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Journal articles on the topic 'Monkeys Allometry'
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Rodríguez, Rafael L., Jennifer Danzy Cramer, Christopher A. Schmitt, Tegan J. Gaetano, J. Paul Grobler, Nelson B. Freimer, and Trudy R. Turner. "The static allometry of sexual and nonsexual traits in vervet monkeys." Biological Journal of the Linnean Society 114, no. 3 (December 30, 2014): 527–37. http://dx.doi.org/10.1111/bij.12440.
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Strasser, Elizabeth. "Hindlimb proportions, allometry, and biomechanics in old world monkeys (primates, cercopithecidae)." American Journal of Physical Anthropology 87, no. 2 (February 1992): 187–213. http://dx.doi.org/10.1002/ajpa.1330870207.
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Turnquist, Jean E., and Matthew J. Kessler. "Free-ranging Cayo Santiago rhesus monkeys (Macaca mulatta): I. Body size, proportion, and allometry." American Journal of Primatology 19, no. 1 (1989): 1–13. http://dx.doi.org/10.1002/ajp.1350190102.
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Ito, Tsuyoshi, Takeshi Nishimura, and Masanaru Takai. "Allometry and Interspecific Differences in the Facial Cranium of Two Closely Related Macaque Species." Anatomy Research International 2011 (May 25, 2011): 1–7. http://dx.doi.org/10.1155/2011/849751.
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Interpreting evolutionary history of macaque monkeys from fossil evidence is difficult, because their evolutionary fluctuations in body size might have removed or formed important morphological features differently in each lineage. We employed geometric morphometrics to explore allometric trajectories of craniofacial shape in two closely related species, Macaca fascicularis and M. fuscata. These two species exhibit a single shared allometric trajectory in superoinferior deflection of the anterior face, indicating that the differences in this feature can be explained by size variation. In contrast, two parallel trajectories are demonstrated in craniofacial protrusion, indicating that even if they are comparable in size, M. fuscata has a higher and shorter face than M. fascicularis. The degree of facial protrusion is most likely a critical feature for phyletic evaluation in the fascicularis group. Such analyses in various macaques would help to resolve controversies regarding phyletic interpretations of fossil macaques.
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Aviles, P., A. Pateman, R. San Roman, M. J. Guillén, F. Gómez De Las Heras, and D. Gargallo-Viola. "Animal Pharmacokinetics and Interspecies Scaling of Sordarin Derivatives following Intravenous Administration." Antimicrobial Agents and Chemotherapy 45, no. 10 (October 1, 2001): 2787–92. http://dx.doi.org/10.1128/aac.45.10.2787-2792.2001.
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ABSTRACT Sordarin derivatives constitute a new group of synthetic antifungal agents that selectively inhibit fungal protein synthesis. They have demonstrated in vitro activity against the most important fungal pathogens, both yeast and filamentous. This new family of compounds has also shown in vivo activity against murineCandida albicans, Histoplasma capsulatum, andCoccidioides immitis experimental infections, as well as against Pneumocystis carinii pneumonia in rats. After intravenous dosing in animals, both the area under the concentration-time curve and the elimination half-life were highest in Cynomolgus monkeys, followed by those in rats, mice, and rabbits. The volume of distribution at steady state for sordarin derivatives was similar in all species tested. The clearance in rats and mice was higher than for other species. GM 237354, a sordarin derivative, was characterized by high serum protein binding in mouse, rat, and monkey serum (unbound fraction, ≤5%). An indirect evaluation of the effect of liver function upon the metabolism of this class of compounds has been made in animals with impaired liver function such as Gunn rats, as well as in allometric studies that showed better correlations of half-life to liver blood flow than to animal body weight. Linearity of the main pharmacokinetic parameters was demonstrated after intravenous dosing of the representative compound GM 193663 at 10 and 20 mg/kg of body weight in rats. Allometry was used to determine whether human pharmacokinetic parameters can be predicted from animal data by regression analysis against body weight and liver blood flow. All these results have demonstrated that the human pharmacokinetics of sordarin derivatives can be forecast from animal data.
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Monson, Tesla A., Jeffrey L. Coleman, and Leslea J. Hlusko. "Craniodental Allometry, Prenatal Growth Rates, and the Evolutionary Loss of the Third Molars in New World Monkeys." Anatomical Record 302, no. 8 (November 25, 2018): 1419–33. http://dx.doi.org/10.1002/ar.23979.
