Detailed investigation of a gamma-cyclodextrin inclusion complex with L-thyroxine for improved pharmaceutical formulations

Thyroxine is a naturally occurring human hormone produced by the thyroid gland. Clinical applications of thyroxine to treat several chronic disorders are limited by poor water solubility and instability under physiological conditions. An inclusion complex of levo-thyroxine (l-thyroxine), the active form of the hormone with gamma cyclodextrin (gamma-CD) has been obtained and studied with the aim of improving oral delivery rather than the injection formulation of the sodium salt. In addition to greater patient acceptability, inclusion complexes often improve aqueous solubility and bioavailability, stability, and reduce toxicity of drugs, thus providing enhanced pharmaceutical formulations. Physicochemical characterization of the inclusion complex was carried out using Fourier transform infrared spectroscopy, X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy and proton nuclear magnetic resonance spectroscopy. Intermolecular dipolar interactions for the inclusion complex were also studied using 2 dimensional ROESY experiments. Formation of the inclusion complex between the protons H3 and H5 of cyclodextrin with aromatic protons of thyroxine was confirmed by their dipolar interaction. Molecular modelling was used to understand the basis for the complex formation and predict the formation of other complexes. Interestingly, we found that l-thyroxine forms an inclusion complex only with the larger gamma-CD and not with other available alpha and beta forms.

Use of combined liothyronine and thyroxine therapy for consumptive hypothyroidism associated with hepatic haemangiomas in infancy

Hepatic haemiangiomas in infancy are rare. An association with hypothyroidism has been previously reported and is believed to be secondary to the conversion of thyroxine (fT4) to biologically inactive reverse triiodothyronine (rT3) by type 3 iodothyronine deiodinase (D3). We report a case that responded well to the combined use of liothyronine and thyroxine therapy.

Avaliação terapêutica e posológica da levotiroxina sódica em cães com hipotiroidismo primário adquirido

O hipotireoidismo primário adquirido é uma endocrinopatia frequentemente diagnosticada na espécie canina. A terapia consiste na suplementação oral com levotiroxina sódica (L-tiroxina), no entanto vários protocolos terapêuticos têm sido propostos pela literatura, com doses variando 11 a 44µg/kg uma a duas vezes ao dia, visto à grande variabilidade de absorção e meia-vida plasmática do fármaco. Foram estudados 30 cães com hipotiroidismo primário adquirido (13 machos e 17 fêmeas, idade média de 7,9±1,9 anos e peso médio de 19,1±12,6 kg) atendidos no Hospital Veterinário da Universidade Guarulhos (UnG) e no Serviço de Endocrinologia de duas clínicas particulares da cidade de São Paulo (2009-2011), com o objetivo de avaliar a posologia e a frequência de administração da L-tiroxina, mais frequentemente utilizada, capaz de garantir um controle terapêutico satisfatório, avaliado através dos sinais clínicos e do teste pós-tiroxina, além de correlacionar a dose de tiroxina empregada com o peso dos animais. A dose média de tiroxina utilizada em nossa casuística foi de 16,9±3,1µg/kg, sendo a frequência de administração a cada 12 horas em 50% dos casos. Para se investigar uma possível correlação entre o peso e a dosagem de tiroxina utilizada, uma vez que cães de pequeno porte apresentam maior taxa metabólica que cães de grande porte, os animais foram agrupados em grupo A, cães com peso <10 Kg (n=12/30; 7,7±2,1 kg) e grupo B, cães com peso >10 kg (n=18/30, 26,8±10,7 kg). A dose média de tiroxina empregada nos grupos A e B não apresentaram diferença estatística e foram, respectivamente, 16±3µg/kg e 17±3µg/kg. A frequência de administração foi 50% a cada 24 horas e 50% a cada 12 horas para ambos os grupos. Dessa forma, a dose de tiroxina não parece se correlacionar com o peso do animal, sendo imprevisível quem deverá receber dose e frequência máxima da medicação. O protocolo deve ser individualizado e o paciente devidamente monitorado.

Approach to and Treatment of Goiters

The main causes of simple diffuse goiter (SDG) and multinodular goiter (MNG) are iodine deficiency, increase in serum thyroid-stimulating hormone (TSH) level, natural goitrogens, smoking, chronic malnutrition, and lack of selenium, iron, and zinc. Increasing evidence suggests that heredity is equally important. Treatment of SDG and MNG still focuses on L-thyroxine-suppressive therapy surgery. Radioiodine alone or preceded by recombinant human TSH stimulation is widely used in Europe and other countries. Each of these therapeutic options has advantages and disadvantages, with acute and long-term side effects.

