A co-formulation of pramlintide and insulin A21G (ADO09) improves postprandial glucose and short-term control of mean glucose, time in range, and body weight versus insulin aspart in adults with type 1 diabetes.

AIM: Pramlintide improves postprandial glucose but requires additional injections. We investigated the pharmacokinetics/pharmacodynamics, efficacy and safety of ADO09, pramlintide/insulin A21G co-formulation, in type 1 diabetes (T1D). MATERIALS AND METHODS: This double-blinded, randomized, two-period cross-over study compared prandial administration of ADO09 or insulin aspart over 24 days in T1D using either ≤40 U bolus insulin per day [low-dose group (LD), n = 28] or 40-75 U [high-dose group (HD), n = 16]. Glycaemic responses through continuous glucose monitoring, and pharmacokinetics/pharmacodynamics profiles following mixed-meal-tolerance tests were evaluated at baseline and at the end of treatment. RESULTS: Glucose increments from 0 to 4 h after mixed-meal-tolerance test (primary endpoint) were 39% (not statistically significantly) lower with ADO09 in the low-dose group and 69% lower in the high-dose group. Mean continuous glucose monitoring glucose during ambulatory treatment was lower with ADO09 than with aspart (LD: -8.2 ± 7.9 mg/dl, p = .0001; HD: -7.0 ± 10 mg/ml, p = .0127), and time-in-range (70-180 mg/dl) improved (LD: +4%, p = .0134; HD: +4%, p = .0432). Body weight declined significantly with ADO09 (LD: -0.8 kg; HD: -1.6 kg). Hypoglycaemic events were slightly more frequent with ADO09 versus aspart (LD: 142 vs. 115; HD: 96 vs. 79). Gastrointestinal events occurred more frequently with ADO09 but were generally transient, and no other safety signals were identified. CONCLUSIONS: In comparison with aspart, ADO09 was well tolerated and effective in T1D across a wide range of dosage, significantly improving the average blood glucose level and body weight during 24 days of ambulatory treatment. Meal test profiles confirmed improvement of glycaemic patterns and other responses with ADO09.

Better glycaemic control with BioChaperone glargine lispro co-formulation than with insulin lispro Mix25 or separate glargine and lispro administrations after a test meal in people with type 2 diabetes.

Because of its physico-chemical properties, insulin glargine is usually not mixable with rapid insulins. BioChaperone BC147 is a polyanionic amphiphilic polymer, solubilizing insulin glargine at neutral pH, and thus enabling stable glargine formulation with fast-acting insulin lispro (BioChaperone glargine lispro co-formulation [BC Combo]). We investigated pharmacokinetic (PK) endpoints and postprandial glucose (PPG) control after administration of BC Combo (75% insulin glargine, 25% insulin lispro), insulin lispro Mix25 (LMix) and separate injections of insulins glargine (75% total dose) and lispro (25% total dose [G + L]) immediately before ingestion of a mixed meal in people with type 2 diabetes mellitus (T2DM), using a randomized, double-blind, double-dummy crossover study design. Participants received individualized bolus doses (mean 0.62 U/kg) of BC Combo, LMix or G + L, together with a solid mixed meal (610 kcal, 50% carbohydrate, 30% fat, 20% protein). Insulin dosages were kept constant for each study day. Thirty-nine participants with T2DM (mean ± SD age and glycated haemoglobin 60.8 ± 7.5 years and 64 ± 6 mmol/mol, respectively) were randomized. BC Combo improved the predefined primary endpoint, early PPG control, compared to LMix (incremental area under the blood glucose concentration-time curve from 0 to 2 hours after the meal [ΔAUCBG,0-2h ] reduction of 18%; P = 0.0009) and G + L (ΔAUCBG,0-2h reduction of 10%; P = 0.0450). The number of mealtime hypoglycaemic episodes per participant was lower with BC Combo (22 episodes in 14 participants) compared to LMix (43 episodes in 20 participants; P = 0.0028), but not significantly different from G + L (28 episodes in 19 participants; P = 0.2523). BC Combo demonstrated superior early PPG control with fewer hypoglycaemic episodes compared to LMix and superior early PPG control compared to separate G + L administrations.

