RESUMEN

BACKGROUND: Extensive scientific and clinical evidence indicates that continuous delivery of a dopaminergic agent is associated with significant reduction in motor complications compared with intermittent oral dosing with the same agent. There has been an intensive effort to develop a method of providing continuous plasma levels of a dopaminergic agent that avoids the need for surgical therapy or an infusion system. Studies in MPTP-treated monkeys demonstrate that once-weekly injections of polymer-linked rotigotine provide continuous plasma levels and antiparkinsonian benefits. METHODS: We performed a multicenter open-label, multiple-ascending-dose-ranging cohort study to evaluate the safety, tolerability, and pharmacokinetics of polymer-linked rotigotine in PD patients. RESULTS: A total of 19 patients were evaluated in 4 cohorts in doses of 20 50, 100, and 200 mg of polymer-linked rotigotine, administered subcutaneously once weekly. The study demonstrated remarkably stable dose-related plasma levels of total and free rotigotine with no accumulation or dumping. Treatment was generally safe and well tolerated. One subject in the 50-mg group discontinued because of hives, which cleared rapidly with antihistamine treatment. CONCLUSIONS: This study demonstrates that once-a-week subcutaneous administration of polymer-linked rotigotine provides relatively constant plasma levels of rotigotine and is safe and well tolerated. These findings suggest that this convenient method of delivery of rotigotine has the potential to treat or prevent motor complications in PD patients without the need for a surgical procedure or an infusion system. This approach may also prove applicable to other agents such as apomorphine that can be linked to this polymer © 2020 International Parkinson and Movement Disorder Society.

Asunto(s)

Enfermedad de Parkinson , Administración Cutánea , Estudios de Cohortes , Agonistas de Dopamina/uso terapéutico , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Plasma , Polímeros/uso terapéutico , Tetrahidronaftalenos/uso terapéutico , Tiofenos

RESUMEN

Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including "wearing-off" and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)-approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ-conjugated constructs ("fast": SER-212; "moderate": SER-213; and "slow": SER-214) using in vitro hydrolysis, normal male Sprague-Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6-hydroxydopamine (6-OHDA) infusions, treated acutely with POZ-rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ-rotigotine formulations SER-213 and SER-214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER-214 led to antiparkinsonian effects in DA-lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER-214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER-214 could represent a significant advance in the treatment of PD, with potential to be a viable, once-per-week therapy for PD patients.

Asunto(s)

Antiparkinsonianos/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Tetrahidronaftalenos/uso terapéutico , Tiofenos/uso terapéutico , Animales , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacocinética , Modelos Animales de Enfermedad , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacocinética , Sistemas de Liberación de Medicamentos , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/farmacocinética , Tiofenos/administración & dosificación , Tiofenos/farmacocinética , Resultado del Tratamiento

RESUMEN

Poly(2-ethyl 2-oxazoline) (PEOZ) is a water-soluble, stable and biocompatible polymer that was prepared in a linear form for the conjugation of protein biomolecules. Polymers of molecular weights ranging from 5 to 20 kDa, with an aldehyde or an amine functional terminal group, were synthesized with narrow polydispersities. To assess the suitability of the polymer for therapeutic application, granulocyte colony stimulating factor (G-CSF) was used as a model protein for PEOZ conjugation. Two coupling strategies were employed, namely the chemical N-terminal reductive amination and the enzymatic transglutaminase (TGase) mediated glutamine conjugation. The secondary structure of the protein, measured by circular dichroism, was maintained upon PEOZylation and the stability of conjugates toward aggregation at 37 °C was improved compared to G-CSF. The potency of PEOZ-G-CSF mono-conjugates was tested in vitro by cell proliferation assays and in vivo by studying the effects on white blood cell and neutrophil count increases in normal rats. The results have shown that PEOZ is suitable for protein conjugation by both chemical and enzymatic methods and that the conjugates of G-CSF retained high biological activity, both in vitro and in vivo.

Asunto(s)

Portadores de Fármacos/química , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/química , Poliaminas/química , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Estabilidad de Medicamentos , Electroforesis en Gel de Poliacrilamida , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Recuento de Leucocitos , Leucocitos/citología , Leucocitos/efectos de los fármacos , Masculino , Ratones , Datos de Secuencia Molecular , Peso Molecular , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Estabilidad Proteica , Estructura Secundaria de Proteína , Ratas , Ratas Sprague-Dawley , Solubilidad , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción

RESUMEN

Polyoxazoline polymers with methyl (PMOZ), ethyl (PEOZ), and propyl (PPOZ) side chains were prepared by the living cationic polymerization method and purified by ion-exchange chromatography. The following properties of polyoxazoline (POZ) were measured: apparent hydrodynamic radius by aqueous size-exclusion chromatography, relative lipophilicity by reverse-phase chromatography, and viscosity by cone-plate viscometry. The PEOZ polymers of different molecular weights were first functionalized and then conjugated to model biomolecules such as bovine serum albumin, catalase, ribonuclease, uricase, and insulin. The conjugates of catalase, uricase, and ribonuclease were tested for in vitro activity using substrate-specific reaction methods. The conjugates of insulin were tested for glucose lowering activity by injection to naïve Sprague-Dawley rats. The conjugates of BSA were injected into New Zealand white rabbits and serum samples were collected periodically and tested for antibodies to BSA. The safety of POZ was also determined by acute and chronic dosing to rats. The results showed that linear polymers of POZ with molecular weights of 1 to 40 kDa can easily be made with polydispersity values below 1.10. Chromatography results showed that PMOZ and PEOZ have a hydrodynamic volume slightly lower than PEG; PEOZ is more lipophilic than PMOZ and PEG; and PEOZ is significantly less viscous than PEG especially at the higher molecular weights. When PEOZ was attached to the enzymes catalase, ribonuclease, and uricase, the in vitro activity of the resultant bioconjugates depended on the extent of protein modification. POZ conjugates of insulin lowered blood glucose levels for a period of 8 h when compared to 2 h for insulin alone. PEOZ, like PEG, was also able to successfully attenuate the immunogenic properties of BSA. The POZ polymers (10 and 20 kDa) are safe when administered intravenously to rats, and the maximum tolerated dose (MTD) was greater than 2 g/kg. Blood counts, serum chemistry, organ weights, and the histopathology of key organs were normal. These results conclude that POZ has the desired drug delivery properties for a new biopolymer.

Asunto(s)

Sistemas de Liberación de Medicamentos , Poliaminas/farmacocinética , Amidas/síntesis química , Amidas/química , Amidas/farmacocinética , Animales , Bovinos , Cromatografía por Intercambio Iónico , Eritrocitos/química , Eritrocitos/efectos de los fármacos , Femenino , Insulina/química , Masculino , Ratones , Modelos Animales , Estructura Molecular , Poliaminas/síntesis química , Poliaminas/química , Proteínas/química , Conejos , Ratas , Ratas Sprague-Dawley , Distribución Tisular

RESUMEN

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