Effect of combined thyroxine and cortisol treatment on hatching of eggs, post-embryonic growth and survival of larvae of Heteropneustes fossilis

In order to record the effects of thyroxine and cortisol (individual/combined) on hatching, post-embryonic growth and survival of larvae of Heteropneustes fossilis, newly fertilized eggs were given bath immersion treatments of L-thyroxine (T sub(4); 0.05 mg/l), cortisol (0.50 mg/l) and T sub(4)+ cortisol (0.05 mg/l+0.50 mg/l) for 15 days. Hatching of eggs, growth and survival of the larvae improved significantly (P<0.001) in the hormone treated groups as compared to those of control. The frequency of deformities was reduced in the combined hormone treatment group. The present observations suggest that the advanced digestive function probably induced by T sub(4)+cortisol treatment might have resulted in improvement in food utilization during the critical phases of first feeding and promoted vital developmental processes resulting in uniform growth, decreased mortality, better survival and transformation of larvae to juveniles. This combined hormone therapy appears to have practical utility in fish hatchery practice for better success in larval rearing.

Structure Elucidation and Characterization of Different Thyroxine Polymorphs

Thyroid hormones regulate almost every process in the body, including body temperature, growth, and heart rate. They influence carbohydrate metabolism, protein synthesis and breakdown, and cardiovascular, renal, and brain function. Two new polymorphs of synthetic L-thyroxine (T4) are reported and the effect of polymorphism on the solubility of this important hormone is shown. Conformational changes were also discovered to have a remarkable effect on the strength of halogen bonding and the reactivity of the CI bonds, which could have a significant effect on the hormone activity.

Efeito protetor da coenzima Q10 sobre os danos oxidativos da L-Tiroxina no músculo sóleo de ratos: Fabiana Barreiro de Freitas Silva. -

Pós-graduação em Ciência Animal - FMVA

Efeito da coenzima Q10 nos danos oxidativos induzidos pela L-tiroxina no músculo sóleo de ratos

Introduction: skeletal muscles are dynamic tissue that can change their phenotypic characteristics providing a better functional adaptation to different stimuli. L-thyroxine is a hormone produced by the thyroid gland and has been used as an experimental model for stimulation of oxidative stress in skeletal muscle. Coenzyme Q10 (CoQ10) is a fat-soluble provitamin endogenously synthesized and found naturally in foods such red meat, fish, cereals, broccoli and spinach. It has antioxidant properties and potential in the treatment of degenerative and neuromuscular diseases. Objective: to evaluate the protective effect of CoQ10 in the soleus muscle of rats against the oxidative damage caused by L-thyroxine. Methods: the rats were divided in four groups of six animals each: Group 1 (control); Group 2 (coenzyme Q10); Group 3 (L-thyroxine), and Group 4 coenzyme Q10 and L-thyroxine). After euthanasia, blood was collected and serum activity of the enzymes creatine kinase (CK) and aspartate aminotransferase (AST) was analyzed. In the soleus muscle homogenates the factors related to oxidative stress were assessed. Results: CoQ10 protected the soleus muscle against the damage caused by L-thyroxine and favored the maintenance of the antioxidant enzymes glutathione reductase and glutathione peroxidase, the concentration of decreased and oxidized glutathione, and prevented lipid peroxidation. Conclusion: the results indicate that CoQ10 protects rat soleus muscle from oxidative damage caused by L-thyroxine.

