AIM: To evaluate the efficacy of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D) using derived time-in-range (dTIR). METHODS: Participant-level data from LixiLan-L, LixiLan-O and LixiLan-G were pooled and dTIR (70-180 mg/dL), derived time-above-range (> 180 mg/dL) and derived time-below-range (dTBR; < 70 mg/dL) were calculated from participant seven-point self-monitored blood glucose profiles. RESULTS: This pooled analysis included data from 2420 participants receiving iGlarLixi (n = 1093), iGlar (n = 836), Lixi (n = 234) or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) (n = 257). Numerically greater improvements in least square (LS) means dTIR were seen from baseline to end of treatment (EOT) with iGlarLixi (25.7%) versus iGlar (15.8%), Lixi (11.7%) or GLP-1 RA (16.2%). At EOT, the mean (standard deviation) dTBR was 0.71% ± 3.4%, 0.61% ± 3.2%, 0.08% ± 1.0% and 0.0% ± 0.0% for iGlarLixi, iGlar, Lixi and GLP-1 RA, respectively. In a subgroup analysis, participants aged younger than 65 years (n = 1690) and 65 years or older (n = 713) showed numerically greater improvements in LS means dTIR from baseline to EOT with iGlarLixi versus iGlar, Lixi or GLP-1 RA. CONCLUSIONS: iGlarLixi achieved improvements in dTIR, with low dTBR values, providing further evidence to inform clinical outcomes with the use of iGlarLixi.
- MeSH
- agonisté receptoru pro glukagonu podobný peptid 1 MeSH
- diabetes mellitus 2. typu * farmakoterapie krev MeSH
- dospělí MeSH
- fixní kombinace léků MeSH
- glykovaný hemoglobin analýza metabolismus účinky léků MeSH
- hypoglykemika * terapeutické užití MeSH
- inzulin glargin * terapeutické užití MeSH
- krevní glukóza * účinky léků metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- peptidy * terapeutické užití aplikace a dávkování MeSH
- randomizované kontrolované studie jako téma MeSH
- receptor pro glukagonu podobný peptid 2 MeSH
- selfmonitoring glykemie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- fixní kombinace léků MeSH
- glykovaný hemoglobin analýza účinky léků metabolismus MeSH
- hypoglykemika * terapeutické užití MeSH
- inzulin glargin * terapeutické užití aplikace a dávkování MeSH
- krevní glukóza účinky léků metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- peptidy * terapeutické užití aplikace a dávkování MeSH
- receptor pro glukagonu podobný peptid 2 MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
The serious spread of antibiotic-resistant Staphylococcal aureus strains is alarming. This is reflected by the measures governments and health-related bodies are offering to ease antibiotic drug development. Finding new active agents, preferably with novel mechanism of action, or even finding new targets for drug development are essential. In this review, we summarize the current status of novel antistaphylococcal agents undergoing clinical trials. We mainly discuss antistaphylococcal small molecules and peptides in the text with a special focus on their chemistry, while antistaphylococcal immunotherapy (antibodies) are mentioned in a summative table. This review shall serve as a summary that influences future synthetic efforts in the antistaphyloccocals development field.
Peptides, as potential therapeutics continue to gain importance in the search for active substances for the treatment of numerous human diseases, some of which are, to this day, incurable. As potential therapeutic drugs, peptides have many favorable chemical and pharmacological properties, starting with their great diversity, through their high affinity for binding to all sort of natural receptors, and ending with the various pathways of their breakdown, which produces nothing but amino acids that are nontoxic to the body. Despite these and other advantages, however, they also have their pitfalls. One of these disadvantages is the very low stability of natural peptides. They have a short half-life and tend to be cleared from the organism very quickly. Their instability in the gastrointestinal tract, makes it impossible to administer peptidic drugs orally. To achieve the best pharmacologic effect, it is desirable to look for ways of modifying peptides that enable the use of these substances as pharmaceuticals. There are many ways to modify peptides. Herein we summarize the approaches that are currently in use, including lipidization, PEGylation, glycosylation and others, focusing on lipidization. We describe how individual types of lipidization are achieved and describe their advantages and drawbacks. Peptide modifications are performed with the goal of reaching a longer half-life, reducing immunogenicity and improving bioavailability. In the case of neuropeptides, lipidization aids their activity in the central nervous system after the peripheral administration. At the end of our review, we summarize all lipidized peptide-based drugs that are currently on the market.
INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease that secondarily leads to axonal loss and associated brain atrophy. Disease-modifying drugs (DMDs) have previously been studied for their ability to affect specific immunity. This study investigates the effect of interferon beta-1a (INF) and glatiramer acetate (GA) administration on changes in innate immunity cell populations. METHODS: Sixty Caucasian female patients with relapsing-remitting MS undergo blood sample testing for 15 blood parameters at baseline, 1 month, 3 months, and 6 months after treatment by GA or IFN (started as their first-line DMD). RESULTS: A statistically significant difference in the change after 6 months was found in the parameter monocytes (relative count) in the group of patients treated with IFN. The median increase was 27.8%. Changes in many of the other 15 parameters studied were 10-20%. CONCLUSION: Innate immunity has long been neglected in MS immunopathology. The findings suggest that IFN treatment may modulate the immune response in MS by affecting monocyte function and may provide insight into the mechanisms of action of IFN in MS.
- MeSH
- glatiramer acetát terapeutické užití MeSH
- interferon beta 1a terapeutické užití MeSH
- interferon beta terapeutické užití MeSH
- lidé MeSH
- peptidy terapeutické užití MeSH
- přirozená imunita MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie patologie MeSH
- roztroušená skleróza * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Natalizumab is a humanized recombinant monoclonal IgG4 antibody used in the treatment of multiple sclerosis. Commonly used methods for natalizumab and anti-natalizumab antibodies quantification are enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay, respectively. Measurement of therapeutic monoclonal antibodies can be challenging due to the resemblance to human plasma immunoglobulins. Recent developments in mass spectrometry enables to analyze vast variety of large protein molecules. The aim of this study was to develop a LC-MS/MS method for determining natalizumab in human serum and cerebrospinal fluid (CSF) and apply it to clinical settings. For successful quantification, it was necessary to find specific sequences of peptides in natalizumab. This immunoglobulin was treated with dithiothreitol and iodoacetamide, cleaved with trypsin into short specific peptides and determined on a UPLC-MS/MS system. An Acquity UPLC BEH C18 column at 55 °C and gradient elution was used for analysis. Intra- and interassay accuracies and precisions were tested at four concentration levels. Precision was determined by coefficients of variation and was in the range of 0.8-10.2 %, with accuracy in the range of 89.8-106.4 %. The concentration of natalizumab in patient samples ranged from 1.8 to 193.3 μg/mL. The method was validated according to the European Medicines Agency (EMA) guideline, met all acceptance criteria for accuracy and precision, and is suitable for clinical applications. In comparison to immunoassay, which can be elevated by cross-reaction with endogenous immunoglobulins, the results of developed LC-MS/MS method are more accurate and specific.
- MeSH
- chromatografie kapalinová metody MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- lidé MeSH
- natalizumab terapeutické užití MeSH
- peptidy terapeutické užití MeSH
- roztroušená skleróza * farmakoterapie MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Peptidy produkované mitochondriemi (mitochondrial-derived peptides, MDPs) jsou kódovány mitochon- driální DNA. Mezi MDP patří humanin, ribosomální ribonukleová kyselina typu c (ribosomal ribonucleic acid type c, MOTS-c) a malé humanin-like peptidy 1-6 (SHLP1-6). Ve stresových situacích MDP podporují aktivitu mitochondrií a napomáhají přežití buněk; kromě toho ovlivňují metabolismus, odpověď na stres i zánět jak in vivo, tak in vitro. Výzkum v poslední době prokázal, že MDP hrají významnou úlohu v rozvoji kardiovaskulárních onemocnění (KVO). Mezi další možné faktory patří ischemie, neúspěšná reperfuze, fibróza a dysfunkce koronární mikrocirkulace. Peptidy produkované mitochondriemi mohou sloužit jako markery KVO nebo se stát cílem léčby KVO. Do této skupiny peptidů patří humanin, MOTS-c a SHLP. Humanin snižuje oxidační stres cestou inhibice aktivity mitochondriálního komplexu 1. Je prokázáno, že MDP účinně pomáhají léčit metabolické poruchy včetně diabetu 2. typu. Humanin může sloužit jako marker aktivity mitochondrií v léčbě KVO nebo přímo v léčbě endoteliální dysfunkce. Tento přehled se zabývá novými možnostmi využití humaninu a jeho biologickým významem v léčbě KVO.
