Metamorphic microdiamond formation is controlled by water activity, phase transitions and temperature.

Metamorphic diamonds hosted by major and accessory phases in ultrahigh-pressure (UHP) metamorphic terranes represent important indicators of deep subduction and exhumation of continental crust at convergent plate boundaries. However, their nucleation and growth mechanisms are not well understood due to their small size and diversity. The Bohemian microdiamond samples represent a unique occurrence of monocrystalline octahedral and polycrystalline cubo-octahedral microdiamonds in two different metasedimentary rock types. By combining new and published data on microdiamonds (morphology, resorption, associated phases, carbon isotope composition) with P-T constraints from their host rocks, we demonstrate that the peak P-T conditions for the diamond-bearing UHP rocks cluster along water activity-related phase transitions that determine the microdiamond features. With increasing temperature, the diamond-forming medium changes from aqueous fluid to hydrous melt, and diamond morphology evolves from cubo-octahedral to octahedral. The latter is restricted to the UHP-UHT rocks exceeding 1100 °C, which is above the incongruent melting of phengite, where microdiamonds nucleate along a prograde P-T path in silicate-carbonate hydrous melt. The observed effect of temperature on diamond morphology supports experimental data on diamond growth and can be used for examining growth conditions of cratonic diamonds from kimberlites, which are dominated by octahedra and their resorbed forms.

Timing of geological events in the lunar highlands recorded in shocked zircon-bearing clasts from Apollo 16.

Apollo 16 soil-like regolith breccia 65745,7 contains two zircon-bearing clasts. One of these clasts is a thermally annealed silica-rich rock, which mineralogically has affinities with the High Alkali Suite (Clast 1), and yields zircon dates ranging from 4.08 to 3.38 Ga. The other clast is a KREEP-rich impact melt breccia (Clast 2) and yields zircon dates ranging from 3.97 to 3.91 Ga. The crystalline cores of both grains, which yield dates of ca 3.9 Ga, have undergone shock pressure modification at less than 20 GPa. We interpret that the U-Pb chronometer in these zircon grains has been partially reset by the Imbrium basin-forming event when the clasts were incorporated into the Cayley Plains ejecta blanket deposit. The zircon grains in Clast 1 have been partially decomposed, resulting in a breakdown polymineralic texture, with elevated U, Pb and Th abundances compared with those in the crystalline zircon. These decomposed areas exhibit younger dates around 3.4 Ga, suggesting a secondary high-pressure, high-temperature event, probably caused by an impact in the local Apollo 16 highlands area.

Pb-Pb ages and initial Pb isotopic composition of lunar meteorites: NWA 773 clan, NWA 4734, and Dhofar 287.

Constraining the duration of magmatic activity on the Moon is essential to understand how the lunar mantle evolved chemically through time. Determining age and initial isotopic compositions of mafic lunar meteorites is a critical step in defining the periods of magmatic activity that occurred during the history of the Moon and to constrain the chemical characteristics of mantle components involved in the sources of the magmas. We have used the in situ Pb-Pb SIMS technique to investigate eight lunar gabbros and basalts, including six meteorites from the Northwest Africa (NWA) 773 clan (NWA 2727, NWA 2700, NWA 3333, NWA 2977, NWA 773, and NWA 3170), NWA 4734, and Dhofar 287A. These samples have been selected as there is no clear agreement on their age and they are all from the dominant low titanium chemical group. We have obtained ages of 2981 ± 12 Ma for NWA 4734 and 3208 ± 22 Ma for Dhofar 287. For the NWA 773 clan, four samples (the fine-grained basalt NWA 2727 and the three gabbros NWA 773, NWA 2977, NWA 3170) out of six yielded isochron-calculated ages that are identical within uncertainties and yielding an average age of 3086 ± 5 Ma. The age obtained for the fine-grained basalt NWA 2700 is not precise enough for comparison with the other samples. The gabbroic sample NWA 3333 yielded an age of 3038 ± 20 Ma suggesting that two distinct magmatic events may be recorded in the meteorites of the NWA 773 clan. The present study aims to identify and assess all potential issues that are associated with different ways to date lunar rocks using U-Pb-based methods. To achieve this, we have compared the new ages with the previously published data set. The entire age data set from lunar mafic meteorites was also screened to identify data showing analytical issues and evidence of resetting and terrestrial contamination. The data set combining the ages of mafic lunar meteorites and Apollo rocks suggests pulses of magmatic activity with two distinct phases between 3950 and 3575 Ma and between 3375 and 3075 Ma with the two phases separated by a gap of approximately 200 Ma. The evolution of the Pb initial ratios of the low-Ti mare basalts between approximately 3400 and 3100 Ma suggests that these rocks were progressively contaminated by a KREEP-like component.