Il craniofaringioma nel bambino e nell'adolescente. Luci ed ombre durante il follow-up

Introduction. Craniopharyngioma (CF) is a malformation of the hypothalamicpituitary region and it is the most common nonglial cerebral tumor in children with an high overall survival rate. In some case severe endocrinologic and metabolic sequelae may occur during follow up. 50% of patients (pts), in particular those with radical removal of suprasellar lesions, develop intractable hyperphagia and morbid obesity, with dyslypidemia and high cardiovascular risk. We studied the auxological and metabolic features of a series of 29 patients (18 males) treated at a mean age of 7,6 years, followed up in our Centre from 1973 to 2008 with a mean follow up of 8,3 years. Patients features at the onset. 62% of pts showed as first symptoms of disease visual impairment and neurological disturbancies (headache); 34% growth arrest; 24% signs of raised intracranial pressure and 7% diabetes insipidus. Diagnosis. Diagnosis of CF was reached finally by TC or MRI scans which showed endo-suprasellar lesion in 23 cases and endosellar tumour in 6 cases. Treatment and outcome. 25/29 pts underwent surgical removal of CF (19 by transcranial approach and 6 by endoscopic surgery); 4 pts underwent stereotactic surgery as first line therapy. 3 pts underwent local irradiation with yttrium-90, 5 pts post surgery radiotherapy. 45% of pts needed more than one treatment procedure. Results. After CF treatment all patients suffered from 3 or more pituitary hormone deficiencies and diabetes insipidus. They underwent promptly substitutive therapy with corticosteroids, l-thyroxine and desmopressin. In 28/29 pts we found growth hormone (GH) deficiency. 20/28 pts started GH substitutive therapy and 15 pts reached final height(FH) near target height(TH). 8 pts were not GH treated for good growth velocity, even without GH, or for tumour residual. They reached in 2 cases FH over TH showing the already known phenomenon of growth without GH. 38% of patients showed BMI SDS >2 SDS at last assessment, in particular pts not GH treated (BMI 2,5 SDS) are more obese than GH treated (BMI 1,2 SDS). Lipid panel of 16 examined pts showed significative differencies among GH treated (9 pts) and not treated (7 pts) with better profile in GH treated ones for Total Cholesterol/C-HDL and C-LDL/C-HDL. We examined intima media thickness of common carotid arteries in 11 pts. 3/4 not GH treated pts showed ultrasonographic abnormalities: calcifications in 2 and plaque in 1 case. Of them 1 pt was only 12,6 years old and already showed hypothalamic obesity with hyperphagia, high HOMA index and dyslipidemia. In the GH treated group (7) we found calcifications in 1 case and a plaque in another one. GH therapy was started in the young pt with carotid calcifications, with good improvement within 6 months of treatment. 5/29 pts showed hypothalamic obesity, related to hypothalamic damage (type of surgical treatment, endo-suprasellar primitive lesion, recurrences). 48% of patients recurred during follow up ( mean time from treatment: 3 years) and underwent, in some cases up to 4 transcranial surgical treatments. GH seems not to increase recurrence rate since 40% of GH treated recurred vs 66,6% of not GH treated pts. Discussion. Our data show the extereme difficulties that occur during follow up of craniopharyngioma treated patients. GH therapy should be offered to all patients even with good growth velocity after CF treatment, to avoid dislypidemia and reduce cardiovascular risk. The optimal therapy is not completely understood and whether gross tumor removal or partial surgery is the best option remains to be decided only on one patient tumour features and hypothalamic involvement. In conclusion the gold standard treatment of CF remains complete tumour removal, when feasible, or partial resection to preserve hypothalamic function in endosuprasellar large neoplasms.

Efecto del consumo concomitante de inhibidores de bomba protones y levotiroxina : revisión sistemática y metaanálisis

Estudios afirman que la acidez gástrica es importante en la absorción de levotiroxina (LT4) con resultados controversiales sobre la interacción entre inhibidores de bomba de protones (IBP) y LT4. El objetivo del estudio fue establecer el efecto del uso concomitante de LT4 e IBP en los niveles de TSH en pacientes adultos con hipotiroidismo primario. Se realizó una revisión sistemática mediante búsqueda en Medline, Embase, Lilacs, Bireme, Scielo, Cochrane y Universidad de York, Access Pharmacy, Google Scholar, Dialnet y Opengray. La búsqueda no se limito por lenguaje. Se evaluó el efecto en la diferencia de medias de TSH luego del consumo de LT4 y luego del consumo concomitante con IBP. Se hizo un metaanálisis, análisis de subgrupos y análisis de sensibilidad utilizando el programa Review Manager 5.3. Se eligieron 5 artículos para el análisis cualitativo y 3 para el metaanálisis. La calidad de los estudios fue buena y el riesgo de sesgos bajo. La diferencia de medias obtenida fue 0.21 mUI/L (IC95%: 0.02-0.40; p=0.03; I2:0%). En el análisis de subgrupos en pacientes mayores de 55 años la diferencia de medias fue 0.21 mUI/L (IC95%: 0.01-0.40; p=0.27; I2:19%). En el análisis de sensibilidad se excluyo el estudio con mayor muestra y la diferencia de medias fue 0.49 mUI/L (IC95%: -0.12 a 1.11; p=0.12; I2:0%). La diferencia de medias de TSH luego del consumo concomitante no se considera clínicamente significativa pues no representa riesgo para el paciente. Son necesarios estudios clínicos aleatorizados y evaluar el efecto en los niveles de T4 libre.

