Chronic intermittent hypoxia and acetaminophen induce synergistic liver injury in mice

Obstructive sleep apnoea (OSA) leads to chronic intermittent hypoxia (CIH) during sleep. Obstructive sleep apnoea has been associated with liver injury. Acetaminophen (APAP; known as paracetamol outside the USA) is one of the most commonly used drugs which has known hepatotoxicity. The goal of the present study was to examine whether CIH increases liver injury, hepatic oxidative stress and inflammation induced by chronic APAP treatment. Adult C57BL/6J mice were exposed to CIH or intermittent air (IA) for 4 weeks. Mice in both groups were treated with intraperitoneal injections of either APAP (200 mg kg⁻¹) or normal saline daily. A combination of CIH and APAP caused liver injury, with marked increases in serum alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyl transferase and total bilirubin levels, whereas CIH alone induced only elevation in serum AST levels. Acetaminophen alone did not affect serum levels of liver enzymes. Histopathology revealed hepatic necrosis and increased apoptosis in mice exposed to CIH and APAP, whereas the liver remained intact in all other groups. Mice exposed to CIH and APAP exhibited decreased hepatic glutathione in conjunction with a fivefold increase in nitrotyrosine levels, suggesting formation of toxic peroxynitrite in hepatocytes. Acetaminophen or CIH alone had no effect on either glutathione or nitrotyrosine. A combination of CIH and APAP caused marked increases in pro-inflammatory chemokines, monocyte chemoattractant protein-1 and macrophage inflammatory protein-2, which were not observed in mice exposed to CIH or APAP alone. We conclude that CIH and chronic APAP treatment lead to synergistic liver injury, which may have clinical implications for patients with OSA.     

Body packers: a plea for conservative treatment

Background  

The incidence of smuggling and transporting of illegal drugs by internal concealment, also known as body packing, is increasing in the Western world. The objective of this study was to determine the outcome of conservative and surgical approaches in body packers.     

Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka

Chronic kidney disease of uncertain etiology (CKDu) in North Central Province of Sri Lanka has become a key public health concern in the agricultural sector due to the dramatic rise in its prevalence and mortality among young farmers. Although cadmium has been suspected as a causative pathogen, there have been controversies. To date, the pathological characteristics of the disease have not been reported. Histopathological observations of 64 renal biopsies obtained at Anuradhapura General Hospital from October 2008 to July 2009 were scored according to Banff 97 Working Classification of Renal Allograft pathology. The correlations between the histological observations and clinical parameters were statistically analyzed. Interstitial fibrosis and tubular atrophy with or without nonspecific interstitial mononuclear cell infiltration was the dominant histopathological observation. Glomerular sclerosis, glomerular collapse, and features of vascular pathology such as fibrous intimal thickening and arteriolar hyalinosis were also common. Although hypertension was identified as one of the common clinical features among the cases, it did not influence the histopathological lesions in all the cases. This study concludes that tubulointerstitial damage is the major pathological lesion in CKDu. Exposure(s) to an environmental pathogen(s) should be systematically investigated to elucidate such tubulointerstitial damage in CKDu.     

Homocysteine and blood pressure

Several studies, some population-based, have linked plasma homocysteine levels to blood pressure, especially systolic pressure. The strength of this association is weak, but may be underestimated due to inaccurate blood pressure measurements. In addition, the association may be confounded by renal function. Observations that homocysteine-lowering therapies with folic acid-based treatments have been followed by decreases in blood pressure, however, raise the possibility that the link between homocysteine and blood pressure is real, which is important as homocysteine levels can easily be lowered by folic acid-based regimens. Mechanisms that could explain the relationship between homocysteine and blood pressure include increased arterial stiffness, endothelial dysfunction with decreased availability of nitric oxide, low folate status, and insulin resistance. So far, however, no evidence has been provided that these mechanisms are operative in humans. Ongoing large intervention studies with homocysteine-lowering vitamins may indicate whether blood pressure is indeed lowered by these vitamins, whether the blood pressure decrease, if any, is explained by the decrease in homocysteine levels, and whether a vitamin treatment-associated decrease in cardiovascular morbidity (if any) is explained by the decrease in blood pressure.     