Simultaneous Pu and U Isotope Nuclear Forensics on an Environmentally Recovered Hot Particle.

An environmentally recovered, mixed Pu-U hot particle from the Thule accident, Greenland has been analyzed by Scanning Electron Microscopy and a large-geometry Secondary Ion Mass Spectrometry based Scanning Ion Imaging (SII) method for simultaneous 235,236,238U and 239,240Pu isotope compositions. This SII technique permits the visual assessment of the spatial distribution of the isotopes of U and Pu and can be used to obtain quantitative isotope ratios in any user-defined square region up to a few 100 µm in size. The particle measured here has two resolvable U isotopic compositions with a single composition of weapons grade Pu. The bulk of the particle has enriched U and weapons-grade Pu with 235U/238U, 236U/238U, and 240Pu/239Pu of 1.12 ± 0.04, 0.006 ± 0.002, 0.054 ± 0.004, respectively (2σ). The Pu isotopic ratio was consistent across the sample but 239Pu/238Uraw decreased from 1.99 ± 0.07 to 0.11 ± 0.04 (2σ) corresponding to the area of the particle with a resolvably different U isotope composition. This portion of the particle has 235U/238U, 236U/238U, and 240Pu/239Pu ratios of 0.11 ± 0.04, 0.001 ± 0.002, and 0.05 ± 0.04, respectively (2σ). The origin of the less enriched U could be environmental that mixed with the particle or heterogeneously enriched U from the weapons. The heterogeneity of hot particles on a micrometer scale highlights the need for spatially resolved techniques to avoid mixing during a bulk or whole particle analysis, as the mixing end-members here would have been lost, and the measured ratios would have been inaccurate.

Hadean geodynamics inferred from time-varying 142Nd/144Nd in the early Earth rock record.

Tracking the secular evolution of 142Nd/144Nd anomalies is important towards understanding the crust-mantle dynamics in the early Earth. Excessive scatter in the published data, however, precludes identifying the fine structure of 142Nd/144Nd evolution as the expected variability is on the order of few parts per million. We report ultra-high precision 142Nd/144Nd data for Eoarchean and Palaeoarchean rocks from the Isua Supracrustal Belt (SW Greenland) that show a well-resolved 142Nd/144Nd temporal variability suggesting progressive convective homogenisation of the Hadean Isua depleted mantle. This temporally decreasing 142Nd/144Nd signal provides a direct measure of early mantle dynamics, defining a stirring timescale of <250 Myr consistent with vigorous convective stirring in the early mantle. The 142Nd/144Nd evolution suggests protracted crustal residence times of ~1000-2000 Myr, inconsistent with modern-style plate tectonics in the Archean. In contrast, a stagnant-lid regime punctuated by episodes of mantle overturns accounts for the long life-time estimated here for the Hadean proto-crust.

The Neoarchaean surficial sulphur cycle: An alternative hypothesis based on analogies with 20th-century atmospheric lead.

