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Fetal Exposure to Antidiabetic Drugs: The Role of the PlacentaPollex, Erika 01 September 2010 (has links)
Gestational diabetes, a common medical complication in pregnancy, may lead to severe fetal consequences if left untreated. A major concern with the use of antidiabetic drugs in pregnancy is the potential for placental transfer and fetal toxicity. The presence of endocytic pathways and several ABC transporter proteins has been demonstrated in the human placenta and are believed to play an important role in determining fetal exposure to drugs used in pregnancy. The objective of this thesis is to investigate the safety and transfer of the oral hypoglycemic agent, glyburide, and the new long acting insulin analog, insulin glargine, across the human placenta.
The oral antidiabetic, glyburide, has been shown to be actively effluxed across the placenta in the fetal to maternal direction. The transport of glyburide in the presence of a breast cancer resistance protein (BCRP) inhibitor was investigated in the dually perfused human placenta model. The results of the perfusion studies indicate that BCRP plays a role in protecting the fetus from the accumulation of glyburide. Subsequently, cellular studies were carried out to determine the effect of the naturally occurring single nucleotide polymorphism within the coding region of BCRP (C421A/Q141K) on glyburide transport. Results suggest that glyburide transport may be reduced in the presence of the Q141K polymorphism.
While insulin remains as the gold standard, the potential for maternal hypoglycemia with insulin injection has resulted in the development of insulin analogs. Insulin glargine, a human insulin analog, has a long half life with no pronounced peak when compared to currently used NPH insulin. Human placental perfusion experiments examining the extent and rate of transfer of insulin glargine across the placenta demonstrated that, at therapeutic concentrations, insulin glargine does not cross the placenta to a measurable extent. To further determine the fetal safety of insulin glargine therapy compared with NPH insulin, a systematic review and meta-analysis were performed. No evidence was identified for increased adverse fetal outcomes with the use of insulin glargine during pregnancy. Overall, the results of this research serve to provide improved treatment options for women with diabetes in pregnancy.
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Fetal Exposure to Antidiabetic Drugs: The Role of the PlacentaPollex, Erika 01 September 2010 (has links)
Gestational diabetes, a common medical complication in pregnancy, may lead to severe fetal consequences if left untreated. A major concern with the use of antidiabetic drugs in pregnancy is the potential for placental transfer and fetal toxicity. The presence of endocytic pathways and several ABC transporter proteins has been demonstrated in the human placenta and are believed to play an important role in determining fetal exposure to drugs used in pregnancy. The objective of this thesis is to investigate the safety and transfer of the oral hypoglycemic agent, glyburide, and the new long acting insulin analog, insulin glargine, across the human placenta.
The oral antidiabetic, glyburide, has been shown to be actively effluxed across the placenta in the fetal to maternal direction. The transport of glyburide in the presence of a breast cancer resistance protein (BCRP) inhibitor was investigated in the dually perfused human placenta model. The results of the perfusion studies indicate that BCRP plays a role in protecting the fetus from the accumulation of glyburide. Subsequently, cellular studies were carried out to determine the effect of the naturally occurring single nucleotide polymorphism within the coding region of BCRP (C421A/Q141K) on glyburide transport. Results suggest that glyburide transport may be reduced in the presence of the Q141K polymorphism.
While insulin remains as the gold standard, the potential for maternal hypoglycemia with insulin injection has resulted in the development of insulin analogs. Insulin glargine, a human insulin analog, has a long half life with no pronounced peak when compared to currently used NPH insulin. Human placental perfusion experiments examining the extent and rate of transfer of insulin glargine across the placenta demonstrated that, at therapeutic concentrations, insulin glargine does not cross the placenta to a measurable extent. To further determine the fetal safety of insulin glargine therapy compared with NPH insulin, a systematic review and meta-analysis were performed. No evidence was identified for increased adverse fetal outcomes with the use of insulin glargine during pregnancy. Overall, the results of this research serve to provide improved treatment options for women with diabetes in pregnancy.
