[Problems and adverse reactions related to opioid analgesics in Colombia]. / Problemas y reacciones adversas relacionadas con analgésicos opioides en Colombia.

INTRODUCTION: The prevalence of pathologies that generate chronic pain is high (10-40%), as is the use of opioids. In Colombia, these drugs rank among the first in terms of prescriptions and the number of deaths related to their consumption is rising (0.71/1,000,000 inhabitants). This study seeks to characterise opioid-related problems (ORP) and the variables associated with their resolution. MATERIALS AND METHODS: It is a study based on secondary information. Incidences were calculated using Ministry of Health data and characteristics related to non-recoverable adverse reactions (ADRs) were determined. RESULTS: Altogether 4,437 problems were identified in 3,063 patients (39.51%, male), adults (45 years old; IQR: 29-62). The most common opioids were tramadol (46.49%, 5 mg; IQR: 5-5) and morphine (19.65%, 3 mg; IQR: 2.6-5). The majority of ORP were ADRs (93.15%) and of these, 32.28% were severe. Women had proportionally more gastrointestinal and neurological disorders, while men had a higher frequency of vascular, psychiatric, urinary and haematological problems (p < 0.05). These reactions did not resolve in 8.39%, and prognosis was associated with oral administration - odds ratio (OR): 9.24; 95% confidence interval (CI 95%): 6.36-13.42; severity (OR: 3.96; CI 95%: 2.71-5.76); age (OR: 1.01; CI 95%: 1.001-1.01); weak opioids (OR: 0.57; CI 95%: 0.4-0.84); and neurological-cardiovascular reactions (OR: 0.36; CI 95%: 0.21-0.61). CONCLUSIONS: Interventions to optimise the prescription of opioids should be encouraged to prevent ADRs with poor prognosis. Studies should be conducted to further investigate the impact of gender and route of administration on the occurrence of ADRs, as well as the severity of skin and gastrointestinal problems, which may be underestimated.

TITLE: Problemas y reacciones adversas relacionadas con analgésicos opioides en Colombia.Introducción. Las patologías que generan dolor crónico tienen alta prevalencia (10-40%), así como el consumo de opioides. En Colombia, estos medicamentos ocupan los primeros lugares de prescripción y existe un incremento en las muertes relacionadas con su consumo (0,71/1.000.000 habitantes). Este estudio busca caracterizar los problemas relacionados con opioides (PRM) y las variables asociadas con su resolución. Materiales y métodos. Es un estudio basado en información secundaria. Se calcularon las incidencias con datos del Ministerio de Salud y se determinaron las características relacionadas con reacciones adversas (RAM) no recuperables. Resultados. Se identificaron 4.437 problemas en 3.063 pacientes (39,51%, hombres), adultos (45 años; RIC: 29-62). Los opioides más comunes fueron tramadol (46,49%, 5 mg; RIC: 5-5) y morfina (19,65%, 3 mg; RIC: 2,6-5). La mayoría de los PRM fueron RAM (93,15%), y de éstas, el 32,28% fueron graves. Las mujeres presentaron proporcionalmente más alteraciones gastrointestinales y neurológicas, mientras que los hombres tuvieron una mayor frecuencia de problemas vasculares, psiquiátricos, urinarios y hematológicos (p menor de 0,05). Estas reacciones no se resolvieron en el 8,39% y el pronóstico se asoció con la administración oral ­odds ratio (OR): 9,24; intervalo de confianza al 95% (IC 95%): 6,36-13,42­, gravedad (OR: 3,96; IC 95%: 2,71-5,76), edad (OR: 1,01; IC 95%: 1,001-1,01), opioides débiles (OR: 0,57; IC 95%: 0,4-0,84) y reacciones neurológicas-cardiovasculares (OR: 0,36; IC 95%: 0,21-0,61). Conclusiones. Se sugiere fomentar intervenciones para optimizar la prescripción de opioides y así prevenir RAM con pobre pronóstico. Deben realizarse estudios que profundicen en el impacto del sexo y la vía de administración sobre la ocurrencia de RAM, así como la gravedad de los problemas cutáneos y gastrointestinales, que podría subestimarse.