We revisit the S-isotope systematics of sedimentary pyrite in a shaly limestone from the ca. 2.52 Ga Gamohaan Formation, Upper Campbellrand Subgroup, Transvaal, South Africa. The analysed rock is interpreted to have been deposited in a water depth of ca. 50-100 m, in a restricted sub-basin on a drowning platform. A previous study discovered that the pyrites define a nonzero intercept δ34 SV-CDT -Δ33 S data array. The present study carried out further quadruple S-isotope analyses of pyrite, confirming and expanding the linear δ34 SV-CDT -Δ33 S array with an δ34 S zero intercept at ∆33 S ca. +5. This was previously interpreted to indicate mixing of unrelated S-sources in the sediment environment, involving a combination of recycled sulphur from sulphides that had originally formed by sulphate-reducing bacteria, along with elemental sulphur. Here, we advance an alternative explanation based on the recognition that the Archaean seawater sulphate concentration was likely very low, implying that the Archaean ocean could have been poorly mixed with respect to sulphur. Thus, modern oceanic sulphur systematics provide limited insight into the Archaean sulphur cycle. Instead, we propose that the 20th-century atmospheric lead event may be a useful analogue. Similar to industrial lead, the main oceanic input of Archaean sulphur was through atmospheric raindown, with individual giant point sources capable of temporally dominating atmospheric input. Local atmospheric S-isotope signals, of no global significance, could thus have been transmitted into the localised sediment record. Thus, the nonzero intercept δ34 SV-CDT -Δ33 S data array may alternatively represent a very localised S-isotope signature in the Neoarchaean surface environment. Fallout from local volcanic eruptions could imprint recycled MIF-S signals into pyrite of restricted depositional environments, thereby avoiding attenuation of the signal in the subdued, averaged global open ocean sulphur pool. Thus, the superposition of extreme local S-isotope signals offers an alternative explanation for the large Neoarchaean MIF-S excursions and asymmetry of the Δ33 S rock record.

Cell-specific nitrogen- and carbon-fixation of cyanobacteria in a temperate marine system (Baltic Sea).

We analysed N2 - and carbon (C) fixation in individual cells of Baltic Sea cyanobacteria by combining stable isotope incubations with secondary ion mass spectrometry (SIMS). Specific growth rates based on N2 - and C-fixation were higher for cells of Dolichospermum spp. than for Aphanizomenon sp. and Nodularia spumigena. The cyanobacterial biomass, however, was dominated by Aphanizomenon sp., which contributed most to total N2 -fixation in surface waters of the Northern Baltic Proper. N2 -fixation by Pseudanabaena sp. and colonial picocyanobacteria was not detectable. N2 -fixation by Aphanizomenon sp., Dolichospermum spp. and N. spumigena populations summed up to total N2 -fixation, thus these genera appeared as sole diazotrophs within the Baltic Sea's euphotic zone, while their mean contribution to total C-fixation was 21%. Intriguingly, cell-specific N2 -fixation was eightfold higher at a coastal station compared to an offshore station, revealing coastal zones as habitats with substantial N2 -fixation. At the coastal station, the cell-specific C- to N2 -fixation ratio was below the cellular C:N ratio, i.e. N2 was assimilated in excess to C-fixation, whereas the C- to N2 -fixation ratio exceeded the C:N ratio in offshore sampled diazotrophs. Our findings highlight SIMS as a powerful tool not only for qualitative but also for quantitative N2 -fixation assays in aquatic environments.

Does a Heavy Fe-Isotope Composition of Akilia Quartz-Amphibole-Pyroxene Rocks Necessitate a BIF Origin?

The age and origin of the quartz-amphibole-pyroxene (qap) gneiss from the island of Akilia, southern West Greenland, have been the subject of intense debate since the light C-isotope composition of graphite inclusions in apatite was interpreted to indicate the presence of Earth's earliest biological activity. Although this claim for biogenic relicts has been vigorously challenged, the possibility that the rocks might represent some of Earth's earliest water-lain sediments and, hence, a suitable repository for life remains an open question. While some workers have suggested that the entire sequence represents an originally mafic-ultramafic igneous precursor subsequently modified by metasomatism, quartz injection, high-grade metamorphism, and extreme ductile deformation, others maintain that at least a small part of the sequence retains geochemical characteristics indicative of a chemical sedimentary origin. Fractionated Fe isotopes with δ(56)Fe values similar to those observed in Isua BIF have been reported from high-SiO2 units of qap and used to support a chemical sedimentary protolith for the qap unit. Here, we present new Fe isotope data from all lithologic variants in the qap gneiss on Akilia, including layers of undisputed ultramafic igneous origin. Since the latter require introduction of fractionated Fe into at least part of the qap unit, we argue that Fe isotopes must therefore be treated with considerable caution when used to infer BIF for part or all of the qap protolith.