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A Cost-Effectiveness Analysis Comparing Glargine Versus Rosiglitazone or Pioglitazone for Patients Failing Metformin Plus a SulfonylureaSpaeth, Brianne, Fontana, Barbara January 2008 (has links)
Class of 2008 Abstract / Objectives: To determine the cost-effectiveness of adding a thiazolidinedione (TZD) versus insulin glargine (glargine) as a triple regimen for treatment of Type 2 diabetes mellitus for patients not controlled with metformin and a sulfonylurea.
Methods: A decision analytic model was developed to compare the clinical outcomes and costs of triple therapy with either a TZD or glargine. Published literature was used to determine treatment efficacy and the frequency of clinically important adverse effects. Cost data were obtained from the 2007 Physician Fee Reference and North Carolina Industrial Commission website. The decision tree was built using TreeAge software. Clinical outcome measures included HgA1c (A1C) control, hypoglycemia frequency, and the development of edema associated with the use of these medications. A Monte Carlo probabilistic sensitivity analysis was conducted to determine the mean and 95% CIs for both treatment efficacy and costs.
Results: There was no statistically significant difference in the efficacy of adding either a TZD or glargine in achieving a goal A1C ≤ 7%. However, glargine triple therapy was estimated to be significantly less costly than TZD triple therapy ($3,161/yr; 95% CI $3,116 to $3,356 versus $3,769/yr; 95% CI $3,667 to $3,902, respectively).
Conclusions: Most patients requiring triple therapy for the management of T2DM should receive glargine rather than a TZD due to the significantly lower cost producing similar clinical efficacy.
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Insulin Glargine and Cancer Risk: An Opinion Statement of the Endocrine and Metabolism Practice and Research Network of the American College of Clinical PharmacyEdwards, Krystal L., Riche, Daniel M., Stroup, Jeffrey S., Goldman-Levine, Jennifer D., Padiyara, Rosalyn S., Cross, L. B., Kane, Michael P. 01 September 2010 (has links)
Diabetes mellitus has reached epidemic proportions worldwide, eliciting extensive research on both the disease process and its treatment. Regardless of diabetes type, the progressive nature of the disease makes insulin the long-term mainstay of diabetes management. Recently, the insulin analog glargine was reported in several epidemiologic studies to be associated with an increased risk of cancer. Inconsistent study results and media attention have caused much angst and concern to health care professionals and the general population. A clear understanding of the current evidence is needed to adequately develop a patient-oriented risk:benefit assessment. Members of the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy evaluated available evidence to provide guidance and discussion on the risk of cancer with insulin glargine use. We believe the current link between insulin glargine and cancer is tenuous but merits further evaluation. An independent analysis of all available glargine clinical trial data should be performed, and a vigorous postmarketing safety study of glargine should be conducted. Until more substantial data are available, however, neither the choice of initial insulin therapy nor insulin maintenance regimens should be influenced by the current information linking insulin glargine to cancer.
