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1.
Haemophilia ; 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38698539

RESUMO

INTRODUCTION: Plasminogen deficiency is an ultra rare disease whose patients may develop ligneous lesions if untreated. Prophylactic replacement therapy with plasma derived plasminogen, Ryplazim, is efficient in treating lesions and could benefit from pharmacokinetic (PK) tailoring. AIM: The objectives of this study are to develop, evaluate and integrate into the WAPPS-Hemo platform a Population PK model supporting prophylactic replacement therapy for Plasminogen deficient patients. METHODS: Population PK modelling and evaluations followed the same protocol performed for factor VIII and IX concentrates. Limited sampling analysis used dosing and sampling scenarios in accordance with recommended treatment for Ryplazim. RESULTS: The population PK model, derived from 16 participants included in previous clinical studies, was a 2-compartment model whose variability was best described by fat-free mass. Evaluations showed that the model described well the data and Bayesian forecasting in limited sampling environment led to acceptable precision for PK parameters relevant to plasminogen treatment. CONCLUSION: The model was integrated into the WAPPS-Hemo webservice to help individualize prophylactic treatment in plasminogen deficient patients. Prospective PK data to be collected through the WAPPS-Hemo database will be used to better understand plasminogen PK and improve patient care.

2.
Haemophilia ; 29(6): 1556-1564, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37674358

RESUMO

AIM: An open-label phase 2/3 study of plasminogen, human-tvmh administered intravenously in paediatric and adult subjects with type 1 plasminogen deficiency was conducted. Interim data was previously reported. The final data on 15 subjects who completed the study up to a maximum of 124 weeks are reported here. METHODS: The primary objectives were to evaluate efficacy of plasminogen replacement therapy on clinically evident or visible lesions during 48 weeks of dosing and to achieve an increase in trough plasminogen activity levels by at least an absolute 10% above baseline during 12 weeks of treatment. RESULTS: The primary efficacy endpoint was achieved, as 100% of subjects (n = 11) with visible and assessable non-visible lesions at baseline demonstrated ≥ 50% improvement after 48 weeks of study drug treatment with plasminogen, human-tvmh. All subjects achieved the targeted ≥ 10% increase in trough plasminogen activity above baseline through Week 12. Plasminogen, human-tvmh at a dose of 6.6 mg/kg administered every 2-5 days for 48 weeks and every 1-7 days for up to 124 weeks was well tolerated. CONCLUSION: This study provides additional evidence regarding the long-term safety and clinical utility of replacement therapy with human plasminogen for the treatment of children and adults with type 1 plasminogen deficiency. Plasminogen, human-tvmh received marketing approval on June 4, 2021. This trial was registered at www. CLINICALTRIALS: gov as #NCT02690714.


Assuntos
Plasminogênio , Humanos , Criança , Adulto , Resultado do Tratamento
3.
Artigo em Inglês | MEDLINE | ID: mdl-36387348

RESUMO

COVID-19 symptoms can cause substantial disability, yet no therapy can currently reduce their frequency or duration. We conducted a double-blind placebo-controlled trial of hesperidin 1000 mg once daily for 14 days in 216 symptomatic nonvaccinated COVID-19 subjects. Thirteen symptoms were recorded after 3, 7, 10, and 14 days. The primary endpoint was the proportion of subjects with any of four cardinal (group A) symptoms: fever, cough, shortness of breath, or anosmia. At the baseline, symptoms in decreasing frequency were as follows: cough (53.2%), weakness (44.9%), headache (42.6%), pain (35.2%), sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%), and irritability/confusion (3.2%). Group A symptoms in the placebo vs. hesperidin group were 88.8% vs. 88.5% (day 1) and reduced to 58.5 vs. 49.4% at day 14 (OR 0.69, 95% CI 0.38-1.27, p = 0.23). At day 14, 15 subjects in the placebo group and 28 in the hesperidin group failed to report their symptoms. In an attrition bias analysis imputing "no symptoms" to missing values, the hesperidin group showed reduction of 14.5% of group A symptoms from 50.9% to 36.4% (OR: 0.55, 0.32-0.96, p = 0.03). Anosmia, the most frequent persisting symptom (29.3%), was lowered by 7.3% to 25.3% in the hesperidin group vs. 32.6% in the placebo group (p = 0.29). The mean number of symptoms in the placebo and hesperidin groups was 5.10 (SD 2.26) vs. 5.48 (SD 2.35) (day 1) and 1.40 (SD 1.65) vs. 1.38 (SD 1.76) (day 14) (p = 0.92). In conclusion, most nonvaccinated COVID-19 infected subjects remain symptomatic after 14 days with anosmia being the most frequently persisting symptom. Hesperidin 1 g daily may help reduce group A symptoms. Earlier treatment of longer duration and/or higher dosage should be tested.

