A precision medication study of atomoxetine in children with attention deficit hyperactivity disorder: CYP2D6 genetic testing and therapeutic drug monitoring / 中国当代儿科杂志

Atomoxetine is the first non-stimulant drug for the treatment of children and adults with attention deficit hyperactivity disorder (ADHD), and its safety and efficacy show significant differences in the pediatric population. This article reviews the genetic factors influencing the pharmacokinetic differences of atomoxetine from the aspect of the gene polymorphisms of the major metabolizing enzyme CYP2D6 of atomoxetine, and then from the perspective of therapeutic drug monitoring, this article summarizes the reference ranges of the effective concentration of atomoxetine in children with ADHD proposed by several studies. In general, there is an association between the peak plasma concentration of atomoxetine and clinical efficacy, but with a lack of data from the Chinese pediatric population. Therefore, it is necessary to establish related clinical indicators for atomoxetine exposure, define the therapeutic exposure range of children with ADHD in China, and combine CYP2D6 genotyping to provide support for the precision medication of atomoxetine.

Tratamiento del trastorno por déficit de atención con hiperactividad en la práctica clínica habitual: Estudio retrospectivo / Treatment of attention-deficit/hyperactivity disorder in clinical practice. A retrospective study

El trastorno por déficit de atención e hiperactividad (TDAH) es un trastorno del neurodesarrollo complejo y heterogéneo, de carácter crónico, de etiología multifactorial, principalmente debida a factores genéticos y ambientales. Realizamos un estudio analítico retrospectivo del tratamiento de niños diagnosticados de TDAH. Se estudió una muestra de 82 niños diagnosticados de TDAH (74.4% niños y 25.6% niñas). El 96.3% de los casos presentaba algún trastorno asociado. El tratamiento farmacológico fue el tratamiento de elección (90.2%). El 46.0% recibía metilfenidato de liberación inmediata, un 51.4% metilfenidato de liberación sostenida y la atomoxetina solo se recetó en un 2.7% de los casos. El 20.3% de la muestra abandonó en algún momento el tratamiento farmacológico. El tratamiento farmacológico fue la opción más utilizada en nuestra muestra, y el metilfenidato de liberación inmediata el fármaco de elección para inicio del tratamiento. Se utilizan poco las alternativas a los estimulantes. No se encontraron diferencias significativas entre el tipo de tratamiento y el subtipo de TDAH o el género, aunque sí en cuanto a la edad de inicio del tratamiento.

Attention deficit hyperactivity disorder (ADHD) is a complex and heterogeneous neurodevelopmental disorder, of a chronic nature, of multifactorial etiology, mainly due to genetic and environmental factors. We conducted a retrospective analytical study of the t herapeutic management of children diagnosed with ADHD. A sample of 82 children diagnosed with ADHD (74.4% children and 25.6% girls) was studied. 96.3% of the cases presented some associated disorder. Pharmacological treatment was the treatment of choice (90.2%). 46.0% received immediate release methylphenidate, 51.4% sustained release methylphenidate and atomoxetine was only prescribed in 2.7% of patients. 20.3% of the sample abandoned pharmacological treatment at some point. Pharmacological treatment was the most frequent option in our sample, and methylphenidate immediate release the drug of choice for treatment initiation. The alternatives to stimulants are used in very low percentage of the patient. No significant differences were found between the type of treatment regarding the subtype of ADHD or gender, but we found significant difference in relation with the age of onset of treatment.

Evaluación de la efectividad y seguridad de la atomoxetina para déficit atencional en población entre 6 y 19 años: revisión sistemática / Effectiveness and safety of atomoxetine for ADHD in population between 6 and 19 years: a systematic review

