Ingredientes Farmacéuticos Activos Potencialmente Inapropiados en Adultos Mayores: Lista IFAsPIAM: Panel de Consenso Argentino.

OBJECTIVES: To perform a list agreed by Argentinean experts and adapted to the local context containing potentially inappropriate (PI) medications in old people (OP) usingthe Delphi consensus technique optimized for this subject. METHODS: A preliminary list of potentially inappropriate medications (PIM) was drawn up based on foreign PIM lists and a selective search in the scientific literature. The iterative Delphi process was used to submit the active pharmaceutical ingredients (APIs) of the preliminary PIM list to the panel of Argentinean experts. The analysis of theanswers to determine the arrival to the consensus was carried out applying three criteria specially defined for this purpose. RESULTS: After two Delphi rounds, it was not reached agreement about 12 APIs. The List of explicit criteria for PIAPIs for use in OP (IFAsPIAM List) was finally constituted by 128 APIs corresponding to 9 groups of the ATC classification system to which they were organized. In addition to each API, information justifying the unfavorable benefit/risk profile and therapeutic alternatives or recommendations/precautions was recorded. The group with the most PI APIs was N (NervousSystem) (60; 47%) followed by groups C (Cardiovascular) and M (Musculoskeletal). CONCLUSION: This study presents the first Latin American list of PIM in OP developed using an expert consensus technique. The IFAs PIAM List would contribute to the rational use of drugs in elderly population, constituting a valuable tool in Argentinean public health.

Haemodynamic and tubular renal dysfunction in rats with sustained arterial calcinosis.

1. In humans, two of the principal characteristics of vascular ageing are arterial wall calcification and decreased arterial distensibility, which induce organ damage. To amplify arterial calcium accumulation in laboratory animals, it is necessary to use an overdose of vitamin D(3). 2. The aim of the present study was to assess the impact of arterial calcium overload on renal function. 3. Adult male Wistar rats were randomly divided into two groups: control and treated rats. Treated rats were injected 10 days before the experiment with a single dose of vitamin D(3) (300 000 IU/kg, i.m.). 4. Treated rats showed a decrease in renal blood flow and glomerular filtration rate. Tubular parameters were not modified under basal conditions. In contrast, a statistically significant increase in the fractional excretion of Na, K, Ca and H(2)O were observed in treated rats after the acute increment of sodium distal delivery, suggesting that the reabsorptive capacity of the thick ascending limb may be altered in treated rats. 5. Thus, Na(+)/K(+)-ATPase activity was evaluated in homogenates from renal cortex and medulla. Rats with arterial calcinosis presented a diminished activity of Na(+)/K(+)-ATPase in medulla homogenates. 6. An increment in the abundance of the Na-K-2Cl cotransporter (NKCC2) was observed in renal medulla homogenates from treated rats. It is suggested that this may compensate for the inefficiency of Na(+)/K(+)-ATPase under basal conditions but, in the presence of acute distal sodium overload, the increment in NKCC2 abundance may not be sufficient to compensate for the decrease in Na(+)/K(+)-ATPase activity. 7. In summary, in our experimental model of arterial calcinosis, renal function is impaired, presenting a vascular compromise and altered function of the medullar thick ascending limb that becomes evident in the presence of acute high distal sodium delivery.

Renal elimination of organic anions in rats with bilateral ureteral obstruction.

Urinary tract obstruction is an important cause of acute renal failure. Several abnormalities in renal tubular function may occur in obstructive nephropathy. The tubular secretion of organic anions is an important function of the kidney that eliminates potentially toxic organic anions from the body, however, the mechanisms involved in organic anions renal elimination in rats with bilateral ureteral obstruction (BUO) have not been elucidated. In this study, it was evaluated the renal handling of p-aminohippurate (PAH) in adult male Wistar rats with BUO. A diminished renal clearance of PAH was observed in BUO rats as consequence of a diminution in the secreted load of this organic anion. The increase in the abundance of organic anions transporter 1 (OAT1) and the absence of modification in cortical renal blood flow, measured with fluorescence microspheres, do not explain the altered secretion of PAH. The diminished Na,K-ATPase activity in cortex from obstructed kidneys might condition OAT1 function. Additionally, it is also possible to conclude that in the presence of BUO, PAH clearance is not a good estimate of renal plasma flow.

Early manifestation of nephropathy in rats with arterial calcinosis.