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DESENVOLVIMENTO E VALIDAÇÃO DE MÉTODOS CROMATOGRÁFICOS PARA AVALIAÇÃO DE TEOR/POTÊNCIA DE INSULINA GLARGINA / DEVELOPMENT AND VALIDATION OF CHROMATOGRAPHIC METHODS FOR THE CONTENT/POTENCY EVALUATION OF INSULIN GLARGINESchramm, Vanessa Grigoletto 30 March 2016 (has links)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / hans, and is secreted into the bloodstream. It plays and important role in regulating the
metabolic activities of the body, particularly the homeostasis of the blood glucose. Insulin
glargine is a recombinant human insulin analogue produced by DNA technology using a
strain of Escherichia coli and the insulin glargine differ only by three amino acids from
human insulin. Reversed-phase liquid chromatography (RP-LC) and size exclusion liquid
chromatography (SE-LC) methods were developed and validated for the assessment of insulin
glargine in biopharmaceutical formulations. A RP-LC method was carried out on a Jupiter C4 column (250 mm x 4.6 mm i.d.), maintained at 30 ºC. The mobile phase A consisted of 0.05
M sodium sulphate buffer, pH 2.5, and the mobile phase B was acetonitrile. The SE-LC
method was carried out on a BioSep-SEC-S 2000 column (300 mm x 7.8 mm i.d.),
maintained at 25 ºC. The mobile phase consisted of 0.03 M MES acid buffer, pH 2.5, run
isocratically at a flow rate of 0.6 mL/min. Chromatographic separation was obtained with
retention times of 7.5 min, and 9.9 min, and was linear over the concentration range of 0.05 -
200 μg/mL (R2 = 0.9998) and 0.02 - 180 μg/mL (R2 = 0.9999), respectively, for RP-LC and
SE-LC, with photodiode array (PDA) detection at 214 nm and 200 nm for RP-LC and SE-LC
methods, respectively. The limits of detection and quantitation were 0.018 and 0.054 μg/mL,
respectively, for the RP-LC and 0.009 and 0.027 μg/mL, for the SE-LC. Specificity was
established in degradation studies, which also showed that there was no interference of the
excipients. Equally, the accuracy was 100.13% and 99.38%, with bias lower than 0.85% and
than 0.86%. The validated methods were applied for the determination of insulin glargine and
related proteins and high molecular mass, in biotechnology-derived products, giving lower
mean differences of the estimated content/potencies of 0.21% and 0.16% for the RP-LC and
SE-LC related, compared to the in vitro cell culture assay. It is concluded that represents a
contribution to establish alternatives to monitor stability, quality control and thereby assure
therapeutic efficacy of the biotechnology-derived medicine. / A insulina humana é um hormônio secretado pelas células β, das ilhotas de
Langerhans, e regula os níveis sanguíneos de glicose. A insulina glargina é produzida pela
tecnologia do DNA recombinante, expressa em Escherichia coli, e difere da insulina humana
pela modificação da aspargina na posição 21 da cadeia A por uma glicina, além da adição de
dois resíduos de arginina C-terminais na cadeia B. No presente trabalho foram desenvolvidos
e validados métodos por cromatografia líquida em fase reversa (CL-FR) e por exclusão
molecular (CL-EM) para a avaliação de insulina glargina em formulações biofarmacêuticas.
No método por CL-FR, foi utilizada coluna Júpiter C4 (250 mm x 4,6 mm d.i.), mantida a 30
ºC. A fase móvel A foi constituída por tampão sulfato de sódio 0,05 M, pH 2,5, e a fase móvel
B por acetonitrila, eluídas com fluxo constante de 0,5 mL/min. No método por CL-EM foi
utilizada coluna BioSep-SEC-S 2000 (300 mm x 7.8 mm d.i.), mantida a 25 ºC. A fase móvel
foi constituída de tampão MES 0,03 M, pH 2,5, eluída em vazão isocrática de 0,6 mL/min.
Para ambos os métodos utilizou-se detector de arranjo de diodos (DAD) com detecções em
214 nm e 200 nm para CL-FR e CL-EM, respectivamente. A separação cromatográfica foi
obtida nos tempos de 7,5 e 9,9 min, sendo linear na faixa de concentração de 0,05 - 200
μg/mL (R2 = 0,9998) e 0,02 - 180 μg/mL (R2 = 0,9999), respectivamente, para os métodos
por CL-FR e CL-EM. Os limites de detecção e quantificação foram 0,018 e 0,054 μg/mL,
respectivamente, para o método por CL-FR e 0,009 e 0,027 μg/mL por CL-EM. A
especificidade foi avaliada em estudos de degradação, que também demonstraram que não
houve interferência dos excipientes. A exatidão foi 100,13 e 99,38%, com bias inferior a 0,85
e 0,86%, respectivamente, para os métodos por CL-FR e CL-EM. Os métodos propostos
foram aplicados para avaliação da potência de insulina glargina, de proteínas relacionadas
agregados de alta massa molecular em formulações biofarmacêuticas, e os resultados foram
comparados com o bioensaio por cultura de células in vitro, observando-se diferenças das
médias de teor/potência 0,21% e 0,16% inferiores para os métodos por CL-FR e CL-EM.