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Ledevin, Ronan, and Daisuke Koyabu. "Patterns and Constraints of Craniofacial Variation in Colobine Monkeys: Disentangling the Effects of Phylogeny, Allometry and Diet." Evolutionary Biology 46, no. 1 (January 31, 2019): 14–34. http://dx.doi.org/10.1007/s11692-019-09469-7.
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Young, Jesse W., David Fernández, and John G. Fleagle. "Ontogeny of long bone geometry in capuchin monkeys ( Cebus albifrons and Cebus apella ): implications for locomotor development and life history." Biology Letters 6, no. 2 (October 28, 2009): 197–200. http://dx.doi.org/10.1098/rsbl.2009.0773.
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Studies of a diverse array of animals have found that young individuals often have robust bones for their body size (i.e. augmented cross-sectional dimensions), limiting fracture risk despite general musculoskeletal immaturity. However, previous research has focused primarily on precocial taxa (e.g. rodents, lagomorphs, bovids, goats and emu). In this study, we examined the ontogenetic scaling of humeral and femoral cross-sectional robusticity in a mixed-longitudinal sample of two slow-growing, behaviourally altricial capuchin monkeys. Results showed that, when regressed against biomechanically appropriate size variables (i.e. the product of body mass and bone length), humeral and femoral bending strengths generally scale with negative allometry, matching the scaling patterns observed in previous studies of more precocial mammals. Additionally, bone strength relative to predicted loads (e.g. ‘safety factors’) peaks at birth and rapidly decreases during postnatal growth, falling to less than 5 per cent of peak values by weaning age. We suggest that increased safety factors during early ontogeny may be an adaptation to mitigate injury from falling during initial locomotor efforts. Overall, the results presented here suggest that ontogenetic declines in relative long bone strength may represent a common pattern among mammals that is perhaps preadaptive for different purposes among different lineages.
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Jones, J., D. Lee, I. Smukste, D. Cui, M. G. Bursavich, D. Troast, C. Zhong, et al. "P037 Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of MORF-057 support its clinical development as an oral selective α4β7 integrin inhibitor." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S149—S150. http://dx.doi.org/10.1093/ecco-jcc/jjab076.166.
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Abstract Background MORF-057 is a potent and selective small molecule inhibitor of the α 4β 7 integrin. Using a receptor occupancy (RO) assay under physiologically relevant conditions, MORF-057 achieves 90% α 4β 7 RO at approximately 10 nM in human whole blood. The current studies evaluate nonclinical pharmacokinetics (PK) and properties of absorption, distribution, metabolism, and excretion (ADME) to enable dose/exposure projection to humans. Methods PK studies were conducted in mouse, rat, dog, and monkey following intravenous (IV) and oral administration. ADME studies were conducted in vitro and in rats using carbon-14 [14C] labeled MORF-057. MORF-057 levels were quantified using liquid chromatography coupled with tandem mass spectrometry. Human PK was predicted based on body weight allometry, well-stirred and semi-physiological models. Results MORF-057 exhibited low to moderate clearance (CL) in animals with species dependent volume of distribution (Vdss) resulting in half-lives of 1.1 to 2.7 hours (Table 1). Following an oral dose, absorption was high with bioavailability ranging from 15% to 49%. MORF-057 is highly protein bound and distribution of [14C]MORF-057 derived radioactivity in rat was predominantly in the small intestine wall, liver, and stomach wall. Rifampin, an inhibitor of organic anion transporting polypeptides, decreased MORF-057 clearance by 3-fold in monkeys suggesting MORF-057 elimination involves hepatic uptake transport. MORF-057 is further cleared via CYP3A metabolism followed by biliary/fecal elimination of metabolites. MORF-057 is predicted to have moderate bioavailability (40%) and CL (6.5 mL/min/kg) in humans. Wajima transformation shows good agreement of the normalized PK across animal species, with a predicted human concentration-time profile supporting >90% α 4β 7 RO at trough following 200 mg twice daily dose (Figure 1). Conclusion These data demonstrate that MORF-057 is well absorbed and PK properties in animals support the potential for achieving high α4β7 RO following oral administration in humans. These nonclinical results provided a basis for the progression of MORF-057 into a first-in-human Phase 1 clinical study assessing safety, pharmacokinetics, and receptor occupancy (results being reported separately).
