Does Telotristat Have a Role in Preventing Carcinoid Heart Disease?

Carcinoid heart disease (CHD) is a frequent and life-threatening complication in patients with carcinoid tumors. Its clinical management is challenging is some cases since serotonin-induced valve fibrosis leads to heart failure. Telotristat is an inhibitor of tryptophan-hydroxylase (TPH), a key enzyme in serotonin production. Telotristat use in patients with carcinoid syndrome and uncontrollable diarrhea under somatostatin analogs is approved, but its specific role in patients with CHD is still not clear. IN this context, we aimed to explore the effect of telotristat in heart fibrosis using a mouse model of serotonin-secreting metastasized neuroendocrine neoplasm (NEN). To this aim, four treatment groups (n = 10/group) were evaluated: control, monthly octreotide, telotristat alone, and telotristat combined with octreotide. Plasma serotonin and NT-proBNP levels were determined. Heart fibrosis was histologically evaluated after 6 weeks of treatment or when an individual mouse's condition was close to being terminal. Heart fibrosis was observed in all groups. Non-significant reductions in primary tumor growth were observed in all of the treated groups. Feces volume was increased in all groups. A non-significant decrease in feces volume was observed in the octreotide or telotristat-treated groups, while it was significantly reduced with the combined treatment at the end of the study compared with octreotide (52 g reduction; p < 0.01) and the control (44.5 g reduction; p = 0.05). Additionally, plasma NT-proBNP decreased in a non-significant, but clinically relevant, manner in the octreotide (28.2% reduction), telotristat (45.9% reduction), and the octreotide + telotristat (54.1% reduction) treatment groups. No significant changes were observed in plasma serotonin levels. A similar non-significant decrease in heart valve fibrosis was observed in the three treated groups. In conclusion, Telotristat alone and especially in combination with octreotide decreases NT-proBNP levels in a mouse model of serotonin-secreting metastasized NEN, when compared with the control and octreotide, but its effect on heart valve fibrosis (alone and in combination) was not superior to octreotide in monotherapy.

Contextualization of the concept of nociplastic pain in irritable bowel syndrome.

The objective of this letter to the editor is to contextualize the concept of "nociplastic pain" in functional digestive disorders, especially in irritable bowel syndrome (IBS); and try to differentiate it from the term central sensitization, increasingly used in the literature, and with notable relevance in the pathophysiology of IBS.

Advances in the Management of Acute Postsurgical Pain: A Review.

Despite the millions of surgeries performed every year around the world, postoperative pain remains prevalent and is often addressed with inadequate or suboptimal treatments. Chronic postsurgical pain is surprisingly prevalent, and its rate varies with the type of surgery, as well as with certain patient characteristics. Thus, better clinical training is needed as well as patient education. As pain can be caused by more than one mechanism, multimodal or balanced postsurgical analgesia is appropriate. Pharmacological agents such as opioid and nonopioid pain relievers, as well as adjuvants and nonpharmacologic approaches, can be combined to provide better and opioid-sparing pain relief. Many specialty societies have guidelines for postoperative pain management that emphasize multimodal postoperative analgesia. These guidelines are particularly helpful when dealing with special populations such as pregnant patients or infants and children. Pediatric pain control, in particular, can be challenging as patients may be unable to communicate their pain levels. A variety of validated assessment tools are available for diagnosis. Related to therapy, most guidelines agree on the fact that codeine should be used with extreme caution in pediatric patients as some may be "rapid metabolizers" and its use may be life-threatening. Prehabilitation is a preoperative approach that prepares patients in advance of elective surgery with conditioning exercises and other interventions to optimize their health. Prehabilitation may have aerobic, strength-training, nutritional, and counseling components. Logistical considerations and degree of patient adherence represent barriers to effective prehabilitation programs. Notwithstanding all this, acute postoperative pain represents a clinical challenge that has not yet been well addressed.

