The pharmacogenetics of NAT2 enzyme maturation in perinatally HIV exposed infants receiving isoniazid

The roles of the NAT2 genotype and enzyme maturation on isoniazid pharmacokinetics were investigated in South African infants with perinatal HIV exposure enrolled in a randomized, double-blind, controlled trial of isoniazid for prevention of tuberculosis disease and latent infection. Plasma concentration-time measurements of isoniazid from 151 infants (starting at 3-4 months of age) receiving isoniazid 10 to 20 mg/kg/d orally during the course of the 24-month study were incorporated in a population analysis along with NAT2 genotype, body weight, age, and sex. The results showed a different NAT2 enzyme maturation profile for each of the 3 acetylation groups, with the 70-kg body weight-normalized typical apparent clearance for the fast and intermediate acetylators increasing from 14.25 L/h and 10.88 L/h at 3 months of age to 22.84 L/h and 15.58 L/h at 24 months of age, respectively, with no significant change in the apparent clearance of the slow group during this period. A hypothesis is proposed to explain the genotype-dependent enzyme maturation processes for the NAT2 enzyme.     

The Role of Gap Junction Channels During Physiologic and Pathologic Conditions of the Human Central Nervous System

Gap junctions (GJs) are expressed in most cell types of the nervous system, including neuronal stem cells, neurons, astrocytes, oligodendrocytes, cells of the blood brain barrier (endothelial cells and astrocytes) and under inflammatory conditions in microglia/macrophages. GJs connect cells by the docking of two hemichannels, one from each cell with each hemichannel being formed by 6 proteins named connexins (Cx). Unapposed hemichannels (uHC) also can be open on the surface of the cells allowing the release of different intracellular factors to the extracellular space. GJs provide a mechanism of cell-to-cell communication between adjacent cells that enables the direct exchange of intracellular messengers, such as calcium, nucleotides, IP(3), and diverse metabolites, as well as electrical signals that ultimately coordinate tissue homeostasis, proliferation, differentiation, metabolism, cell survival and death. Despite their essential functions in physiological conditions, relatively little is known about the role of GJs and uHC in human diseases, especially within the nervous system. The focus of this review is to summarize recent findings related to the role of GJs and uHC in physiologic and pathologic conditions of the central nervous system.     

Targeting cardiac natriuretic peptides in the therapy of diabetes and obesity

Introduction: Atrial and B-type Natriuretic Peptides (NP) are cardiac hormones with potent cardiovascular and metabolic effects. They signal through the NPRA/cGMP system and are inactivated by a clearance receptor NPRC and neutral endopeptidases (NEP). Recombinant ANP and BNP are currently used as drug treatment for acute decompensated congestive heart failure. Recent literature indicate that a defective NP system is linked to obesity and predict the risk of type 2 diabetes (T2D).

Areas covered: This article reviews recent epidemiological, clinical and preclinical evidences that NP system deficiency may be causal of obesity and T2D. The molecular mechanisms of the NP pathway in several metabolic target tissues are presented. The therapeutic potential of NP in obesity and T2D is discussed.

Expert opinion: Targeting the NP pathway may offer a novel therapeutic avenue for the management of obesity and T2D. The benefit/risk of drugs increasing circulating NP levels by blocking NPRC and NEP, and/or enhancing NPRA signaling should be assessed in obese and type 2 diabetic individuals.     

Diazine indole acetic acids as potent, selective, and orally bioavailable antagonists of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) for the treatment of allergic inflammatory diseases

New classes of CRTH2 antagonists, the pyridazine linker containing indole acetic acids, are described. The initial hit 1 had good potency but poor permeability, metabolic stability, and PK. Initial optimization led to compounds of type 2 with low oxidative metabolism but poor oral bioavailability. Poor permeability was identified as a liability for these compounds. Addition of a linker between the indole and diazine moieties afforded a series with good potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. 32 was identified as the development track candidate. It was potent in cell based, binding, and whole blood assays and exhibited good PK profile. It was efficacious in mouse models of contact hypersensitivity (1 mg/kg b.i.d.) and house dust (20 mg/kg q.d.) when dosed orally. In sheep asthma, administration at 1 mg/kg iv completely blocked the LAR and AHR and attenuated the EAR phase.     

