Pharmacokinetics of a new fixed-dose combination of candesartan cilexetil, hydrochlorothiazide, and rosuvastatin in healthy adult subjects.

BACKGROUND: A fixed-dose combination (FDC) of candesartan cilexetil, hydrochlorothiazide and rosuvastatin (CC/HCTZ/RSV) has been developed to enhance patient compliance in the primary prevention of cardiovascular diseases. OBJECTIVE: To evaluate if the combination of the product components in the new FDC capsule formulation affects their respective pharmacokinetic and in vitro dissolution patterns. MATERIALS AND METHODS: In vitro dissolution profiles were compared in USP-43 and in biorelevant dissolution media. In vivo comparisons were obtained in a randomized, open-label, single-dose, two-treatment, two-way crossover study in 24 healthy subjects. During each treatment period, subjects received the test formulation (FDC hard capsule containing CC/HCTZ/RSV) or the reference formulation (co-administration of a FDC CC/HCTZ tablet and a RSV tablet). Plasma samples were collected periodically over 48 hours post-dose. Safety and tolerability were assessed. RESULTS: Dissolution profiles of all active drugs in the Test (capsule) and Reference Products (as tablets) were within the tolerance dissolution criteria of USP-43 conditions. HCTZ dissolution profiles were closely similar whereas those for RSV and CC did not match at specific pHs. In the pharmacokinetic study, the 90% confidence intervals (CIs) for the geometric least-square mean ratios of Cmax, AUC0-last, and AUC0-inf were 0.95 - 1.18, 0.95 - 1.15 and 0.95 - 1.13 (CC); 0.91 - 1.10, 0.96 - 1.08, and 0.96 - 1.09 (HCTZ) and 0.82 - 1.23, 0.81 - 1.13, and 0.82 - 1.12 (RSV), respectively. All adverse events were mild. CONCLUSION: The new FDC product (Sinlip Prevent), a stable FDC hard capsule, was bioequivalent (similar pharmacokinetics) when compared to the co-administration of the components and may be considered as a suitable and simplified medication for cardiovascular disease management.

Active Role of the Buffer in the Proton-Coupled Electron Transfer of Immobilized Iron Porphyrins.

Evaluation of the proton-coupled electron transfer thermodynamics of immobilized hemin is challenging due to the disparity of its electrochemical titration curves reported in the literature. Deviations from the one-electron, one-proton transfer at circumneutral pHs have been commonly ascribed to either the formation of dimeric species or the ionization of a second iron-bound water molecule. Herein, however, we report on non-idealities in the more acidic region, whose onset and extent vary with the nature and concentration of the commonly used phosphate and acetate buffers. It is shown that these deviations originate in the ligand-exchange binding between the oxidized aquo-hemin complex and the anionic components of the buffer, so that they are restricted to the pH interval where these forms coexist. A stepwise approach was developed to quantify unambiguously the apparent and intrinsic binding equilibrium constants. The apparent binding equilibrium constant exhibits a peak-shaped pH dependence, whose maximum is located at approximately the midpoint between the pKa of the iron-bound water and the first pKa of the buffer, and its magnitude is greater for the phosphate than for the acetate buffer. But strikingly, the opposite trend was found for the magnitude of the intrinsic binding equilibrium constants determined from the apparent ones, due to the different relative locations of the phosphoric and acetic pKa values with respect to that of the oxidized aquo-hemin. To probe the role of the heme propionic residues, a similar study was carried out with a propionic-free iron porphyrin containing eight ethyl residues. These substituents decrease the acidity of the iron-bound water, strengthen the iron(III)-acetate binding, weaken the iron(III)-dihydrogen phosphate binding, and enable the binding between iron(III) and monohydrogen phosphate, which was hampered in hemin by the presence of the negatively charged propionate residues. Overall, this work provides a more complete speciation of immobilized iron porphyrins under acidic conditions than previously considered, showing the substitutional lability of the aqua ligand in the oxidized state of the iron center and the reluctance of its hydroxyl counterpart to anion exchange. Knowledge of these redox- and pH-dependent bindings with the buffer components is crucial for a rigorous quantification of the proton-coupled electron transfer and the electrocatalytic activity of iron porphyrins.

