{ "document_id": 14403, "page": 8, "width_pt": 589, "height_pt": 783, "rotation": 0, "pipeline_version": "paddleocr-vl-1.6+paul-48", "engine": "paddleocr_vl", "source_run_id": 14517, "item_count": 33, "counts_by_type": { "formula": 1, "header": 3, "text": 29 }, "build_ms": 7, "items": [ { "id": "p8.1", "order": 1, "type": "header", "bbox": { "l": 42.4656, "t": 761.6433, "r": 62.6187, "b": 752.0447 }, "text": "1318", "attrs": { "block_label": "number" }, "level": 2 }, { "id": "p8.2", "order": 2, "type": "header", "bbox": { "l": 68.3768, "t": 761.8832, "r": 257.6725, "b": 751.0849 }, "text": "Journal of Natural Products, 2008, Vol. 71, No. 7", "attrs": { "block_label": "header" }, "level": 2 }, { "id": "p8.3", "order": 3, "type": "header", "bbox": { "l": 515.5849, "t": 761.1633, "r": 548.9336, "b": 751.3249 }, "text": "Reviews", "attrs": { "block_label": "header" }, "level": 2 }, { "id": "p8.4", "order": 4, "type": "text", "bbox": { "l": 39.5866, "t": 741.7263, "r": 285.5031, "b": 635.1827 }, "text": "emetic principles of paw paw, and this explains the effectiveness of the old fluid extract of paw paw seeds as sold by Eli Lilly and Company at the end of the 1800s as a fast-acting emetic.[p8.4.1] Thus, emesis is a safety factor should someone ingest excessive amounts of any paw paw product; indeed, nausea and vomiting can occur if too many of the paw paw fruits are eaten. The question remained that the emetic dose might be less than the therapeutic dose and, thus, prevent clinical usefulness. In such a case, antinausea drugs, as commonly employed with anticancer agents, might be needed.", "children": [ { "id": "p8.4.1", "order": 5, "type": "text", "bbox": { "l": 39.5866, "t": 741.7263, "r": 285.5031, "b": 635.1827 }, "text": "¹¹¹", "attrs": { "inline": true, "text_offset": 189, "text_span": 8, "bbox_estimated": true } } ] }, { "id": "p8.5", "order": 6, "type": "text", "bbox": { "l": 40.0664, "t": 635.1827, "r": 285.5031, "b": 421.8553 }, "text": "Using the brine shrimp test, a biologically standardized ([p8.5.1] 0.5 ppm) extract of paw paw twigs was prepared, and capsules (containing the standardized extract) were tested in male beagle dogs in an ascending oral dosing schedule. The testing was performed at White Eagle Toxicology Laboratories (Doylestown, PA).[p8.5.2] There was a gradual increase in signs of emesis and loose stools as the doses were increased, but it was impossible to reach a harmful or a fatal dose due to the emetic effect. There were no effects on alertness, appetite, or weight. The doses ranged from 50 mg four times a day (qid) to 800 mg qid. Five to seven resting days were permitted between doses. At the maximum dose (800 mg qid/dog), there were no severe effects (other than emesis and loose stools). Thus, any acutely toxic effects are conveniently avoided by emesis. Following oral dosage, emesis is always a safety valve to prevent any life-threatening systemic effects. Since the previous murine studies involved ip injections and the mice, which could not eliminate the injected materials by vomiting, still survived at the effective doses, it was obvious that favorable therapeutic indexes for the acetogenins must exist and that oral dosing would be safe, provided no chronic toxicities would occur.", "children": [ { "id": "p8.5.1", "order": 7, "type": "formula", "bbox": { "l": 40.0664, "t": 635.1827, "r": 285.5031, "b": 421.8553 }, "text": "(LC₅₀ 0.5 ppm)", "attrs": { "latex": "(\\mathrm{LC}_{50} 0.5 \\text{ ppm})", "inline": true, "text_offset": 58, "text_span": 8, "bbox_estimated": true, "alt": "LC sub 50 0.5 ppm", "mathml": "(LC500.5 ppm)" } }, { "id": "p8.5.2", "order": 8, "type": "text", "bbox": { "l": 40.0664, "t": 635.1827, "r": 285.5031, "b": 421.8553 }, "text": "^{[112]}", "attrs": { "inline": true, "text_offset": 318, "text_span": 8, "bbox_estimated": true } } ] }, { "id": "p8.6", "order": 9, "type": "text", "bbox": { "l": 40.5462, "t": 422.0953, "r": 285.2631, "b": 188.1312 }, "text": "Epidemiological reports, from the island of Guadeloupe in the West Indies, have associated the dietary consumption of the fruits and teas (made from the leaves) of Annona muricata, A. reticulata, and A. squamosa with an atypical form of Parkinsonism.