the macaque brainstem, Phox2b distribution and the primate retrotrapezoid nucleus. This description should help bridging the gap between rodents and humans for the description of key respiratory structures in the brainstem.
Assuntos
Tronco Encefálico/anatomia & histologia , Tronco Encefálico/metabolismo , Proteínas de Homeodomínio/metabolismo , Macaca fascicularis/anatomia & histologia , Macaca fascicularis/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/metabolismo , Animais , Feminino , Imageamento Tridimensional , Masculino , Neurônios/citologia , RNA Mensageiro/metabolismoRESUMO
A set of herpes simplex virus type 1 (HSV-1) amplicon vectors expressing the light chains (LC) of botulinum neurotoxins (BoNT) A, B, C, D, E and F was constructed. Their properties have been assessed in primary cultures of rat embryonic dorsal root ganglia (DRG) neurons, and in organotypic cultures of explanted DRG from adult rats. Following infection of primary cultures of rat embryonic DRG neurons, the different BoNT LC induced efficient cleavage of their corresponding target Soluble N-ethylmaleimide-sensitive-factor Attachment protein Receptor (SNARE) protein (VAMP, SNAP25, syntaxin). A similar effect was observed following infection by BoNT-A LC of organotypic cultures of adult rat DRG. To quantify and compare the functional activities of the different BoNT LC, the inhibition of calcitonin gene-related protein (CGRP) secretion was assessed in DRG neurons following infection by the different vectors. All BoNT-LC were able to inhibit CGRP secretion although to different levels. Vectors expressing BoNT-F LC displayed the highest inhibitory activity, while those expressing BoNT-D and -E LC induced a significantly lower CGRP release inhibition. Cleavage of SNARE proteins and inhibition of CGRP release could be detected in neuron cultures infected at less than one transducing unit (TU) per neuron, showing the extreme efficacy of these vectors. To our knowledge this is the first study investigating the impact of vector-expressed transgenic BoNT LC in sensory neurons.
Assuntos
Toxinas Botulínicas/genética , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Gânglios Espinais/metabolismo , Herpesvirus Humano 1/genética , Neurotoxinas/genética , Proteínas SNARE/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Células Cultivadas , Feminino , Gânglios Espinais/virologia , Vetores Genéticos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/virologiaRESUMO
INTRODUCTION: Despite recent promising clinical results, the underlying mechanism of action of low-intensity extracorporeal shockwave therapy (Li-ESWT) for erectile dysfunction (ED) is mostly unclear and currently under investigation. AIM: To systematically identify and evaluate evidence regarding the basic science behind Li-ESWT for ED, discuss and propose a putative mechanism of action, address the limitations, and imply insights for further investigation in the field. METHODS: Using Cochrane's methodologic recommendations on scoping studies and systematic reviews, we conducted a systematic scoping review of the literature on experimental research regarding Li-ESWT for ED and other pathologic conditions. The initial systematic search was carried between January and November 2017, with 2 additional searches in April and August 2018. All studies that applied shockwave treatment at an energy flux density >0.25 mJ/mm2 were excluded from the final analysis. MAIN OUTCOME MEASURE: We primarily aimed to clarify the biological responses in erectile tissue after Li-ESWT that could lead to improvement in erectile function. RESULTS: 59 publications were selected for inclusion in this study. 15 experimental research articles were identified on Li-ESWT for ED and 44 on Li-ESWT for other pathologic conditions. Li-ESWT for ED seems to improve erectile function possibly through stimulation of mechanosensors, inducing the activation of neoangiogenesis processes, recruitment and activation of progenitor cells, improving microcirculation, nerve regeneration, remodeling of erectile tissue, and reducing inflammatory and cellular stress responses. CLINICAL IMPLICATIONS: Improving our understanding of the mechanism of action of Li-ESWT for ED can help us improve our study designs, as well as suggest new avenues of investigation. STRENGTHS & LIMITATIONS: A common limitation in all these studies is the heterogeneity of the shockwave treatment application and protocol. CONCLUSION: Li-ESWT for ED, based on current experimental studies, seems to improve erectile function by inducing angiogenesis and reversing pathologic processes in erectile tissue. These studies provide preliminary insights, but no definitive answers, and many questions remain unanswered regarding the mechanism of action, as well as the ideal treatment protocol. Sokolakis I, Dimitriadis F, Teo P, et al. The Basic Science Behind Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction: A Systematic Scoping Review of Pre-Clinical Studies. J Sex Med 2019;16:168-194.
Assuntos
Disfunção Erétil/terapia , Tratamento por Ondas de Choque Extracorpóreas , Ensaios Clínicos como Assunto , Humanos , MasculinoRESUMO
Erectile dysfunction (ED), which worldwide is likely to affect in excess of 300 million men by 2025, is often either untreated or insufficiently treated. It can be a prelude to other serious illnesses and may be a cause or consequence of depression in affected individuals. Among men younger than 60 years of age, ED can be a robust early-stage indicator of vascular disease and type 2 diabetes. Untreated or inadequately treated ED can also be a sign of poor communication between health professionals and service users of all ages. Improved treatment of ED could cost-effectively prevent premature deaths and avoidable morbidity. The extension of community pharmacyâbased health care would enable more men living with ED to safely access effective medications, along with appropriate diagnostic services and support for beneficial lifestyle changes such as smoking cessation in conveniently accessible settings. The task of introducing improved methods of affordably addressing problems linked to ED exemplifies the strategic challenges now facing health care systems globally. Promoting professionally supported self-care in pharmacies has the potential to meet the needs of aging populations in progressively more effective ways.
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Disfunção Erétil/tratamento farmacológico , Farmacêuticos/organização & administração , Papel Profissional , Doenças Cardiovasculares , Humanos , Masculino , Política Pública , AutocuidadoRESUMO
AIMS: Five-α reductase inhibitor (5ARI) therapy has been associated with sexual dysfunction in some patients. This study assessed the impact of a fixed-dose combination of the 5ARI dutasteride 0.5 mg and the α1 -adrenoceptor antagonist tamsulosin 0.4 mg (DUT-TAM FDC) on Men's Sexual Health Questionnaire (MSHQ) domain scores in patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH). METHODS: This was a post hoc analysis of a double-blind, randomised, placebo-controlled, parallel-group, multicentre study in sexually active patients, aged ≥50 years, with a confirmed clinical diagnosis of BPH. Sexual activity, sexual desire, and bother domain scores of the MSHQ were assessed at baseline and at Months 1, 3, 6, 9, and 12. Correlation between MSHQ sexual activity/desire scores and ejaculation, erection, and satisfaction domains at baseline was also evaluated. RESULTS: In the intent-to-treat population (N = 489), 243 and 246 patients were randomised to DUT-TAM FDC and placebo groups, respectively. Compared with placebo, DUT-TAM FDC therapy resulted in statistically significant reductions (worsening) from baseline in adjusted mean MSHQ sexual activity and bother domain scores at Months 1, 3, 6, 9, and 12 (all P < 0.05) and in adjusted mean MSHQ sexual desire domain scores at Months 6, 9, and 12 (all P < 0.05). Significant moderate correlations in the expected direction were observed at baseline between the sexual activity/desire domains and the ejaculation, erection, and satisfaction domains (P < 0.0001). CONCLUSIONS: These findings help clarify the degree and impact of libido changes in sexually active men treated with DUT-TAM FDC and may support clinical decision-making.