Concluí-se que representa contribuição para estabelecer procedimentos para monitorar a
estabilidade, o controle da qualidade, garantindo a segurança e eficácia terapêutica do
produto biotecnológico.
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Untersuchungen zur Wirtschaftlichkeit langwirksamer Insuline bei Patienten mit insulinbehandeltem Typ-2-Diabetes mellitus in DeutschlandDippel, Franz-Werner 18 February 2013 (has links) (PDF)
Die Erkrankung Diabetes mellitus stellt eine wesentliche medizinische und ökonomische Her-ausforderung für das deutsche Gesundheitssystem dar. Weitgehend ungeklärt sind jedoch die Kostenunterschiede alternativer Behandlungsstrategien. In der vorliegenden Arbeit wurde die Wirtschaftlichkeit von Insulin glargin gegenüber relevanten Therapiealternativen bei Patien¬ten mit insulinbehandeltem Typ-2-Diabetes aus der Perspektive der deutschen GKV unter-sucht. Dazu wurden vier pharmakoökonomische Evaluationen mittels Kosten-Minimierungs-Ansatz auf der Basis von Studien- und Routinedaten durchgeführt. Die therapeutische Äqui-valenz der verglichenen Behandlungsverfahren wurde als gesichert vorausgesetzt.
In allen vier Wirtschaftlichkeitsanalysen konnte die Kosteneffektivität von Insulin glargin ge-genüber relevanten Komparatoren gezeigt werden. Beim Vergleich der basalunterstützten ora-len Therapie (BOT) mit der prandialen Insulintherapie (SIT) ergaben sich auf Basis der APOLLO-Studie jährliche Pro-Kopf-Einsparungen in Höhe von 722 € zugunsten von Insulin glargin. Geringere Behandlungskosten zeigten sich auch gegenüber Insulin detemir in der BOT auf Basis der Rosenstock-RCT sowie in der Basal-Bolus-Therapie (ICT) auf Basis der Hollander-RCT. Die jährlichen Pro-Kopf-Einsparungen zugunsten von Insulin glargin betru-gen 486 € in der BOT und 684 € in der ICT. Schließlich ergab auch der Behandlungs¬kosten¬vergleich von Insulin glargin mit dem langwirksamen NPH-Insulin auf der Basis ambulanter Routinedaten niedrigere jährliche Behandlungskosten zugunsten von Insulin glargin. Die Ein-sparungen pro Patient und Jahr betrugen 198 € und waren unabhängig vom Behandlungsre-gime (BOT oder ICT).
Die Ergebnisse der vorliegenden Arbeit unterstreichen den Stellenwert qualitätsgesicherter Wirtschaftlichkeitsanalysen zur rationalen Ressourcenallokation im Rahmen der Insulin¬therapie des Typ-2-Diabetes mellitus.
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Untersuchungen zur Wirtschaftlichkeit langwirksamer Insuline bei Patienten mit insulinbehandeltem Typ-2-Diabetes mellitus in DeutschlandDippel, Franz-Werner 20 December 2012 (has links)
Die Erkrankung Diabetes mellitus stellt eine wesentliche medizinische und ökonomische Her-ausforderung für das deutsche Gesundheitssystem dar. Weitgehend ungeklärt sind jedoch die Kostenunterschiede alternativer Behandlungsstrategien. In der vorliegenden Arbeit wurde die Wirtschaftlichkeit von Insulin glargin gegenüber relevanten Therapiealternativen bei Patien¬ten mit insulinbehandeltem Typ-2-Diabetes aus der Perspektive der deutschen GKV unter-sucht. Dazu wurden vier pharmakoökonomische Evaluationen mittels Kosten-Minimierungs-Ansatz auf der Basis von Studien- und Routinedaten durchgeführt. Die therapeutische Äqui-valenz der verglichenen Behandlungsverfahren wurde als gesichert vorausgesetzt.