Infección por VIH: carga viral plasmática intratratamiento en la era del "Indetectable = Intransmisible" / HIV infection: Plasma viral load intratratization in the era of the "undetectable = non transmissible"

Se acepta que los individuos infectados por el virus de la inmunodeficiencia humana (HIV) son incapaces de transmitir la infección por vía sexual mientras sus niveles de carga viral plasmática se mantengan indetectables. Con el propósito de estudiar qué porcentaje de infectados por el HIV cumple esa condición estudiamos una población de pacientes asistidos regularmente en un hospital general de agudos de la ciudad de Buenos Aires. Se incluyeron 298 individuos, 162 de ellos de sexo masculino (54.36%) con una edad (promedio ± desvío estándar) de 47.83 ± 11.69 años y un recuento de células CD4+ de 693.93 ± 363.87 x 106 células / mL de sangre periférica. La carga viral plasmática fue indetectable en 230 de los individuos estudiados (77.81%). Los 68 restantes (22.82%) mostraron en promedio 9856.67 ± 70922.11 copias / mL, siendo estos niveles mayores en hombres que en mujeres (17379.39 ± 95521.51 copias / mL vs 895.78 ± 5952.99 copias / mL, respectivamente; p=0.015, Student t test), lo que explicaría los recuentos de linfocitos CD4+ significativamente menores hallados en hombres.187 de 231 individuos que recibían su primer tratamiento antiretroviral (TARV) mostraron cargas virales indetectables (80,95%) versus 42 de 67 pacientes que habían recibido dos o más esquemas de tratamiento antirretroviral (61,69%; p= 0.002, prueba de 2 ). Estos resultados muestran que un porcentaje importante de infectados por el HIV continúan presentando cargas virales plasmáticas detectables a pesar del TARV, siendo capaces de transmitir la infección por vía sexual a sus parejas

It is widely accepted that HIV-infected subjects are incapable to transmit sexually the infection while their plasmatic viral load remains undetectable. In order to assess the percentage of HIV infected patients showing undetectable viral loads during their antiviral treatment we studied a population of patients regularly assisted at a general hospital. A total of 298 patients (162 men; 54.36%) were admitted to the study. The mean age was (mean ± standard deviation) 47.83 ± 11.69 years, and the mean CD4+ cell count was 693.93 ± 363.87 x 106 cells / mL. These variables did not showed statistically significative differences between men and women. Plasmatic viral load was undetectable in 230 patients (77.81%). The remaining 68 patients (22.82%) showed a mean of 9856.67 ± 70922 copies / mL. These values were higher in men than in women (17379.39 ± 95521.51 copies / mL vs 895.78 ± 5952.99 copies / mL, respectively; p=0.015, Student t test). In line with these findings, CD4+ cell count was significantly lower in men (575.10 ± 345.14 cells / L vs. 707.04 ± 373.46 cells / L, respectively; p=0.0019, Student t test). 187 out of 231 patients receiving their first antiretroviral treatment showed undetectable viral loads (80,95%), while only 42 out of 67 patients having previously received other antiretroviral schemes had undetectable levels of plasmatic viral load (61,69%; p= 0.002, 2 ). These findings show that an important number of patients may keep detectable levels of plasmatic viral load during antiretroviral treatment, being therefore capable to sexually transmit the infection to their couples.

Green discoloration of the urine following sedation with propofol for colonoscopy.

Propofol (2,6-diisopropylphenol) is the most widely used drug for endoscopic procedures under deep sedation. We present the clinical case of an 83-year-old man who underwent a colonoscopy under sedation with propofol, observing a green discolouration of the urine during the procedure.

New Insights Into the Pharmacological Management of Postoperative Pain: A Narrative Review.

Postoperative pain is prevalent and often undertreated. There is a risk that untreated or suboptimally treated postoperative pain may transition into chronic postoperative pain, which can be challenging to treat. Clinical guidelines recommend the use of multimodal analgesia, including non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and, in some cases, opioids. NSAIDs are a broad class of drugs with different attributes such as cyclo-oxygenase (COX)-1 or COX-2 selectivity, onset of action, and analgesic potency. NSAIDs are associated with gastrointestinal and cardiovascular side effects and should be administered at the lowest effective dose for the shortest effective duration but can be effective in postoperative pain. The role of opioids in postoperative analgesia is long-standing but has recently come under scrutiny. Opioids are often used in multimodal analgesic combinations in such a way as to minimize the total consumption of opioids without sacrificing analgesic benefit. Special clinical considerations are required for surgical patients already on opioid regimens or with opioid use disorder. A particularly useful fixed-dose combination product for postoperative analgesia is dexketoprofen-tramadol, which confers safe and effective postoperative pain control and reduces the risk of persistent postoperative pain.