Safety of ceftriaxone in paediatrics: a systematic review.

OBJECTIVE: To determine the safety of ceftriaxone in paediatric patients and systematically evaluate the categories and incidences of adverse drug reactions (ADRs) of ceftriaxone in paediatric patients. METHODS: We performed a systematic search in Medline, PubMed, Cochrane Central Register of Controlled Trials, EMBASE, CINAHL, International Pharmaceutical Abstracts and bibliographies of relevant articles up to December 2018 for all types of studies that assessed the safety of ceftriaxone in paediatric patients aged ≤18 years. RESULTS: 112 studies met the inclusion criteria involving 5717 paediatric patients who received ceftriaxone and reported 1136 ADRs. The most frequent ADRs reported in prospective studies were gastrointestinal (GI) disorders (37.4 %, 292/780), followed by hepatobiliary disorders (24.6%, 192/780). Serious ADRs leading to withdrawal or discontinuation of ceftriaxone were reported in 86 paediatric patients. Immune haemolytic anaemia (34.9%, 30/86) and biliary pseudolithiasis (26.7%, 23/86) were the two major causes. Haemolytic anaemia following intravenous ceftriaxone led to death in 11 children whose primary disease was sickle cell disease. Almost all biliary pseudolithiasis are reversible. However, the incidence was high affecting one in five paediatric patients (20.7%). CONCLUSIONS: GI ADRs are the most common toxicity of ceftriaxone in paediatric patients. Immune haemolytic anaemia and biliary pseudolithiasis are the most serious ADRs and the major reasons for discontinuation of ceftriaxone. Immune haemolytic anaemia is more likely in children with sickle cell disease and may cause death. Ceftriaxone should be used with caution in children with sickle cell disease. TRIAL REGISTRATION NUMBER: CRD42017055428.

Pharmacological Characteristics of Anxiolytics on Acetylcholine-Induced Contractions in Rat Detrusor Smooth Muscle.

INTRODUCTION: Benzodiazepine anxiolytics are believed to cause urination disorders due to their anticholinergic effects. OBJECTIVE: This study was carried out to investigate the potential inhibitory effects of 15 clinically available anxiolytics in Japan on acetylcholine (ACh)-induced contractions in rat detrusor smooth muscle (DSM) to predict whether these anxiolytics could induce urination disorders. METHODS: -Effects of anxiolytics on contractions induced by ACh and 80 mmol/L KCl solution in rat DSM and effects of anxiolytics on specific binding of [N-methyl-3H]scopolamine ([3H]NMS) in mouse cerebral cortex were investigated. RESULTS AND CONCLUSIONS: ACh-induced contractions in rat DSM were inhibited by clotiazepam and diazepam (benzodiazepine anxiolytics) at concentrations that were clinically relevant. These contractions were also significantly inhibited by paroxetine, escitalopram (selective serotonin reuptake inhibitors -[SSRIs]), and hydroxyzine (a histamine H1 receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. At a concentration of 10-5 mol/L, paroxetine, escitalopram, and hydroxyzine inhibited 80 mmol/L high-KCl solution-induced rat DSM contractions but not clotiazepam and diazepam. Paroxetine, escitalopram, and hydroxyzine also inhibited specific binding of [3H]NMS in mouse cerebral cortex but clotiazepam and diazepam did not. In contrast to the effects of the abovementioned anxiolytics, ACh-induced contractions were not significantly affected by tofisopam, alprazolam, lorazepam, bromazepam, oxazolam, chlordiazepoxide, clonazepam, ethyl loflazepate (benzodiazepine anxiolytics), fluvoxamine (an SSRI), or tandospirone (a serotonin 5-HT1A receptor agonist). These findings suggest that most clinically used anxiolytics are not likely to result in anticholinergic-induced urination disorders within their clinically achievable blood concentration ranges. However, clotiazepam and diazepam may induce urination disorders within their clinical dose ranges via nonanticholinergic inhibition of DSM contractility.