The role of catechol-O-methyltransferase (COMT) and the effects of COMT inhibition in brain and in cardiovascular and renal pathophysiology

Catechol-O-methyltransferase (COMT) metabolizes catecholamines such as dopamine (DA), noradrenaline (NA) and adrenaline, which are vital neurotransmitters and hormones that play important roles in the regulation of physiological processes. COMT enzyme has a functional Val158Met polymorphism in humans, which affects the subjects COMT activity. Increasing evidence suggests that this functional polymorphism may play a role in the etiology of various diseases from schizophrenia to cancers. The aim of this project was to provide novel biochemical information on the physiological and especially pathophysiological roles of COMT enzyme as well as the effects of COMT inhibition in the brain and in the cardiovascular and renal system. To assess the roles of COMT and COMT inhibition in pathophysiology, we used four different study designs. The possible beneficial effects of COMT inhibition were studied in double-transgenic rats (dTGRs) harbouring human angiotensinogen and renin genes. Due to angiotensin II (Ang II) overexpression, these animals exhibit severe hypetension, cardiovascular and renal end-organ damage and mortality of approximately 25-40% at the age of 7-weeks. The dTGRs and their Sprague-Dawley controls tissue samples were assessed with light microscopy, immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and high-pressure liquid chromatography (HPLC) to evaluate the tissue damages and the possible protective effects pharmacological intervention with COMT inhibitors. In a second study, the consequence of genetic and pharmacological COMT blockade in blood pressure regulation during normal and high-sodium was elucidated using COMT-deficient mice. The blood pressure and the heart rate were measured using direct radiotelemetric blood pressure surveillance. In a third study, the effects of acute and subchronic COMT inhibition during combined levodopa (L-DOPA) + dopa decarboxylase inhibitor treatment in homocysteine formation was evaluated. Finally, we assessed the COMT enzyme expression, activity and cellular localization in the CNS during inflammation-induced neurodegeneration using Western blotting, HPLC and various enzymatic assays. The effects of pharmacological COMT inhibition on neurodegeneration were also studied. The COMT inhibitor entacapone protected against the Ang II-induced perivascular inflammation, renal damage and cardiovascular mortality in dTGRs. COMT inhibitors reduced the albuminuria by 85% and prevented the cardiovascular mortality completely. Entacapone treatment was shown to ameliorate oxidative stress and inflammation. Furthermore, we established that the genetic and pharmacological COMT enzyme blockade protects against the blood pressure-elevating effects of high sodium intake in mice. These effects were mediated via enhanced renal dopaminergic tone and suggest an important role of COMT enzyme, especially in salt-sensitive hypertension. Entacapone also ameliorated the L-DOPA-induced hyperhomocysteinemia in rats. This is important, since decreased homocysteine levels may decrease the risk of cardiovascular diseases in Parkinson´s disease (PD) patients using L-DOPA. The Lipopolysaccharide (LPS)-induced inflammation and subsequent delayed dopaminergic neurodegeneration were accompanied by up-regulation of COMT expression and activity in microglial cells as well as in perivascular cells. Interestingly, similar perivascular up-regulation of COMT expression in inflamed renal tissue was previously noted in dTGRs. These results suggest that inflammation reactions may up-regulate COMT expression. Furthermore, this increased glial and perivascular COMT activity in the central nervous system (CNS) may decrease the bioavailability of L-DOPA and be related to the motor fluctuation noted during L-DOPA therapy in PD patients.

