»Treatment Resistance« Enigma Resolved by Pharmacogenomics − A Case Study of Clozapine Therapy in Schizophrenia / Enigma »Terapo-Rezistence« Razrešena Uz Pomoć Farmakogenomike - Prikaz Slućaja Terapije Klozapinom U Shizofreniji

Summary The introduction of antipsychotic medication in the 1950s forever changed the outlook on the treatment of schizophrenia, although there is still a large proportion of patients who do not reach functional recovery. At least 30% of patients do not respond to clozapine, the tricyclic dibenzodiazepine with complex pharmacological actions, which was proven to be more effective than any other antipsychotic in the treatment of schizophrenia. According to most of the therapeutic guidelines for schizophrenia, clozapine is the third line therapy for patients who did not respond to other antipsychotics. Large inter-individual variability exists for clozapine bioavailability and plasma steadystate concentrations and clearance. Clozapine is metabolized by the cytochrome P450 oxidase enzyme family (CYP450). Cytochrome P450 1A2 (CYP1A2), which is polymorphically expressed in humans, is the main enzyme of clozapine metabolism. This case report addresses the influence of CYP1A2*1F genetic polymorphism on cloza - pine metabolism, explains the primary non-response of a young patient with schizophrenia due to increased gene expression in homozygous genotype *1F/*1F (increased metabolism of clozapine) and underlies the importance of personalizing schizophrenia treatment by means of genetic and other molecular tools, at least in the cases of »treatment resistance«.

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Oxygen Economy of Cytochrome P450: What Is the Origin of the Mixed Functionality as a Dehydrogenase−Oxidase Enzyme Compared with Its Normal Function?

Journal of the American Chemical Society ◽

10.1021/ja0318737 ◽

2004 ◽

Vol 126 (16) ◽

pp. 5072-5073 ◽

Cited By ~ 48

Author(s):

Devesh Kumar ◽

Samuël P. de Visser ◽

Sason Shaik

Keyword(s):

Cytochrome P450 ◽

Normal Function ◽

Oxidase Enzyme

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H2-antagonist in IgE-mediated type I hypersensitivity reactions: what literature says so far?

Clinical and Molecular Allergy ◽

10.1186/s12948-021-00143-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Matteo Borro ◽

Simone Negrini ◽

Andrew Long ◽

Sharon Chinthrajah ◽

Giuseppe Murdaca

Keyword(s):

Receptor Antagonist ◽

Inflammatory Responses ◽

Type I ◽

Line Therapy ◽

H2 Antagonist ◽

Amino Acid Histidine ◽

Third Line Therapy ◽

Ige Mediated ◽

Third Line ◽

Type I Hypersensitivity

AbstractHistamine is a monoamine synthesized from the amino acid histidine that is well-known for its role in IgE-mediated anaphylaxis but has shown pleiotropic effects on the immune system, especially in order to promote inflammatory responses. H1-receptor antagonist are common drugs used in mild/moderate allergic reactions whereas H2-receptor antagonist are commonly administered in gastric ulcer but showed some properties in allergy too. The EAACI guidelines for diagnosis and treatment of anaphylactic reactions recommend their use as third-line therapy in adjunct to H1-antagonists. The purpose of this article is to produce a complete summary of findings and evidence known so far about the usefulness of H2-receptor antagonist in allergic reactons.

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Metastatic non-small-cell lung cancer: consensus on pathology and molecular tests, first-line, second-line, and third-line therapy

Annals of Oncology ◽

10.1093/annonc/mdr150 ◽

2011 ◽

Vol 22 (7) ◽

pp. 1507-1519 ◽

Cited By ~ 89

Author(s):

E. Felip ◽

C. Gridelli ◽

P. Baas ◽

R. Rosell ◽

R. Stahel

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Small Cell ◽

Second Line ◽

Small Cell Lung ◽

First Line ◽

Molecular Tests ◽

Line Therapy ◽

Third Line Therapy ◽

Third Line

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Persistence to Biologic Therapy among Patients with Spondyloarthritis: An Observational Study using the OPAL Dataset

The Journal of Rheumatology ◽

10.3899/jrheum.201551 ◽

2021 ◽

pp. jrheum.201551

Author(s):

Hedley Griffiths ◽

Tegan Smith ◽

Christopher Mack ◽

Jo Leadbetter ◽

Belinda Butcher ◽

...

Keyword(s):

Disease Activity ◽

Treated Group ◽

Treatment Persistence ◽

Kaplan Meier ◽

Time Period ◽

Sampling Window ◽

Biologic Dmard ◽

Australian Cohort ◽

Third Line Therapy ◽

Third Line

Objective To describe the treatment response and persistence to biologic DMARD (bDMARD) therapy in patients with ankylosing spondylitis (AS) in a real-world Australian cohort. Methods This was a retrospective, non-interventional cohort study that extracted data for patients with AS from the Optimising Patient outcomes in Australian rheumatology (OPAL) dataset for the period Aug-2006 to Sep-2019. Patients were classified as either bDMARD initiators if they commenced a bDMARD during the sampling window, or bDMARD naïve if they did not. Results were summarised descriptively. Treatment persistence was calculated using Kaplan-Meier methods. Differences in treatment persistence were explored using log-rank tests. Results 5048 patients with AS were identified. 2597 patients initiated bDMARDs and 2451 remained bDMARD naïve throughout the study window. Treatment with first, second and third line bDMARDs significantly reduced disease activity. Median persistence on first line bDMARDs was 96 months (95% CI 85 to 109), declining to 19 months (95% CI 16 to 22) in second line, and 14 months (95% CI 11 to 18) in third line therapy. Median persistence was longest for the golimumab treated group in all lines of therapy and shortest for the etanercept group. Differences in persistence rates according to the time-period that bDMARDs were prescribed (pre-and post-2012) were also seen for etanercept and adalimumab. Conclusion In this cohort all bDMARDs effectively reduced disease activity. Patients remained on their first bDMARD longer than subsequent agents. Median persistence was longest for the golimumab treated group in all lines of therapy and shortest for the etanercept group.

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