Efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes (PIONEER 11): a double-blind, Phase IIIa, randomised trial.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the efficacy and safety of oral semaglutide monotherapy vs placebo in a predominantly Chinese population with type 2 diabetes insufficiently controlled with diet and exercise alone. METHODS: The Peptide Innovation for Early Diabetes Treatment (PIONEER) 11 trial was a double-blind, randomised, Phase IIIa trial conducted across 52 sites in the China region (mainland China and Taiwan), Hungary, Serbia and Ukraine. Eligible participants were ≥18 years (≥20 years in Taiwan), had a diagnosis of type 2 diabetes with HbA1c 53-86 mmol/mol (7.0-10.0%) and were not receiving any glucose-lowering drugs. After a 4-week run-in period in which participants were treated with diet and exercise alone, those who fulfilled the randomisation criteria were randomised (1:1:1:1) using a web-based randomisation system to receive once-daily oral semaglutide 3 mg, 7 mg or 14 mg or placebo for 26 weeks (using a 4-week dose-escalation regimen for the higher doses). Randomisation was stratified according to whether participants were from the China region or elsewhere. The primary and confirmatory secondary endpoints were change from baseline to week 26 in HbA1c and body weight (kg), respectively. Safety was assessed in all participants exposed to at least one dose of the trial product. RESULTS: Between October 2019 and October 2021, a total of 774 participants were screened and 521 participants were randomised to oral semaglutide 3 mg (n=130), 7 mg (n=130), 14 mg (n=130) or placebo (n=131); most participants (92.5%, n=482) completed the trial, with 39 participants prematurely discontinuing treatment. The number of participants contributing to the trial analyses was based on the total number of participants who were randomised at the beginning of the trial. The majority of participants were male (63.7%), and the mean age of participants was 52 years. At baseline, mean HbA1c and body weight were 63 mmol/mol (8.0%) and 79.6 kg, respectively. Oral semaglutide resulted in significantly greater reductions in HbA1c than placebo at week 26 (p<0.001 for all doses). The estimated treatment differences (ETDs [95% CIs]) for oral semaglutide 3 mg, 7 mg and 14 mg vs placebo were -11 (-13, -9) mmol/mol, -16 (-18, -13) mmol/mol and -17 (-19, -15) mmol/mol, respectively. The corresponding ETDs in percentage points (95% CI) vs placebo were -1.0 (-1.2, -0.8), -1.4 (-1.6, -1.2) and -1.5 (-1.8, -1.3), respectively. Significantly greater reductions in body weight were also observed for oral semaglutide 7 mg and 14 mg than for placebo at week 26 (ETD [95% CI] -1.2 kg [-2.0 kg, -0.4 kg; p<0.01] and -2.0 kg [-2.8 kg, -1.2 kg; p<0.001], respectively), but not for oral semaglutide 3 mg (ETD [95% CI] -0.0 kg [-0.9 kg, 0.8 kg; not significant]). Similar reductions in HbA1c and body weight were observed in the Chinese subpopulation, which represented 74.9% of participants in the overall population. Adverse events (AEs) occurred in between 65.4% and 72.3% of participants receiving oral semaglutide (for all doses) and 57.3% of participants with placebo. Most AEs were mild to moderate in severity, with few serious AEs reported; the most commonly reported AEs were gastrointestinal-related and were more frequent with semaglutide (all doses) than with placebo. The proportion of AEs was slightly higher in the Chinese subpopulation. CONCLUSIONS/INTERPRETATION: Oral semaglutide resulted in significantly greater reductions in HbA1c across all doses and in significant body weight reductions for the 7 mg and 14 mg doses when compared with placebo in predominantly Chinese participants with type 2 diabetes insufficiently controlled by diet and exercise alone. Oral semaglutide was generally well tolerated, with a safety profile consistent with that seen in the global PIONEER trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04109547. FUNDING: Novo Nordisk A/S.

Taxonomic and environmental distribution of bacterial amino acid auxotrophies.