In vascular smooth muscle, calcium overload is a highly pathogenic event, which increases with advancing age. An increase in the calcium content of arterial wall may be produced in rats by treatment with vitamin D3. The aim of this study was to evaluate the renal clearance of sulfanilamide (a model organic anion, preferentially eliminated by the kidneys) and other parameters of global renal function in rats with arterial calcinosis. Arterial calcinosis was produced in adult rats by means of a single dose of vitamin D3 (300,000 UI/kg bw, i.m.) 5 days before the experiment. Treated rats showed a large increase in calcium content of aortic tissue and an increase in systolic arterial pressure. No modifications were observed in plasma calcium levels and in plasma lipid profiles. Statistically significant decrements were observed in renal clearance of sulfanilamide, in renal blood flow, in fractional excretion of sodium and potassium. A slight decrease, not statistically different, was observed in the glomerular filtration rate. Rats with arterial calcinosis also showed an increment of total calcium levels in renal tissue, in fractional excretion of calcium and in the expression of organic anion transporter 1 (OAT1). Histological studies revealed tubular alterations. In summary, modifications in hemodynamics and tubular parameters are early manifestations of nephropathy in rats with arterial calcinosis, some of which may account for the changes observed in organic anions renal depuration. It is important to mention that the decrease in clearance of organic anions were seen in spite of the increase in expression of OAT1.

Role of BSP/bilirubin binding protein on p-aminohippurate transport in rat kidney.

BSP/Bilirubin binding protein (BBBP) is a protein located on the sinusoidal membrane of the liver that transport several organic anions. The aim of this investigation was to determine whether BBBP is present in the kidney and its role in p-aminohippurate transport (PAH). Anti-BBBP antibodies inhibited PAH uptake in brush border membrane vesicles (BBMV) and Na(+)-independent PAH uptake in basolateral membrane vesicles (BLMV). Western blot studies revealed positivity to antiBBBP antibodies in both BBMV and BLMV. So BBBP is also expressed in the kidneys and accounts, at least in part, for the renal tubular transport of PAH.

Compensation increase in organic anion excretion in rats with acute biliary obstruction: role of the renal organic anion transporter 1.

The purpose of the present study was to examine in rats the effects of acute bile duct ligation on the expression of the organic anion transporter 1 in the kidney and the consequences of these effects on the systemic clearance of organic anions, particularly on P-aminohippurate (PAH) clearance, since it has been viewed as the prototypic organic anion. Male Wistar rats underwent bile duct ligation (BDL rats). Pair-fed sham-operated rats served as controls. All studies were carried out 21 h after surgery. Our data revealed that BDL rats had a higher expression of organic transporter 1 protein in kidney cortex homogenates. Accordingly, systemic clearance of PAH and urinary excretion of PAH were both higher in BDL rats. These findings suggest that impairment of the liver function after BDL is followed by a distinct and statistically significant increase in renal excretion of PAH, indicating a possible compensation mechanism.

Sex differences in p-aminohippuric acid transport in rat kidney: role of membrane fluidity and expression of OAT1.

Sex differences in the kinetic parameters of p-aminohippuric acid (PAH) transport in brush border (BBMV) and basolateral (BLMV) membrane vesicles from kidney cortex have been observed. Membrane fluidity of BBMV was higher in females as compared with male rats as indicated by anisotropy values (0.1897 +/- 0.0010 vs. 0.2003 +/- 0.0014, p < 0.05, for females and males respectively). Membrane fluidity of BLMV were similar in both sexes. Western blot studies revealed that OAT1 protein in female BLMV was present at only 40% of level found in BLMV from male rats. The lower expression of OAT1 in BLMV in association with the higher BBMV fluidity (which may affect the affinity of PAH transporter in this membrane domain) observed in females may be responsible, at least in part, for the gender difference described in renal PAH secretion.

Effects of gender on the pharmacokinetics of drugs secreted by the renal organic anions transport systems in the rat.

The importance of considering sex differences in drug handling studies was admitted recently. The present work evaluates the sex influences on the pharmacokinetics of para-aminohippuric acid (PAH), the reference substance for the renal organic anion transports systems, and furosemide (FS), a standard loop diuretic which is also a substrate for this transport system. Female rats displayed a lower PAH and FS systemic clearance, and a lower value of the elimination rate microconstant from the central compartment for both drugs. These results may be explained by the diminution of the renal clearance of both PAH and FS observed in females. In summary, sex modifies the pharmacokinetics of organic anions. Although additional experimental work must be done to bridge the gap between studies using animals and humans, the reported experimental observations may have potentially important pharmacological implications. So, caution must be exercised in administering drugs like organic anions to females.