Introducción: el Trastorno por déficit de atención e hiperactividad (TDAH) dispone de intervenciones farmacológicas como los psicoestimulantes. El más usado es el metilfenidato y posteriormente se ha incluido la atomoxetina. Objetivo: identificar, sintetizar y evaluar la mejor evidencia disponible sobre la efectividad y seguridad de la atomoxetina en el tratamiento en déficit atencional en la población de 6 a 19 años. Métodos: se realizó una revisión sistemática de estudios de intervenciones, que evaluaron efectividad comparada de atomoxetina con placebo y metilfenidato. Las medidas fueron funcionamiento educacional, funcionamiento psicosocial, calidad de vida y efectos adversos. Se consultó en bases de datos hasta febrero de 2012 en inglés y castellano: PubMed, LILACS, Cochrane, DARE y National Guideline Clearinghouse. Los artículos incluidos fueron evaluados por dos investigadores en forma independiente. Resultados: de los 108 estudios encontrados inicialmente, se incluyeron 11, entre ellos 5 revisiones sistemáticas, un artículo primario y 5 guías clínicas. Conclusiones: la atomoxetina se recomienda como segunda opción en el TDAH por ser superior al placebo, cuando falla el metilfenidato o hay presencia de comorbilidades.

Introduction: Attention deficit hyperactivity disorder (ADHD) is generally treated with pharmacological interventions such as psychostimulants. The most used widely used one is methylphenidate followed by atomoxetine. Purpose: To identify, synthesize and evaluate the best available evidence on the effectiveness and safety of atomoxetine in ADHD treatment in the 6-19 year-old population. Methods: A systematic review of intervention studies that evaluated effectiveness of atomoxetine compared with placebo and methylphenidate was conducted. Outcomes assessed were educational functioning, psychosocial functioning, quality of life and adverse effects. The search was done up to February 2012 in English and Spanish in the following databases: PubMed/MEDLINE, LILACS, Cochrane, DARE and National Guideline Clearinghouse. The articles were independently evaluated by two investigators. Results: Of the 108 studies found initially, 11 were included, among which five systematic reviews, one primary article and 5 clinical guidelines. Conclusions: Atomoxetine is recommended as a second option in ADHD and was found to be superior to placebo. Its use is recommended when methylphenidate fails or comorbidities are present.

Floppy iris syndrome with oral imipramine: A case series.

Intraoperative floppy iris syndrome (IFIS) has commonly been seen with long-term use of α1-adrenoceptor blocking agents. We observed IFIS in three patients during phacoemulsification due to oral imipramine therapy. The three patients took imipramine for 25 years, 10 months and 1 year, respectively. However, only the first patient was on oral therapy at the time of surgery, while the other two patients had stopped 4 months and 2 months prior to undergoing phacoemulsification. The first and third patients developed complete IFIS features, while the second had only partial IFIS characteristics. Phacoemulsification could be completed in all three patients without any complication. None of these patients had history of taking any of the α1-adrenoceptor blocking agents. This is the first anecdotal report of IFIS with the oral use of imipramine and hence further evidences are required to ascertain the association of oral imipramine therapy and IFIS. However, ophthalmologists undertaking phacoemulsification on patients on imipramine therapy should be alert for the occurrence of IFIS.

Duloxetine versus placebo in the treatment of patients with diabetic neuropathic pain in China / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Duloxetine, a selective serotonin and noradrenaline reuptake inhibitor, has been shown to be effective in treatment of diabetic peripheral neuropathic pain and approved for the management of patients with diabetic peripheral neuropathic pain (DPNP) in the United States, European Union, and many other countries. This study assessed the efficacy and safety of duloxetine in Chinese patients with diabetic peripheral neuropathic pain.</p><p><b>METHODS</b>This double-blind, randomized, placebo-controlled, flexible-dose study treated adult patients with diabetic peripheral neuropathic pain and baseline Brief Pain Inventory (BPI) 24-hour average pain severity ratings ≥ 4 with duloxetine 60 mg to 120 mg once daily or placebo for 12 weeks. Dose adjustments of duloxetine or matching placebo were based upon investigator's judgment of clinical response. Change from baseline to endpoint in BPI average pain was the primary efficacy outcome. Secondary outcome measures included BPI-severity and -Interference, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, EuroQol: 5 Dimensions, Athens Insomnia Scale, and safety measures.</p><p><b>RESULTS</b>Of 215 patients randomized, 88.4% and 82.1% of patients in placebo and duloxetine groups, respectively, completed the study. Mean change from baseline to endpoint in BPI average pain was not statistically different between the treatment groups (P = 0.124). Duloxetine- treated patients showed significantly greater pain reduction compared with those in placebo group at weeks 1, 2, and 4 (P = 0.004, P = 0.009, and P = 0.006, respectively), but not at weeks 8 (P = 0.125) and 12 (P = 0.107). Duloxetine-treated patients experienced statistically significant improvement in Patient Global Impression of Improvement, Clinical Global Impression of Severity, area under the curve for pain relief, BPI-severity pain right now, and BPI-interference walking ability. Patients treated with duloxetine 120 mg once daily showed significantly greater pain reduction on the Brief Pain Inventory average pain score relative to placebo. Duloxetine-treated patients reported nausea, somnolence, anorexia, and dysuria significantly more than placebo.</p><p><b>CONCLUSIONS</b>Although the primary study endpoint was not achieved, the overall observed response pattern suggests the efficacy of duloxetine in the treatment of Chinese patients with diabetic peripheral neuropathic pain. The safety profile for duloxetine is similar to that reported in other global trials.</p>