Adductor canal block performed 20 hours after total knee arthroplasty to improve postoperative analgesia and functional recovery: a double-blind randomized controlled clinical trial.

BACKGROUND: The goal of postoperative pain protocols in total knee arthroplasty (TKA) is to get pain free patients throughout severe pain period without impairing walking ability. The aim of the study was to investigate if an adductor canal block performed 20 hours after TKA, in patients treated with systemic analgesia and intraoperative local infiltration anesthesia (LIA), improves postoperative pain and functional outcomes. METHODS: A prospective randomized, double-blinded controlled study was conducted. One hundred eighty-three patients undergoing primary TKA were randomized to receive either a sham block or an adductor canal block with 20 mL of ropivacaine 0.5%. The primary outcome was resting and dynamic pain scores using the Numerical Pain Rating Scale (NPRS). Secondary outcomes included opioid rescue requirements, quadriceps and adductor muscle strength, patient ability for ambulation and complications. RESULTS: Two hours after the block, in adductor canal block group NPRS was significantly lower at rest (1 [0-2] vs. 3 [2-5], P<0.001) and with mobilization (5 [3-6] vs. 6 [5-8], P<0.001), and quadriceps strength was significantly higher (3.7 [2.7-6] vs. 3 (1.7-4.9), P=0.023). The differences were not maintained beyond 24 hours post-block. In the first 24 hours the percentage of patients with tramadol requirements was lower in the adductor canal block group (36 [38.3] vs. 52 [58.4], P=0.006). Other secondary outcomes were similar between groups. There were no patient falls. CONCLUSIONS: An adductor canal block done 20 hours after total knee arthroplasty reduces pain and opioid requirements without increasing the risk of falls. An optimal pain control, especially at movement was not achieved.

Manifestaciones extrapulmonares de COVID-19. Una revisión / Extrapulmonary manifestations of covid-19. A review

La enfermedad por coronavirus 2019 (covid-19) se presenta en una amplia variedad de cuadros clínicos que van desde formas completamente asintomáticas o leves hasta una enfermedad rápidamente progresiva, incluidas manifestaciones pulmonares y extrapulmonares. El SARSCoV-2, el agente etiológico del covid-19, accede a sus células diana a sistema renina-angiotensina. Esta enzima se expresa en células endoteliales vasculares, epitelio tubular renal, células de Leydig en los testículos, pulmones, riñones, cerebro, corazón, vasculatura y tracto gastrointestinal. ,,,,,, Como tal, las manifestaciones clínicas del covid-19 se explican por la distribución tisular de la ECA-2. Más allá de la afectación tisular "per se", otra característica patológica es el fenómeno de la "tormenta de citocinas" (CS). El CS es una respuesta inmune exagerada caracterizada por un alto nivel de citocinas inflamatorias circulantes sostenidas en el tiempo. Es rápidamente progresivo y tiene una alta mortalidad. El CS se ha detectado en pacientes críticos con covid-19 y se considera una de las principales causas de síndrome de dificultad respiratoria aguda (SDRA) e insuficiencia multiorgánica. Los niveles séricos de citocinas proinflamatorias aumentan significativamente en pacientes con causar inflamación y lesión del sistema nervioso central (SNC). Respaldando este punto de vista, los niveles de IL-6 se correlacionan positivamente con la gravedad del covid-19. Este síndrome se ha descrito en sepsis, síndrome hemofagocítico y en otras infecciones por coronavirus como el síndrome respiratorio agudo severo (SARS) o el síndrome respiratorio de Oriente Medio (MERS). Aunque la afectación pulmonar se ha descrito bien en muchos informes, las manifestaciones extrapulmonares todavía están mal descritas. Este artículo revisará las manifestaciones no pulmonares del covid-19. Los principales síntomas extrapulmonares comprenden los neurológicos, cardíacos, oftalmológicos, musculares, hematológicos, cutáneos y gastrointestinales, así como la afectación hepática y renal. Cada una de estas manifestaciones puede surgir durante la evolución de la enfermedad o construir su manifestación inicial