4.
Blood ; 131(12): 1301-1310, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29321155

RESUMO

Congenital plasminogen deficiency is caused by mutations in PLG, the gene coding for production of the zymogen plasminogen, and is an ultrarare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes. Left untreated, these lesions may impair organ function and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the manifestations of congenital plasminogen deficiency. An open-label phase 2/3 study of human Glu-plasminogen administered IV at 6.6 mg/kg every 2 to 4 days in 15 patients with congenital plasminogen deficiency is ongoing. Reported here are data on 14 patients who completed at least 12 weeks of treatment. The primary end point was an increase in trough plasminogen activity levels by at least an absolute 10% above baseline. The secondary end point was clinical success, defined as ≥50% improvement in lesion number/size or functionality impact from baseline. All patients achieved at least an absolute 10% increase in trough plasminogen activity above baseline. Clinical success was observed in all patients with clinically visible (conjunctiva and gingiva), nonvisible (nasopharynx, bronchus, colon, kidney, cervix, and vagina), and wound-healing manifestations of the disease. Therapeutic effects were rapid, as all but 2 lesions resolved or improved after 4 weeks of treatment. Human Glu-plasminogen was well tolerated in both children and adults. This study provides critical first evidence of the clinical utility of ongoing replacement therapy with human Glu-plasminogen for the treatment of children and adults with congenital plasminogen deficiency. This trial was registered at www.clinicaltrials.gov as #NCT02690714.


Assuntos
Transtornos Herdados da Coagulação Sanguínea , Plasminogênio , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Herdados da Coagulação Sanguínea/sangue , Transtornos Herdados da Coagulação Sanguínea/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Plasminogênio/administração & dosagem , Plasminogênio/deficiência , Plasminogênio/farmacocinética
5.
Eur J Neurosci ; 32(5): 826-39, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20646064

RESUMO

The mechanism and routes through which peptide tyrosine-tyrosine (PYY) exerts its anorectic effects are still largely unknown. In the present study, we investigated the roles of the area postrema (AP), subfornical organ (SFO) and vagus nerve in mediating the anorectic effect of PYY using PYY(3-36) conjugated to human serum albumin (PYY(3-36)-HSA) in rats. PYY(3-36)-HSA is a large molecule that does not penetrate the blood-brain barrier, and thus provides a useful tool to discriminate between the central (brain) and peripheral actions of this peptide. PYY(3-36)-HSA induced significant reductions in food and body weight gain up to 24 h after administration. The anorectic effect of PYY(3-36)-HSA was delayed for 2 h in rats in which both AP and SFO were ablated, while lesion of either of these circumventricular organs in isolation did not influence the feeding responses to PYY(3-36)-HSA. The PYY(3-36)-HSA-induced anorectic effect was also reduced during the 3- to 6-h period following subdiaphragmatic vagotomy. Lesions of AP, SFO and AP/SFO as well as subdiaphragmatic vagotomy blunted PYY(3-36)-HSA-induced expression of c-fos mRNA in specific brain structures including the bed nucleus of stria terminalis, central amygdala, lateral-external parabrachial nucleus and medial nucleus of the solitary tract. In addition, subdiaphragmatic vagotomy inhibited the neuronal activation induced by PYY(3-36)-HSA in AP and SFO. These findings suggest that the anorectic effect and brain neuronal activation induced by PYY(3-36)-HSA are dependent on integrity of AP, SFO and subdiaphragmatic vagus nerve.