Exceptional sensitivity of metal-aryl bond energies to ortho-fluorine substituents: influence of the metal, the coordination sphere, and the spectator ligands on M-C/H-C bond energy correlations.

DFT calculations are reported of the energetics of C-H oxidative addition of benzene and fluorinated benzenes, Ar(F)H (Ar(F) = C(6)F(n)H(5-n), n = 0-5) at ZrCp(2) (Cp = eta(5)-C(5)H(5)), TaCp(2)H, TaCp(2)Cl, WCp(2), ReCp(CO)(2), ReCp(CO)(PH(3)), ReCp(PH(3))(2), RhCp(PH(3)), RhCp(CO), IrCp(PH(3)), IrCp(CO), Ni(H(2)PCH(2)CH(2)PH(2)), Pt(H(2)PCH(2)CH(2)PH(2)). The change in M-C bond energy of the products fits a linear function of the number of fluorine substituents, with different coefficients corresponding to ortho-, meta-, and para-fluorine. The values of the ortho-coefficient range from 20 to 32 kJ mol(-1), greatly exceeding the values for the meta- and para-coefficients (2.0-4.5 kJ mol(-1)). Similarly, the H-C bond energies of Ar(F)H yield ortho- and para-coefficients of 10.4 and 3.4 kJ mol(-1), respectively, and a negligible meta-coefficient. These results indicate a large increase in the M-C bond energy with ortho-fluorine substitution on the aryl ring. Plots of D(M-C) vs D(H-C) yield slopes R(M-C/H-C) that vary from 1.93 to 3.05 with metal fragment, all in excess of values of 1.1-1.3 reported with other hydrocarbyl groups. Replacement of PH(3) by CO decreases R(M-C/H-C) significantly. For a given ligand set and metals in the same group of the periodic table, the value of R(M-C/H-C) does not increase with the strength of the M-C bond. Calculations of the charge on the aryl ring show that variations in ionicity of the M-C bonds correlate with variations in M-C bond energy. This strengthening of metal-aryl bonds accounts for numerous experimental results that indicate a preference for ortho-fluorine substituents.

Validation of the M-C/H-C bond enthalpy relationship through application of density functional theory.

Density functional theory has been used to calculate H-C and M-C bond dissociation enthalpies in order to evaluate the feasibility of correlating relative M-C bond enthalpies Delta H(M-C)rel with H-C bond enthalpies Delta H(H-C) via computational methods. This approach has been tested against two experimental correlations: a study of (a) Rh(H)(R)(Tp')(CNCH2CMe3) [R = hydrocarbyl, Tp' = HB(3,5-dimethylpyrazolyl)3] (Wick, D. D.; Jones, W. D. Organometallics 1999, 18, 495) and (b) Ti(R)(silox)2(NHSit-Bu3) (silox = OSit-Bu3) (Bennett, J. L.; Wolczanski, P. T. J. Am. Chem. Soc. 1997, 119, 10696). We show that the observation that M-C bond enthalpies increase more rapidly with different substituents than H-C bond enthalpies is reproduced by theory. Quantitative slopes of the correlation lines are reproduced within 4% of the experimental values with a B3PW91 functional and with very similar correlation coefficients. Absolute bond enthalpies are reproduced within 6% for H-C bonds, and relative bond enthalpies for M-C bonds are reproduced within 30 kJ mol(-1) for Rh-C bonds and within 19 kJ mol(-1) for Ti-C bonds. Values are also calculated with the BP86 functional.

Barriers of hydrogen abstraction vs halogen exchange: an experimental manifestation of charge-shift bonding.