Coronavirus disease 2019 (covid-19) presents in a wide variety of clinical pictures ranging from completely asymptomatic or mild forms to rapidly progressive disease, including pulmonary and extrapulmonary manifestations. SARS-CoV-2 ­the etiological agent of covid-19- access to their target cells via a transmembrane protein, the angiotensin-converting enzyme II (ACE2). ACE-2 is a type-I metallocarboxypeptidase with homology to ACE, an essential enzyme in the Renin-Angiotensin System. [1] This enzyme is expressed in vascular endothelial cells, renal tubular epithelium, Leydig cells in the testes, lungs, kidneys, brain, heart, vasculature, and gastrointestinal tract.[2-7] As such, the clinical manifestations of covid-19 are explained by the tissular distribution of ACE-2. Beyond the tissular affectation "per se", another pathological feature is the "cytokine storm" phenomenon (CS). CS is an exaggerated immune response characterized by a high level of circulating inflammatory cytokines sustained over time. It is rapidly progressive and has a high mortality. CS has been detected in critical patients with covid-19 and it is considered a major cause of acute respiratory distress syndrome (ARDS) and multiorgan failure. Serum levels of proinflammatory cytokines are significantly increased in patients with ARDS, and their levels are positively correlated with mortality.[8, 9] CS may also cause inflammation and injury of the Central Nervous System (CNS) Supporting this view, IL-6 levels positively correlate with covid-19 severity.[10] This syndrome has been described in sepsis, hemophagocytic syndrome and in other coronavirus infections like the severe acute respiratory syndrome (SARS) or the Middle East respiratory syndrome (MERS). Although lung involvement has been well described in many reports, extra-pulmonary manifestations are still poorly described. This paper will review the non-pulmonary manifestations of covid-19. Main extra-pulmonary symptoms comprise the neurologic, cardiac, ophthalmologic, muscular, hematologic, cutaneous, and gastrointestinal ones, as well as hepatic and renal involvement. Each one of these manifestations can arise during the disease evolution or constitute their initial manifestation.

Tramadol/Dexketoprofen Analgesic Efficacy Compared with Tramadol/Paracetamol in Moderate to Severe Postoperative Acute Pain: Subgroup Analysis of a Randomized, Double-Blind, Parallel Group Trial-DAVID Study.

INTRODUCTION: Recently the DAVID study demonstrated the better analgesic efficacy of tramadol hydrochloride/dexketoprofen 75/25 mg (TRAM/DKP) over tramadol hydrochloride/paracetamol 75/650 mg (TRAM/paracetamol) in a model of moderate to severe acute pain following surgical removal of an impacted third molar. The aim of this subpopulation analysis was to gain a deeper understanding of the relationship between baseline pain intensity (PI) level and the effectiveness in pain control of the TRAM/DKP combination in comparison with the TRAM/paracetamol combination. This will further improve and facilitate the accurate design of future acute pain studies for the use of the TRAM/DKP combination. METHODS: Patients experiencing at least moderate pain, defined as a PI score ≥ 4 in an 11-point numerical rating scale (NRS) were stratified according to NRS-PI at baseline (NRS ≥ 4, 5, 6, 7, or 8) or aggregated in two groups: (i) moderate pain, NRS-PI ≥ 4 to ≤ 6; (ii) severe pain, NRS-PI > 6. Analgesic efficacy was assessed at pre-specified time points by using pain relief (PAR) on a 5-point verbal rating scale (VRS) and PI on an 11-point NRS. The primary endpoint was total PAR over 6 h post-dose (TOTPAR6); secondary endpoints included, among others, the time course of mean PAR and PI scores over 8 h, TOTPAR over 2, 4, and 8 h post-dose, and the sum of PI difference (SPID) over 2, 4, 6, and 8 h. Safety evaluation was based on the incidence, seriousness, intensity, and causal relationship of treatment-emergent adverse events (TEAEs). RESULTS: The analgesic efficacy evaluated by TOTPAR6 (primary endpoint) remained steady across increasing baseline PI-NRS cutoff groups with TRAM/DKP, but not with TRAM/paracetamol. The study also demonstrated the superiority of TRAM/DKP combination over TRAM/paracetamol in terms of TOTPAR over 2, 4, and 8 h post-dose and SPID at 2, 4, 6, and 8 h post-dose in both baseline PI groups (moderate or severe); similarly, the time course of PAR and PI indicated better efficacy with TRAM/DKP as soon as 30 min and up to 4-6 h. The incidence of adverse drug reactions was not increased in the severe baseline PI group. CONCLUSION: Overall, the results of this subgroup analysis of the DAVID study confirmed the superiority of the analgesic efficacy of TRAM/DKP vs TRAM/paracetamol, irrespective of the baseline PI.