Many microorganisms are auxotrophic-unable to synthesize the compounds they require for growth. With this work, we quantify the prevalence of amino acid auxotrophies across a broad diversity of bacteria and habitats. We predicted the amino acid biosynthetic capabilities of 26,277 unique bacterial genomes spanning 12 phyla using a metabolic pathway model validated with empirical data. Amino acid auxotrophy is widespread across bacterial phyla, but we conservatively estimate that the majority of taxa (78.4%) are able to synthesize all amino acids. Our estimates indicate that amino acid auxotrophies are more prevalent among obligate intracellular parasites and in free-living taxa with genomic attributes characteristic of 'streamlined' life history strategies. We predicted the amino acid biosynthetic capabilities of bacterial communities found in 12 unique habitats to investigate environmental associations with auxotrophy, using data compiled from 3813 samples spanning major aquatic, terrestrial, and engineered environments. Auxotrophic taxa were more abundant in host-associated environments (including the human oral cavity and gut) and in fermented food products, with auxotrophic taxa being relatively rare in soil and aquatic systems. Overall, this work contributes to a more complete understanding of amino acid auxotrophy across the bacterial tree of life and the ecological contexts in which auxotrophy can be a successful strategy.

Effect of Various Dosing Schedules on the Pharmacokinetics of Oral Semaglutide: A Randomised Trial in Healthy Subjects.

BACKGROUND: Prescribing information instructs taking oral semaglutide (a glucagon-like peptide-1 analogue) in the fasting state, followed by a post-dose fasting period of ≥ 30 min. This trial compared the recommended dosing schedule with alternative schedules. METHODS: This was a randomised, single-centre, multiple-dose, open-label, five-armed, parallel-group trial in healthy subjects who received once-daily oral semaglutide (3 mg for 5 days followed by 7 mg for 5 days). Subjects (n = 156) were randomised to five dosing schedules: 2-, 4-, or 6-h pre-dose fast followed by a 30-min post-dose fast (treatment arms: 2 h-30 min, 4-30 min, 6 h-30 min); 2-h pre-dose fast followed by an overnight post-dose fast (treatment arm: 2 h-night); or overnight pre-dose fast followed by a 30-min post-dose fast (reference arm: night-30 min). Semaglutide plasma concentration was measured regularly until 24 h after the 10th dose. Endpoints included area under the semaglutide plasma concentration-time curve during a 24-h interval after the 10th dose (AUC0-24h) (primary endpoint) and maximum observed semaglutide plasma concentration after the 10th dose (Cmax) (secondary endpoint). RESULTS: Compared with an overnight pre-dose fast (reference arm: night-30 min), shorter pre-dose fasting times in the 2 h-night, 2 h-30 min, 4 h-30 min, and 6 h-30 min treatment arms resulted in significantly lower semaglutide AUC0-24h and Cmax after the 10th dose (estimated treatment ratio ranges: 0.12-0.43 and 0.11-0.44, respectively; p < 0.0001 for all comparisons). Semaglutide AUC0-24h and Cmax after the 10th dose were similar for the 2 h-30 min and 2 h-night treatment arms. CONCLUSION: This trial supports dosing oral semaglutide in accordance with prescribing information, which requires dosing in the fasting state. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04513704); registered August 14, 2020.

Oral semaglutide is a human glucagon-like peptide-1 analogue that has been approved for the treatment of type 2 diabetes. It has been established that taking oral semaglutide with food or large volumes of water decreases absorption of the drug in the body. Current prescribing information instructs taking oral semaglutide on an empty stomach (known as the fasting state), with 120 mL/4 oz of water, then waiting for at least 30 min before consuming any food, water, or taking other oral medications. This study investigates whether different dosing schedules for oral semaglutide could potentially offer more flexibility to patients in the timing of their oral semaglutide dosing. The trial, conducted in healthy volunteers, compares the dosing schedule described in the prescribing information with different fasting times before (pre-dose) and after (post-dose) taking oral semaglutide during the day or evening, to see if there were any effects on the concentration of drug in the body. Compared to the recommended overnight fasting period, shorter pre-dose fasting periods of 2­6 h with a 30-min post-dose fast considerably reduced semaglutide exposure in the body. Similarly, semaglutide exposure was also reduced with a 2-h pre-dose fast combined with post-dose overnight fasting. These findings further support the current prescribing information, which states that patients should take their oral semaglutide dose after an overnight fast.

Introduction and transmission of SARS-CoV-2 lineage B.1.1.7, Alpha variant, in Denmark.