[p8.6.1] Postural instability with early falls, prominent frontal lobe dysfunction, and pseudobulbar palsy were common, and 75% of the patients were unresponsive to treatment with L-dopa. All three patients, on whom postmortem studies were performed, showed, upon neuropathological examination, an accumulation of tau proteins, predominantly in the midbrain. These neurological symptoms were similar to a Parkinsonism-dementia complex previously observed on the island of Guam in the Pacific, and this complex is now proposed to be associated with consumption of the Annonaceae.[p8.6.2] Also, atypical Parkinsonism, associated with the Annonaceae, was observed on New Caledonia in the Pacific,[p8.6.3] and in Afro-Caribbean and Indian populations now living in England.[p8.6.4] The disease appears to be chronic, with the average age in the first Guadeloupe study of 74 years (range 42–84).[p8.6.5] Especially in the younger patients, the symptoms show a regression after stopping the consumption of the annonaceous foods. Patients with severe and rapid progression of the disease often ate the fruits together with the seeds.", "children": [ { "id": "p8.6.1", "order": 10, "type": "text", "bbox": { "l": 40.5462, "t": 422.0953, "r": 285.2631, "b": 188.1312 }, "text": "¹¹³⁻¹¹⁵", "attrs": { "inline": true, "text_offset": 250, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.6.2", "order": 11, "type": "text", "bbox": { "l": 40.5462, "t": 422.0953, "r": 285.2631, "b": 188.1312 }, "text": "¹¹⁶", "attrs": { "inline": true, "text_offset": 828, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.6.3", "order": 12, "type": "text", "bbox": { "l": 40.5462, "t": 422.0953, "r": 285.2631, "b": 188.1312 }, "text": "^{117,118}", "attrs": { "inline": true, "text_offset": 943, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.6.4", "order": 13, "type": "text", "bbox": { "l": 40.5462, "t": 422.0953, "r": 285.2631, "b": 188.1312 }, "text": "¹¹⁹", "attrs": { "inline": true, "text_offset": 1019, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.6.5", "order": 14, "type": "text", "bbox": { "l": 40.5462, "t": 422.0953, "r": 285.2631, "b": 188.1312 }, "text": "¹¹³", "attrs": { "inline": true, "text_offset": 1140, "text_span": 8, "bbox_estimated": true } } ] }, { "id": "p8.7", "order": 15, "type": "text", "bbox": { "l": 40.0664, "t": 187.6512, "r": 285.743, "b": 27.1158 }, "text": "At first the atypical Parkinsonism was attributed to the benzyl-isoquinoline alkaloids that are well known as phytochemical components of the Annonaceae;[p8.7.1] some of these alkaloids are known to cause neurotoxicity including Parkinsonism.[p8.7.2] However, toxic levels of rotenone, an inhibitor of ETS complex I, also can induce degeneration of multiple neuronal systems,[p8.7.3] and the annonaceous acetogenins, as new complex I inhibitors, thus, became suspect as potential neurotoxins. Annonacin (3) is the most abundant acetogenin in A. muricata;[p8.7.4] it comprises about 70% of a mixture of over 30 acetogenins, most of which, like 3, are of the mono-THF type.[p8.7.5] Compound 3 was found to induce nigral and striatal neurodegeneration after subacute administration employing iv infusion in rats,[p8.7.6] and this study followed in vitro studies[p8.7.7] in which 3 was cytotoxic to dopaminergic and nondopaminergic neurons by impairment of energy production. In primary cultures of rat striatal neurons, treated for 48 h, there was a concentration-dependent decrease in ATP levels, a redistribution of tau protein from the axons to the cell body, and cell death; the ATP depletion caused by 3 resulted in a transport of mitochondria to the cell soma and induced changes in the intracellular distribution of tau that are reminiscent of neurogenic diseases. [p8.7.8]", "children": [ { "id": "p8.7.1", "order": 