Ultralente

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Michael Rosario Defelippis - One of the best experts on this subject based on the ideXlab platform.

  • research articlespreparation of a microcrystalline suspension formulation of lysb28prob29 human insulin with Ultralente properties
    Journal of Pharmaceutical Sciences, 1999
    Co-Authors: Jane P Richards, Mary P Stickelmeyer, Bruce H Frank, Michelle Barbeau, Jerry Radziuk, David G Smith, Michael Rosario Defelippis
    Abstract:

    The monomeric analogue, LysB28ProB29‐human insulin (LysPro), has been crystallized using similar conditions employed to prepare extended‐acting insulin Ultralente formulations. In the presence of zinc ions, sodium acetate and sodium chloride, but without phenolic preservative, LysPro surprisingly forms small rhombohedral crystals with similar morphology to human insulin Ultralente crystals with a mean particle size of 20 ± 1 µm. X‐ray powder diffraction studies on the LysPro crystals prior to dilution in Ultralente vehicle ([NaCl] = 1.2 M) revealed the presence of T3R3f hexamers. Consistent with human insulin Ultralente preparations, LysPro crystals formulated as an Ultralente suspension ([NaCl] = 0.12 M) contain T6 hexamers indicating that a conformational change occurs in the hexamer units of the crystals upon dilution of the salt concentration. The pharmacological properties of subcutaneously administered Ultralente LysPro (ULP) were compared to Ultralente human insulin (UHI) using a conscious dog model (n = 5) with glucose levels clamped at basal. There were no statistically significant differences between the kinetic and dynamic responses of ULP compared to UHI [Cmax (ng/mL): 3.58 ± 0.76, ULP and 3.61 ± 0.66, UHI; Tmax (min): 226 ± 30, ULP and 185 ± 42, UHI; Rmax (mg/kg min): 11.2 ± 1.9, ULP and 13.3 ± 2.0, UHI; and TRmax (min): 336 ± 11, ULP and 285 ± 57, UHI]. Although the Pro to Lys sequence inversion destabilizes insulin self‐assembly and greatly alters the time action of soluble LysPro preparations, this modification has now been found neither to prevent the formation of Ultralente crystals in the absence of phenolics nor to compromise the protracted activity of the insulin analogue suspension.

  • preparation of a microcrystalline suspension formulation of lysb28prob29 human insulin with Ultralente properties
    Journal of Pharmaceutical Sciences, 1999
    Co-Authors: Jane P Richards, Mary P Stickelmeyer, Bruce H Frank, Michelle Barbeau, Jerry Radziuk, David G Smith, Michael Rosario Defelippis
    Abstract:

    Abstract The monomeric analogue, Lys B28 Pro B29 ‐human insulin (LysPro), has been crystallized using similar conditions employed to prepare extended‐acting insulin Ultralente formulations. In the presence of zinc ions, sodium acetate and sodium chloride, but without phenolic preservative, LysPro surprisingly forms small rhombohedral crystals with similar morphology to human insulin Ultralente crystals with a mean particle size of 20 ± 1 µm. X‐ray powder diffraction studies on the LysPro crystals prior to dilution in Ultralente vehicle ([NaCl] = 1.2 M) revealed the presence of T 3 R 3 f hexamers. Consistent with human insulin Ultralente preparations, LysPro crystals formulated as an Ultralente suspension ([NaCl] = 0.12 M) contain T 6 hexamers indicating that a conformational change occurs in the hexamer units of the crystals upon dilution of the salt concentration. The pharmacological properties of subcutaneously administered Ultralente LysPro (ULP) were compared to Ultralente human insulin (UHI) using a conscious dog model ( n = 5) with glucose levels clamped at basal. There were no statistically significant differences between the kinetic and dynamic responses of ULP compared to UHI [ C max (ng/mL): 3.58 ± 0.76, ULP and 3.61 ± 0.66, UHI; T max (min): 226 ± 30, ULP and 185 ± 42, UHI; R max (mg/kg min): 11.2 ± 1.9, ULP and 13.3 ± 2.0, UHI; and T Rmax (min): 336 ± 11, ULP and 285 ± 57, UHI]. Although the Pro to Lys sequence inversion destabilizes insulin self‐assembly and greatly alters the time action of soluble LysPro preparations, this modification has now been found neither to prevent the formation of Ultralente crystals in the absence of phenolics nor to compromise the protracted activity of the insulin analogue suspension.

