A case study on Sitagliptin drug products and Sitagliptin/Metformin drug products concerning contamination with N-nitrosamines was performed using two newly developed analytical methods for determination of N-nitroso-triazolopyrazine (NTTP; 7-nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine) and its precursor triazolopyrazine (3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine). The method for determination of triazolopyrazine was previously unpublished, the method for determination of NTTP was published only for analysis of active pharmaceutical ingredient Sitagliptin and not the drug forms. Solving the N-nitrosamine contamination is requested by regulatory authorities all over the world and thus is vital for all pharmaceutical companies. The solution always requires a sensitive analytical method. Both newly developed methods use liquid chromatography coupled with mass spectrometry (single quadrupole analyzer in case of triazolopyrazine and triple quadrupole analyzer in case of NTTP). Separation of triazolopyrazine was achieved on a column Acquity CSH C18 using a mobile phase consisting of aqueous ammonium formate buffered at pH 4.2 and acetonitrile. Detection was performed using positive electrospray and selected ion monitoring at m/z 193. Separation of NTTP was achieved on a column Acquity HSS T3 using a mobile phase consisting of 0.1 % formic acid in water and methanol. Detection was performed using positive electrospray and multiple reaction monitoring at transitions m/z 222.15→42.05 (collision energy 17 eV) and m/z 222.15→192.15 (collision energy 11 eV). Two issues specific to NTTP and triazolopyrazine previously not described in scientific literature were successfully troubleshooted. Spontaneous degradation of Sitagliptin to triazolopyrazine and methyl (R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate was solved by using N,N-dimethylformamide as sample solvent during development of the method for quantitation of triazolopyrazine. A bad peak shape of NTTP due to the presence of rotamers of NTTP was successfully troubleshooted by increasing column temperature. Both methods were used during an optimization study of manufacturing of Sitagliptin and Sitagliptin/Metformin drug products. The goal of the study was to decrease NTTP content in the final drug product under the strict legislative limit set by Federal Drug Agency. The efficacy of several solutions was proven, but could not be fully disclosed due to Intellectual Property Protection policy of Zentiva. Instead, a brief review of recently published strategies to cope with N-nitrosamine contamination is presented.
- MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- hypoglykemika terapeutické užití MeSH
- inzulin glargin terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- kombinace léků sitagliptin a metformin terapeutické užití MeSH
- kombinovaná farmakoterapie metody MeSH
- lidé MeSH
- pioglitazon terapeutické užití MeSH
- sitagliptin fosfát * terapeutické užití MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- sulfonylmočovinové sloučeniny terapeutické užití MeSH
- Check Tag
- lidé MeSH
- MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- fixní kombinace léků MeSH
- hypoglykemika farmakologie terapeutické užití MeSH
- kombinace léků sitagliptin a metformin farmakologie terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- vildagliptin farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
The main health care challenges associated with diabetic patients are glycemic control. Insulin defection has been regarded as the mainstay which needs to be tackled to avoid glucose over presence in the circulatory system. These challenges have always been conjoined with the patient's redox status, hence, oxidants/antioxidants determine the fate of pancreatic tissue status and they are reciprocally interrelated. Various remedies have been utilized by patients themselves and healthcare workers to control hyperglycemia if any. Herbal and pharmacological therapy were always being used hand in hand. Herein, we are demonstrating the antioxidant effect of propolis and its role in modulation of lipid profile in type 2 diabetic patients using vitamin E for comparison in sequential mode i.e. vitamin E used for 8 weeks followed one-week washout period and then propolis therapy started in the same group of patients (n = 45). Thereby a sample of serum has been collected in the first visit (baseline and vitamin E started, followed by collecting serum after 8 weeks (second visit); followed by commencing of propolis after a washout week from the second visit, at the third visit another serum sample collected from all patients. Serum was analyzed for oxidant/antioxidant status represented by malondialdehyde (MDA) and total antioxidant status (TAS). Additionally, lipid profile has been measured from the same samples. The results indicate that both propolis and vitamin E positively modulated the measured parameters with superiority of propolis over vitamin E in improving these measured biomolecules. To conclude, propolis is an overall safe natural product and is inducing such positive effects in the diabetic patient, we do advise these patients to start propolis therapy as an adjuvant medication to control these deleterious biomolecules.