Mitochondrial-derived peptides (MDPs) are encoded by mitochondrial DNA. MDPs include humanin, ribosomal ribonucleic acid type c (MOTS-c), and small humanin-like peptides 1-6 (SHLP1-6). In times of stress, they support mitochondrial activity and cell survival. MDPs influence cell survival, metabolism, stress response, and inflammation in vivo and in vitro. Recent research shows MDPs play a significant role in cardiovascular disease (CVD) development. In addition, possible pathogenic pathways include ischemia, reperfusion damage, fibrosis, and coronary microcirculatory dysfunction. CVD biomarkers or therapy targets, MDPs. This group of peptides includes humanin, MOTS-c, and SHLPs. Humanin reduces oxidative stress by inhibiting mitochondrial complex 1 activity. MDPs have been shown to help metabolic illnesses including type 2 diabetes. Humanin may be utilized as a marker for mitochondrial activity in cardiovascular illness or as an endothelial dysfunction treatment. This review will address humanin's novel roles and its biological relevance in cardiovascular diseases.
- Klíčová slova
- Humanin,
- MeSH
- kardiovaskulární nemoci * etiologie farmakoterapie patofyziologie MeSH
- lidé MeSH
- oxidační stres MeSH
- peptidy dějiny farmakologie fyziologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
The emergence of communicable and non-communicable diseases has posed a health challenge for millions of people worldwide and is a major threat to the economic and social development in the coming century. The occurrence of the recent pandemic, SARS-CoV-2, caused by lethal severe acute respiratory syndrome coronavirus 2, is one such example. Rapid research and development of drugs for the treatment and management of these diseases have become an incredibly challenging task for the pharmaceutical industry. Although, substantial attention has been paid to the discovery of therapeutic compounds from natural sources having significant medicinal potential, their synthesis has made a slow progress. Hence, the discovery of new targets by the application of the latest biotechnological and synthetic biology approaches is very much the need of the hour. Polyketides (PKs) and non-ribosomal peptides (NRPs) found in bacteria, fungi and plants are a diverse family of natural products synthesized by two classes of enzymes: polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS). These enzymes possess immense biomedical potential due to their simple architecture, catalytic capacity, as well as diversity. With the advent of the latest in-silico and in-vitro strategies, these enzymes and their related metabolic pathways, if targeted, can contribute highly towards the biosynthesis of an array of potentially natural drug leads that have antagonist effects on biopolymers associated with various human diseases. In the face of the rising threat from multidrug-resistant pathogens, this will further open new avenues for the discovery of novel and improved drugs by combining natural and synthetic approaches. This review discusses the relevance of polyketides and non-ribosomal peptides and the improvement strategies for the development of their derivatives and scaffolds, and how they will be beneficial for future bioprospecting and drug discovery.
- Klíčová slova
- Cotadutid,
- MeSH
- chronická renální insuficience * farmakoterapie MeSH
- diabetes mellitus 2. typu * farmakoterapie MeSH
- hmotnostní úbytek účinky léků MeSH
- lidé MeSH
- peptidy * farmakologie terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- komentáře MeSH
- souhrny MeSH
- MeSH
- hepcidiny fyziologie MeSH
- peptidy terapeutické užití MeSH
- železo * metabolismus MeSH
- Publikační typ
- biografie MeSH
- rozhovory MeSH
- O autorovi
- Ganz, Tomáš, 1948- Autorita