Iron Overload Exacerbates Busulfan-Melphalan Toxicity Through a Pharmacodynamic Interaction in Mice

Purpose

Busulfan-melphalan high-dose chemotherapy followed by autologous stem cell transplantation is an essential consolidation treatment of high-risk neuroblastoma in children. Main treatment limitation is hepatic veno-occlusive disease, the most severe and frequent extra-hematological toxicity. This life threatening toxicity has been related to a drug interaction between busulfan and melphalan which might be increased by prior disturbance of iron homeostasis, i.e. an increased plasma ferritin level.

Methods

We performed an experimental study of busulfan and melphalan pharmacodynamic and pharmacokinetics in iron overloaded mice.

Results

Iron excess dramatically increased the toxicity of melphalan or busulfan melphalan combination in mice but it did not modify the clearance of either busulfan or melphalan. We show that prior busulfan treatment impairs the clearance of melphalan. This clearance alteration was exacerbated in iron overloaded mice demonstrating a pharmacokinetic interaction. Additionally, iron overload increased melphalan toxicity without altering its pharmacokinetics, suggesting a pharmacodynamic interaction between iron and melphalan. Based on iron homeostasis disturbance, we postulated that prior induction of ferritin, through Nrf2 activation after oxidative stress, may be associated with the alteration of melphalan metabolism.

Conclusion

Iron overload increases melphalan and busulfan-melphalan toxicity through a pharmacodynamic interaction and reveals a pharmacokinetic drug interaction between busulfan and melphalan.

     

Is ultraviolet B irradiance inversely associated with incidence rates of endometrial cancer: an ecological study of 107 countries

OBJECTIVE: The purpose of this study was to perform an ecological analysis of the relationship between low levels of ultraviolet B (UVB) irradiance and age-standardized incidence rates of endometrial cancer by country, controlling for known confounders. METHODS: The contributions of UVB irradiance, cloud cover, intake of energy from animal sources, proportion of population overweight, skin pigmentation, per capita cigarette consumption, per capita health expenditure, and total fertility rates, to age-standardized incidence rates of endometrial cancer in 107 countries were assessed using multiple regression. RESULTS: Incidence rates were higher at higher latitudes (R2=0.47, p<0.01). According to multiple regression, UVB irradiance adjusted for cloud cover was negatively associated with incidence rates (p=0.02), while proportion of population overweight (p=0.004), intake of energy from animal sources (p=0.01) and per capita health expenditure (p<0.0001) were positively associated with incidence rates (overall R2=0.73, p<0.0001). CONCLUSION: An association was found between low UVB irradiance, high intake of energy from animal sources, per capita health expenditure, proportion of population overweight, and incidence rates.     

Study of the plethysmographic amplification factor during vasodilator treatment. Healthy subject versus primary Raynaud phenomenon

Digital arterial circulation before and after administration of a vasodilator orally was explored by mercury gauge pulsed plethysmography and photoplethysmography in 12 patients with primary Raynaud's phenomenon and results compared with those of 10 healthy volunteers. The amplification factor F, ratio of amplitude in reactive hyperemia over amplitude at rest was determined in the index before and after 8 mg daily of dihydroergokryptine over 4 weeks. Before treatment, for each of the two plethysmographic technics, a significant increase in mean factor F values was noted in the patients with Raynaud's phenomenon when compared with healthy controls. This is due to a decline in digital arterial flow at rest. Using the mercury gauge plethysmograph, a significant reduction in factor F was observed after vasodilator treatment corresponding to an increase in digital flow at rest without increase in flow during hyperemia. Using photoplethysmography, no significant variation in factor F was noted after treatment. Mercury gauge plethysmography, which measures global digital blood flow appears to be a more sensitive method than photoplethysmography, which measures dermal and hypodermal blood flow, for follow-up of effects of vasodilator treatment on Raynaud's phenomenon.