- MeSH
- biochemická analýza krve metody přístrojové vybavení MeSH
- diabetes mellitus 2. typu * farmakoterapie krev MeSH
- kombinace léků sitagliptin a metformin aplikace a dávkování MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipidy krev MeSH
- malondialdehyd krev MeSH
- oxidační stres účinky léků MeSH
- propolis aplikace a dávkování farmakologie MeSH
- statistika jako téma MeSH
- vitamin E aplikace a dávkování farmakologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- klinická studie MeSH
- Geografické názvy
- Irák MeSH
- MeSH
- diabetes mellitus 2. typu * epidemiologie farmakoterapie MeSH
- fixní kombinace léků MeSH
- hypoglykemika terapeutické užití MeSH
- inhibitory dipeptidylpeptidasy 4 farmakokinetika farmakologie terapeutické užití MeSH
- kombinace léků sitagliptin a metformin farmakologie terapeutické užití MeSH
- komplikace diabetu etiologie farmakoterapie MeSH
- lidé MeSH
- metabolický syndrom epidemiologie farmakoterapie MeSH
- Check Tag
- lidé MeSH
Diabetes mellitus 2. typu je nejčastější metabolickou chorobou současnosti. Má progredující charakter a vzniká při kombinaci porušené sekrece inzulinu a jeho působení v cílových tkáních. U nemocných s diabetem nacházíme často další abnormity (centrální obezitu, zvýšené riziko srdečního selhání, dyslipidemii, arteriální hypertenzi a další). Toto onemocnění postihuje ve stáří až třetinu české populace. Pokud léčíme seniory s diabetem, přihlížíme kromě přítomných komorbidit také k jejich kognitivním schopnostem. Vždy se snažíme, aby léčba byla bezpečná. U křehkých pacientů musíme často velmi pečlivě zvažovat, který postup zvolit ve druhém léčebném kroku, když terapie metforminem selhává nebo ji nelze zahájit. Vyhýbáme se lékům vyvolávajícím hypoglykemii (inzulin, deriváty sulfonylurey). Gliptiny, inhibitory dipeptidylpeptidázy 4 (DPP‐4), představují bezpečnou skupinu antidiabetik zejména u starších diabetiků. Kazuistika pojednává o příznivém účinku včasného nasazení sitagliptinu u subkompenzované pacientky s diabetem.
Type 2 diabetes mellitus is the most common metabolic disease today. It has a progressive character and arises from the combination of impaired insulin secretion and its action in target tissues. We often find other abnormalities in patients with diabetes (central obesity, increased risk of heart failure, dyslipidemia, arterial hypertension and others). The disease affects up to a third of the Czech population in old age. When we treat the elderly with diabetes, we consider the comorbidities present and their cognitive abilities. We always try to keep the treatment safe. In frail patients, we often must carefully consider the course of action in the second treatment step when metformin therapy fails or cannot be used. We avoid drugs that cause hypoglycemia (insulin, sulfonylureas). Gliptins, dipeptidyl peptidase 4 (DPP‐4) inhibitors, are a safe class of antidiabetic drugs, especially in the elderly. The case report discusses the beneficial effect of early use of sitagliptin in sub‐compensated diabetics.
- MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- hypoglykemie diagnóza MeSH
- hypoglykemika farmakologie terapeutické užití MeSH
- kombinace léků sitagliptin a metformin aplikace a dávkování farmakologie terapeutické užití MeSH
- křehký senior MeSH
- lidé MeSH
- metformin aplikace a dávkování farmakologie terapeutické užití MeSH
- senioři nad 80 let MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- senioři nad 80 let MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