This paper shows that the differences between the barriers of the halogen exchange reactions, in the H + XH systems, and the hydrogen abstraction reactions, in the X + HX systems (X = F, Cl, Br), measure the covalent-ionic resonance energies of the corresponding X-H bonds. These processes are investigated using CCSD(T) calculations as well as the breathing-orbital valence bond (BOVB) method. Thus, the VB analysis shows that (i) at the level of covalent structures the barriers are the same for the two series and (ii) the higher barriers for halogen exchange processes originate solely from the less efficient mixing of the ionic structures into the respective covalent structures. The barrier differences, in the HXH vs XHX series, which decrease as X is varied from F to I, can be estimated as one-quarter of the covalent-ionic resonance energy of the H-X bond. The largest difference (22 kcal/mol) is calculated for X = F in accord with the finding that the H-F bond possesses the largest covalent-ionic resonance energy, 87 kcal/mol, which constitutes the major part of the bonding energy. The H-F bond belongs to the class of "charge-shift" bonds (Shaik, S.; Danovich, D.; Silvi, B.; Lauvergnat, D. L.; Hiberty, P. C. Chem. Eur. J. 2005, 21, 6358), which are all typified by dominant covalent-ionic resonance energies. Since the barrier difference between the two series is an experimental measure of the resonance energy quantity, in the particular case of X = F, the unusually high barrier for the fluorine exchange reaction emerges as an experimental manifestation of charge-shift bonding.

Electrochemical and theoretical study of the redox properties of transition metal complexes with [Pt2S2] cores.

The oxidation processes undergone by the [Pt2(mu-S)2] core in [Pt2(P[intersection]P)2(mu-S)2](P[intersection]P = Ph2P(CH2)nPPh2, n= 2,3) complexes have been analysed on the basis of electrochemical measurements. The experimental results are indicative of two consecutive monoelectronic oxidations after which the [Pt2(mu-S)2] core evolves into [Pt2(mu-S2)]2+, containing a bridging disulfide ligand. However, the instability of the monoxidised [Pt2(P[intersection]P)2(mu-S)2]+ species formed initially, which converts into [Pt3(P[intersection]P)3(mu-S)2]2+, hampered the synthesis and characterisation of the mono and dioxidised species. These drawbacks have been surpassed by means of DFT calculations which have also allowed the elucidation of the structural features of the species obtained from the oxidation of [Pt2(P[intersection]P)2(mu-S)2] compounds. The calculated redox potentials corresponding to the oxidation processes are consistent with the experimental data obtained. In addition, calculations on the thermodynamics of possible processes following the degradation of [Pt2(P[intersection]P)2(mu-S)2]+ are fully consistent with the concomitant formation of monometallic [Pt(P[intersection]P)S2)] and trimetallic [Pt3(P[intersection]P)3(mu-S)2]2+ compounds. Extension of the theoretical study on the [Pt2Te2] core and comparisons with the results obtained for [Pt2S2] have given a more general picture of the behaviour of [Pt2X2](X = chalcogenide) cores subject to oxidation processes.

Defluorination of perfluoropropene using Cp*2ZrH2 and Cp2ZrHF: a mechanism investigation from a joint experimental-theoretical perspective.

Cp*(2)ZrH(2) (1) (Cp* = pentamethylcyclopentadienyl) reacts with perfluoropropene (2) to give Cp*(2)ZrHF (3) and hydrodefluorinated products under very mild conditions. Initial C-F bond activation occurs selectively at the vinylic terminal position of the olefin to exchange fluorine for hydrogen. Subsequent hydrodefluorination leads to the formation of the n-propylhydride complex Cp*(2)ZrH(CH(2)CH(2)CH(3)), which can be cleaved with dihydrogen to give propane and 1. A theoretical study of the reaction of Cp*(2)ZrH(2) (Cp* = cyclopentadienyl) and CF(2)[double bond]CF(CF(3)) has been undertaken. Several mechanisms have been examined in detail using DFT(B3PW91) calculations and are discussed for this H/F exchange: (a) internal olefin insertion/beta-fluoride elimination, (b) external olefin insertion/beta-fluoride elimination, and (c) F/H metathesis from either an inside or outside approach. Of these, the first case is found to be energetically preferred. Selective defluorination at the terminal carbon has been shown to be favored over defluorination at the substituted and allylic carbons.

The evolution of [[Ph2P(CH2)nPPh2]Pt(mu-S)2Pt[Ph2P(CH2)nPPh2]] (n=2, 3) metalloligands in protic acids: a cascade of sequential reactions.