In allen vier Wirtschaftlichkeitsanalysen konnte die Kosteneffektivität von Insulin glargin ge-genüber relevanten Komparatoren gezeigt werden. Beim Vergleich der basalunterstützten ora-len Therapie (BOT) mit der prandialen Insulintherapie (SIT) ergaben sich auf Basis der APOLLO-Studie jährliche Pro-Kopf-Einsparungen in Höhe von 722 € zugunsten von Insulin glargin. Geringere Behandlungskosten zeigten sich auch gegenüber Insulin detemir in der BOT auf Basis der Rosenstock-RCT sowie in der Basal-Bolus-Therapie (ICT) auf Basis der Hollander-RCT. Die jährlichen Pro-Kopf-Einsparungen zugunsten von Insulin glargin betru-gen 486 € in der BOT und 684 € in der ICT. Schließlich ergab auch der Behandlungs¬kosten¬vergleich von Insulin glargin mit dem langwirksamen NPH-Insulin auf der Basis ambulanter Routinedaten niedrigere jährliche Behandlungskosten zugunsten von Insulin glargin. Die Ein-sparungen pro Patient und Jahr betrugen 198 € und waren unabhängig vom Behandlungsre-gime (BOT oder ICT).
Die Ergebnisse der vorliegenden Arbeit unterstreichen den Stellenwert qualitätsgesicherter Wirtschaftlichkeitsanalysen zur rationalen Ressourcenallokation im Rahmen der Insulin¬therapie des Typ-2-Diabetes mellitus.:Inhaltsverzeichnis
1 Einführung 1
1.1 Kosten des Diabetes mellitus 1
1.2 Epidemiologie des Diabetes mellitus 3
1.3 Behandlung des Diabetes mellitus 4
1.4 Wirtschaftlichkeit in der Diabetestherapie 7
2 Zielsetzung 9
3 Pharmakoökonomische Evaluationen 9
3.1 APOLLO-Studie 9
3.1.1 Design und Ergebnisse der klinischen Studie 9
3.1.2 Zielsetzung der pharmakoökonomischen Analyse 10
3.1.3 Material und Methoden 11
3.1.3.1 Mengenerfassung 11
3.1.3.2 Kostenermittlung 15
3.1.3.3 Sensitivitätsanalysen 18
3.1.4 Ergebnisse 20
3.1.5 Diskussion 24
3.2 Rosenstock-Studie 30
3.2.1 Design und Ergebnisse der klinischen Studie 30
3.2.2 Zielsetzung der pharmakoökonomischen Analyse 31
3.2.3 Material und Methoden 31
3.2.4 Ergebnisse 34
3.2.5 Diskussion 36
3.3 Hollander-Studie 39
3.3.1 Design und Ergebnisse der klinischen Studie 39
3.3.2 Zielsetzung der pharmakoökonomischen Analyse 40
3.3.3 Material und Methoden 40
3.3.4 Ergebnisse 42
3.3.5 Diskussion 44
3.4 LIVE-SPP-Studie 47
3.4.1 Design der Beobachtungsstudie 47
3.4.2 Zielsetzung der pharmakoökonomischen Analyse 48
3.4.3 Patienten und Methoden 48
3.4.3.1 Ein- und Ausschlusskriterien 48
3.4.3.2 Datenerfassung 48
3.4.3.3 Kostenermittlung 49
3.4.3.4 Statistische Auswertung 51
3.4.3.5 Sensitivitätsanalysen 51
3.4.4 Ergebnisse 52
3.4.5 Diskussion 54
4 Bewertung der Ergebnisse im Kontext der aktuellen
pharmakoökonomischen Datenlage 58
4.1 Literaturrecherche 59
4.2 Insulin glargin in der BOT im Vergleich zu anderen