Cyclic vomiting syndrome responding to amitryptiline.

A 7 year girl presented with history of recurrent vomiting and altered sensonium. Laboratory investigators were within normal limits. A diagnosis of cyclic vomiting syndrome was made and treated with amitryptiline with good results.

Imipramine induced elevation of prolactin levels in patients with HIV/AIDS improved their immune status / La elevación de niveles de prolactina mediante inducción con imipramina mejoró el estatus inmune de pacientes con VIH/SIDA

Prolactin is known to have significant immunomodulatory properties. Imipramine, a monoamine oxidase inhibitor, stimulates prolactin production because it decreases dopamine which inhibits secretion of prolactin. The study objective was to determine if use of imipramine can result in immunological benefits for HIV-positive patients by restoration and preservation of immunological function. A cohort of 19 retroviral positive patients was identified for the prospective study which continued for a 28-week period. Three patients dropped out before the study began. Inclusion criteria accepted only patients on the same highly active antiretroviral therapy (HAART) regimen for a nine-month period and who had reached a plateau with respect to the CD4 cell count and also had no prior history of antidepressant use for a 12-month period. This study had a "before and after" design, patients serving as their own control. The study drug imipramine was prescribed for a 12-week period up to visit 4, and then discontinued for 4-weeks (washout period) at which time blood investigations were done at visit 5. Finally, patients were prescribed the study drug for a further 12-week period to the end of the trial (visit 7). At the 95 per cent probability level, significant differences in average prolactin and CD4 levels from visit 4 to the end of the trial period were recorded. Results showed a trend of prolactin levels decreasing after washout (p = 0.015) and increasing by the end of the trial period once imipramine dispensation had recommenced (p = 0.006). With respect to the CD4 cell count, there was a significant increase after wash-out (p = 0.022). These results indicate a trend to immune boosting in HIV-positive patients who had obtained the maximum response from HAART.

Se sabe que la prolactina posee importantes propiedades inmunomudolatorias. La imipramina, un inhibidor de la monoamino oxidasa, estimula la producción de la prolactina porque disminuye la dopamina, que a su vez inhibe la secreción de prolactina. El objetivo de este estudio fue determinar si el uso de la imipramina puede traer beneficios inmunológicos a los pacientes VIH positivos mediante la restauración y preservación de la función inmunológica. Se identificó una cohorte de 19 pacientes retrovirales positivos, a fin de realizar este estudio prospectivo que continuó por un período de 28 semanas Tres pacientes se retiraron antes de que el estudio comenzara. Los criterios de inclusión aceptaban sólo pacientes que tuvieran el mismo régimen de terapia antiretroviral altamente activa (HAART) por un período de nueve meses, que hubieran alcanzado un nivel de estabilización con respecto al conteo de células CD4, y que no hubieran además tenido con anterioridad una historia de uso de anti-depresantes por espacio de 12 meses. Este estudio tuvo un diseño "antes y después", sirviendo los pacientes como su propio control. La imipramina para el estudio fue prescrita por un período de 12 semanas hasta la visita 4, y luego descontinuada por 4 semanas para un reposo farmacológico (período de lavado), realizándose entonces pruebas de sangre en la visita 5. Finalmente se prescribió el medicamento de estudio a los pacientes por un nuevo período de 12 semanas hasta el final del ensayo (visita 7). En el nivel de probabilidad del 95 por ciento, se registraron diferencias significativas en los niveles promedio de prolactina y CD4 desde la visita 4 hasta el final del período de ensayo. Los resultados mostraron una tendencia de los niveles de prolactina a descender tras el lavado (p = 0.015) y a aumentar hacia el final del período de ensayo, una vez que la dispensación de imipramina hubiese recomenzado (p = 0.006). Con respecto al conteo de células de CD4, hubo un aumento significativo luego del lavado (p = 0.022).

