RESUMO
Privigen(®) (immune globulin intravenous [human], 10% liquid) and Hizentra(®) (immune globulin subcutaneous [human], 20% liquid) are stabilized by proline. The clinical implications of administering proline-containing immunoglobulin products to patients with defects of proline metabolism have not been addressed; Privigen and Hizentra are contraindicated in these patients. Some patients with chromosome 22q11.2 deletion syndrome have elevated proline levels; however, only 3-4% of patients also have an immunodeficiency that requires IgG therapy. This review summarizes the evidence related to the safety and pharmacokinetics of proline assessed in Privigen and Hizentra preclinical and clinical studies, and subsequent implications for patients with defects in proline metabolism. Clinical data indicate that proline does not accumulate after Privigen or Hizentra treatment and is not associated with adverse events. There is no evidence to suggest that patients with defects of proline metabolism would be affected by transient elevations in plasma proline following Privigen and/or Hizentra treatment.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Excipientes , Imunoglobulina G , Imunoglobulinas Intravenosas , Prolina , Animais , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Estabilidade de Medicamentos , Excipientes/efeitos adversos , Excipientes/farmacocinética , Excipientes/uso terapêutico , Doenças Genéticas Inatas/tratamento farmacológico , Doenças Genéticas Inatas/genética , Humanos , Imunoglobulina G/efeitos adversos , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/farmacocinética , Imunoglobulinas Intravenosas/uso terapêutico , Prolina/efeitos adversos , Prolina/farmacocinética , Prolina/uso terapêuticoRESUMO
We have established a rapid, homogeneous, cell-based, and highly sensitive assay for guanosine 3'-5'-cyclic monophosphate (cGMP) that is suitable for fully automated ultra-high-throughput screening. In this assay system, cGMP production is monitored in living cells via Ca2+ influx through the olfactory cyclic nucleotide-gated cation channel CNGA2, acting as the intracellular cGMP sensor. A stably transfected Chinese hamster ovary (CHO) cell line was generated recombinantly expressing soluble guanylate cyclase, CNGA2, and aequorin as a luminescence indicator for the intracellular calcium concentration. This cell line was used to screen more than 900,000 compounds in an automated ultra-high-throughput screening assay using 1536-well microtiter plates. In this way, we have been able to identify BAY 58-2667, a member of a new class of amino dicarboxylic acids that directly activate soluble guanylate cyclase. The assay system allows the real-time cGMP detection within living cells and makes it possible to screen for activators and inhibitors of enzymes involved in the nitric oxide/cGMP pathway.