Chemotherapy and Anticancer Drugs Adjustment in Obesity: A Narrative Review.

BACKGROUND: Obese individuals have higher rates of cancer incidence and cancer- related mortality. The worse chemotherapy outcomes observed in this subset of patients are multifactorial, including the altered physiology in obesity and its impact on pharmacokinetics, the possible increased risk of underdosing, and treatment-related toxicity. AIMS: The present review aimed to discuss recent data on physiology, providing just an overall perspective and pharmacokinetic alterations in obesity concerning chemotherapy. We also reviewed the controversies of dosing adjustment strategies in adult and pediatric patients, mainly addressing the use of actual total body weight and ideal body weight. METHODS: This narrative review tried to provide the best evidence to support antineoplastic drug dosing strategies in children, adolescents, and adults. RESULTS: Cardiovascular, hepatic, and renal alterations of obesity can affect the distribution, metabolism, and clearance of drugs. Anticancer drugs have a narrow therapeutic range, and variations in dosing may result in either toxicity or underdosing. Obese patients are underrepresented in clinical trials that focus on determining recommendations for chemotherapy dosing and administration in clinical practice. After considering associated comorbidities, the guidelines recommend that chemotherapy should be dosed according to body surface area (BSA) calculated with actual total body weight, not an estimate or ideal weight, especially when the intention of therapy is the cure. CONCLUSION: The actual total body weight dosing appears to be a better approach to dosing anticancer drugs in both adults and children when aiming for curative results, showing no difference in toxicity and no limitation in treatment outcomes compared to adjusted doses.

Potential Role of Adult Hippocampal Neurogenesis in Traumatic Brain Injury.

Traumatic brain injury (TBI) is a serious cause of disability and death among young and adult individuals, displaying complex pathophysiology including cellular and molecular mechanisms that are not fully elucidated. Many experimental and clinical studies investigated the potential relationship between TBI and the process by which neurons are formed in the brain, known as neurogenesis. Currently, there are no available treatments for TBI's long-term consequences being the search for novel therapeutic targets, a goal of highest scientific and clinical priority. Some studies evaluated the benefits of treatments aimed at improving neurogenesis in TBI. In this scenario, herein, we reviewed current pre-clinical studies that evaluated different approaches to improving neurogenesis after TBI while achieving better cognitive outcomes, which may consist in interesting approaches for future treatments.

Traumatic brain injury biomarkers in pediatric patients: a systematic review.

Traumatic brain injury (TBI) is the main cause of pediatric trauma death and disability worldwide. Recent studies have sought to identify biomarkers of TBI for the purpose of assessing functional outcomes. The aim of this systematic review was to evaluate the utility of TBI biomarkers in the pediatric population by summarizing recent findings in the medical literature. A total of 303 articles were retrieved from our search. An initial screening to remove duplicate studies yielded 162 articles. After excluding all articles that did not meet the inclusion criteria, 56 studies were gathered. Among the 56 studies, 36 analyzed serum biomarkers; 11, neuroimaging biomarkers; and 9, cerebrospinal fluid (CSF) biomarkers. Most studies assessed biomarkers in the serum, reflecting the feasibility of obtaining blood samples compared to obtaining CSF or performing neuroimaging. S100B was the most studied serum biomarker in TBI, followed by SNE and UCH-L1, whereas in CSF analysis, there was no unanimity. Among the different neuroimaging techniques employed, diffusion tensor imaging (DTI) was the most common, seemingly holding diagnostic power in the pediatric TBI clinical setting. The number of cross-sectional studies was similar to the number of longitudinal studies. Our data suggest that S100B measurement has high sensitivity and great promise in diagnosing pediatric TBI, ideally when associated with head CT examination and clinical decision protocols. Further large-scale longitudinal studies addressing TBI biomarkers in children are required to establish more accurate diagnostic protocols and prognostic tools.

Renal sympathetic denervation for resistant hypertension: where do we stand after more than a decade / Denervação simpática renal para hipertensão resistente: situação depois de mais de uma década

Abstract Despite the current availability of safe and efficient drugs for treating hypertension, a substantial number of patients are drug-resistant hypertensives. Aiming this condition, a relatively new approach named catheter-based renal denervation was developed. We have now a clinically relevant time window to review the efficacy of renal denervation for treating this form of hypertension. This short review addresses the physiological contribution of renal sympathetic nerves for blood pressure control and discusses the pros and cons of renal denervation procedure for the treatment of resistant hypertension.

Resumo Em que pese a atual disponibilidade de medicamentos seguros e eficientes para o tratamento da hipertensão, um número significativo de pacientes sofre de hipertensão arterial resistente a tratamento medicamentoso. Em vista dessa condição, foi desenvolvida uma abordagem relativamente nova, denominada denervação renal por cateter. Dispomos atualmente de uma janela de tempo clinicamente relevante para analisar a eficácia da denervação renal no tratamento dessa modalidade de hipertensão. A presente revisão aborda a contribuição fisiológica dos nervos renais simpáticos no controle da pressão arterial e discute os prós e contras do procedimento de denervação renal no tratamento da hipertensão resistente.