Rare complication of antimalarial prophylaxis by doxycycline: drug-related pollakiuria.

We report the case of a French soldier deployed in Chad, who developed disabling pollakiuria after starting antimalarial prophylaxis by doxycycline. This rare secondary effect is not mentioned in reference books.

Urine changing from clear to milky-white.

After sedation with propofol a young man developed milky-white urine. Urinalysis showed a high concentration of uric acid crystals as being responsible. This phenomenon appears to be dose-dependent and is explained in this report. Since it is harmless and self-limiting no extensive analysis is needed when observed.

[Valproic acid toxicity due to misinterpretation of plasma levels: increase in unbound fraction caused by hypoalbuminaemia and renal dysfunction]. / Valproïnezuurintoxicatie door misinterpretatie van plasmaspiegel.

BACKGROUND: Valproic acid is one of the most widely prescribed drugs for the treatment of epilepsy and bipolar disorder. As only the unbound fraction of a medicinal product is pharmacologically active, in some strong protein-bound psychotropic drugs such as valproic acid and phenytoin, a rise in this fraction can lead to severe toxicity. CASE DESCRIPTION: A 65-year-old male with a type 1 bipolar disorder developed a number of neurological symptoms including sluggishness, muscle weakness, difficulty in walking and disorders of micturition after his mood stabiliser was changed to valproic acid. Recognition of drug toxicity was delayed as his total plasma valproic acid levels were within the therapeutic range. Later it became apparent that the patient had toxic unbound valproic acid levels due to hypoalbuminaemia and impaired renal function. CONCLUSION: Clinicians should always consider drug toxicity in patients who show neurological symptoms and use highly protein-bound psychotropic drugs, even if the total plasma concentration of the drug is in the therapeutic range.

Endocrine disruptor bisphenol A is implicated in urinary voiding dysfunction in male mice.

Estrogens, acting synergistically with androgens, are known from animal experiments to be important in lower urinary tract symptoms (LUTS) and benign prostate enlargement. Human exposure to environmental estrogens occurs throughout the life span, but the urologic health risks in men are largely unknown. Bisphenol A (BPA) is an endocrine disruptor implicated in male urogenital malformations. Given the role of estrogens in male LUTS, we studied the effects of BPA administered in combination with testosterone (T) on the urinary voiding behavior of adult male mice. Adult male mice underwent subcutaneous implantation with slow-release pellets of 25 mg BPA or 2.5 mg estradiol-17ß (E2), plus 25 mg T, and were compared with untreated (UNT) mice that underwent sham surgery. We studied urinary voiding behavior noninvasively for 1 mo before treatment and for 4 mo after treatment. After euthanasia, we evaluated bladder volume and mass. Mice treated with T+BPA had increased bladder volume ( P < 0.05) and mass ( P < 0.01) compared with UNT mice. After 4 mo of treatment with T+BPA, three of five mice developed voiding dysfunction in the form of droplet voiding or an intermediate pattern of voiding different from both UNT and T+E2-treated mice. Treatment of male mice with BPA or estradiol induces voiding dysfunction that manifests at later time points, implicating the endocrine disruptor, BPA, as a contributor to male LUTS.

Inhibidores del cotransportador sodio-glucosa tipo 2 y síntomas del tracto urinario inferior en varones, un aspecto a considerar / Sodium glucose cotransporter 2 inhibitors and males lower urinary tract symptoms, an aspect to consider

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Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus living in hot climates.