Halogen Bonding Controls the Regioselectivity of the Deiodination of Thyroid Hormones and their Sulfate Analogues

The type1 iodothyronine deiodinase (1D-1) in liver and kidney converts the L-thyroxine (T4), a prohormone, by outer-ring (5) deiodination to biologically active 3,3,5-triiodothyronine (T3) or by inner-ring (5) deiodination to inactive 3,3,5-triiodothronine (rT3). Sulfate conjugation is an important step in the irreversible inactivation of thyroid hormones. While sulfate conjugation of the phenolic hydroxyl group stimulates the 5-deiodination of T4 and T3, it blocks the 5-deiodination of T4. We show that thyroxine sulfate (T4S) undergoes faster deiodination as compared to the parent thyroid hormone T4 by synthetic selenium compounds. It is also shown that ID-3 mimics, which are remarkably selective to the inner-ring deiodination of T4 and T3, changes the selectivity completely when T4S is used as a substrate. From the theoretical investigations, it is observed that the strength of halogen bonding increases upon sulfate conjugation, which leads to a change in the regioselectivity of ID-3 mimics towards the deiodination of T4S. It has been shown that these mimics perform both the 5- and 5-ring deiodinations by an identical mechanism.

Estudio Costo-Efectividad de Lidocaína tópica como adyuvante a Pregabalina y Gabapentina en dolor neuropático periférico en una I.P.S de Bogotá 2011.

Introducción: el dolor neuropático es una patología de considerable prevalencia e impacto socio-económico en la población latinoamericana, la evidencia clínica sugiere que los ligandos de canales de calcio y el parche de Lidocaína pueden tratar exitosamente el dolor neuropático periférico y localizado. Metodología: se realizo una evaluación económica tipo costo-efectividad, observacional y retrospectiva con datos extraídos de las historias clínicas de pacientes atendidos en la clínica de dolor de la IPS. La variable primaria de efectividad fue la mejoría del dolor medida mediante escala visual análoga. Resultados: se estudiaron 94 pacientes tratados con: Gabapentina (G) 21, Pregabalina (P) 24, Gabapentina+ lidocaína (G/P) 24, Pregabalina + Lidocaína (P/L) 25, los costos asociados al tratamiento son los siguientes COP$114.070.835, COP$105.855.920, COP$88.717.481 COP$89.854.712 respectivamente, el número de pacientes con mejoría significativa de dolor fue: 8,10,9 y 21 pacientes respectivamente. El ICER de G/L con respecto a G fue: COP$ -25.353.354. El ICER de P/L con respecto a P fue: COP$ -1.454.655. Conclusiones: la adición del parche de lidocaína a la terapia regular con P/L represento una disminución de consumo de recursos en salud como uso de medicamentos co-analgésicos, analgésicos de rescate y fármacos para controlar reacciones adversas, de la misma forma que consultas a profesionales de la salud. Cada paciente manejado con P/L representa un ahorro de COP $1.454.655 al contrario si se manejase con el anticonvulsivante de manera exclusiva, en el caso de G/L este ahorro es de COP $ 25.353.354 frente a G sola.

Thyroid hormones alter the adenine nucleotide hydrolysis in adult rat blood serum

The effects of ATP, ADP, and adenosine in the processes of platelet aggregation, vasodilatation, and coronary flow have been known for many years. The sequential hydrolysis of ATP to adenosine by soluble nucleotidases constitutes the main system for rapid inactivation of circulating adenine nucleotides. Thyroid disorders affect a number of biological factors including adenosine levels in different fractions. Then, we intend to investigate if the soluble nucleotidases responsible for the ATP, ADP, and AMP hydrolysis are affected by variations in the thyroid hormone levels in blood serum from adult rats. Hyperthyroidism was induced by daily intraperitoneal injections of L-thyroxine (T4) (2.5 and 10.0 mu g/100 g body weight, respectively) for 7 or 14 days. Hypothyroidism was induced by thyroidectomy and methimazole (0.05%) added to their drinking water during 7 or 14 days. The treatments efficacy was confirmed by determination of hemodynamic parameters and cardiac hypertrophy evaluation. T4 treatment predominantly inhibited, and hypothyroidism (14 days after thyroidectomy) predominantly increased the ATP, ADP, and AMP hydrolysis in rat blood serum. These results suggest that both excess and deficiency of thyroid hormones can modulate the ATP diphosphohydrolase and 5`-nucleotidase activities in rat blood serum and consequently modulate the effects mediated by these enzymes and their products in vascular system. (C) 2010 International Union of Biochemistry and Molecular Biology, Inc.