  • Preparation of a microcrystalline suspension formulation of LysB28ProB29‐human insulin with Ultralente properties
    Journal of Pharmaceutical Sciences, 1999
    Co-Authors: Jane P Richards, Mary P Stickelmeyer, Bruce H Frank, Michelle Barbeau, Jerry Radziuk, G.david Smith, Michael Rosario Defelippis
    Abstract:

    Abstract The monomeric analogue, Lys B28 Pro B29 ‐human insulin (LysPro), has been crystallized using similar conditions employed to prepare extended‐acting insulin Ultralente formulations. In the presence of zinc ions, sodium acetate and sodium chloride, but without phenolic preservative, LysPro surprisingly forms small rhombohedral crystals with similar morphology to human insulin Ultralente crystals with a mean particle size of 20 ± 1 µm. X‐ray powder diffraction studies on the LysPro crystals prior to dilution in Ultralente vehicle ([NaCl] = 1.2 M) revealed the presence of T 3 R 3 f hexamers. Consistent with human insulin Ultralente preparations, LysPro crystals formulated as an Ultralente suspension ([NaCl] = 0.12 M) contain T 6 hexamers indicating that a conformational change occurs in the hexamer units of the crystals upon dilution of the salt concentration. The pharmacological properties of subcutaneously administered Ultralente LysPro (ULP) were compared to Ultralente human insulin (UHI) using a conscious dog model ( n = 5) with glucose levels clamped at basal. There were no statistically significant differences between the kinetic and dynamic responses of ULP compared to UHI [ C max (ng/mL): 3.58 ± 0.76, ULP and 3.61 ± 0.66, UHI; T max (min): 226 ± 30, ULP and 185 ± 42, UHI; R max (mg/kg min): 11.2 ± 1.9, ULP and 13.3 ± 2.0, UHI; and T Rmax (min): 336 ± 11, ULP and 285 ± 57, UHI]. Although the Pro to Lys sequence inversion destabilizes insulin self‐assembly and greatly alters the time action of soluble LysPro preparations, this modification has now been found neither to prevent the formation of Ultralente crystals in the absence of phenolics nor to compromise the protracted activity of the insulin analogue suspension.

  • structural and morphological characterization of Ultralente insulin crystals by atomic force microscopy evidence of hydrophobically driven assembly
    Biophysical Journal, 1998
    Co-Authors: Michael Rosario Defelippis, Bruce H Frank, Mark L Brader, Michael D Ward
    Abstract:

    Although x-ray crystal structures exist for many forms of insulin, the hormone involved in glucose metabolism and used in the treatment of diabetes, x-ray structural characterization of therapeutically important long-acting crystalline Ultralente insulin forms has been elusive because of small crystal size and poor diffraction characteristics. We describe tapping-mode atomic force microscopy (TMAFM) studies, performed directly in crystallization liquor, of Ultralente crystals prepared from bovine, human, and porcine insulins. Lattice images obtained from direct imaging of crystal planes are consistent with R3 space group symmetry for each insulin type, but the morphology of the human and porcine crystals observed by AFM differs substantially from that of the bovine insulin crystals. Human and porcine Ultralente crystals exhibited large, molecularly flat (001) faces consisting of hexagonal arrays of close packed hexamers. In contrast, bovine Ultralente crystals predominantly exhibited faces with cylindrical features assignable to close-packed stacks of insulin hexamers laying in-plane, consistent with the packing motif of the (010) and (011) planes. This behavior is attributed to a twofold increase in the hydrophobic character of the upper and lower surfaces of the donut-shaped insulin hexamer in bovine insulin compared to its human and porcine counterparts that results from minor sequence differences between these insulins. The increased hydrophobicity of these surfaces can promote hexamer-hexamer stacking in precrystalline aggregates or enhance attachment of single hexamers along the c axis at the crystal surface during crystal growth. Both events lead to enhanced growth of ?hk0? planes instead of (001). The insulin hexamers on the (010) and (110) faces are exposed "edge-on" to the aqueous medium, such that solvent access to the center of the hexamer and to solvent channels is reduced compared to the (001) surface, consistent with the slower dissolution and reputed unique basal activity of bovine Ultralente insulin. These observations demonstrate that subtle variations in amino acid sequence can dramatically affect the interfacial structure of crystalline proteins.