Possible role of citalopram and desipramine against sleep deprivation-induced anxiety like-behavior alterations and oxidative damage in mice.

Sleep is an essential physiological process for maintaining physical, mental, and emotional health. Sleep deprivation and associated disorders like depression and anxiety are one of the major problems now-days. The present study was designed to explore the neuroprotecitve effect of citalopram and desipramine on 72 hr sleep deprivation-induced behavioral alterations and oxidative damage in mice. Various behavioral tests (plus maze, zero maze, mirror chamber, actophotometer), body weight followed by oxidative parameters (malondialdehyde level, glutathione, catalase, nitrite and protein) were assessed. Treatment with citalopram (5 and 10 mg/kg, ip) and desipramine (10 and 20 mg/kg, ip) for 5 days significantly improved locomotor activity, anti-anxiety like behavior in all paradigms tasks (mirror chamber, plus maze, zero maze) as compared to control (72 hr sleep-deprived). Biochemically, citalopram and desipramine treatment significantly restored depleted reduced glutathione, catalase activity, attenuated raised lipid peroxidation and nitrite level as compared to control (72 hr sleep-deprived) animals. Results of present study suggest that citalopram (5 and 10mg/kg, ip) and desipramine (10 and 20 mg/kg, ip) have neuroprotective effect against sleep deprivation-induced behavior alteration and oxidative damage in mice.

Bleeding gums: duloxetine may be the cause.

Duloxetine is a newly introduced drug. It is being prescribed for the management of diabetic neuropathic pain and major depressive disorder. The most frequently observed adverse events with duloxetine are nausea, dry mouth and somnolence, constipation, diarrhea, decreased appetite, weight loss, feeling of fatigue, dizziness, somnolence, hypohidrosis, decreased libido and erectile dysfunction. One of the patients being prescribed the drug developed bleeding gums on being started with the drug which resolved on stopping it. We hereby report this case.

La insulinoterapia intensificada más antineuríticos es superior a antineurítico puro en neuropatía diabética dolorosa / Intensified insulin therapy plus antineuritic medication is more effective than antineuritics alone in painful diabetic neuropathy

Background: The basis of the treatment of painful diabetic neuropathy is the use of drugs that block the transmission of pain (antineuritics) and a good metabolic control of underlying disease. Aim: To describe the outcomes of 17 type-2 diabetics with painful neuropathy, treated between 1988 and 2005 with symptomatic therapy plus intensified insulin. Material and methods: Review of medical records of 17 type-2 diabetic patients, aged 63±11 years and a duration of diabetes of 15±8 years. All patients received intensified insulin therapy with 0.35 units/kg of NPH insulin (2/3 before breakfast and 1/3 evening meal), plus capillary glucose measurements and regular insulin (with sliding-scale centered in ~0.1 units/kg) before the 3 main meals. All patients were also treated with gabapentin, nortriptyline or clomipramine. Pain was assessed using a visual analog score of 10 points. Results: After 1 year, glycosilated hemoglobin decreased from 10.0±1.4 percent to 7.7±1.2 percent (p~=0.003). Pain decreased from 10 to 5.1±3.3 at one month, 2.3±3.2 at six months, and 3.1±3.6 at 1 year (p <0.01). There was a direct statistical correlation between the reduction of HbA1C and pain decline (r =0.736; p =0.037). Pain scores were lower than those reported elsewhere for Pregabalin (n =76; p =0.05), Lamotrigine (n =27; p <0.0005), Topiramate (n =208; p <0.005), and Gabapentin (n =84; p <0.025). The lack of difference to Sodium Valproate (n =21; p =0.07) had borderline significance. Conclusions: The addition of intensified insulin therapy to the symptomatic treatment of painful neuropathy in type-2 diabetics, significantly enhanced the reduction of pain. The lowering of glycosilated hemoglobin was a significant predictor of success in pain reduction.