What controls the unusual melting profiles of small AuNPs/DNA complexes.

The effect of the addition of low concentrations of an inner electrolyte on ds-DNA CT-DNA (calf thymus DNA) and ss-DNA conformational changes induced by small N-(2-mercaptopropionyl)glycine gold nanoparticles (AuNPs) is here studied in detail by using different spectroscopic and structural techniques. The high affinity of ss-DNA to AuNPs compared with ds-DNA is easily demonstrated by the results of competitive binding with SYBR Green I (SG). Additionally, it is proven that at 25.0 °C, AuNPs/ds-DNA and AuNPs/ss-DNA complexes undergo a transition from extended-coil to more compact structures when the AuNPs concentration (CAuNPs) is increased, which for the ds-DNA system is accompanied by partial denaturation. Particularly, for the AuNPs/ss-DNA system all of these techniques confirm that at a high CAuNPs, the compaction process is followed by a discrete transition to aggregation and an increase in structure size. A thorough analysis of the conformational changes described indicates that these processes are larger in low salt concentration and at high temperature. However, the most striking feature of this work is the abnormal melting temperature profiles (Tm) registered at high R = CAuNPs/CDNA ratios, which are remarkable and of interest for chemical sensing. At a suitable R ratio, which varies depending on CNaCl, a complex melting profile for the AuNPs/ds-DNA system was registered with two characteristic transitions: Tm,1 = 65.0 °C and Tm,2 = 95.0 °C. The highly sensitive atomic force microscopy technique performed at 25.0 °C and 65.0 °C also showed a different behaviour in both ss- and AuNPs/ds-DNA systems, which explains the characteristic melting curves. Specifically for the AuNPs/ss-DNA system, AFM at 25.0 °C revealed the formation of large-sized aggregates formed by AuNPs/ss-DNA compact structures linked by AuNPs. However, when both AuNPs/ds-DNA and AuNPs/ss-DNA complexes were incubated at 65.0 °C, the formation of highly stable ordered structures was always visualized at high R. Therefore, this shows that some key parameters for effective control of the formation of DNA/RNA-linked particles are: the selection of an optimal temperature below the ds-DNA melting point, an appropriate CAuNPs, and the addition of low CNaCl. The optimization of these parameters for each AuNPs/DNA system could improve biological sensing and DNA/RNA delivery.

Reversible DNA compaction induced by partial intercalation of 16-Ph-16 gemini surfactants: evidence of triple helix formation.

The interaction between calf thymus DNA and the gemini surfactants N,N'-[α,ω-phenylenebis(methylene)bis [N,N'-dimethyl-N-(1-hexadecyl)]-ammonium dibromide], p-16-Ph-16 (α = 1, ω = 3) and m-16-Ph-16 (α = 1, ω = 2), has been investigated via circular dichroism, fluorescence and UV-vis spectroscopy, zeta potential, dynamic light scattering, and AFM microscopy. Measurements were carried out in aqueous media at different molar ratios, R = (C16-Ph-16)/CDNA and C16-Ph-16 always below the critical micellar concentration (CMC) of the surfactant. Under these conditions, DNA undergoes two reversible conformational changes, compaction and decompaction, due to interaction with the surfactant molecules at low and high molar ratios, respectively. The extent of such conformational changes is correlated with both the degree of surfactant partial intercalation, and the size and charge of the surfactant aggregates formed, in each case. Comparison of the results shows that the para-form of the surfactant intercalates into the DNA to a major extent; therefore, the compaction/decompaction processes are more effective. Among these, the structure of the resulting 16-Ph-16/DNA decompacted complex is worthy of note. For the first time it can be demonstrated that the partial intercalation of the 16-Ph-16 gemini surfactants induces the formation of triplex DNA-like structures at a high R ratio.