BACKGROUND: In early 2021, the SARS-CoV-2 lineage B.1.1.7 (Alpha variant) became dominant across large parts of the world. In Denmark, comprehensive and real-time test, contact-tracing, and sequencing efforts were applied to sustain epidemic control. Here, we use these data to investigate the transmissibility, introduction, and onward transmission of B.1.1.7 in Denmark. METHODS: We analyzed a comprehensive set of 60,178 SARS-CoV-2 genomes generated from high-throughput sequencing by the Danish COVID-19 Genome Consortium, representing 34% of all positive cases in the period 14 November 2020 to 7 February 2021. We calculated the transmissibility of B.1.1.7 relative to other lineages using Poisson regression. Including all 1976 high-quality B.1.1.7 genomes collected in the study period, we constructed a time-scaled phylogeny, which was coupled with detailed travel history and register data to outline the introduction and onward transmission of B.1.1.7 in Denmark. RESULTS: In a period with unchanged restrictions, we estimated an increased B.1.1.7 transmissibility of 58% (95% CI: [56%, 60%]) relative to other lineages. Epidemiological and phylogenetic analyses revealed that 37% of B.1.1.7 cases were related to the initial introduction in November 2020. The relative number of cases directly linked to introductions varied between 10 and 50% throughout the study period. CONCLUSIONS: Our findings corroborate early estimates of increased transmissibility of B.1.1.7. Both substantial early expansion when B.1.1.7 was still unmonitored and continuous foreign introductions contributed considerably to case numbers. Finally, our study highlights the benefit of balanced travel restrictions and self-isolation procedures coupled with comprehensive surveillance efforts, to sustain epidemic control in the face of emerging variants.

Oral Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Glucose-Lowering Medication: PIONEER Subgroup Analyses.

INTRODUCTION: The efficacy and safety of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist, were investigated in patients with type 2 diabetes (T2D) in the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) programme. The current post-hoc exploratory subgroup analyses evaluated outcomes by background medication and insulin regimen subgroups. METHODS: Data from patients in the PIONEER 3-5, 7 and 8 trials receiving once-daily oral semaglutide (14 mg/flexibly dosed) or a comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg) were analysed for efficacy (glycated haemoglobin [HbA1c] and body weight changes from baseline to planned end of treatment) and safety outcomes. Patients were grouped according to background medication (metformin, sulphonylurea, thiazolidinedione, sodium-glucose cotransporter-2 inhibitor, insulin, or combinations thereof). Efficacy outcomes were analysed using the trial product estimand (which assumes that patients remained on the trial product without rescue medication use). A separate analysis by background insulin regimen (basal, premixed or basal-bolus) was done for PIONEER 8 using the treatment policy estimand (regardless of trial product discontinuation or rescue medication use). Safety outcomes were analysed descriptively for all patients. RESULTS: In total, 2836 patients receiving oral semaglutide 14 mg/flexibly dosed or comparators were included. Baseline characteristics were generally similar across background medication subgroups within each trial. Diabetes duration tended to be longer in patients receiving more background medications. Greater HbA1c and body weight reductions were seen across background medication subgroups with oral semaglutide (changes from baseline: - 1.0 to - 1.5% and - 2.2 to - 5.0 kg, respectively) than with comparators (except for similar HbA1c reductions vs liraglutide). There were no statistically significant interactions by treatment and background medication subgroup for change in HbA1c or body weight except for change in HbA1c (background insulin vs insulin plus metformin) in PIONEER 8 (p = 0.0408). Changes in HbA1c and body weight were generally similar across insulin regimen subgroups, without significant treatment interactions by subgroup, and the total daily insulin dose was decreased for patients receiving oral semaglutide. The incidence of adverse events was generally similar in background medication subgroups. CONCLUSION: Oral semaglutide was effective at lowering HbA1c and body weight, regardless of background medications, and appears suitable for a broad range of patients with T2D in combination with other glucose-lowering agents. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02607865 (PIONEER 3), NCT02863419 (PIONEER 4), NCT02827708 (PIONEER 5), NCT02849080 (PIONEER 7) and NCT03021187 (PIONEER 8).

How patients in Denmark acquire their medicines: overview, data sources and implications for pharmacoepidemiology.