Tratramento neonatal com inibidor seletivo da recaptação de noradrenalina altera o consumo alimentar e a ingestão hídrica na vida adulta em ratos / Neonatal treatment with selective noradrenaline reuptake inhibitor alter the food and water intake in adult life in rats

RESUMO: Durante o período crítico de desenvolvimento do sistema nervoso, o organismo é vulnerável a agressões de diversas naturezas, que podem acarretar transtornos morfofuncionais na vida adulta. A construção do comportamento alimentar é vulnerável a estas agressões, sendo importante para a sobrevivência da espécie e, portanto, alvo de estudos. O objetivo deste trabalho foi estudar o efeito da manipulação farmacológica do sistema noradrenérgico, através da inibição da recaptação de noradrenalina, durante o período neonatal e as repercussões dessa agressão sobre o consumo alimentar, na vida adulta. Os animais foram tratados diariamente, durante os 21ºdias de vida com reboxetina (20mg/Kg de peso), um inibidor seletivo da recaptação de noradrenalina (NARI) ou solução salina (NaCI 0,9por cento). Aos 60 dias foi avaliado o consumo alimentar e a ingestão hídrica. Os animais tratados com salina. Concluímos que a agressão farmacológica do sistema noradrenérgico durante o perídoso neonatal, pode alterar de forma duradoura o consumo alimentar e a ingestão hídrica. Essas alterações sugerem que o tratamento pode alterar morfofucionalmente estruturas relacionadas a regulação do comportamento alimentar e da ingestão hídrica, levando a alterações comportamentais na vida adulta

Effect of chlorpromazine, imipramine and lithium on MAO-A and MAO-B activity in rat brain mitochondria.

Drugs with efficacy in psychiatric disorders affect the function of central neurotransmitter amines, which are inactivated primarily by monoamine oxidase (MAO). Effect of these drugs on the two types of MAO (MAO-A and MAO-B) has been studied in rat brain. The result showed that chlorpromazine (CPZ) and imipramine (IMI) at concentrations of 1x10(-2), 5x10(-3) and 2.5x10(-3) M inhibited rat brain mitochondrial MAO-A activity in vitro by 82, 50, 39 and 86, 74, 38 %, respectively. CPZ at concentrations of 5x10(-3), 2.5x10(-3), 1x10(-3) M inhibited rat brain mitochondrial MAO-B activity in vitro by 83, 55, 39 %, respectively, while IMI at concentrations of 5x10(-4), 2.5x10(-4), 1x10(-4) M inhibited the in vitro enzyme activity by 43, 35, 21 %, respectively. Lithium at concentration of 5x10(-3) M could not either inhibit MAO-A or MAO-B in the mitochondrial fraction of rat brain.

Analgesia in phasic and tonic pain tests in a pharmacological model of autotomy.

Self-mutilation or self-injurious behaviour is a well known behavioural disorder in humans. The proposition that this behaviour in animals is a response to chronic pain of peripheral nerve injury has been met with controversy. In the present study a pharmacological model, which produces no sensory or motor loss was used to study how autotomy is related to pain. In a group of rats autotomy was induced by amphetamine in phenoxybenzamine and reserpine treated animals. The pain tests, both phasic and tonic were then performed. The results of this study showed that a total analgesia was produced in both phasic and tonic pain tests, in animals that exhibited autotomy. Injection of naloxone in these animals prevented autotomy. A correlation between autotomy and no pain is suggested in this pharmacological model of autotomy.