Weak coordination between leaf structure and function among closely related tomato species.

Theory predicts that natural selection should favor coordination between leaf physiology, biochemistry and anatomical structure along a functional trait spectrum from fast, resource-acquisitive syndromes to slow, resource-conservative syndromes. However, the coordination hypothesis has rarely been tested at a phylogenetic scale most relevant for understanding rapid adaptation in the recent past or for the prediction of evolutionary trajectories in response to climate change. We used a common garden to examine genetically based coordination between leaf traits across 19 wild and cultivated tomato taxa. We found weak integration between leaf structure (e.g. leaf mass per area) and physiological function (photosynthetic rate, biochemical capacity and CO2 diffusion), even though all were arrayed in the predicted direction along a 'fast-slow' spectrum. This suggests considerable scope for unique trait combinations to evolve in response to new environments or in crop breeding. In particular, we found that partially independent variation in stomatal and mesophyll conductance may allow a plant to improve water-use efficiency without necessarily sacrificing maximum photosynthetic rates. Our study does not imply that functional trait spectra, such as the leaf economics spectrum, are unimportant, but that many important axes of variation within a taxonomic group may be unique and not generalizable to other taxa.

Leaf responses to drought stress in Mediterranean accessions of Solanum lycopersicum: anatomical adaptations in relation to gas exchange parameters.

In a previous study, important acclimation to water stress was observed in the Ramellet tomato cultivar (TR) from the Balearic Islands, related to an increase in the water-use efficiency through modifications in both stomatal (g(s)) and mesophyll conductances (g(m)). In the present work, the comparison of physiological and morphological traits between TR accessions grown with and without water stress confirmed that variability in the photosynthetic capacity was mostly explained by differences in the diffusion of CO2 through stomata and leaf mesophyll. Maximization of gm under both treatments was mainly achieved through adjustments in the mesophyll thickness and porosity and the surface area of chloroplasts exposed to intercellular airspace (S(c)). In addition, the lower g(m) /S(c) ratio for a given porosity in drought-acclimated plants suggests that the decrease in gm was due to an increased cell wall thickness. Stomatal conductance was also affected by drought-associated changes in the morphological properties of stomata, in an accession and treatment-dependent manner. The results confirm the presence of advantageous physiological traits in the response to drought stress in Mediterranean accessions of tomato, and relate them to particular changes in the leaf anatomical properties, suggesting specific adaptive processes operating at the leaf anatomical level.

Improving the understanding of DNA-propanediyl-1,3-bis(dodecyldimethylammonium) dibromide interaction using thermodynamic, structural and kinetic approaches.

A kinetic, thermodynamic and structural study of the interaction of the gemini surfactant propanediyl-1,3-bis(dimethyldodecylammonium dibromide) (12-3-12.2Br) with calf thymus DNA was carried out at several ionic strengths (NaCl) in aqueous solutions. A new 12-3-12(2+)-selective membrane was prepared in order to gain insight into the factors that control the binding of 12-3-12.2Br to DNA. We used ethidium bromide (EB) as a fluorescence probe to follow the kinetics of the interaction by using the stopped-flow fluorescence technique. The results can be explained in terms of a reaction mechanism involving two consecutive reversible (fast and slow) steps. The fast step was attributed to the union/separation of the surfactant with/from the DNA polynucleotide. Changes in the kinetic constants in the forward and backward directions were discussed in terms of the Brönsted-Pitzer equation and of the increase in hydrophobic interactions of the surfactant tails as a consequence of salting-out effects, respectively. The slow step corresponds to a conformational change of the surfactant-DNA complex to a more compacted form. The equilibrium constant, calculated from the forward and reverse rate constants of these steps, agrees with the results obtained from potentiometric titration using a 12-3-12-(2+) selective electrode.

Upper gastrointestinal tract transit times of tablet and drinkable solution formulations of alendronate: a bioequivalence and a quantitative, randomized study using video deglutition.