Aaron Le Compte - One of the best experts on this subject based on the ideXlab platform.

Robert A Rizza - One of the best experts on this subject based on the ideXlab platform.

  • glycemic variation and hypoglycemia in patients with well controlled type 1 diabetes on a multiple daily insulin injection program with use of glargine and Ultralente as basal insulin
    Endocrine Practice, 2007
    Co-Authors: Yogish C Kudva, Ananda Basu, Gregory D Jenkins, Guillermo M Pons, Debra A Vogelsang, Robert A Rizza, Steven A Smith, William L Isley
    Abstract:

    OBJECTIVE: To evaluate glycemic variation and hypoglycemia in patients with well-controlled type 1 diabetes receiving multiple daily insulin injections during glargine and Ultralente use as basal insulin in a clinical trial. METHODS: Twenty-two patients (12 men and 10 women; median age, 43 years), with a hemoglobin A1c level <7.8%, were randomized in a crossover design to receive either insulin glargine or Ultralente insulin as basal insulin for 4 months each, with insulin aspart as prandial insulin. Continuous glucose monitoring and the Fear of Hypoglycemia questionnaire were used at baseline and at the end of each treatment period. RESULTS: Whereas the mean amplitude of glycemic excursions showed a correlation with the area under the curve of blood glucose <3.89 mmol/L per day, the number of periods during the day with hypoglycemia was significantly correlated with the M value. Measures of glycemic variation did not differ significantly between glargine and Ultralente treatment. With use of glargine therapy, the SD of blood glucose levels showed a tendency to be lower and the SD of nocturnal blood glucose concentrations was significantly lower. Glucose concentrations were significantly lower during the 1 hour before and the 3 hours after lunch with use of Ultralente. The "Worry" scale on the Fear of Hypoglycemia questionnaire was less during Ultralente therapy and correlated with the number of times blood glucose concentrations were <3.89 mmol/L daily. CONCLUSION: Measures of glycemic variability and hypoglycemia need to be studied more in clinical trials of glycemic control in patients with type 1 diabetes. Glycemic variability is less, particularly at night, with glargine as basal insulin.

  • Glycemic variation and hypoglycemia in patients with well-controlled type 1 diabetes on a multiple daily insulin injection program with use of glargine and Ultralente as basal insulin.
    Endocrine Practice, 2007
    Co-Authors: Yogish C Kudva, Ananda Basu, Gregory D Jenkins, Guillermo M Pons, Debra A Vogelsang, Robert A Rizza, Steven A Smith, William L Isley
    Abstract:

    OBJECTIVE: To evaluate glycemic variation and hypoglycemia in patients with well-controlled type 1 diabetes receiving multiple daily insulin injections during glargine and Ultralente use as basal insulin in a clinical trial. METHODS: Twenty-two patients (12 men and 10 women; median age, 43 years), with a hemoglobin A1c level

  • randomized controlled clinical trial of glargine versus Ultralente insulin in the treatment of type 1 diabetes
    Diabetes Care, 2005
    Co-Authors: Yogish C Kudva, Ananda Basu, Gregory D Jenkins, Guillermo M Pons, Debra A Vogelsang, Robert A Rizza, Steven A Smith, Lori L Quandt, Julie A Gebel, William L Isley
    Abstract:

    OBJECTIVE —Multiple daily insulin injection programs are commonly accompanied by considerable glycemic variation and hypoglycemia. We conducted a randomized crossover design clinical trial to compare glargine with Ultralente insulin as a basal insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS —To determine whether the use of glargine insulin as a basal insulin would result in a comparable HbA 1c and less glycemic variation and hypoglycemia than Ultralente insulin, 22 individuals (aged 44 ± 14 years [±SD], 55% men) with type 1 diabetes who were experienced with multiple daily insulin injections and had an HbA 1c of RESULTS —Treatment with glargine resulted in lower mean HbA 1c (6.82 ± 0.13 vs. 7.02 ± 0.13, difference: 0.2 ± 0.08, P = 0.026), less nocturnal variability (plasma glucose 49.06 ± 4.74 vs. 62.36 ± 5.21 mg/dl, P = 0.04), and less hypoglycemia (24.5 ± 2.99 vs. 31.3 ± 4.04 events, P = 0.05), primarily due to less daytime hypoglycemia ( P = 0.002). On the other hand, serious hypoglycemia and average glucose concentration measured with continuous subcutaneous glucose monitoring did not differ. CONCLUSIONS —We conclude that while use of either Ultralente or glargine as a basal insulin can result in excellent glycemic control, treatment with glargine is associated with slightly but significantly lower HbA 1c and less nocturnal glycemic variability and hypoglycemia.

  • use of human Ultralente as the basal insulin component in treatment of patients with iddm
    Diabetes Research and Clinical Practice, 1991
    Co-Authors: Susan L Freeman, Peter C Obrien, Robert A Rizza
    Abstract:

    Abstract To determine the suitability of a single subcutaneous evening injection of human Ultralente (UL) as the basal component of an intensive insulin therapy program, insulin concentrations were measured in five insulin-dependent diabetic volunteers over a 40-h period. Each patient had been maintained on a human UL-based program for at least one month prior to the study. All short-acting insulin was withheld during the study. The onset of action of human UL was 2 to 4 h, and a broad, variable peak was observed between 6 and 12 h after each injection. We concluded that human UL does not provide constant basal insulin concentrations. When human UL is considered as part of an intensive insulin therapy program, this potential disadvantage must be weighed against the potential advantage of low antigenicity.

  • Differences Between Prebreakfast and Late Afternoon Glycemic Responses to Exercise in IDDM Patients
    Diabetes Care, 1990
    Co-Authors: J. Jeffrey Ruegemer, Robert A Rizza, Ray W. Squires, H. M. Marsh, Morey W. Haymond, Philip E. Cryer, John M. Miles
    Abstract:

    Little information is available regarding the optimal timing of exercise in insulin-dependent diabetes mellitus (IDDM) patients. In this study, six IDDM patients receiving Ultralente-based intensive insulin therapy were studied during 30 min of exercise (∼60% Vo 2max ), before breakfast, and at 1600. On two other occasions, they were studied at rest. Plasma glucose increased from 6.7 ± 0.4 to 9.1 ± 0.4 mM during morning exercise ( P P P

Jason Wong - One of the best experts on this subject based on the ideXlab platform.

Bruce H Frank - One of the best experts on this subject based on the ideXlab platform.

  • research articlespreparation of a microcrystalline suspension formulation of lysb28prob29 human insulin with Ultralente properties
    Journal of Pharmaceutical Sciences, 1999
    Co-Authors: Jane P Richards, Mary P Stickelmeyer, Bruce H Frank, Michelle Barbeau, Jerry Radziuk, David G Smith, Michael Rosario Defelippis
    Abstract:

    The monomeric analogue, LysB28ProB29‐human insulin (LysPro), has been crystallized using similar conditions employed to prepare extended‐acting insulin Ultralente formulations. In the presence of zinc ions, sodium acetate and sodium chloride, but without phenolic preservative, LysPro surprisingly forms small rhombohedral crystals with similar morphology to human insulin Ultralente crystals with a mean particle size of 20 ± 1 µm. X‐ray powder diffraction studies on the LysPro crystals prior to dilution in Ultralente vehicle ([NaCl] = 1.2 M) revealed the presence of T3R3f hexamers. Consistent with human insulin Ultralente preparations, LysPro crystals formulated as an Ultralente suspension ([NaCl] = 0.12 M) contain T6 hexamers indicating that a conformational change occurs in the hexamer units of the crystals upon dilution of the salt concentration. The pharmacological properties of subcutaneously administered Ultralente LysPro (ULP) were compared to Ultralente human insulin (UHI) using a conscious dog model (n = 5) with glucose levels clamped at basal. There were no statistically significant differences between the kinetic and dynamic responses of ULP compared to UHI [Cmax (ng/mL): 3.58 ± 0.76, ULP and 3.61 ± 0.66, UHI; Tmax (min): 226 ± 30, ULP and 185 ± 42, UHI; Rmax (mg/kg min): 11.2 ± 1.9, ULP and 13.3 ± 2.0, UHI; and TRmax (min): 336 ± 11, ULP and 285 ± 57, UHI]. Although the Pro to Lys sequence inversion destabilizes insulin self‐assembly and greatly alters the time action of soluble LysPro preparations, this modification has now been found neither to prevent the formation of Ultralente crystals in the absence of phenolics nor to compromise the protracted activity of the insulin analogue suspension.

  • preparation of a microcrystalline suspension formulation of lysb28prob29 human insulin with Ultralente properties
    Journal of Pharmaceutical Sciences, 1999
    Co-Authors: Jane P Richards, Mary P Stickelmeyer, Bruce H Frank, Michelle Barbeau, Jerry Radziuk, David G Smith, Michael Rosario Defelippis
    Abstract:

    Abstract The monomeric analogue, Lys B28 Pro B29 ‐human insulin (LysPro), has been crystallized using similar conditions employed to prepare extended‐acting insulin Ultralente formulations. In the presence of zinc ions, sodium acetate and sodium chloride, but without phenolic preservative, LysPro surprisingly forms small rhombohedral crystals with similar morphology to human insulin Ultralente crystals with a mean particle size of 20 ± 1 µm. X‐ray powder diffraction studies on the LysPro crystals prior to dilution in Ultralente vehicle ([NaCl] = 1.2 M) revealed the presence of T 3 R 3 f hexamers. Consistent with human insulin Ultralente preparations, LysPro crystals formulated as an Ultralente suspension ([NaCl] = 0.12 M) contain T 6 hexamers indicating that a conformational change occurs in the hexamer units of the crystals upon dilution of the salt concentration. The pharmacological properties of subcutaneously administered Ultralente LysPro (ULP) were compared to Ultralente human insulin (UHI) using a conscious dog model ( n = 5) with glucose levels clamped at basal. There were no statistically significant differences between the kinetic and dynamic responses of ULP compared to UHI [ C max (ng/mL): 3.58 ± 0.76, ULP and 3.61 ± 0.66, UHI; T max (min): 226 ± 30, ULP and 185 ± 42, UHI; R max (mg/kg min): 11.2 ± 1.9, ULP and 13.3 ± 2.0, UHI; and T Rmax (min): 336 ± 11, ULP and 285 ± 57, UHI]. Although the Pro to Lys sequence inversion destabilizes insulin self‐assembly and greatly alters the time action of soluble LysPro preparations, this modification has now been found neither to prevent the formation of Ultralente crystals in the absence of phenolics nor to compromise the protracted activity of the insulin analogue suspension.