AIMS: Patients with type 2 diabetes mellitus (T2DM) have increased risk of adverse events (AEs; e.g. dehydration, hypoglycaemia) in hot weather. This analysis assessed the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with T2DM who live in hot climates. METHODS: This post hoc analysis evaluated patients with T2DM using pooled data from four 26-week, placebo-controlled studies (N=2,313) and data from a 104-week, active-controlled study (add-on to metformin vs glimepiride; N=1,450). Changes in HbA1c, fasting plasma glucose (FPG), body weight and blood pressure (BP) were assessed in subsets of patients living in hot climates (pooled, placebo-controlled studies, n=611; active-controlled study, n=307) and those living in other climates (i.e. other climate subset; pooled, placebo-controlled studies, n=1,702; active-controlled study, n=1,143). Safety was assessed based on AE reports. RESULTS: Canagliflozin 100 and 300 mg lowered HbA1c, FPG, body weight and BP vs placebo over 26 weeks and glimepiride over 104 weeks in the hot climate subsets. Canagliflozin was generally well tolerated in the hot climate subsets, with a higher incidence of AEs related to the mechanism of SGLT2 inhibition (i.e. genital mycotic infections). Volume depletion-related AEs were low across groups. CONCLUSION: Canagliflozin improved glycaemic control, lowered body weight and BP, and was generally well tolerated in patients with T2DM living in hot climates compared with placebo over 26 weeks or glimepiride over 104 weeks. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT01081834, NCT01106677, NCT01106625, NCT01106690, NCT00968812.

Effect of SSRIs and SNRIs on Nocturnal Urinary Frequency.

BACKGROUND: Existing data suggest that selective serotonin uptake inhibitors (SSRIs) may have an impact on urinary frequency. OBJECTIVE: To evaluate the impact of SSRIs and selective noradrenaline reuptake inhibitors (SNRIs) on nocturnal urinary frequency. METHODS: This was a retrospective study comparing nocturnal urinary frequency in individuals on SSRI or SNRI therapy versus no therapy during nocturnal polysomnography in a 14-month period at a sleep center. RESULTS: A total of 316 individuals were studied: 94 in the SSRI/SNRI group and 222 controls. No statistically significant difference was found in nocturnal urinary frequency between those on SSRI/SNRI therapy and the control group (0.40 vs 0.34 bathroom visits/night, P = 0.40). The degree of urinary frequency was higher in sertraline users (0.61 bathroom visits/night) compared with duloxetine users (0.18 visits/night, 2-tailed P = 0.04). A post hoc analysis suggested that the difference between these 2 agents is a class effect (SSRIs vs SNRIs, 2-tailed P = 0.03). The sample size did not allow conclusive comparison of either the SSRI or the SNRI group with the control group. CONCLUSION: SSRI/SNRI agents as a combined group do not appear to have a significant impact on nocturnal urinary frequency. The SSRIs and SNRIs may have an opposite effect on nocturnal frequency.

A review of antidepressant-induced urinary hesitancy: a focus on levomilnacipran ER including two case presentations(5633).

INTRODUCTION: Levomilnacipran ER was recently FDA approved as Fetzima® for the treatment of MDD. Urinary hesitancy can be an adverse event associated with levomilnacipran treatment. AREAS COVERED: This manuscript details the longitudinal course of levomilnacipran-induced urinary hesitancy in 2 cases that were in a pivotal clinical trial, examining possible predisposing factors and treatment issues. This manuscript also reviews the literature comparing urinary hesitancy associated with levomilnacipran versus other antidepressants. Antidepressants that are potent norepinephrine reuptake inhibitors like levomilnacipran, may have increased rates of associated urinary hesitancy. The latter can cause significant discomfort and a compromised quality of life. Occasionally, it can progress to urinary retention necessitating an emergency medical intervention. EXPERT OPINION: All patients being treated with antidepressants should be carefully monitored for this side effect. Discontinuation of treatment or reduction of the dose of antidepressant frequently relieves urinary hesitancy; alternatively, treatment with an alpha1A antagonist, e.g., tamsulosin may relieve antidepressant-induced urinary hesitancy within hours to days; such strategies allow for continued antidepressant treatment without urinary hesitancy recurring. Thus, with appropriate clinical care, the benefits using levomilnacipran outweigh its risks.