The means by which patients acquire their medications differ between countries, and a knowledge of this is essential when conducting and interpreting pharmacoepidemiological studies. The aim of this paper is to provide an overview of how patients obtain medicines in Denmark, to relate these to nationwide registries available for research and to discuss the implications for research. Health services are predominantly tax-funded in Denmark, with dentistry and some medicine bought at community pharmacies being exceptions, involving partial reimbursement of charges. The paper gives an overview of prescription medicines acquired from community pharmacies (including magistral preparations), over-the-counter medicines, vaccinations and in-hospital medicine including so-called "free medicine" (in Danish: "vederlagsfri medicin"). "Free medicine" is medicines for a defined list of diseases and indications that is provided free of charge to patients in outpatient clinics. The paper also describes the content of the various Danish data sources about medicine use, summarizes their strengths and limitations, and exemplifies the ways of evaluating their completeness. An example is provided of the regional variation in the means by which medicines are acquired.

Effects of high-dose, intravenous lipid emulsion on laboratory tests in humans: a randomized, placebo-controlled, double-blind, clinical crossover trial.

Background Intravenous lipid emulsion (ILE) is used to treat drug poisonings. The resultant hyperlipemia may affect laboratory tests but the consequences are poorly characterized. In a clinical trial we therefore investigated the effects of ILE on laboratory tests analyzed on common analytical platforms (Roche® cobas 8000 and SYSMEX® flow-cytometry). Methods Ten healthy participants each completed 4 trial days (two with ILE and two with placebo). ILE (5.25 mL/kg) was administered from 12.5 to 30 min from baseline. At 0, 30 and 60 min, blood samples were drawn for measurement of 20 analytes. We investigated the effects of ILE on analyte levels and frequencies of exceedance of predefined analyzer hemolysis (H) or lipemia (L)-index cut-offs and test-specific reference change values (RCVs) on ILE-days. If the results were blocked due to exceedance of index values, we manually extracted the results. Results Sixteen out of 20 tests were blocked because H- or L-index cut-offs were exceeded on ILE-days. Differences in analyte levels between ILE- and placebo-days above the RCV were observed for aspartate aminotransferase, total calcium, lactate dehydrogenase (LDH), sodium and neutrophils. Mean values outside the normal range after ILE were observed for LDH (219 U/L), sodium (135.3 mmol/L) and total calcium (2.1 mmol/L). Conclusions ILE-infusion caused report failure of nearly all laboratory tests performed on a cobas 8000-platform, but it was possible to manually retrieve the results. For most test results - particularly alkaline phosphatase, bilirubin, phosphate and carbamide - the consequences of ILE were marginal, and the effects of ILE were reduced at the 60-min timepoint.

Do Bone Graft and Cracking of the Sclerotic Cavity Improve Fixation of Titanium and Hydroxyapatite-coated Revision Implants in an Animal Model?