Hafnium isotope evidence for a transition in the dynamics of continental growth 3.2 Gyr ago.

Earth's lithosphere probably experienced an evolution towards the modern plate tectonic regime, owing to secular changes in mantle temperature. Radiogenic isotope variations are interpreted as evidence for the declining rates of continental crustal growth over time, with some estimates suggesting that over 70% of the present continental crustal reservoir was extracted by the end of the Archaean eon. Patterns of crustal growth and reworking in rocks younger than three billion years (Gyr) are thought to reflect the assembly and break-up of supercontinents by Wilson cycle processes and mark an important change in lithosphere dynamics. In southern West Greenland numerous studies have, however, argued for subduction settings and crust growth by arc accretion back to 3.8 Gyr ago, suggesting that modern-day tectonic regimes operated during the formation of the earliest crustal rock record. Here we report in situ uranium-lead, hafnium and oxygen isotope data from zircons of basement rocks in southern West Greenland across the critical time period during which modern-like tectonic regimes could have initiated. Our data show pronounced differences in the hafnium isotope-time patterns across this interval, requiring changes in the characteristics of the magmatic protolith. The observations suggest that 3.9-3.5-Gyr-old rocks differentiated from a >3.9-Gyr-old source reservoir with a chondritic to slightly depleted hafnium isotope composition. In contrast, rocks formed after 3.2 Gyr ago register the first additions of juvenile depleted material (that is, new mantle-derived crust) since 3.9 Gyr ago, and are characterized by striking shifts in hafnium isotope ratios similar to those shown by Phanerozoic subduction-related orogens. These data suggest a transitional period 3.5-3.2 Gyr ago from an ancient (3.9-3.5 Gyr old) crustal evolutionary regime unlike that of modern plate tectonics to a geodynamic setting after 3.2 Gyr ago that involved juvenile crust generation by plate tectonic processes.

Pharmacokinetics and safety of CXA-101, a new antipseudomonal cephalosporin, in healthy adult male and female subjects receiving single- and multiple-dose intravenous infusions.

CXA-101 is a novel, broad-spectrum cephalosporin with excellent antipseudomonal activity. A Phase 1 study was performed to determine the safety, tolerability, and pharmacokinetics of CXA-101 after single- and multiple-dose intravenous administration over 1 h to healthy male and female subjects. In part 1 of the study, five cohorts of eight subjects each (six receiving CXA-101 and two receiving a placebo) received single ascending doses of 250, 500, 1,000, 1,500, and 2,000 mg. In part 2, cohorts 1 and 2 received 500 mg and 1,000 mg, respectively, every 8 h, and cohort 3 received 1,500 mg every 12 h; each cohort received dosing for 10 days. Standard safety and tolerability assessments were performed. Blood and urine pharmacokinetic samples were assayed by a validated bioanalytical method and analyzed using standard noncompartmental methodology. All 64 subjects completed dosing; none withdrew from the study. Drug-related systemic adverse events were infrequent and mild. Mild, non-treatment-limiting infusion site events occurred during multiple-dose administration. No clinically significant laboratory or electrocardiographic finding or dose-limiting toxicity was observed. CXA-101 exhibited dose-linear pharmacokinetics; the mean plasma half-life was approximately 2.3 h. More than 90% of the administered dose was eliminated unchanged through renal excretion. In summary, CXA-101 administered as a 1-hour infusion was generally safe and well tolerated in single doses up to 2,000 mg and in multiple doses up to 3 g daily over 10 days. The favorable safety and predictable pharmacokinetic profile of CXA-101 support its continuing clinical development for the treatment of serious bacterial infections.