The bioequivalence and upper digestive tract transit time of a drinkable solution of 70 mg/100 mL alendronate was compared to reference tablets. A randomized, single- dose, two-way crossover study of the rate of urinary recovery of alendronate during 36 h (AE((0-36 h))) by HPLC, in 104 healthy young male volunteers, showed that AE((0-36 h)) and the maximum excretion rate (R (max)) were within the accepted range of bioequivalence 81.8-105.7 and 81.7-106.2, respectively. To characterize the oesophageal passage time of the two alendronate formulations, we performed a randomized, controlled study, in 24 healthy men and women (mean 52 years old), who took the formulations standing or lying down, by an X-ray video deglutition system. When taken in the standing position, both formulations had equal mean transit times from mouth to stomach and tablet disintegration but data dispersion was significantly smaller with the liquid form. When taken in lying position, drinkable alendronate had shorter and less variable median transit times compared to the tablets. These results show that the drinkable alendronate formulation is bioequivalent to the tablets and may be advantageous in patients in whom the transit or disintegration of the tablets is impaired.

Protein phosphatases: possible bisphosphonate binding sites mediating stimulation of osteoblast proliferation.

We investigated the existence of a bisphosphonate (BP) target site in osteoblasts. Binding assays using [³H]-olpadronate ([³H]OPD) in whole cells showed the presence of specific, saturable and high affinity binding for OPD (K(d)=1.39 ± 0.33 µM) in osteoblasts. [³H]OPD was displaced from its binding site by micromolar concentrations of lidadronate, alendronate and etidronate (K(d)=1.42 ± 0.15 µM, 2.00 ± 0.2 µM and 2.4 ± 0.4 µM, respectively), and by millimolar concentrations of the non-permeant protein phosphatase (PP) substrates p-nitrophenylphosphate and α-naphtylphosphate. PP inhibitors orthovanadate, NaF or vpb(bipy) did not displace [³H]OPD. As expected, specific OPD binding was detected in the plasma membrane of ROS 17/2.8 cells, although significant BP binding was also found intracellularly. Moreover, OPD increased DNA synthesis in these cells with a temporal profile similar to the protein tyrosine phosphatase (PTP) inhibitors, Na3VO4 and vpb(bipy); but different from a general PP inhibitor (NaF). The stimulatory effect of OPD and PTP inhibitors on osteoblast proliferation was inhibited by the protein tyrosine kinase inhibitors genistein and geldanamycin. These results provide new evidence on the existence of a BP target in osteoblastic cells, presumably a PTP, which may be involved in the stimulatory action of BPs on osteoblast proliferation.

[Biomedicine philately]. / La filatelia biomedica.

Biomedicine is a vast field in philately or stamp collecting. It opens the topic the image of the goddess Hygeia, issued in a stamp from Nevis Island dated 1861. The first physicians to appear printed in stamps, in 1869, were three American constitutionalists, but only in 1937 there appear Dutch physicians as an acknowledgement of their contribution to public health. In Argentina the first stamp officially related to the topic was issued in 1944, to raise funds for the victims of the San Juan earthquake. Florentino Ameghino was the first scientist included in 1954, and in 1967 a stamp was issued in honour of Dr. Cecilia Grierson. Afterwards, Argentinean philately has recognized several of our scientists and physicians, congresses, universities, health campaigns, dentistry topics, chemistry, and nursery, among others, promoting a large amount of philatelic material in acknowledgement of the social value that Argentinean biomedical science has gained locally and abroad. Probably, it is a scientist, Dr. Bernardo Houssay, the Argentinean who has more often appeared in international philately.

Reorientation of thiols during 2D self-assembly: interplay between steric and energetic factors.