BACKGROUND: We previously introduced a manual surgical technique that makes small perforations (cracks) through the sclerotic bone shell that typically forms during the process of aseptic loosening ("crack" revision technique). Perforating just the shell (without violating the proximal cortex) can maintain overall bone continuity while allowing marrow and vascular elements to access the implant surface. Because many revisions require bone graft to fill defects, we wanted to determine if bone graft could further increase implant fixation beyond what we have experimentally shown with the crack technique alone. Also, because both titanium (Ti6Al4V) and hydroxyapatite (HA) implant surfaces are used in revisions, we also wanted to determine their relative effectiveness in this model. QUESTIONS/PURPOSES: We hypothesized that both (1) allografted plasma-sprayed Ti6Al4V; and (2) allografted plasma-sprayed HA-coated implants inserted with a crack revision technique have better fixation compared with a noncrack revision technique in each case. METHODS: Under approval from our Institutional Animal Care and Use Committee, a female canine animal model was used to evaluate the uncemented revision technique (crack, noncrack) using paired contralateral implants while implant surface (Ti6Al4V, HA) was qualitatively compared between the two (unpaired) series. All groups received bone allograft tightly packed around the implant. This revision model includes a cylindrical implant pistoning 500 µm in a 0.75-mm gap, with polyethylene particles, for 8 weeks. This engenders a bone and tissue response representative of the metaphyseal cancellous region of an aseptically loosened component. At 8 weeks, the original implants were revised and followed for an additional 4 weeks. Mechanical fixation was assessed by load, stiffness, and energy to failure when loaded in axial pushout. Histomorphometry was used to determine the amount and location of bone and fibrous tissue in the grafted gap. RESULTS: The grafted crack revision improved mechanical shear strength, stiffness, and energy to failure (for Ti6Al4V 27- to 69-fold increase and HA twofold increases). The histomorphometric analysis demonstrated primarily fibrous membrane ongrowth and in the gap for the allografted Ti6Al4V noncrack revisions. For allografted HA noncrack revisions, bone ongrowth at the implant surface was observed, but fibrous tissue also was present in the inner gap. Although both Ti6Al4V and HA surfaces showed improved fixation with grafted crack revision, and Ti6Al4V achieved the highest percent gain, HA demonstrated the strongest overall fixation. CONCLUSIONS: The results of this study suggest that novel osteoconductive or osteoinductive coatings and bone graft substitutes or tissue-engineered constructs may further improve bone-implant fixation with the crack revision technique but require evaluation in a rigorous model such as presented here. CLINICAL RELEVANCE: This experimental study provides data on which to base clinical trials aimed to improve fixation of revision implants. Given the multifactorial nature of complex human revisions, such a protocoled clinical study is required to determine the clinical applicability of this approach.

Assessment of the effect of 24-hour aldosterone administration on protein abundance in fluorescence-sorted mouse distal renal tubules by mass spectrometry.

BACKGROUND/AIMS: Aldosterone exerts multiple long-term effects on the distal renal tubules. The aim of this study was to establish a method for identifying proteins in these tubules that change in abundance by only 24-hour aldosterone administration. METHODS: Mice endogenously expressing green fluorescent protein (eGFP) in the connecting tubule and cortical collecting ducts were treated with a subcutaneous injection of 2.0 mg/kg aldosterone or vehicle (n = 5), and sacrificed 24 h later. Suspensions of single cells were obtained enzymatically, and eGFP-positive cells were isolated by fluorescence-activated cell sorting (FACS). Samples of 100 µg of proteins were digested with trypsin and labeled with 8-plex isobaric tags for relative and absolute quantitation reagents and processed for liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: FACS yielded 1.4 million cells per mouse. The LC-MS/MS spectra were matched to peptides by the SEQUEST search algorithm, which identified 3,002 peptides corresponding to 506 unique proteins, of which 20 significantly changed abundance 24 h after aldosterone injection. CONCLUSION: We find the method suitable and useful for studying hormonal effects on protein abundance in distal tubular segments.

The effect of pretreating morselized allograft bone with rhBMP-2 and/or pamidronate on the fixation of porous Ti and HA-coated implants.

BMPs stimulate new bone formation, but may also accelerate bone resorption. We added rhBMP-2 and pamidronate to morselized bone allograft packed around uncemented HA-coated and non-coated porous Ti implants in sixteen dogs. Each dog received four implants where the allograft was added (1) nothing, (2) BMP, (3) BP, and (4) BMP+BP. After four weeks, the untreated control implants had better mechanical fixation than all other treatment groups. The rhBMP-2-treated group had abundant formation of new bone on and around the implant. However, almost all allografts were resorbed, rendering the implant mechanically unstable. In the pamidronate-treated group the allograft was preserved, but the implants were covered by fibrous tissue and there was almost no new bone formation. This was also the case for the combined BMP+BP group, although fibrous tissue was absent on these implants. The HA-coated implants had more than twice as good mechanical fixation and improved osseointegration compared to the corresponding Ti implants. RhBMP-2 raised the total metabolic turnover of bone within the allograft with a net negative result on implant fixation. Pamidronate virtually blocked bone metabolism, also when combined with rhBMP-2. The results warrant a conservative approach and emphasize the importance of identifying a therapeutic window for these substances prior to clinical use.

Tuning the self-assembly of lanthanide triple stranded heterobimetallic helicates by ligand design.