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Zou, Peng, Nan Zheng, Yanke Yu, Shanghai Yu, Wei Sun, Donna McEachem, Yongsheng Yang, Lawrence X. Yu, Shaomeg Wang, and Duxin Sun. "Preclinical Pharmacokinetics of MI-219, a Novel Human Double Minute 2 (HDM2) Inhibitor and Prediction of Human Pharmacokinetics." Journal of Pharmacy & Pharmaceutical Sciences 15, no. 2 (April 11, 2012): 265. http://dx.doi.org/10.18433/j34s4n.
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Purpose. The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vdss) of MI-219 in humans. Methods. Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and fu corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration–time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vdss (Wajima’s method). In addition, simultaneous interspecies scaling of CL, Vdss and concentration–time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). Results. Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vdss showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h-1*kg-1. Human Vdss predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (VT/fuT) method was between 0.93-1.40 L*kg-1. Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima’s transformations. Conclusions. The predicted human pharmacokinetics is useful for the design of first-in-human study.
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Hurwitz, Selwyn J., Michael J. Otto, and Raymond F. Schinazi. "Comparative Pharmacokinetics of Racivir®, (±)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine in Rats, Rabbits, Dogs, Monkeys and HIV-Infected Humans." Antiviral Chemistry and Chemotherapy 16, no. 2 (April 2005): 117–27. http://dx.doi.org/10.1177/095632020501600204.
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Racivir® is a 50:50 racemic mixture of the (–)- and (+)-β-enantiomers of 2′-deoxy-3′-thia-5-fluorocytosine (FTC), which is being developed for the treatment of HIV and hepatitis B virus (HBV). The (+)-enantiomer of FTC is approximately 10–20-fold less potent than (–)-FTC, but it selects for a different HIV mutation in human lymphocytes. Plasma concentrations from a group of 54 rats, 12 pregnant rabbits and 60 dogs enrolled in large toxicity studies using a wide variety of oral doses, were compared using non-compartment pharmacokinetic modelling versus dose, treatment duration, species and gender. The pharmacokinetics of Racivir® were also compared with those of a previously published pharmacokinetic study in rhesus monkeys and with data from HIV-infected human male volunteers. The (+)-FTC, but not the (–)-enantiomer, can be deaminated to the non-toxic inactive metabolite (+)-FTU. Therefore, the plasma exposure to (+)-FTU was also determined. The order of relative plasma exposure to (+)-FTU was rhesus monkeys > humans > pregnant rabbits > dogs > rats. Allometric scaling was performed to relate systemic clearance/fraction of drug absorbed (Cl/F) and terminal phase volume of distribution (Vβ/F) versus species body weights. No individual animal species mimicked the Cl/F values in humans. However, allometric scaling using a combination of rats, pregnant rabbits and monkeys predicted the mean human Cl/F value better than a combination of rats and rabbits only (within 0.24 and SD of mean vs 0.81 SD of the observed mean value). Similarly, human Vβ/F values were best predicted using a combination of rat and monkey data (within 0.64 SD of mean value). Species demonstrating greater deamination to (+)-FTU tended to have greater than predicted Cl/F values. The Cmax values of dogs were the closest to humans, but were statistically different. This study highlights the importance of selecting animal species that demonstrate similar cytidine deaminase activity to humans when performing preclinical dosing studies on Racivir® other antiviral agents that are substrates for mammalian cytidine deaminases.
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NATORI, Masahito. "Allometric Scaling in the Molars of Titi Monkeys." Primate Research 18, no. 1 (2002): 59–67. http://dx.doi.org/10.2354/psj.18.59.
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Mahmood, Iftekhar. "Interspecies Scaling of Antibody–Drug Conjugates (ADC) for the Prediction of Human Clearance." Antibodies 10, no. 1 (January 7, 2021): 1. http://dx.doi.org/10.3390/antib10010001.
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Allometric scaling is a useful tool for the extrapolation of pharmacokinetic parameters from animals to humans. The objective of this study was to predict human clearance of antibody–drug conjugates (ADC) allometrically from one to three animal species and compare the predicted human clearance with the observed human clearance. For three animal species allometric scaling, the “Rule of Exponents” (ROE) was used. The results of the study indicated that three-species allometric scaling in association with the ROE provides acceptable prediction (within 0.5–2-fold prediction error) of human clearance. The two-species allometric scaling resulted in substantial prediction error. One-species scaling using a fixed exponent of 1.0 provided acceptable prediction error (within 0.5–2-fold) by monkey, rat, and mouse, in which monkey and rat were comparable. Overall, the predicted human clearance values of ADCs from animal(s) was good. The allometric method proposed in this article can be used to predict human clearance from the animal data and subsequently to select the first-in-human dose of ADCs.
