METABOLIC INVESTIGATIONS OF THE PIPERIDINE-TYPE PHENOTHIAZINE ANTIPSYCHOTIC AGENTS WITH EMPHASIS ON THE LACTAM METABOLITES
Bibliographic record
Abstract
Thioridazine, mesoridazine and sulforidazine are piperidine-type phenothiazine antipsychotic agents, which only differ from one another in the oxidative state of the sulfur atom at the 2-position of the phenothiazine ring. These drugs are extensively metabolized in humans and animals. There has been no systematic investigation of the metabolites in any species although there is substantial documentation that the pathways include S-oxidations of both the phenothiazine ring and side chain sulfur atoms, aromatic hydroxylation of the phenothiazine ring followed by conjugation and N-demethylation of the piperidine ring N-substituent. There are few reports on the metabolism of the piperidine ring itself; thioridazine N-oxide is a minor metabolite of thioridazine in rat and tentative identification has been made of the lactams of mesoridazine ring sulfoxide and sulforidazine ring suifoxide in the urine of patients. For other drugs with saturated nitrogen-containing heterocyclic ring systems, including piperidine, it is well established in various species that the metabolites include the lactams, ring opened products and N- oxides. Therefore, studies were conducted to investigate systematically the metabolic profiles in urine after oral administration of thioridazine, mesoridazine and sulforidazine in rat, dog and human, which included the definitive identification and quantification of those metabolites resultant from metabolism of the piperidine ring such as lactam and N-oxide derivatives. Synthetic procedures were developed for the lactam analogues of thioridazine, mesoridazine and sulforidazine, their corresponding lactam ring sulfoxides, the lactam of sulforidazine ring sulfone and the N-oxide of sulforidazine. In addition, sulforidazine was synthesized and an investigational new drug certificate was obtained that enabled its administration to human.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".