The heterobitopic ligands L(AB4) and L(AB5) have been designed and synthesised with the ultimate aim of self-assembling dual-function lanthanide complexes containing either a magnetic and a luminescent probe or two luminescent probes emitting at different wavelengths. They react with lanthanide ions to form complexes of composition [Ln(2)(L(ABX))(3)](6+) of which three (X = 4; Ln = Pr, Nd, Sm) have been isolated and characterised by means of X-ray diffraction. The unit cells contain triple-stranded helicates in which the three ligand strands are wrapped tightly around the two lanthanide ions. In acetonitrile solution the ligands form not only homobimetallic, but also heterobimetallic complexes of composition [Ln(1)Ln(2)(L(ABX))(3)](6+) when reacted with a pair of different lanthanide ions. The yield of heterobimetallic complexes is analyzed in terms of both the difference in ionic radii of the lanthanide ions and of the inherent tendency of the ligands to form high percentages of head-head-head (HHH) helicates in which all three ligand strands are oriented in the same direction with respect to the Ln-Ln vector. The latter is very sensitive to slight modifications of the tridentate coordinating units.

Thermodynamics of dimerization in solution as a rational tool for inducing nematic vs. smectic organizations in lanthanidomesogens.

The judicious tuning of simple thermodynamic parameters controlling dimerization processes in solution induces a rational switch between smectic and nematic organizations in thermotropic lanthanide-containing liquid crystals.

Thermodynamic parameters governing the self-assembly of head-head-head lanthanide bimetallic helicates.

The heterobitopic ligands L ABX (X=1, 2, 3, 4 or 5), differing only by a Cl or NEt(2) substituent, have been designed to complex with a pair of lanthanide ions to form triple-stranded bimetallic helicates of overall composition [Ln2(L ABX)3]6+. The percentage of HHH (head-head-head) isomer, in which each of the three ligand strands coordinates to the same lanthanide ion with the same coordination unit, is deciding the ability of the ligands to selectively form heterobimetallic complexes containing one luminescent and one magnetic or two different luminescent ions. It deviates significantly from the statistical value of 25 % and ranges from 6-20 % for L AB2 complexes to 93-96 % for L AB4 complexes. The equilibrium between HHT (head-head-tail) and HHH isomers has been investigated in detail for homobimetallic helicates (Ln=Y, La, Ce, Pr, Nd, Sm, Eu, Lu) by means of variable temperature NMR and thermodynamic parameters have been determined. The equilibrium is characterized by small values of DeltaH and DeltaS, which vary in opposite direction along the lanthanide series for complexes with the same ligand in a way that keeps the value of DeltaG almost constant. The results are interpreted in terms of differences in interstrand stacking, ion-dipole interactions and metal-metal repulsion.

Systemic alendronate treatment improves fixation of press-fit implants: a canine study using nonloaded implants.

Bone resorption associated with local trauma occurring during insertion of joint prostheses is recognized as an early event. Being an osteoclastic inhibitor, alendronate is a potential candidate means to decrease early periprosthetic bone resorption and thereby improve implant fixation. We investigated the influence of oral alendronate treatment on early implant fixation in two implant interface settings representing sites of an implant that are in contact with surrounding bone, and other sites without intimate bone contact. One plasma-sprayed cylindrical titanium implant (6 mm diameter) was inserted into each proximal tibia of 16 dogs. On one side the implant was inserted press-fit whereas on the contralateral side, the implants were surrounded by a 2 mm concentric gap. Oral alendronate (0.5 mg/kg/day) was given 2 weeks following surgery to eight dogs. The dogs were euthanized after 10 weeks of alendronate treatment. Bone ongrowth (bone in contact with implant surface) was estimated using the linear intercept technique and shear strength was calculated as the slope on a load-displacement curve. For the press fit implants, alendronate treatment significantly increased bone ongrowth from 24% to 29% and significantly increased ultimate shear strength from 1.26 to 3.72 MPa. Also, the fraction of periprosthetic bone significantly increased from 10% to 18%. For implants surrounded by a gap, alendronate neither stimulated nor impaired implant fixation, bone ingrowth, or new bone formation in the gaps. Because early implant stability is an important predictor of longevity, systemic alendronate treatment could be an important clinical tool to positively influence the early stages of implant incorporation.

Alendronate treatment in the revision setting, with and without controlled implant motion: an experimental study in dogs.