Given the nucleophilicity of the [Pt(2)S(2)] ring, the evolution of [Pt(2)(mu-S)(2)(P intersection P)(2)] (P intersection P=1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp)) metalloligands in the presence of the simplest electrophilic species, the proton, has been studied. Combined use of experimental and theoretical data has allowed the whole set of reactions ensuing the protonation of the [Pt(2)S(2)] core to be established. The titration of [Pt(2)(mu-S)(2)(P intersection P)(2)] with HCl or HClO(4) was monitored mainly by (31)P[(1)H] NMR and mass techniques. Characterization of all the species involved was completed with the determination of the crystal structure of [Pt(SH)(2)(P intersection P)], for dppe and dppp, and [Pt(3)(mu(3)-S)(2)(dppp)(3)](PF(6))(2). The first protonation step of the [Pt(2)S(2)] core leads to the stable [Pt(2)(mu-S)(mu-SH)(P intersection P)(2)](+) complex, but the second step implies disintegration of the ring, thus giving rise to various mononuclear species. The subsequent evolution of some of these species allows regeneration of [Pt(2)(mu-S)(mu-SH)(P intersection P)(2)](+), evidencing the cyclic nature of this process. Whereas the reaction pathway is essentially common for both phosphine ligands, dppe and dppp, the different coordinating ability of Cl(-) or ClO(4) (-) determines the nature of the final products, [PtCl(2)(P intersection P)], [Pt(3)(mu(3)-S)(2)(P intersection P)(3)]Cl(2) or [Pt(3)(mu(3)-S)(2)(P intersection P)(3)](ClO(4))(2). DFT calculations have corroborated the thermodynamic feasibility of the reactions proposed on the basis of experimental data.

Bond energy M-C/H-C correlations: dual theoretical and experimental approach to the sensitivity of M-C bond strength to substituents.

DFT methods are used to quantify the relationship between M-C and H-C bond energies; for MLn = Re(eta5-C5H5)(CO)2H and fluorinated aryl ligands, theoretical and experimental investigations of ortho-fluorine substitution indicate a much larger increase in the M-C than in the H-C bond energy, so stabilising C-H activation products.

Diverse evolution of [[Ph(2)P(CH(2))(n)PPh(2)]Pt(mu-S)(2)Pt[Ph(2)P(CH(2))(n)PPh(2)]] (n = 2, 3) metalloligands in CH(2)Cl(2).

The nucleophilicity of the [Pt(2)S(2)] core in [[Ph(2)P(CH(2))(n)PPh(2)]Pt(mu-S)(2)Pt[Ph(2)P(CH(2))(n)PPh(2)]] (n = 3, dppp (1); n = 2, dppe (2)) metalloligands toward the CH(2)Cl(2) solvent has been thoroughly studied. Complex 1, which has been obtained and characterized by X-ray diffraction, is structurally related to 2 and consists of dinuclear molecules with a hinged [Pt(2)S(2)] central ring. The reaction of 1 and 2 with CH(2)Cl(2) has been followed by means of (31)P, (1)H, and (13)C NMR, electrospray ionization mass spectrometry, and X-ray data. Although both reactions proceed at different rates, the first steps are common and lead to a mixture of the corresponding mononuclear complexes [Pt[Ph(2)P(CH(2))(n)PPh(2)](S(2)CH(2))], n = 3 (7), 2 (8), and [Pt[Ph(2)P(CH(2))(n)PPh(2)]Cl(2)], n = 3 (9), 2 (10). Theoretical calculations give support to the proposed pathway for the disintegration process of the [Pt(2)S(2)] ring. Only in the case of 1, the reaction proceeds further yielding [Pt(2)(dppp)(2)[mu-(SCH(2)SCH(2)S)-S,S']]Cl(2) (11). To confirm the sequence of the reactions leading from 1 and 2 to the final products 9 and 11 or 8 and 10, respectively, complexes 7, 8, and 11 have been synthesized and structurally characterized. Additional experiments have allowed elucidation of the reaction mechanism involved from 7 to 11, and thus, the origin of the CH(2) groups that participate in the expansion of the (SCH(2)S)(2-) ligand in 7 to afford the bridging (SCH(2)SCH(2)S)(2-) ligand in 11 has been established. The X-ray structure of 11 is totally unprecedented and consists of a hinged [(dppp)Pt(mu-S)(2)Pt(dppp)] core capped by a CH(2)SCH(2) fragment.