Behandlungsregimen (SIT und CT) 62
4.2.1 4T-Studie 62
4.2.2 HEART2D-Studie 63
4.2.3 PHAZIT-Studie 64
4.2.4 LAPTOP-Studie (Deutschland) 65
4.2.5 Diabetes-Mellitus-Modell (1) 66
4.2.6 LAPTOP-Studie (Kanada, Österreich) 67
4.2.7 Zusammenfassung (Regimevergleiche) 67
4.3 Insulin glargin in der BOT versus Insulin detemir in der BOT 68
4.3.1 L2T3-Studie 69
4.3.2 Persistenzanalyse (1) 71
4.3.3 Zusammenfassung 72
(Insulin glargin versus Insulin detemir in der BOT)
4.4 Insulin glargin in der ICT versus Insulin detemir in der ICT 72
4.4.1 LIVE-COM-Studie 73
4.4.2 Wiesner-Studie (Typ-1-Diabetes) 76
4.4.3 IMS-Datenbankanalyse-1 (Typ-1-Diabetes) 80
4.4.4 Indirekter Vergleich (Typ-1-Diabetes) 82
4.4.5 Zusammenfassung 84
(Insulin glargin versus Insulin detemir in der ICT)
4.5 Weitere Studien zum Vergleich von Insulin glargin und
Insulin detemir 84
4.5.1 LIVE-KK-2-Studie 84
4.5.2 InsightHealth-Datenbankanalyse-1 86
4.5.3 Zusammenfassung 89
(Insulin glargin versus Insulin detemir)
4.6 Insulin glargin versus NPH-Insulin in der BOT und ICT 91
4.6.1 LIVE-SPP-Studie 92
4.6.2 Persistenzanalyse (2) 94
4.6.3 Diabetes-Mellitus-Modell (2) 95
4.6.4 Endpunkstudien 96
4.6.5 LIVE-DE-Studie 97
4.6.6 LIVE-KK-1-Studie 102
4.6.7 InsightHealth-Datenbankanalyse-2 103
4.6.8 IMS-Datenbankanalyse-2 (Typ-1-Diabetes) 104
4.6.9 Discrete Event Simulation-D (Typ-1-Diabetes) 106
4.6.10 Discrete Event Simulation-CH (Typ-1-Diabetes) 108
4.6.11 LIVE-GERI-Studie 109
4.6.12 Zusammenfassung 110
(Insulin glargin versus NPH-Insulin)
5 Zusammenfassung 111
6 Literaturverzeichnis 118
7 Publikationen 134
7.1 Comparison of treatment costs in inadequately controlled type 2 135
diabetes in Germany based on the APOLLO trial with insulin
glargine. Journal of Medical Economics 2009; 12(2): 87-97
7.2 Comparison of one-year costs of type 2 diabetes treatment with 146
insulin glargine or insulin detemir in a basal supported oral
therapy (BOT) in Germany. International Journal of Clinical
Pharmacology and Therapeutics 2010; 2: 129-137
7.3 Cost comparison of insulin glargine with insulin detemir in a 155
basal-bolus regime with mealtime insulin aspart in type 2 diabetes
in Germany. German Medical Science 2010; 8: Doc 17 doi:
10.3205/000106
7.4 Resource utilisation and costs in patients with type 2 diabetes 164
treated with insulin glargine or conventional basal insulin under
real-world conditions in Germany: LIVE-SPP study. Journal of
Medical Economics 2008; 11: 695-712
8 Anlagen 182
8.1 Erklärung über die eigenständige Abfassung der Arbeit 182
8.2 Lebenslauf 183
8.3 Danksagung 185
8.4 Veröffentlichungen 186
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