Rational design of a combination medication for the treatment of obesity.

Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro-opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo-controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of beta-endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.\

The crystallization age of eucrite zircon.

Eucrites are a group of meteorites that represent the first planetary igneous activity following metal-silicate differentiation on an early planetesimal, similar to Asteroid 4 Vesta, and, thus, help date geophysical processes occurring on such bodies in the early solar system. Using the short-lived radionuclide (182)Hf as a relative chronometer, we demonstrate that eucrite zircon crystallized quickly within 6.8 million years of metal-silicate differentiation. This implies that mantle differentiation on the eucrite parent body occurred during a period when internal heat from the decay of (26)Al and (60)Fe was still available. Later metamorphism of eucrites took place at least 8.9 million years after the zircons crystallized and was likely caused by heating from impacts, or by burial under hot material excavated by impacts, rather than from lava flows. Thus, the timing of eucrite formation and of mantle differentiation is constrained.

Spatial and temporal operation of the Scotia Sea ecosystem: a review of large-scale links in a krill centred food web.

The Scotia Sea ecosystem is a major component of the circumpolar Southern Ocean system, where productivity and predator demand for prey are high. The eastward-flowing Antarctic Circumpolar Current (ACC) and waters from the Weddell-Scotia Confluence dominate the physics of the Scotia Sea, leading to a strong advective flow, intense eddy activity and mixing. There is also strong seasonality, manifest by the changing irradiance and sea ice cover, which leads to shorter summers in the south. Summer phytoplankton blooms, which at times can cover an area of more than 0.5 million km2, probably result from the mixing of micronutrients into surface waters through the flow of the ACC over the Scotia Arc. This production is consumed by a range of species including Antarctic krill, which are the major prey item of large seabird and marine mammal populations. The flow of the ACC is steered north by the Scotia Arc, pushing polar water to lower latitudes, carrying with it krill during spring and summer, which subsidize food webs around South Georgia and the northern Scotia Arc. There is also marked interannual variability in winter sea ice distribution and sea surface temperatures that is linked to southern hemisphere-scale climate processes such as the El Niño-Southern Oscillation. This variation affects regional primary and secondary production and influences biogeochemical cycles. It also affects krill population dynamics and dispersal, which in turn impacts higher trophic level predator foraging, breeding performance and population dynamics. The ecosystem has also been highly perturbed as a result of harvesting over the last two centuries and significant ecological changes have also occurred in response to rapid regional warming during the second half of the twentieth century. This combination of historical perturbation and rapid regional change highlights that the Scotia Sea ecosystem is likely to show significant change over the next two to three decades, which may result in major ecological shifts.

Magmatic and crustal differentiation history of granitic rocks from Hf-O isotopes in zircon.

Granitic plutonism is the principal agent of crustal differentiation, but linking granite emplacement to crust formation requires knowledge of the magmatic evolution, which is notoriously difficult to reconstruct from bulk rock compositions. We unlocked the plutonic archive through hafnium (Hf) and oxygen (O) isotope analysis of zoned zircon crystals from the classic hornblende-bearing (I-type) granites of eastern Australia. This granite type forms by the reworking of sedimentary materials by mantle-like magmas instead of by remelting ancient metamorphosed igneous rocks as widely believed. I-type magmatism thus drives the coupled growth and differentiation of continental crust.

Micro-scale sulphur isotope evidence for sulphur cycling in the late Archean shallow ocean.