Nocturnal panic attacks

The panic-respiration connection has been presented with increasing evidences in the literature. We report three panic disorder patients with nocturnal panic attacks with prominent respiratory symptoms, the overlapping of the symptoms with the sleep apnea syndrome and a change of the diurnal panic attacks, from spontaneous to situational pattern. The implication of these findings and awareness to the distinct core of the nocturnal panic attacks symptoms may help to differentiate them from sleep disorders and the search for specific treatment

The impact of heterogeneity on the diagnosis and treatment of interstitial cystitis / O impacto da heterogeneidade no diagnóstico e tratamento da cistite intersticial

A cistite intersticial (CI) é uma doença cuja etiologia permanece desconhecida. A CI é um dos estados mais incômodos na prática urológica. Geralmente afeta mulheres, que apresenta sintomas de dor ao encherem a bexiga e freqüência urinária. A CI é uma síndrome heterogênea e é, freqüentemente, dividida em dois subtipos. Comparada à CI clássica, a do tipo näo-ulcerativa difere por apresentar aspectos sintomáticos, endoscópicos e histológicos diferentes, além da resposta aos vários tipos de tratamento. Esta revisäo é uma introduçäo à síndrome da CI, no que diz respeito a características clínicas e critérios de diagnóstico. Uma variedade de modalidades de tratamento têm sido sugeridas ao longo dos anos, e säo aqui revisadas e avaliadas, entre as quais estäo a hidrodistençäo da bexiga, a terapia de instilaçäo intravesical, a medicaçäo oral e a estimulaçäo elétrica transcutânea do nervo, a ressecçäo transuretral do tecido doente da bexiga, a cistectomia supratrigonal seguida de enterocistoplastia e derivaçäo urinário.

Evidence for presence of GABA-ergic receptor mediated dispersion in isolated scale melanophores of a carp, Cirrhinus mrigala Ham.

Effects of GABA-ergic agonists and antagonists were examined on the melanophores of a carp C. mrigala in vitro. GABA and baclofen both induced concentration - related dispersion in fish melanophores. Denervation of the melanophores by reserpine treatment potentiated the sensitivity of the melanophores to GABA. While denervation by cooling treatment inhibited the sensitivity of the melanophores to GABA, atropine, bicuculline and pentylenetetrazole all inhibited the dispersal responses of the melanophores induced by higher concentrations of GABA. 5-aminovaleric acid also significantly inhibited the dispersion of the melanophores induced either by GABA or baclofen. It is concluded that GABA-ergic agonist induced dispersal responses in C mrigala melanophores are mediated through specific GABA receptors. The presence of both GABAA and GABAB receptors in this fish melanophores has been indicated.

Serotonergic mechanism in imipramine induced antinociception in rat tail flick test.

Substantial evidence has accumulated that spinally projecting serotonergic neurons modulate nociception. However, the exact receptor subtypes that mediate the antinociceptive response of serotonin within the spinal cord continue to be a subject of debate. Therefore, we explored the effect of serotonergic system on imipramine induced antinociception by using 5-Hydroxytryptamine-3 (5HT3) receptor antagonist ondansetron and 5-Hydroxytryptamine-2 (5HT2) receptor antagonist mianserine, and depletion of brain 5-Hydroxytryptamine (5HT) with p-chlorophenyl alanine (PCPA). Male wistar strain rats were pretreated with either ondansetron (0.5 mg/kg, i.p.) or mianserine (1 mg/kg, i.p.). After 15 minutes, rats received injection of imipramine (10 mg/kg). Nociception was assessed by tail-flick method. Imipramine (2 mg, 5 mg, 10 mg, and 20 mg/kg) produce antinociceptive response in the dose dependent manner. Prior treatment with 5HT3 antagonist, Ondansetron and 5HT2 antagonist, mianserine reduce the antinociceptive response of imipramine. In PCPA treated rats imipramine (10 mg/kg) failed to produce antinociception. These results indicate that the 5HT plays an important role in imipramine induced antinociception.