INTRODUCTION: Bisphosphonates have been proposed to delay or prevent loosening of joint replacement implants by reducing bone resorption. It is known, however, that implant motion prevents the bone anchorage necessary to maintain secure implant fixation. METHODS: We used our experimental implant model with controlled motion to evaluate the relative effects of implant motion and bisphosphonate. We implemented our established 8-week experimental revision protocol to obtain a bony and soft tissue setting of revision joint replacement in 16 dogs. At 8 weeks, we had stabilized half of the implants. The other half of the implants continued pistoning. Half of the dogs were exposed to alendronate (oral). RESULTS: Stabilization of the revision implant was more effective at improving fixation (higher shear strength) than administering alendronate. As expected, the fibrous membrane remained under unstable conditions, even with alendronate. With alendronate and stabilized implants, increased bone was observed near the sclerotic shell of the revision cavity, but it was reduced with alendronate when the implant was unstable. INTERPRETATION: Our findings suggest that it may be difficult for alendronate administration alone to rescue implants that are already loose. In implants that have not progressed to loosening, alendronate may increase bone density at the border with the sclerotic shell, but the effect of this bone in delaying eventual loosening is not known.

Lanthanide triple-stranded helicates: controlling the yield of the heterobimetallic species.

Two unsymmetrical ditopic hexadentate ligands designed for the simultaneous recognition of two different trivalent lanthanide ions have been synthesized, L(AB2) and L(AB3), where A represents a tridentate benzimidazole-pyridine-benzimidazole coordination unit, B2 a diethylamine-substituted benzimidazole-pyridine-carboxamide one, and B3 a chlorine-substituted benzimidazole-pyridine-carboxamide moiety. Under stoichiometric 2:3 (Ln/L) conditions, these ligands self-assemble with lanthanide ions to yield triple-stranded bimetallic helicates. The crystal structures of four helicates with L(AB3) of composition [LnLn'(L(AB3))3](ClO4)6.solv (CeCe, PrPr, PrLu, NdLu) show the metal ions embedded into a helical structure with a pitch of about 13.2-13.4 A. The metal ions lie at a distance of 9.1-9.2 A and are nine-coordinated by the three ligand strands, which are oriented in a HHH (head-head-head) fashion, where all ligand strands are oriented in the same direction. In the presence of a pair of different lanthanide ions in acetonitrile solution, the ligand L(AB3) shows selectivity and gives high yields of heterobimetallic complexes. L(AB2) displays less selectivity, and this is shown to be directly related to the tendency of this ligand to form high yields of HHT (head-head-tail) isomer. A fine-tuning of the HHH left arrow over right arrow HHT equilibrium and of the selectivity for heteropairs of Ln(III) ions is therefore at hand.

Spectroscopic, magnetochemical, and crystallographic study of cesium iron phosphate hexahydrate: characterization of the electronic structure of the iron(II) hexa-aqua cation in a quasicubic environment.

Spectroscopic, magnetochemical, and crystallographic data are presented for CsFe(H2O)6PO4, a member of a little-known isomorphous series of salts that facilitates the study of hexa-aqua ions in a quasicubic environment. Above 120 K, the deviations from cubic symmetry are minimal, as shown by the first example of an iron(II) Mössbauer spectrum that exhibits no measurable quadrupole splitting. Two crystallographically distinct [Fe(OH2)6]2+ complexes are identified from inelastic neutron-scattering (INS) experiments conducted between 2 and 15 K. The data are modeled with the ligand-field Hamiltonian, H = lambdaLs + betaB(kL + 2s) + Delta(tet){Lz2 - (1/3)L(L + 1)} + Delta(rhom){Lx2 - Ly2}, operating in the ground-term (5)T(2g) (Oh) basis. An excellent reproduction of INS, Mössbauer, HF-EPR, and magnetochemical data are obtained in the 2 and 15 K temperature regimes with the following parameters: lambda = -80 cm(-1); k = 0.8; site A Delta(tet) = 183 cm(-1), Delta(rhom)= 19 cm(-1); site B Delta(tet) = 181 cm(-1), Delta(rhom)= 12 cm(-1). The corresponding zero-field-splitting (ZFS) parameters of the conventional S = 2 spin Hamiltonian are as follows: site A D = 12.02 cm(-)(1), E = 2.123 cm(-1); site B D = 12.15 cm(-1), E = 1.37 cm(-1). A theoretical analysis of the variation of the energies of the low-lying states with respect to displacements along selected normal coordinates of the [Fe(OH2)6]2+, shows the zero-field splitting to be extremely sensitive to small structural perturbations of the complex. The expressions derived are discussed in the context of spin-Hamiltonian parameters reported for the [Fe(OH2)6]2+ cation in different crystalline environments.