We report in situ secondary ion mass spectrometer sulphur isotope data for sedimentary pyrite from the 2.52 Ga Upper Campbellrand Subgroup, Transvaal, South Africa. The analysed sedimentary rocks represent a transition in depositional environment from very shallow to deeper water, with strong sedimentological, facies distribution and geochemical evidence for the presence of a shallow redox chemocline. Data were obtained directly in thin section in order to preserve petrographic context. They reveal a very large extent of isotopic fractionation both in mass-independent (MIF) and in mass-dependent fractionation (MDF) on unprecedentedly small scale. In the shallow-water microbical carbonates, three types of pyrite were identified. The texturally oldest pyrite is found as small, isotopically little fractionated grains in the microbial mats. Large (several mm) spheroidal pyrite concretions, which postdate the mat pyrite, record strong evidence for an origin by bacterial sulphate reduction. Rare pyrite surrounding late fenestral calcite is inferred to have formed from recycled bacterial pyrite on account of the slope of its correlated MIF and MDF array. This latter type of pyrite was also found in an interbedded black shale and a carbonate laminite. In a deeper water chert, pyrite with very heavy sulphur indicates partial to almost complete sulphate reduction across a chemocline whose existence has been inferred independently. The combined picture from all the studied samples is that of a sulphate availability-limited environment, in which sulphur was cycled between reservoirs according to changing redox conditions established across the chemocline. Cycling apparently reduced the extent of recorded sulphur isotope fractionation relative to what is expected from projection in the correlated MIF and MDF arrays. This is consistent with regionally relatively high free oxygen concentrations in the shallow water, permitting locally strong MDF. Our new observations add to the growing evidence for a complex, fluctuating evolution of free atmospheric oxygen between c. 2.7 Ga and 2.3 Ga.

Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial.

BACKGROUND: Recombinant fibroblast growth factor-2 (rFGF-2) improves perfusion in models of myocardial and hindlimb ischaemia. We investigated whether one or two doses of intra-arterial rFGF-2 improves exercise capacity in patients with moderate-to-severe intermittent claudication. METHODS: 190 patients with intermittent claudication caused by infra-inguinal atherosclerosis were randomly assigned (1:1:1) bilateral intra-arterial infusions of placebo on days 1 and 30 (n=63); rFGF-2 (30 microg/kg) on day 1 and placebo on day 30 (single-dose, n=66); or rFGF-2 (30 microg/kg) on days 1 and 30 (double-dose, n=61). Primary outcome was 90-day change in peak walking time. Secondary outcomes included ankle-brachial pressure index and safety. The main analysis was per protocol. FINDINGS: Before 90 days, six patients had undergone peripheral revascularisation and were excluded, and ten withdrew or had missing data. 174 were therefore assessed for primary outcome. Peak walking time at 90 days was increased by 0.60 min with placebo, by 1.77 min with single-dose, and by 1.54 min with double-dose. By ANOVA, the difference between groups was p=0.075. In a secondary intention-to-treat analysis, in which all 190 patients were included, the difference was p=0.034. Pairwise comparison showed a significant difference between placebo and single-dose (p=0.026) but placebo and double-dose did not differ by much (p=0.45). Serious adverse events were similar in all groups. INTERPRETATION: Intra-arterial rFGF-2 resulted in a significant increase in peak walking time at 90 days; repeat infusion at 30 days was no better than one infusion. The findings of TRAFFIC provide evidence of clinical therapeutic angiogenesis by intra-arterial infusion of an angiogenic protein.

Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial.

BACKGROUND: Single-bolus intracoronary administration of fibroblast growth factor-2 (FGF2) improved symptoms and myocardial function in a phase I, open-label trial in patients with coronary artery disease. We conducted the FGF Initiating RevaScularization Trial (FIRST) to evaluate further the efficacy and safety of recombinant FGF2 (rFGF2). METHODS AND RESULTS: FIRST is a multicenter, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of rFGF2 at 0, 0.3, 3, or 30 microg/kg (n=337 patients). Efficacy was evaluated at 90 and 180 days by exercise tolerance test, myocardial nuclear perfusion imaging, Seattle Angina Questionnaire, and Short-Form 36 questionnaire. Exercise tolerance was increased at 90 days in all groups and was not significantly different between placebo and FGF-treated groups. rFGF2 reduced angina symptoms as measured by the angina frequency score of the Seattle Angina Questionnaire (overall P=0.035) and the physical component summary scale of the Short-Form 36 (pairwise P=0.033, all FGF groups versus placebo). These differences were more pronounced in highly symptomatic patients (baseline angina frequency score < or =40 or Canadian Cardiovascular Society score of III or IV). None of the differences were significant at 180 days because of continued improvement in the placebo group. Adverse events were similar across all groups, except for hypotension, which occurred with higher frequency in the 30-microg/kg rFGF2 group. CONCLUSIONS: A single intracoronary infusion of rFGF2 does not improve exercise tolerance or myocardial perfusion but does show trends toward symptomatic improvement at 90 (but not 180) days.