Assuntos
Depressores do Apetite/farmacologia , Regulação do Apetite/fisiologia , Ingestão de Alimentos/fisiologia , Peptídeo YY/farmacologia , Albumina Sérica/farmacologia , Órgão Subfornical/fisiologia , Animais , Regulação do Apetite/efeitos dos fármacos , Área Postrema/efeitos dos fármacos , Área Postrema/fisiologia , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Encéfalo/fisiologia , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Insulina/sangue , Masculino , Neurônios/fisiologia , Fragmentos de Peptídeos , Peptídeo YY/química , Ratos , Ratos Wistar , Albumina Sérica/química , Órgão Subfornical/efeitos dos fármacos , Vagotomia/métodos , Nervo Vago/fisiologia
6.
J Biol Chem ; 283(49): 34045-52, 2008 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-18809675

RESUMO

Entry inhibitors of human immunodeficiency virus, type 1 (HIV-1) have been the focus of much recent research. C34, a potent fusion inhibitor derived from the HR2 region of gp41, was engineered into a 1:1 human serum albumin conjugate through stable covalent attachment of a maleimido-C34 analog onto cysteine 34 of albumin. This bioconjugate, PC-1505, was designed to require less frequent dosing and less peptide than T-20 and was assessed for its antifusogenic activity both in vitro and in vivo in the SCID-hu Thy/Liv mouse model. PC-1505 was essentially equipotent to the original C34 peptide and to T-20 in vitro. In HIV-1-infected SCID-hu Thy/Liv mice, T-20 lost activity with infrequent dosing, whereas the antiviral potency of PC-1505 was sustained, and PC-1505 was active against T-20-resistant ("DIV") virus with a G36D substitution in gp41. The in vivo results are the direct result of a significantly improved pharmacokinetic profile for the C34 peptide following albumin conjugation. Contrary to previous reports that the gp41 NHR trimer is poorly accessible to C34 fused to protein cargoes of increasing size (Hamburger, A. E., Kim, S., Welch, B. D., and Kay, M. S. (2005) J. Biol. Chem. 280, 12567-12572), these results are the first demonstration of the capacity for a large, endogenous serum protein to gain unobstructed access to the transient gp41 intermediates that exist during the HIV fusion process, and it supports further development of albumin conjugation as a promising approach to inhibit HIV-1 entry.


Assuntos
Albuminas/química , Proteína gp41 do Envelope de HIV/química , Proteína gp41 do Envelope de HIV/farmacologia , Inibidores da Fusão de HIV/farmacologia , HIV-1/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Proteínas Virais de Fusão/química , Sequência de Aminoácidos , Animais , Modelos Animais de Doenças , Enfuvirtida , Inibidores da Fusão de HIV/química , Camundongos , Camundongos SCID , Dados de Sequência Molecular , Peptídeos/química , Ratos , Ratos Sprague-Dawley
7.
Bioconjug Chem ; 16(4): 1000-8, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16029043

RESUMO

A series of human insulin maleimido derivatives with short and long linkers was synthesized by exploiting the variations in the pK(a) values and environment of the three amino groups present in the protein. The syntheses were accomplished in organic solvent because of maleimide's instability in basic aqueous media. The derivatives thus obtained were conjugated to the free thiol on Cys34 of human serum albumin (HSA) and purified. A structure-activity relationship based on in vitro receptor binding and activation results for this series of insulin-HSA conjugates showed that the best compounds were attached at the B1 position of insulin with either short or long linkers. Two conjugates were administered subcutaneously to streptozotocin-induced diabetic rats and found to possess blood glucose normalizing activity up to 8 h post-administration. The return to diabetic plasma glucose levels was not observed within the time frame of the experiment (48 h). In comparison, the insulin-treated group's normalization activity lasted 2 h and returned to a diabetic level at 8 h. The onset of the conjugate activities were delayed by 1 h when compared to the activity of human insulin. The study results led to the identification of CJC-1575 as a potent and long lasting human insulin analogue.