The combination tramadol/dexketoprofen (TRAM/DPK) was recently shown to exert a better analgesic effect than the combination tramadol/paracetamol (TRAM/paracetamol) after surgical removal of impacted lower third molar in a clinical trial enrolling more than 600 patients. A subanalysis of the results of this study was performed to assess if the severity of pain intensity (PI) at baseline might modify the analgesic effect and its duration. The results of the subanalysis showed that the analgesic efficacy of TRAM/DKP was independent of baseline PI and persistent up to 6 h, whereas the effect of TRAM/paracetamol progressively decreased with increasing baseline PI and persisted for a shorter period. The incidence of adverse drug reactions was not increased in patients with severe baseline PI. These results confirmed the better analgesic efficacy of TRAM/DKP vs TRAM/paracetamol, irrespective of the baseline PI.

A retrospective analysis comparing persistence and adherence to treatment with free- vs fixed-dose combination of an alpha blocker and an antimuscarinic agent in men with LUTS in Spain.

INTRODUCTION: Combination therapy with an alpha blocker (AB) plus an antimuscarinic (AM) is recommended for men with moderate-to-severe mixed lower urinary tract symptoms (LUTS) when monotherapy is not effective in relieving storage symptoms. This study compared treatment persistence and adherence with an AB plus AM fixed-dose combination (FDC) vs an AB plus AM free-dose combination in men with LUTS in Spain. METHODS: Retrospective study using the Spanish IQVIA Cegedim Electronic Medical Records database. Men prescribed AB plus AM combination therapy were included in an FDC or free-dose combination cohort based on their index treatment. Treatment persistence was the time from index date to first discontinuation of ≥1 of the two index drugs over 12 months. Adherence was measured using the fixed medication possession ratio (MPR). RESULTS: Of 3114 patients identified, 999 were included (FDC, n = 790; free-dose combination, n = 209). Median (95% CI) persistence was longer in the FDC (125 [109-151] days) than in the free-dose combination (31 [31-36] days) cohort (hazard ratio [HR], 2.9; 95% CI, 2.4-3.4; P < .0001). The 12-month persistence rates were 31.1% (FDC cohort) and 8.9% (free-dose cohort). The mean (SD) fixed MPR was higher in the FDC cohort (48.8 [37.2]) compared with the free-dose cohort (23.1 [28.4]); more patients in the FDC cohort (34.2%) than in the free-dose cohort (10.0%) were adherent (MPR ≥ 80%). The probability of treatment persistence and adherence increased with age (>80 vs <65 years, persistence HR, 0.7 [95% CI, 0.5-0.9]; MPR difference, 12.5), polypharmacy (persistence HR, 0.7 [95% CI, 0.6-0.9]; MPR difference, 10.7) and previous use of AB (persistence HR, 0.8 [95% CI, 0.7-1.0]; MPR difference, 5.7) or AB/AM combinations (persistence HR, 0.7 [95% CI, 0.5-0.9]; MPR difference, 11.1). CONCLUSIONS: Treatment with an AB/AM FDC is associated with better persistence and adherence vs a free-dose combination in men with LUTS in Spain.