Design of the therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (TRAFFIC) trial.

The Therapeutic Angiogenesis With Recombinant Fibroblast Growth Factor-2 for Intermittent Claudication (TRAFFIC) is a large, randomized, placebo-controlled, regimen-finding trial of intra-arterial recombinant fibroblast growth factor-2 in patients with intermittent claudication. This report describes the major design considerations and end points in TRAFFIC.

Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease.

Fibroblast growth factor-2 (FGF-2) is a heparin-binding protein capable of inducing angiogenesis in multiple animal models of chronic ischemia. The pharmacokinetics and pharmacodynamics of a single dose of recombinant FGF-2 (rFGF-2) administered by intracoronary or intravenous infusion were evaluated in a Phase I trial in 66 patients with severe coronary artery disease. rFGF-2 displayed biphasic elimination with a mean studywide distribution t1/2 of 21 minutes and a mean apparent terminal elimination t1/2 of 7.6 hours. Systemic exposure to rFGF-2 was comparable following intracoronary or intravenous administration. Peak plasma concentration and area under the concentration-time curve increased proportionally with dose, indicating linear pharmacokinetics over the dose range examined (0.33 to 48.0 micrograms/kg). Greater systemic exposure was observed when heparin was administered closer to rFGF-2 infusion, consistent with slower clearance of heparin/rFGF-2 complexes. Infusion of rFGF-2 was associated with changes in acute hemodynamics. While a clear PK/PD dose-response relationship was not established, a trend toward hypotension and tachycardia with higher rFGF-2 doses was observed.

Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study.

OBJECTIVES: Evaluate the safety, tolerability and preliminary efficacy of intracoronary (IC) basic fibroblast growth factor (bFGF, FGF-2). BACKGROUND: FGF-2 is a heparin-binding growth factor capable of inducing functionally significant angiogenesis in animal models of myocardial ischemia. METHODS: Phase I, open-label dose-escalation study of FGF-2 administered as a single 20-min infusion in patients with ischemic heart disease not amenable to treatment with CABG or PTCA. RESULTS: Fifty-two patients enrolled in this study received IC FGF-2 (0.33 to 48 microg/kg). Hypotension was dose-dependent and dose-limiting, with 36 microg/kg being the maximally tolerated dose. Four patients died and four patients had non-Q-wave myocardial infarctions. Laboratory parameters and retinal examinations showed mild and mainly transient changes during the 6-month follow-up. There was an improvement in quality of life as assessed by Seattle Angina Questionnaire and improvement in exercise tolerance as assessed by treadmill exercise testing (510+/-24 s at baseline, 561+/-26 s at day 29 [p = 0.023], 609+/-26 s at day 57 (p < 0.001), and 633+/-24 s at day 180 (p < 0.001), overall p < 0.001). Magnetic resonance (MR) imaging showed increased regional wall thickening (baseline: 34+/-1.7%, day 29: 38.7+/-1.9% [p = 0.006], day 57: 41.4+/-1.9% [p < 0.001], and day 180: 42.0+/-2.3% [p < 0.001], overall p = 0.001) and a reduction in the extent of the ischemic area at all time points compared with baseline. CONCLUSIONS: Intracoronary administration of rFGF-2 appears safe and is well tolerated over a 100-fold dose range (0.33 to 0.36 microk/kg). Preliminary evidence of efficacy is tempered by the open-label uncontrolled design of the study.