Assuntos
Insulina/química , Albumina Sérica/química , Sequência de Aminoácidos , Animais , Diabetes Mellitus Experimental/terapia , Avaliação Pré-Clínica de Medicamentos , Eletroforese em Gel de Poliacrilamida , Humanos , Insulina/administração & dosagem , Insulina/síntese química , Insulina/farmacocinética , Espectroscopia de Ressonância Magnética , Masculino , Dados de Sequência Molecular , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/síntese química , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacocinética , Albumina Sérica/administração & dosagem , Albumina Sérica/síntese química , Albumina Sérica/farmacocinética , Estreptozocina , Relação Estrutura-Atividade
8.
Endocrinology ; 146(7): 3052-8, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15817669

RESUMO

In vivo bioconjugation to the free thiol on Cys34 of serum albumin by a strategically placed reactive group on a bioactive peptide is a useful tool to extend plasma half-life. Three maleimido derivates of human GH-releasing factor (hGRF)(1-29) were synthesized and bioconjugated to human serum albumin ex vivo. All three human serum albumin conjugates showed enhanced in vitro stability against dipeptidylpeptidase-IV and were bioactive in a GH secretion assay in cultured rat anterior pituitary cells. When the maleimido derivatives were individually administered sc to normal male Sprague Dawley rats, an acute secretion of GH was measured in plasma. The best compound, CJC-1295, showed a 4-fold increase in GH area under the curve over a 2-h period compared with hGRF(1-29). CJC-1295, a tetrasubstituted form of hGRF(1-29) with an added N epsilon-3-maleimidopropionamide derivative of lysine at the C terminus, was selected for further pharmacokinetic evaluation, where it was found to be present in plasma beyond 72 h. A Western blot analysis of the plasma of a rat injected with CJC-1295 showed the presence of a CJC-1295 immunoreactive species on the band corresponding to serum albumin, appearing after 15 min and remaining in circulation beyond 24 h. These results led to the identification of CJC-1295 as a stable and active hGRF(1-29) analog with an extended plasma half-life.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Hormônio Liberador de Hormônio do Crescimento/análogos & derivados , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Fragmentos de Peptídeos/farmacologia , Adeno-Hipófise/metabolismo , Albumina Sérica/farmacologia , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Animais , Células Cultivadas , Proteínas de Ligação a DNA/efeitos dos fármacos , Dipeptidil Peptidase 4/farmacologia , Estabilidade de Medicamentos , Hormônio Liberador de Hormônio do Crescimento/administração & dosagem , Hormônio Liberador de Hormônio do Crescimento/genética , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio Liberador de Hormônio do Crescimento/farmacocinética , Meia-Vida , Humanos , Injeções Subcutâneas , Masculino , Dados de Sequência Molecular , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacocinética , Ratos , Ratos Sprague-Dawley , Sermorelina/farmacocinética , Albumina Sérica/metabolismo , Fatores de Transcrição/efeitos dos fármacos
9.
Bioorg Med Chem Lett ; 14(17): 4395-8, 2004 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-15357960

RESUMO

A series of analogs of GLP-1(7-36) amide containing a Nepsilon-(2-[2-[2-(3-maleimidopropylamido)ethoxy]ethoxy]acetyl)lysine has been synthesized and the resulting derivatives were bioconjugated to Cys34 of human serum albumin (HSA). The GLP-1-HSA bioconjugates were analyzed in vitro to assess the stabilizing effect of bioconjugation in the presence of DPP-IV as well as GLP-1 receptor binding and activation. Compound 9 (CJC-1131) having the point of attachment to albumin at the C-terminal of GLP-1 and a D-alanine substitution at position 8 was identified as having the best combination of stability and bioactivity.


Assuntos
Maleimidas/química , Maleimidas/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Albumina Sérica/metabolismo , Sequência de Aminoácidos/genética , Animais , Células CHO , Cricetinae , Glucagon , Peptídeo 1 Semelhante ao Glucagon , Peptídeos Semelhantes ao Glucagon , Humanos , Dados de Sequência Molecular , Fragmentos de Peptídeos/genética , Ligação Proteica/fisiologia
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