Reorientation of thiols during their 2D self-assembly is well established; however, little is known about its energetics and the factors that control its onset. We have developed a new strategy to determine the critical reorientational surface concentration (crsc) of thiols at the substrate/solution interface, which makes use of a cathodic stripping protocol. Its application to distinct homologous series of alkylthiols shows that the magnitude of the crsc and its variation with the molecular size is strongly dependent on the nature of the terminal group. Methyl-terminated alkylthiols reorient close to the saturation coverage of the lying-down phase, thus following their molecular size trend; whereas reorientation of alkylthiols bearing a negatively charged end group starts well below the monolayer coverage of the lying-down phase, with its onset being almost independent of the molecular size. Hydroxy-terminated alkylthiols show an intermediate behavior. A theoretical approach is developed to determine the reorientation equilibrium constant from the crsc value. The standard free energy of reorientation has been found to vary linearly with the alkyl chain length, and to increase upon replacing the terminal methyl group by a negatively charged one. A quantitative correlation between the reorientation equilibrium constant and the hydrophobicity of the molecule has been established. Overall, these findings have allowed us to disentangle the role of steric and energetic factors in the onset of the reorientation process of alkylthiols, demonstrating that their interplay can be finely tuned by varying either the alkyl chain length or the nature of the terminal group.

Reducing Allostatic Load in Depression and Anxiety Disorders: Physical Activity and Yoga Practice as Add-On Therapies.

The allostatic load (AL) index constitutes a useful tool to objectively assess the biological aspects of chronic stress in clinical practice. AL index has been positively correlated with cumulative chronic stress (physical and psychosocial stressors) and with a high risk to develop pathological conditions (e.g., metabolic syndrome, cardiovascular pathology, inflammatory disorders) and the so-called stress-related psychiatric disorders, including anxiety and depressive disorders. Chronic stress has negative effects on brain neuroplasticity, especially on hippocampal neurogenesis and these effects may be reversed by antidepressant treatments. Several evidences indicate that non-pharmacological interventions based on physical activity and yoga practice may add synergizing benefits to classical treatments (antidepressant and benzodiazepines) for depression and anxiety, reducing the negative effects of chronic stress. The aim of this review is to provide a general overview of current knowledge on AL and chronic stress in relation to depression and anxiety, physical activity and yoga practice.

Assessment of material, structural, and functional properties of the human skeleton by pQCT systems.

Peripheral quantitative computed tomography (pQCT) systems measure bone parameters noninvasively using low radiation doses. This limits image resolution but is practical for the diagnosis and quantitative monitoring of the properties of the peripheral human skeleton. pQCT determines volumetric bone mineral density separately in trabecular and cortical bone. It may combine densitometry determinations with geometric estimates and use strain-stress indexes, and it may be used to analyze muscle variables in some areas, allowing the study of regional fragility. Experimental and clinical ex vivo studies show that pQCT variables correlate with biomechanical predictors of fragility and/or fractures. Since pQCT was approved by the US Food and Drug Administration in 1997, new skeletal regions (human femur and mandible) have been considered in the development of the system. Basically, pQCT explores intraindividual and interindividual variations in greater detail and compares the impact of skeletal diseases, risk factors, and anabolic and catabolic treatments within a given bone cross section.

25-Hydroxyvitamin D serum levels in rheumatic female patients in southeast Spain: The paradigm of daily optimal sunshine levels and inadequate vitamin D status.

BACKGROUND: Almeria is a region in southeast Spain with optimal sunlight levels, along with low pluvial and pollution rates. If exposure to sunlight is sufficient to maintain adequate levels of vitamin D (25OHD), this population should display high serum levels. OBJECTIVES: To describe 25OHD serum status in women from Almeria and evaluate the impact of long sunlight exposure along the seasons on 25OHD. METHODS: Cross-sectional study, performed in women consecutively recruited from an outpatient rheumatology clinic. Serum levels of 25OHD were assessed in all patients and evaluated according to age (<48 yrs, 48-53 yrs, 54-60 yrs and >60 yrs), season, and presence or absence of menopause. Clinical and laboratory variables that could affect status of vitamin D were also considered. RESULTS: The sample included 319 Caucasian female patients. Mean 25OHD were 30.2ng/ml with 195 (61.1%) exhibiting 25OHD inadequate serum levels. Season had a significant effect on 25OHD levels, with autumn being the season in which 25OHD serum levels remained well above 30ng/ml in all age bands, and winter the season with more levels of insufficiency. Menopause did not modify 25OH serum levels. Women whose age was below 48 and over 60 had inadequate levels of 25OHD during summer. CONCLUSIONS: Optimal levels of sunlight could not overcome the problem of inadequate 25OHD serum levels, particularly in elderly and young female population. Vitamin D supplementation may be recommended predominantly in winter and summer in this population.

