Pioglitazone has a dubious bladder cancer risk but an undoubted cardiovascular benefit

On 8 April 2014, a US jury ordered Takeda and Eli Lilly to pay $9 bn in punitive damages after finding that they had concealed the cancer risks associated with pioglitazone. By contrast, on 28 August 2014, the long‐awaited outcome of the 10‐year Kaiser Permanente Northern California study was announced. That study was specifically designed to investigate whether patients exposed to pioglitazone were at an increased risk of bladder cancer and found no association; thus, at last, the controversial issue has been resolved. A review, in retrospect, of the story of the proposed link between pioglitazone and bladder cancer reveals flaws at every stage. In 2012, a BMJ editorial, in keeping with some other contemporary reports, stated ‘it can confidently be assumed that pioglitazone increases the risk of bladder cancer’. Examination of the information which led to such a statement shows that: 1) the pre‐clinical findings of bladder cancer in male rats is not indicative of human risk; 2) there is no association between bladder cancer and pioglitazone in randomized controlled trials, once cases that could not plausibly be related to treatment are removed; and 3) the observational studies that have suggested a link have over‐extrapolated from the data: pioglitazone‐treated patients had more risk factors for bladder cancer than those not treated with pioglitazone. Meanwhile careful study of randomized controlled trials shows evidence of cardiovascular benefit from pioglitazone in Type 2 diabetes, a condition which results, more than anything, in premature cardiovascular death and morbidity.     

The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

A Chinese adolescent girl with Fechtner-like syndrome

We describe a 15-y-old girl with Fechtner-like syndrome, who is the first Chinese reported to have this rare syndrome. She presented with left homonymous hemianopia and neuroimaging revealed haemorrhage in both parietal and occipital lobes. Peripheral blood smear showed macrothrombocytopenia and intracytoplasmic inclusion bodies inside leucocytes. Thrombocytopenia and proteinuria responded to intravenous immunoglobulin and pulsed methylprednisolone. This case illustrates that life-threatening haemorrhage can occur in patients with Fechtner syndrome. Although there was no effective treatment reported in the literature, high dose steroid and immunoglobulin seemed to be useful in our patient. Our patient also had nephritic-nephrotic syndrome with renal insufficiency, which is unusual in adolescent female patients.     

Serum concentration of calcium and calcitonin in hyperthyroidism caused by Graves' disease]

Serum calcium and calcitonin were determined in 13 patients (12 women and 1 man), ages ranging from 30 to 40 years, with clinical diagnosis of hyperthyroidism due to Graves' Disease, confirmed by serum determinations of T3 and T4, with the purpose of establishing the relationship that these two substances may have in this pathology. The results obtained showed a decrease in seric calcium concentration in relation to a control group (10.02 +/-) 0.48 vs 11.49 +/- 0.28 mg/dl; p less than 0.005) and an increase in calcitonin concentration (193.6 +/- 8.62 vs 116.7 +/- 7.61 pg/ml; p less than 0.0001). We also found a significative negative association (r = -0.69; p less than 0.01) between these two compounds in the group of patients with hyperthyroidism, not being found in the control group.     

Ergosterol biosynthesis inhibition by the thiocarbamate antifungal agents tolnaftate and tolciclate.

The thiocarbamate antimycotics tolnaftate and tolciclate blocked sterol biosynthesis in fungal cells and cell extracts, with accumulation of squalene. This point of action was confirmed by the direct inhibition of microsomal squalene epoxidase from Candida albicans. There was no inhibition of other steps in ergosterol biosynthesis. In whole Candida cells, ergosterol biosynthesis inhibition was not complete at drug concentrations up to 100 mg/liter, whereas full inhibition occurred in a cell-free test system. Rat liver cell-free cholesterol biosynthesis was much less sensitive to the drugs. The biochemical action of tolnaftate and tolciclate is thus similar to that of the allylamine antimycotics naftifine and terbinafine.