Pharmacokinetics and Pharmacodynamics of (+)-Primaquine and (?)-Primaquine Enantiomers in Rhesus Macaques (Macaca mulatta)

Primaquine (PQ) remains the sole available drug to prevent relapse of Plasmodium vivax malaria more than 60 years after licensure. While this drug was administered as a racemic mixture, prior studies suggested a pharmacodynamic advantage based on differential antirelapse activity and/or toxicities of its enantiomers. Oral primaquine enantiomers prepared using a novel, easily scalable method were given for 7 days to healthy rhesus macaques in a dose-rising fashion to evaluate their effects on the blood, liver, and kidneys. The enantiomers were then administered to Plasmodium cynomolgi-infected rhesus macaques at doses of 1.3 and 0.6 mg/kg of body weight/day in combination with chloroquine. The (−)-PQ enantiomer had higher clearance and apparent volume of distribution than did (+)-PQ and was more extensively converted to the carboxy metabolite. There is evidence for differential oxidative stress with a concentration-dependent rise in methemoglobin (MetHgb) with increasing doses of (+)-PQ greater than that seen for (−)-PQ. There was a marked, reversible hepatotoxicity in 2 of 3 animals dosed with (−)-PQ at 4.5 mg/kg. (−)-PQ in combination with chloroquine was successful in preventing P. cynomolgi disease relapse at doses of 0.6 and 1.3 mg/kg/day, while 1 of 2 animals receiving (+)-PQ at 0.6 mg/kg/day relapsed. While (−)-PQ was also associated with hepatotoxicity at higher doses as seen previously, this has not been identified as a clinical concern in humans during >60 years of use. Limited evidence for increased MetHgb generation with the (+) form in the rhesus macaque model suggests that it may be possible to improve the therapeutic window for hematologic toxicity in the clinic by separating primaquine into its enantiomers.     

Sandifer Syndrome an Overlooked Diagnosis?

Three retarded children are described who had marked irritability and abnormal movements of the body and contortions of the neck. These movements were diagnosed as epilepsy and the children were treated with numerous anticonvulsants, without success. Subsequently severe gastro-oesophageal reflux was diagnosed, and treatment of the reflux completely eliminated the abnormal movements. Sandifer syndrome was diagnosed, consisting of abnormal body-movements and contortions of the neck, associated with gastro-oesophageal reflux. Suggestions are made to enable early diagnosis of this syndrome.     

The effect of unsaturated fatty acids in benzyl alcohol on the percutaneous permeation of three model penetrants

The model penetrants butyl paraben (BP), methyl paraben (MP) and caffeine (CF), because of their different octanol/water partition coefficients and postulated routes of permeation through human skin, were selected to assess the enhancing activity of pre-treatment solutions consisting of monounsaturated (oleic (OA) and palmitoleic (PA)) and poly-unsaturated (linoleic (LA)) fatty acids in benzyl alcohol (BA) using Franz diffusion cells and HPLC detection. Prior to assessing the effect of penetrant lipophilicity, MP was chosen to investigate the concentration-dependent effect of fatty acids in pre-treatment solutions. At 5% (w/w) fatty acids in BA, only pre-treatment solutions containing palmitoleic acid (PA) increased the permeation of MP when compared to pre-treatment with BA alone, whereas at higher concentrations (10 and 20%, w/w), all pre-treatment solutions except 10% OA produced a significant increase in MP flux (P<0.05). The general order of fatty acid effectiveness at any concentration was PA>LA>OA. At 20% (w/w) fatty acids in BA, all pre-treatment solutions significantly enhanced the permeation of all three penetrants (P<0.05) and an inverse relationship between penetrant lipophilicity and enhancement effect was observed. The permeation of BP was enhanced to a similar extent by all three fatty acids, whereas PA caused a significantly greater enhancement in the flux of both MP and CF when compared to OA, LA and controls (P<0.05). It was proposed that the synergetic enhancement mechanisms of fatty acids and BA in pre-treatment solutions were augmenting the polar route by way of interactions with both polar and non-polar regions of stratum corneum lipids. Furthermore, the combination of PA and BA appears to be a good candidate as a penetration enhancer for hydrophilic molecules.