16, "type": "text", "bbox": { "l": 40.0664, "t": 187.6512, "r": 285.743, "b": 27.1158 }, "text": "²⁶", "attrs": { "inline": true, "text_offset": 153, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.7.2", "order": 17, "type": "text", "bbox": { "l": 40.0664, "t": 187.6512, "r": 285.743, "b": 27.1158 }, "text": "^{120,121}", "attrs": { "inline": true, "text_offset": 242, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.7.3", "order": 18, "type": "text", "bbox": { "l": 40.0664, "t": 187.6512, "r": 285.743, "b": 27.1158 }, "text": "^{122,123}", "attrs": { "inline": true, "text_offset": 375, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.7.4", "order": 19, "type": "text", "bbox": { "l": 40.0664, "t": 187.6512, "r": 285.743, "b": 27.1158 }, "text": "¹²⁴", "attrs": { "inline": true, "text_offset": 554, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.7.5", "order": 20, "type": "text", "bbox": { "l": 40.0664, "t": 187.6512, "r": 285.743, "b": 27.1158 }, "text": "^{33,34}", "attrs": { "inline": true, "text_offset": 671, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.7.6", "order": 21, "type": "text", "bbox": { "l": 40.0664, "t": 187.6512, "r": 285.743, "b": 27.1158 }, "text": "¹²⁵", "attrs": { "inline": true, "text_offset": 809, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.7.7", "order": 22, "type": "text", "bbox": { "l": 40.0664, "t": 187.6512, "r": 285.743, "b": 27.1158 }, "text": "^{126,127}", "attrs": { "inline": true, "text_offset": 858, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.7.8", "order": 23, "type": "text", "bbox": { "l": 40.0664, "t": 187.6512, "r": 285.743, "b": 27.1158 }, "text": "¹²⁸", "attrs": { "inline": true, "text_offset": 1369, "text_span": 8, "bbox_estimated": true } } ] }, { "id": "p8.8", "order": 24, "type": "text", "bbox": { "l": 303.9768, "t": 741.7263, "r": 549.1735, "b": 678.616 }, "text": "of rat striatal neurons, treated for 48 h, there was a concentration-dependent decrease in ATP levels, a redistribution of tau protein from the axons to the cell body, and cell death; the ATP depletion caused by 3 resulted in a transport of mitochondria to the cell soma and induced changes in the intracellular distribution of tau that are reminiscent of neurogenic diseases. [p8.8.1]", "children": [ { "id": "p8.8.1", "order": 25, "type": "text", "bbox": { "l": 303.9768, "t": 741.7263, "r": 549.1735, "b": 678.616 }, "text": "¹²⁸", "attrs": { "inline": true, "text_offset": 377, "text_span": 8, "bbox_estimated": true } } ] }, { "id": "p8.9", "order": 26, "type": "text", "bbox": { "l": 303.9768, "t": 678.1361, "r": 549.6534, "b": 411.5369 }, "text": "Kirk Pomper is studying paw paws at Kentucky State University with the intention of making the fruits into a better commercial product.[p8.9.1] He has reviewed the data concerning the consumption of the tropical Annonaceae and the association with atypical Parkinsonism, in view of the currently increasing consumption of paw paw fruits in the Midwestern states of the U.S. Might paw paws cause a similar problem? The seasonal consumption of paw paws has never been connected with any neurotoxic effects, but the frozen pulp is becoming available, more and more, for continuous marketing and year-long consumption. In addition, the sales of paw paw extract as a dietary supplement (see the discussion below) are increasing and, with overuse, might have the potential of exposing the public to the possible danger of neurotoxicity. Using the brine shrimp test, the ripe fruits of several paw paw cultivars showed bioactivity in the pulp that, surprisingly, was almost equipotent to that of the twigs; Bill Keller at Nature’s Sunshine Products (NSP, Spanish Fork, UT) then used HPLC/MS/MS analyses to show that the bioactivity in the pulp was due to acetogenins, and the highly potent bis-THF acetogenins, bullatacin (6), bullatalicin (9), and asimicin (1)/trilobacin (7), were predominant.