{"id":"d134b9e3-f292-52c1-9443-c8d208493c23","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-antipyresis-follows-central-prostaglandin","predicate":"reduces","statement":"Prostaglandin E-like activity in cisternal cerebrospinal fluid was usually undetectable or low at normal body temperature and increased, often many-fold, during pyrogen fever irrespective of the route of pyrogen administration, and the antipyretic drugs indomethacin, paracetamol and aspirin injected intraperitoneally during the fever brought down temperature and returned the activity to low levels, with chromatography placing the activity in the zone of the E series prostaglandins, supporting the theory that pyrogens produce fever by increasing prostaglandin synthesis in the preoptic anterior hypothalamic area and that antipyretics of the aspirin type act by inhibiting that synthesis.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"376a2cb7-82c6-5a0c-9260-b3f9013fe92e","mechanism_event_label":"Fever raises a prostaglandin in the fluid round the brain, and this drug brings both down together.","subject":{"id":"a901be21-7915-543c-ac67-c39ef72b0d03","slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"},"object":{"id":"b420598d-d47a-5cb9-8327-70db28928fd0","slug":"csf-prostaglandin-e","display_name":"Prostaglandin E-like activity in cisternal cerebrospinal fluid","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"376a2cb7-82c6-5a0c-9260-b3f9013fe92e","stable_key":"7de430a5-1a36-5231-b931-35cc01d8f3bf:apap-antipyresis-follows-central-prostaglandin-event","event_type":"observed_intervention","label":"Fever raises a prostaglandin in the fluid round the brain, and this drug brings both down together.","description":"Prostaglandin E-like activity in cisternal cerebrospinal fluid was usually undetectable or low at normal body temperature and increased, often many-fold, during pyrogen fever irrespective of the route of pyrogen administration, and the antipyretic drugs indomethacin, paracetamol and aspirin injected intraperitoneally during the fever brought down temperature and returned the activity to low levels, with chromatography placing the activity in the zone of the E series prostaglandins, supporting the theory that pyrogens produce fever by increasing prostaglandin synthesis in the preoptic anterior hypothalamic area and that antipyretics of the aspirin type act by inhibiting that synthesis.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"e0d993a4-e771-56a1-8320-eca3aaa6388a","slug":"pyrogen-fever","display_name":"Fever produced by bacterial pyrogen","entity_type_key":"cellular_process"},"role":"studied_state","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"0e3e9bf3-6419-5c7f-82ab-a1cf15685ddf","slug":"preoptic-hypothalamus","display_name":"The preoptic anterior hypothalamic area","entity_type_key":"cell_type"},"role":"proposed_site","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"5733d7d1-6259-588f-a4a9-4d0dc0133735","slug":"prostaglandin-e2","display_name":"Prostaglandin E2","entity_type_key":"small_molecule"},"role":"identified_class","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"8ac405bf-3ea0-539a-8e5e-abf503dc7081","slug":"aspirin","display_name":"Aspirin / acetylsalicylic acid","entity_type_key":"drug"},"role":"co_tested_drug","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"b4ad67ed-ff1f-5c41-a6a4-040205a3bdf3","slug":"indomethacin","display_name":"Indomethacin","entity_type_key":"small_molecule"},"role":"co_tested_drug","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"f0247ef6-fe4d-5a7d-9621-434407dc3806","slug":"antipyresis","display_name":"Reduction of a raised body temperature","entity_type_key":"cellular_process"},"role":"measured_outcome","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""},{"entity":{"id":"a901be21-7915-543c-ac67-c39ef72b0d03","slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":6,"notes":""},{"entity":{"id":"b420598d-d47a-5cb9-8327-70db28928fd0","slug":"csf-prostaglandin-e","display_name":"Prostaglandin E-like activity in cisternal cerebrospinal fluid","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":7,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/paracetamol-research/4588122.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"274f00794352ea4d44e1ef2c2cf46a094d9a03752d7c485a2d6222e519534aa9\", \"start_char\": 0, \"end_char\": 2254, \"text_sha256\": \"274f00794352ea4d44e1ef2c2cf46a094d9a03752d7c485a2d6222e519534aa9\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Cisternal cerebrospinal fluid sampled from unanaesthetised cats during fever and after antipyretics","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Shigella dysenteriae pyrogen given into the third ventricle, cisterna magna or intravenously, with indomethacin, paracetamol and aspirin","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Bioassay on a stomach strip rather than direct measurement, and prostaglandin E-like activity rather than identified prostaglandin E2. It is the record that connects fever to central prostaglandin and to this drug.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404.","comparator":null,"unit":null,"notes":"","entity":{"slug":"acetaminophen","display_name":"Paracetamol","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Cat","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Fever raises a prostaglandin in the fluid round the brain, and this drug brings both down together.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[apap-p4588122] Effect of pyrogen and antipyretics on prostaglandin acitvity in cisternal c.s.f. of unanaesthetized cats. (1973). https://pubmed.ncbi.nlm.nih.gov/4588122/ DOI: 10.1113/jphysiol.1973.sp010346","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Cerebrospinal fluid and hypothalamus","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"7f977488-ed6e-5e63-a0ae-f70b4173d08e","evidence_kind":"source_excerpt","locator":"Lines 285-296","start_line":285,"end_line":296,"excerpt":"### apap-antipyresis-follows-central-prostaglandin\nProstaglandin E-like activity in cisternal cerebrospinal fluid was usually undetectable or low at normal body temperature and increased, often many-fold, during pyrogen fever irrespective of the route of pyrogen administration, and the antipyretic drugs indomethacin, paracetamol and aspirin injected intraperitoneally during the fever brought down temperature and returned the activity to low levels, with chromatography placing the activity in the zone of the E series prostaglandins, supporting the theory that pyrogens produce fever by increasing prostaglandin synthesis in the preoptic anterior hypothalamic area and that antipyretics of the aspirin type act by inhibiting that synthesis.\nCondition category: normal\nnutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404.\nplain_language: Fever raises a prostaglandin in the fluid round the brain, and this drug brings both down together.\norganism: Cat\ntissue_or_cell_type: Cerebrospinal fluid and hypothalamus\nexperimental_model: Cisternal cerebrospinal fluid sampled from unanaesthetised cats during fever and after antipyretics\nlimitations: Bioassay on a stomach strip rather than direct measurement, and prostaglandin E-like activity rather than identified prostaglandin E2. It is the record that connects fever to central prostaglandin and to this drug.\nexposure: Shigella dysenteriae pyrogen given into the third ventricle, cisterna magna or intravenously, with indomethacin, paracetamol and aspirin\nevidence_span: {\"source_cache\": \"artifacts/paracetamol-research/4588122.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"274f00794352ea4d44e1ef2c2cf46a094d9a03752d7c485a2d6222e519534aa9\", \"start_char\": 0, \"end_char\": 2254, \"text_sha256\": \"274f00794352ea4d44e1ef2c2cf46a094d9a03752d7c485a2d6222e519534aa9\"}\n[apap-p4588122] Effect of pyrogen and antipyretics on prostaglandin acitvity in cisternal c.s.f. of unanaesthetized cats. (1973). https://pubmed.ncbi.nlm.nih.gov/4588122/ DOI: 10.1113/jphysiol.1973.sp010346","model_system":"Cisternal cerebrospinal fluid sampled from unanaesthetised cats during fever and after antipyretics","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [apap-p4588122] Effect of pyrogen and antipyretics on prostaglandin acitvity in cisternal c.s.f. of unanaesthetized cats. 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