Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia

BACKGROUND: Hypophosphatasia (HP) is an inborn error of bone metabolism characterized by a genetic defect in the gene encoding the tissue-nonspecific alkaline phosphatase (TNSALP). There is a lack of knowledge as to how the variability and clinical severity of the HP phenotype (especially pain and walking impairment) are related to metabolic disturbances or impairments, subsequent to the molecular defect. METHODS: We analyzed the changes in clinical symptoms and the prostaglandin (PG) metabolism in response to treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in six children affected by childhood HP. In addition, by exposing HP fibroblasts to pyridoxal phosphate and/or calcium pyrophosphate in vitro, we analyzed whether the alterations in PG levels are sequelae related to the metabolic defect. RESULTS: Childhood HP patients, who often complain about pain in the lower limbs without evident fractures, have systemic hyperprostaglandinism. Symptomatic anti-inflammatory treatment with NSAIDs significantly improved pain-associated physical impairment. Calcium pyrophosphate, but not pyridoxal phosphate, induced cyclooxygenase-2 (COX-2) gene expression and PG production in HP and normal fibroblasts in vitro. CONCLUSION: Clinical features of childhood HP related to pain in the lower legs may be, at least in part, sequelae related to elevated PG levels, secondary to the primary metabolic defect. Consequently, NSAID treatment does improve the clinical features of childhood HP

Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects

Salt-losing tubulopathies with secondary hyperaldosteronism (SLT) comprise a set of well-defined inherited tubular disorders. Two segments along the distal nephron are primarily involved in the pathogenesis of SLTs: the thick ascending limb of Henle’s loop, and the distal convoluted tubule (DCT). The functions of these pre- and postmacula densa segments are quite distinct, and this has a major impact on the clinical presentation of loop and DCT disorders – the Bartter- and Gitelman-like syndromes. Defects in the water-impermeable thick ascending limb, with its greater salt reabsorption capacity, lead to major salt and water losses similar to the effect of loop diuretics. In contrast, defects in the DCT, with its minor capacity of salt reabsorption and its crucial role in fine-tuning of urinary calcium and magnesium excretion, provoke more chronic solute imbalances similar to the effects of chronic treatment with thiazides. The most severe disorder is a combination of a loop and DCT disorder similar to the enhanced diuretic effect of a co-medication of loop diuretics with thiazides. Besides salt and water supplementation, prostaglandin E2-synthase inhibition is the most effective therapeutic option in polyuric loop disorders (e.g., pure furosemide and mixed furosemide–amiloride type), especially in preterm infants with severe volume depletion. In DCT disorders (e.g., pure thiazide and mixed thiazide–furosemide type), renin–angiotensin–aldosterone system (RAAS) blockers might be indicated after salt, potassium, and magnesium supplementation are deemed insufficient. It appears that in most patients with SLT, a combination of solute supplementation with some drug treatment (e.g., indomethacin) is needed for a lifetime

Improved Mitochondrial Function with Diet-Induced Increase in Either Docosahexaenoic Acid or Arachidonic Acid in Membrane Phospholipids

Mitochondria can depolarize and trigger cell death through the opening of the mitochondrial permeability transition pore (MPTP). We recently showed that an increase in the long chain n3 polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA; 22:6n3) and depletion of the n6 PUFA arachidonic acid (ARA; 20:4n6) in mitochondrial membranes is associated with a greater Ca2+ load required to induce MPTP opening. Here we manipulated mitochondrial phospholipid composition by supplementing the diet with DHA, ARA or combined DHA+ARA in rats for 10 weeks. There were no effects on cardiac function, or respiration of isolated mitochondria. Analysis of mitochondrial phospholipids showed DHA supplementation increased DHA and displaced ARA in mitochondrial membranes, while supplementation with ARA or DHA+ARA increased ARA and depleted linoleic acid (18:2n6). Phospholipid analysis revealed a similar pattern, particularly in cardiolipin. Tetralinoleoyl cardiolipin was depleted by 80% with ARA or DHA+ARA supplementation, with linoleic acid side chains replaced by ARA. Both the DHA and ARA groups had delayed Ca2+-induced MPTP opening, but the DHA+ARA group was similar to the control diet. In conclusion, alterations in mitochondria membrane phospholipid fatty acid composition caused by dietary DHA or ARA was associated with a greater cumulative Ca2+ load required to induced MPTP opening. Further, high levels of tetralinoleoyl cardiolipin were not essential for normal mitochondrial function if replaced with very-long chain n3 or n6 PUFAs

Pharmacokinetics of different routes of administration of misoprostol

Background: The pharmacokinetic parameters of four different routes of administration of a single dose of 400 μg of misoprostol were studied. Methods: A total of 40 women undergoing termination of pregnancy by suction evacuation was randomized by computer model to receive 400 μg of misoprostol by one of four routes: (i) sublingual (ii) oral (iii) vaginal and (iv) vaginal with addition of water. Venous blood samples were taken at 0, 1, 2, 5, 10, 20, 30, 45, 60, 120, 240 and 360 min after the administration of misoprostol. Misoprostol acid (MPA) was determined in serum samples using gas chromatography/tandem mass spectrometry. Results: Sublingual misoprostol achieved the highest serum peak concentration (Cmax) (574.8 ± 250.7 pg/ml) of MPA and this was significantly higher than those in the other groups [Oral: 287.6 ± 144.3 pg/ml (P < 0.01), vaginal: 125.2 ± 53.8 pg/ml (P < 0.001) and vaginal with water: 162.8 ± 57.1 pg/ml (P < 0.001)]. The time to peak concentration (Tmax) was similar in both the sublingual (26.0 ± 11.5 min) and oral groups (27.5 ± 14.8 min) and was significantly shorter than those in both vaginal groups. The area under the MPA concentration versus time curve up to 360 min in the sublingual group (743.7 ± 291.2 pg.h/ml) was significantly greater than those in oral (402.8 ± 151.6 pg.h/ml, P < 0.05) and vaginal (433.7 ± 182.6 pg.h/ml, P < 0.05) groups, but no significant difference was found between sublingual and vaginal administration if water (649.3 ± 333.8 pg.h/ml) was added. Conclusion: The new sublingual route of administration of misoprostol demonstrated a great potential to be developed into a method of medical abortion.link_to_subscribed_fulltex