[p8.9.2] One cultivar (Sunflower), however, was lower than the others in acetogenins, showing that the fruit of paw paw, as well as the twigs,[p8.9.3] can vary considerably in acetogenin content and that cultivars with lower acetogenin content in the fruit could be selected for human consumption.", "children": [ { "id": "p8.9.1", "order": 27, "type": "text", "bbox": { "l": 303.9768, "t": 678.1361, "r": 549.6534, "b": 411.5369 }, "text": "¹²⁹", "attrs": { "inline": true, "text_offset": 135, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.9.2", "order": 28, "type": "text", "bbox": { "l": 303.9768, "t": 678.1361, "r": 549.6534, "b": 411.5369 }, "text": "¹³⁰", "attrs": { "inline": true, "text_offset": 1288, "text_span": 8, "bbox_estimated": true } }, { "id": "p8.9.3", "order": 29, "type": "text", "bbox": { "l": 303.9768, "t": 678.1361, "r": 549.6534, "b": 411.5369 }, "text": "^{73,74}", "attrs": { "inline": true, "text_offset": 1430, "text_span": 8, "bbox_estimated": true } } ] }, { "id": "p8.10", "order": 30, "type": "text", "bbox": { "l": 303.7369, "t": 411.5369, "r": 549.8933, "b": 101.9844 }, "text": "One wonders why atypical Parkinsonism has never been reported in people who eat paw paws. Perhaps the bis-THF acetogenins (which predominate in paw paw) are better emetics, and neurotoxic levels are not achievable due to emesis with overconsumption of paw paw. There seem to be no reports of emesis caused by the suspect tropical species. Perhaps the limited consumption of paw paw, which is primarily a short-term seasonal event, avoids the toxicity, which seems to be a cumulative, chronic, problem caused by day to day consumption of the tropical species over a period of several years. Perhaps the neurotoxicity is caused by a synergism between the neurotoxic benzyltetrahydroisoquinoline alkaloids and the mono-THF acetogenins that are peculiar to A. muricata. Perhaps there are genetic factors that predispose some people to atypical Parkinsonism. It is interesting that not everyone is susceptible to the condition; a high percentage (60%) of the Parkinsonism patients in Guadeloupe who consume the suspect foods do not display atypical Parkinsonism.[p8.10.1] Whether it is the vanillin in our ice cream cones, the allyl isothiocyanate and allyl cyanide in our cole slaw, the lycopene and tomatine from the tomatoes on our pizzas, the solanine in our French fried potatoes, the cyanogenic glycosides in our apple seeds, the prussic acid in our tapioca, the acetogenins in our annonaceous fruits, or whatever, our bodies must, each day, detoxify and excrete a whole host of undesirable food chemicals.[p8.10.2] Individuals differ from each other in their capacities to do this. In the meantime, in 2006, Kentucky State University asked the U.S. Food and Drug Administration (FDA) for an opinion on this topic, and their conclusion was that paw paw has a long history of food use and the FDA does not currently have any evidence that paw paw is unsafe to eat.", "children": [ { "id": "p8.10.1", "order": 31, "type": "text", "bbox": { "l": 303.7369, "t": 411.5369, "r": 549.8933, "b": 101.9844 }, "text": "^{[113]}", "attrs": { "inline": true, "text_offset": 1057, "text_span": 9, "bbox_estimated": true } }, { "id": "p8.10.2", "order": 32, "type": "text", "bbox": { "l": 303.7369, "t": 411.5369, "r": 549.8933, "b": 101.9844 }, "text": "^{[131]}", "attrs": { "inline": true, "text_offset": 1507, "text_span": 9, "bbox_estimated": true } } ] }, { "id": "p8.11", "order": 33, "type": "text", "bbox": { "l": 303.4969, "t": 102.9442, "r": 549.8933, "b": 27.5958 }, "text": "There is an old adage that toxicology is simply pharmacology at a higher dose. The relationship between the desired effects and the undesired effects of a drug is defined as the therapeutic index, which, consequently, attempts to quantitate the margin of safety. All drugs are two-edged swords, and few drugs are completely selective at eliciting only the desired effects. If the neurotoxicity studies discussed above are accepted as valid, it can be concluded" } ], "excluded_furniture": { "first": [], "last": [] } }