Skeletal effects of long-term estrogen and testosterone replacement treatment in a man with congenital aromatase deficiency: evidences of a priming effect of estrogen for sex steroids action on bone.

The relative contribution of each sex steroid (i.e. estrogen and androgen) on bone in men and the relationships among sex steroids and changes in BMD and bone strength are still unknown. A defective BMD of bone tissue is constantly present in men with aromatase deficiency. This study evaluates the effects of different regimens of treatment with sex steroids over 7.3 years follow-up on BMD in an adult man affected by aromatase deficiency and by a concomitant mild hypogonadism, as previously described. The aim of the study is to provide additional data on the relative roles of androgens and estrogens in male bone metabolism. The effects of testosterone (T) treatment alone and estrogen (tE(2)) treatment alone as well as the effects of the combined treatment with testosterone and estradiol (T plus tE(2)) on areal BMD (aBMD) at dual-energy X-ray absorptiometry (DXA) and the effects of T plus tE(2) on volumetric BMD (vBMD), particular at cortical site, measured by peripheral quantitative computed tomography (pQCT), are investigated. Hormones and markers of bone turnover were monitored during all phases of the study. Treatment with tE(2) normalized serum estradiol, but only the combined treatment with T plus tE(2) normalized both serum estradiol and testosterone. Markers of bone turnover reached a pattern close to normality during T plus tE(2). The aBMD was little modified by T, but increased more during tE(2). T plus tE(2) resulted in a further increase in both aBMD at DXA and vBMD at pQCT. Cortical thickness increased during T plus tE(2) both in radius and tibia. Only the combined treatment led to optimal parameters of aBMD suggesting that testosterone needs estrogens as a permissive factor for a direct androgen anabolic action on bone in men.

Activation of MAPKs by 1alpha,25(OH)2-Vitamin D3 and 17beta-estradiol in skeletal muscle cells leads to phosphorylation of Elk-1 and CREB transcription factors.

The mitogen activated protein kinases (MAPKs) have been classified into at least six subfamilies, among which ERK1/2, JNK1/2 and p38 MAPK are the most extensively studied. The steroid hormones 1alpha,25-dihydroxy-Vitamin D(3) and 17beta-estradiol promote biological responses through activation of MAPK cascades in various cell types. We previously reported that 1alpha,25(OH)(2)D(3) rapidly (within 1 min) activates p38 MAPK in C2C12 skeletal muscle cells. In this work, using the same muscle cell line, we demonstrate that 1alpha,25(OH)(2)D(3) or 17beta-estradiol phosphorylate and activate ERK1/2 and p38 MAPK after longer treatment intervals, maximal effects seen at 90 and 30 min (ERK1/2) and at 60 and 15 min (p38 MAPK) for these hormones, respectively. Hormone-dependent ERK and p38 activation was abolished by MAPK specific inhibitors U0126 and SB203580. 1alpha,25(OH)(2)D(3) and 17beta-estradiol also induced the phosphorylation of CREB and Elk-1 transcription factors in an ERK1/2-dependent manner. Simultaneous addition of both hormones potentiated CREB phosphorylation. 1alpha,25(OH)(2)D(3)- and 17beta-estradiol-induced c-fos expression, which was mediated by p38 phosphorylation. The action of 17beta-estradiol on c-fos levels was also dependent on ERK1/2. These results suggest that MAPK signalling pathways play an important role in regulating early gene expression through CREB and Elk-1 activation in skeletal muscle cells.

Tolerability of intravenous pamidronate for the treatment of osteoporosis and other metabolic osteopathies: A retrospective analysis.