  • Preparation of a microcrystalline suspension formulation of LysB28ProB29‐human insulin with Ultralente properties
    Journal of Pharmaceutical Sciences, 1999
    Co-Authors: Jane P Richards, Mary P Stickelmeyer, Bruce H Frank, Michelle Barbeau, Jerry Radziuk, G.david Smith, Michael Rosario Defelippis
    Abstract:

    Abstract The monomeric analogue, Lys B28 Pro B29 ‐human insulin (LysPro), has been crystallized using similar conditions employed to prepare extended‐acting insulin Ultralente formulations. In the presence of zinc ions, sodium acetate and sodium chloride, but without phenolic preservative, LysPro surprisingly forms small rhombohedral crystals with similar morphology to human insulin Ultralente crystals with a mean particle size of 20 ± 1 µm. X‐ray powder diffraction studies on the LysPro crystals prior to dilution in Ultralente vehicle ([NaCl] = 1.2 M) revealed the presence of T 3 R 3 f hexamers. Consistent with human insulin Ultralente preparations, LysPro crystals formulated as an Ultralente suspension ([NaCl] = 0.12 M) contain T 6 hexamers indicating that a conformational change occurs in the hexamer units of the crystals upon dilution of the salt concentration. The pharmacological properties of subcutaneously administered Ultralente LysPro (ULP) were compared to Ultralente human insulin (UHI) using a conscious dog model ( n = 5) with glucose levels clamped at basal. There were no statistically significant differences between the kinetic and dynamic responses of ULP compared to UHI [ C max (ng/mL): 3.58 ± 0.76, ULP and 3.61 ± 0.66, UHI; T max (min): 226 ± 30, ULP and 185 ± 42, UHI; R max (mg/kg min): 11.2 ± 1.9, ULP and 13.3 ± 2.0, UHI; and T Rmax (min): 336 ± 11, ULP and 285 ± 57, UHI]. Although the Pro to Lys sequence inversion destabilizes insulin self‐assembly and greatly alters the time action of soluble LysPro preparations, this modification has now been found neither to prevent the formation of Ultralente crystals in the absence of phenolics nor to compromise the protracted activity of the insulin analogue suspension.

  • structural and morphological characterization of Ultralente insulin crystals by atomic force microscopy evidence of hydrophobically driven assembly
    Biophysical Journal, 1998
    Co-Authors: Michael Rosario Defelippis, Bruce H Frank, Mark L Brader, Michael D Ward
    Abstract:

    Although x-ray crystal structures exist for many forms of insulin, the hormone involved in glucose metabolism and used in the treatment of diabetes, x-ray structural characterization of therapeutically important long-acting crystalline Ultralente insulin forms has been elusive because of small crystal size and poor diffraction characteristics. We describe tapping-mode atomic force microscopy (TMAFM) studies, performed directly in crystallization liquor, of Ultralente crystals prepared from bovine, human, and porcine insulins. Lattice images obtained from direct imaging of crystal planes are consistent with R3 space group symmetry for each insulin type, but the morphology of the human and porcine crystals observed by AFM differs substantially from that of the bovine insulin crystals. Human and porcine Ultralente crystals exhibited large, molecularly flat (001) faces consisting of hexagonal arrays of close packed hexamers. In contrast, bovine Ultralente crystals predominantly exhibited faces with cylindrical features assignable to close-packed stacks of insulin hexamers laying in-plane, consistent with the packing motif of the (010) and (011) planes. This behavior is attributed to a twofold increase in the hydrophobic character of the upper and lower surfaces of the donut-shaped insulin hexamer in bovine insulin compared to its human and porcine counterparts that results from minor sequence differences between these insulins. The increased hydrophobicity of these surfaces can promote hexamer-hexamer stacking in precrystalline aggregates or enhance attachment of single hexamers along the c axis at the crystal surface during crystal growth. Both events lead to enhanced growth of ?hk0? planes instead of (001). The insulin hexamers on the (010) and (110) faces are exposed "edge-on" to the aqueous medium, such that solvent access to the center of the hexamer and to solvent channels is reduced compared to the (001) surface, consistent with the slower dissolution and reputed unique basal activity of bovine Ultralente insulin. These observations demonstrate that subtle variations in amino acid sequence can dramatically affect the interfacial structure of crystalline proteins.

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