Comparative Influence of Imidafenacin and Oxybutynin on Voiding Function in Rats with Functional Urethral Obstruction.

An antimuscarinic therapy may increase the risk of voiding dysfunction. However, it is unclear whether the relative risk of voiding dysfunction is different among antimuscarinics. Therefore we determined the potencies both in enhancing the bladder capacity (BC), effectiveness, and in decreasing the maximum urinary flow rate (Qmax), voiding dysfunction, to compare their therapeutic indices.Under urethane anesthesia, urinary flow rate was measured at distal urethra using an ultrasonic flow meter in female Sprague-Dawley rats with functional urethral obstruction induced by a continuous i. v. infusion of α1-adrenoceptor agonist A-61603 (0.03 µg/kg/min). In a separate group of urethane-anesthetized rats without urethral obstruction, an intermittent cystometry was performed to determine BC.Intravenous imidafenacin and oxybutynin produced a significant dose-dependent decrease in Qmax with the minimum doses of 0.03 and 1 mg/kg, respectively. Imidafenacin and oxybutynin markedly increased BC, with minimum doses of 0.01 and 3 mg/kg, respectively. At the minimum dose to increase BC, oxybutynin caused a significant increase in residual urine volume with a significant decrease in voiding efficiency, whereas imidafenacin had no influence on these values. The relative influence index, which is the ratio of the minimum influence dose between in decreasing of Qmax and in increasing of BC, of imidafenacin was 10 fold higher than that of oxybutynin.This study suggests that imidafenacin has a lower relative risk of voiding difficulty compared with oxybutynin in rats. These results provide new information that antimuscarinics may have varying degrees of impact on voiding difficulty.

Single uroflow study as a tool in predicting the possibility of abnormal voiding symptoms after the administration of antimuscarinic agents in treating overactive bladder syndrome.

PURPOSE OF STUDY: The aim of this study was to evaluate the efficacy of uroflowmetry in predicting the possibility of abnormal voiding symptoms following antimuscarinic treatment for overactive bladder syndrome (OAB) in Taiwanese women. MATERIALS AND METHODS: A retrospective study was conducted on women with OAB. Forty-five women with abnormal voiding patterns shown by urodynamic study comprised the main group and 38 women with normal voiding patterns comprised the control group. All patients were prescribed two mg tolterodine once daily for one week. Follow-up on complaints of abnormal voiding symptoms was done one week later. RESULTS: One woman in control group and 12 women in main group complained of abnormal voiding symptoms. There was a significant difference in the occurrence of abnormal voiding symptoms after antimuscarinic administration between main study group and control group (26.7 % vs 2.6 %, p = 0.02). CONCLUSIOn: Uroflowmetry is a non-invasive and simple tool to predict the occurrence of abnormal voiding symptoms after antimuscarinic use.

Involvement of mitochondrial pathway of apoptosis in urothelium in ketamine-associated urinary dysfunction.

BACKGROUND: Long-term use of ketamine results in ketamine-associated urinary dysfunction (KAUD), which is characterized by frequent micturition, urgent urination, urine pain, hematuria, dysuria and urge incontinence. This study aims to examine the effect of ketamine on the urothelium and investigate the underlying mechanisms responsible for KAUD. METHODS: A rat model of KAUD by ketamine injection was developed. Histological changes in bladder tissues were measured by hematoxylin and eosin staining, and apoptosis by the TUNEL assay. Primary bladder epithelial cells were treated with ketamine, and cell proliferation measured by a CellTiter 96 AQ cell proliferation assay, apoptosis assessed by TUNEL assay and levels of apoptosis-related proteins determined by Western blotting. RESULTS: Animals injected with ketamine displayed a decrease in body weight, behavioral signs of addiction, urinary dysfunction and damage to the epithelial layer of the bladder, particularly in the group receiving high-dose ketamine for 3 months. Ketamine increased apoptosis both in bladder tissues and bladder epithelial cells. In addition, ketamine induced the expression of Bax, cytochrome c and capase-3, but inhibited the expression of NF-κB and bcl-2. CONCLUSIONS: These results suggest that the mitochondrial pathway of apoptosis in bladder epithelium may contribute to KAUD.