BACKGROUND: Intravenous disodium pamidronate has been described in the treatment of several osteopathies. Although tolerability has been found to be good in clinical trials, some mild to serious adverse events (AEs) have been reported. OBJECTIVES: The aims of this study were to analyze the toelrability of IV pamidronate in patients being treated for osteoporosis and other metabolic osteopathies and to describe particular patients with relative contraindications, because such cases are not commonly seen in daily clinical practice. METHODS: We performed a retrospective analysis of patients with different osteopathies who were administered IV infusions of pamidronate at doses ranging from 15 to 90 mg/infusion and 15 to 900 mg/year. The study was conducted in patients who had received treatment at the Institute of Metabolic Investigations, University of Salvador, Buenos Aires, Argentina, between January 1995 and December 2003. To rule out dose-related AEs, a comparison was made between patients who received fewer IV infusions and had cumulative doses of 120 to 180 mg/y (less frequent administration [LFA] group) and those patients who received regular infusions and had cumulative doses of >180 mg/year (frequent administration [FA] group). To confirm data obtained from medical records and to assess the occurrence of AEs, attempts were made to interview all patients by phone. The following information was verified for each patient included in the study: the reason for treatment, documented evidence of current diagnostic criteria, and whether the dose administered was adequate to treat the patient's condition. RESULTS: Six hundred eight patients (464 [76.3%]women, 144 [23.7%]men; mean [SD] age, 69 [10] years) with various osteopathies (osteoporosis, 367 [60.4%] of the patients; Paget's disease, 172 [28.3%]; Sudeck's disease, 63 [10.4%]; multiple myeloma, 3 [0.5%]; and bone metastases, 3 [0.5%]) were administered a total of 2933 IV infusions of pamidronate during the study period. We were able to confirm the clinical records of 69.4% (422/608) of the patients by telephone survey; 29.9% (124/415) of those patients experienced extraskeletal AEs (most commonly fever and flu-like symptoms [eg, headache, malaise, fatigue, chills, and asthenia]). The percentage of patients reporting AEs was significantly higher for the LFA group than that of the FA group (91.2 vs 19.5; P < 0.001), although factors other than the frequency of treatment might have had a bearing on this finding. All AEs were mild and transient in both groups of patients, and there were no reports of jaw osteonecrosis in either group. It should be noted that although LFA patients received lower doses of pamidronate per infusion than the FA group, they had higher cumulative doses/year. Biochemical variables for the entire study population were compared with baseline measurements, and no significant changes in mean values were observed. Both serum calcium and 25-hydroxy vitamin D levels remained within normal ranges. On the other hand, there was a transient decrease in white blood cell count (WBCC) in 73 (12.0%) patients, and leukopenia was observed in 8 (1.3%) patients. However, 5 of the 6 patients who were leukopenic at the beginning of treatment had normal WBCCs during follow-up. Platelet count decreased significantly in 20 (3.3%) patients, and 5 (0.8%) patients developed thrombocytopenia. Serum creatinine (sCreat) levels increased significantly in 91 (15.0%) patients. This increase was transient and within normal limits (0.6-1.2 mg/dL) in 79 (86.8%) of those patients but persistent in the other 12 (13.2%), all of whom received higher doses of pamidronate or had other risk factors for renal failure such as advanced age, diabetes, multiple myeloma, or an obstructor disease. Baseline sCreat level for 7 of these 12 patients was >1.20 mg/dL. CONCLUSIONS: Pamidronate administered IV was well tolerated when used for treating osteoporosis or other metabolic osteopathies in our study population. The clinical AEs observed with IV pamidronate administration were not serious and hematologic changes were mild, transient, and not associated with dose, time of treatment, or any particular underlying disease. An increase in sCreat level was the most frequent biochemical complication and was found in patients with additional risk factors for renal failure and particular diseases. Whether certain patients with risk factors for osteoporosis may require even fewer IV administrations of the drug is an issue that remains to be elucidated.