Renal sympathetic denervation for resistant hypertension: where do we stand after more than a decade.

Despite the current availability of safe and efficient drugs for treating hypertension, a substantial number of patients are drug-resistant hypertensives. Aiming this condition, a relatively new approach named catheter-based renal denervation was developed. We have now a clinically relevant time window to review the efficacy of renal denervation for treating this form of hypertension. This short review addresses the physiological contribution of renal sympathetic nerves for blood pressure control and discusses the pros and cons of renal denervation procedure for the treatment of resistant hypertension.

The Renin-Angiotensin System and the Cerebrovascular Diseases: Experimental and Clinical Evidence.

Cerebrovascular Diseases (CVD) comprise a wide spectrum of disorders, all sharing an acquired or inherited alteration of the cerebral vasculature. CVD have been associated with important changes in systemic and tissue Renin-Angiotensin System (RAS). The aim of this review was to summarize and to discuss recent findings related to the modulation of RAS components in CVD. The role of RAS axes is more extensively studied in experimentally induced stroke. By means of AT1 receptors in the brain, Ang II hampers cerebral blood flow and causes tissue ischemia, inflammation, oxidative stress, cell damage and apoptosis. On the other hand, Ang-(1-7) by stimulating Mas receptor promotes angiogenesis in brain tissue, decreases oxidative stress, neuroinflammation, and improves cognition, cerebral blood flow, neuronal survival, learning and memory. In regard to clinical studies, treatment with Angiotensin Converting Enzyme (ACE) inhibitors and AT1 receptor antagonists exerts preventive and therapeutic effects on stroke. Besides stroke, studies support a similar role of RAS molecules also in traumatic brain injury and cerebral aneurysm. The literature supports a beneficial role for the alternative RAS axis in CVD. Further studies are necessary to investigate the therapeutic potential of ACE2 activators and/or Mas receptor agonists in patients with CVD.

Renin angiotensin system molecules and nitric oxide local interactions in the adrenal gland of Trypanosoma cruzi infected rats.

Chagas disease (CD) is a tropical zoonosis caused by the protozoan Trypanosoma cruzi. Severe autonomic dysfunction like reduced cardiac catecholamine-containing or acetylcholinesterase-positive innervation have been reported in CD. Renin-angiotensin system (RAS) seems to participate in the regulation of adrenal catecholamine secretion by adrenal medullary chromaffin cells, which might be dependent of nitric oxide (NO) pathways. To investigate the levels of RAS components in the adrenal gland during the acute infection with Y strain T. cruzi and in response to acute administration of an inhibitor of the enzyme NO synthase, L-NAME. Male Holtzman rats were inoculated intraperitoneally with Y strain T. cruzi and received L-NAME or tap water from one day before the infection until 13 or 17 days post-inoculation (dpi). The concentration of RAS molecules in the adrenal tissue was evaluated by ELISA immunoassay. Angiotensin converting enzyme 1 (ACE1) levels were significantly lower at 17 dpi when compared to 13 dpi. No significant differences were found compared with baseline, and no changes were detected in adrenal tissue levels of angiotensin converting enzyme 2 (ACE2), angiotensin II, or angiotensin-(1-7). Moreover, the treatment with L-NAME did not influence the levels of RAS components in adrenal tissue during the course of T. cruzi infection. We provided the first evidence that levels of RAS molecules change in the adrenal gland during acute phase of T. cruzi infection. Future studies are necessary to fully address the role of NO in RAS-associated adrenal gland function in CD.

Effect of blockade of nitric oxide in heart tissue levels of Renin Angiotensin System components in acute experimental Chagas disease.

Chagas disease (CD) is an important cause of cardiomyopathy in South America. The pathophysiology of CD is still a matter of debate. Renin Angiotensin System (RAS) components are clearly involved in cardiovascular diseases. RAS molecules interact with nitric oxide (NO) pathway in blood vessel and heart tissue. Thus, the aim of this study is to investigate possible changes in RAS molecules during the infection with Y strain T. cruzi and in response to acute administration of an inhibitor of the enzyme NO synthase, l-NAME. Male Holtzman rats were inoculated intraperitoneally with Y strain T. cruzi and received l-NAME or tap water from one day before the infection until 13 or 17 days post infection (dpi). Angiotensin converting enzyme 1 (ACE1) levels were significantly higher at day 17 when compared to baseline in atrium, whereas, in ventricle, ACE2 levels were significantly higher in 13 dpi when compared to baseline. In response to l-NAME treatment, atrium tissue levels of ACE1 were significantly reduced in treated animals at day 17, while Angiotensin-(1-7) concentration in atrium significantly increased in this group at the same time-point. No changes were detected in RAS components in the ventricle. ACE2 levels in Soleus muscle were significantly reduced in treated animals at day 13. In conclusion, changes in RAS molecules were detected during acute phase of T. cruzi infection and the inhibition of NO synthesis clearly interfered with expression of ACE1 and Angiotensin-(1-7) in the atrium.