Evaluation of complications and feasibility of indwelling epidural catheter use for post-operative pain control in dogs in the home environment.

AIMS: The objective of this study was to describe the use of indwelling epidural catheters post-operatively in dogs in a home environment, and to report associated complications. METHODS: Dogs undergoing surgical procedures of the hind limb (n=83) were included in the study and were administered 0.05 or 0.10 mg/kg epidural morphine via an indwelling epidural catheter every 6 hours. Data compiled relating to catheter placement included time of placement, ease of placement and problems encountered, number of attempts of placement, and individual placing the catheter. A client questionnaire was provided to evaluate side effects, complications, pain, and ease of use of the epidural catheter system after discharge from the hospital and catheter removal at home. Side effects were compared between the dogs receiving 0.05 or 0.1 mg/kg epidural morphine. RESULTS: The most common patient complication was abnormal urination patterns (32/82, 39%); specifically dribbling urine where laying, emptying the entire bladder where laying, not urinating for extended periods of time, and taking a longer time to pass urine were reported. There were no significant differences in the number or types of side effects reported in either dosing group. The most common technical issues reported by owners were difficulty getting the needle into the injection port (10/81, 12%) and removing the adhesive covering keeping the epidural catheter system in place (19/78, 24%). There were no reports of inflammation or discharge at the catheter site in any of the dogs. Of the respondents surveyed, 76/79 (97%) found the epidural catheter system easy to use at home in the post-operative period. CONCLUSIONS: Indwelling epidural catheters are a feasible method of administration of post-operative analgesia in the immediate post-operative period in the home environment and were associated with only a few minor complications in this population.

Lesiones del tracto urinario asociadas al consumo de ketamina / Urinary tract lesions associated to ketamine consumption

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Could hyaluronic acid (HA) reduce Bacillus Calmette-Guérin (BCG) local side effects? Results of a pilot study.

BACKGROUND: Bacillus Calmette-Guérin (BCG) is considered the most effective treatment to reduce recurrence and progression of non-muscle invasive bladder cancer (NMIBC) but can induce local side effects leading to treatment discontinuation or interruption. Aim of this exploratory study is to investigate if the sequential administration of Hyaluronic acid (HA) may reduce local side effects of BCG. METHODS: 30 consecutive subjects undergoing BCG intravesical administration for high risk NMIBC were randomized to receive BCG only (Group A) or BCG and HA (Group B). A 1 to 10 Visual Analog Scale (VAS) for bladder pain, International Prostate Symptom Score (IPSS) and number of micturitions per day were evaluated in the two groups before and after six weekly BCG instillations. Patients were also evaluated at 3 and 6 months by means of cystostopy and urine cytology. RESULTS: One out of 30 (3,3%) patients in group A dropped out from the protocol, for local side effects. Mean VAS for pain was significantly lower in group B after BCG treatment (4.2 vs. 5.8, p = 0.04). Post vs. pre treatment differences in VAS for pain, IPSS and number of daily micturitions were all significantly lower in group B. Three patients in group A and 4 in group B presented with recurrent pathology at 6 month follow up. CONCLUSIONS: These preliminary data suggest a possible role of HA in reducing BCG local side effects and could be used to design larger randomized controlled trials, assessing safety and efficacy of sequential BCG and HA administration. TRIAL REGISTRATION: NCT02207608 (ClinicalTrials.gov) 01/08/2014. Policlinico Tor Vergata Ethics Committee, resolution n 69-2011.