Differential effect of a bone morphogenetic protein-7 (OP-1) on primary and revision loaded, stable implants with allograft.

Morselized impacted bone allograft is often used to reconstruct the bone bed in the revision of failed total joint arthroplasties. We hypothesized that addition of the bone morphogenetic protein OP-1 (BMP-7) to bone allograft would improve early implant fixation. We inserted one loaded 6-mm-diameter titanium implant (surrounded by 0.75-mm gap) in each medial condyle of 24 canines. On one side, the implant was inserted in a controlled experimental revision setting resembling the clinical revision situation. A primary implant was inserted on the contralateral side in a previously unoperated site. Three groups were studied: 1) allograft alone, 2) allograft + 0.4 mg OP-1, and 3) allograft + 0.8 mg OP-1. Implant fixation was evaluated at 4 weeks. Grafted implants inserted in the primary setting without OP-1 had better fixation than the grafted revision setting with or without OP-1 (significantly more bone coverage, more mineralized tissue in the gap, and better mechanical interface strength). However, grafted primary implants with OP-1 had impaired fixation compared with grafted primary implants without OP-1 (less bone coverage of the implant and less bone formation in the gap). In contrast, grafted revision implants with OP-1 significantly increased implant fixation compared with grafted revision implants without OP-1 (increased mechanical interface strength and fraction of mineralized tissue in the gap). We found no differences between the two doses in any of the settings. Addition of OP-1 to bone allografted implants may show benefit at sites with impaired bone healing capacities, such as the revision setting.

Supramolecular recognition of heteropairs of lanthanide ions: a step toward self-assembled bifunctional probes.

Three unsymmetrical ditopic hexadentate ligands coded for the recognition of trivalent lanthanide ions have been synthesized, L(AB), L(AC), and L(BC), where A represents a benzimidazole-pyridine-benzimidazole coordination unit, B a benzimidazole-pyridine-carboxamide one, and C a benzimidazole-pyridine-carboxylic acid moiety. Under stoichiometric 2:3 (Ln:L) conditions, these ligands self-assemble with lanthanide ions to yield triple-stranded bimetallic helicates having a sizable stability in acetonitrile: log beta(23) values for Eu are equal to 23.9 +/- 0.5 (L(AB)), 23.3 +/- 0.7 (deprotonated L(AC)), and 29.8 +/- 0.5 (deprotonated L(BC)). The crystal structure of the EuEu helicate with L(AB) shows 9-coordinate metal ions and an HHH (H stands for head) configuration of the helically wrapped ligand strands. In the presence of equimolar quantities of Ln and Ln' ions, L(AB) displays a remarkable predisposition to form HHH-heterobimetallic edifices, as proved both in the solid state by the crystal structures of the LaEu, LaTb, PrEr, and PrLu helicates and in solution by NMR spectroscopy. In all cases, the benzimidazole-pyridine-carboxamide units of the three ligands are bound to the smaller lanthanide ion, a fact further ascertained by high-resolution luminescence data on LaEu and by (1)H NMR. Analysis of the lanthanide-induced (1)H NMR shifts and of the spin-lattice relaxation times of the [LnLu(L(AB))(3)](6+) series (Ln = Ce, Pr, Nd, Sm, Eu) demonstrates the isostructural nature of the complexes in solution and that the crystal structure of LaTb is a good model for the solution structure. The selectivity of L(AB) for heteropairs of Ln(III) ions increases with increasing difference in ionic radius, resulting in 70% of the heterobimetallic species for deltar(i) = 0.1 A and up to 90% for LaLu (deltar(i) = 0.18 A), and corresponding to delta(deltaG) in the range 3-10 kJ.mol(-)(1). The origins of this stabilization are discussed in terms of the donor properties of the coordinating units and of the preferential formation of HHH isomers.