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Oitate, Masataka, Noriko Masubuchi, Takashi Ito, Yoshiyuki Yabe, Tsuyoshi Karibe, Takanori Aoki, Nobuyuki Murayama, Atsushi Kurihara, Noriko Okudaira, and Takashi Izumi. "Prediction of Human Pharmacokinetics of Therapeutic Monoclonal Antibodies from Simple Allometry of Monkey Data." Drug Metabolism and Pharmacokinetics 26, no. 4 (2011): 423–30. http://dx.doi.org/10.2133/dmpk.dmpk-11-rg-011.
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Polk, J. D. "Adaptive and phylogenetic influences on musculoskeletal design in cercopithecine primates." Journal of Experimental Biology 205, no. 21 (November 1, 2002): 3399–412. http://dx.doi.org/10.1242/jeb.205.21.3399.
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SUMMARY Broad allometric studies of the musculoskeletal system have frequently sought to explain how locomotor variables have been influenced by body mass. To examine animals that vary widely in body mass, these studies have included taxa that differ in their locomotor adaptations and phylogenetic relatedness. Because these sources of diversity could obscure the effects of body mass,this study was designed to test the effects of adaptive differences in limb proportions and phylogeny, as well as body mass, on locomotor kinematics and extensor muscle mechanical advantage. More specifically, two hypotheses were tested in a sample of closely related animals: (i) that, among animals with similar body mass, those with longer limb segments should adopt more extended limb postures to moderate the joint and midshaft bending moments that they experience, and (ii) that body mass will have similar influences on joint posture and joint moments in closely related and diverse mammalian samples. Three-dimensional kinematic and synchronous force-platform data were collected for six individual cercopithecine monkeys ranging in mass from 4kg to 24kg and at a range of walking speeds. Comparisons among three monkeys with similar body mass but different limb segment lengths reveal a significant effect of limb proportion on posture. That is, animals with longer limbs frequently use more extended limb postures and can have correspondingly lower joint moments. The scaling of locomotor variables across the entire sample of closely related monkeys was generally similar to published results for a diverse sample of mammals, with larger monkeys having more extended limb postures, lower joint moments and greater effective mechanical advantage (EMA) for their limb extensor musculature. Ankle EMA, however, did not increase with body mass in the primate sample, suggesting that clade-specific adaptive differences (e.g. the use of arboreal supports by primates) may constrain the effects of body mass.
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Colville, Jonathan F., Mike D. Picker, and Richard M. Cowling. "Feeding ecology and sexual dimorphism in a speciose flower beetle clade (Hopliini: Scarabaeidae)." PeerJ 6 (June 20, 2018): e4632. http://dx.doi.org/10.7717/peerj.4632.
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The relationship between feeding ecology and sexual dimorphism is examined in a speciose South African monkey beetle clade. We test whether feeding and mating at a fixed site (embedding guild) is associated with greater levels of sexual dimorphism and possibly sexual selection than species using unpredictable feeding resources (non-embedding guild). Sexual dimorphism was measured using a point scoring system for hind leg and colour across the two feeding guilds for >50% of the regional fauna. Quantification of hind leg dimorphism using a scoring system and allometric scaling were used to identify traits subject to sexual selection. Feeding guild had a significant effect on hind leg dimorphism, with embedders having high and non-embedders low scores. The sessile and defendable distribution of females on stable platform flowers may favour contests and associated hind leg weaponry. In contrast, degree of colour dimorphism between the sexes was not associated with any particular feeding guild, and may serve to reduce male conflict and combat. Embedder males had high proportions (∼76%) of species with positive allometric slopes for almost all hind leg traits. For male non-embedders, only ∼37% of species showed positive scaling relationships. Phylogenetic data, in conjunction with behavioural data on the function of leg weaponry and visual signalling among males is needed to better understand the link between sexual dimorphism and sexual selection in the radiation of the monkey beetles.
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Bol, Kees, Wilfred Marissen, Jeroen Elaissais-Schaap, Paul Tacken, Steef Engels, Liang-Chuan Wang, Arpita Mondal, et al. "814 MCLA-145 (CD137xPD-L1): a potent CD137 agonist and immune checkpoint inhibitor that that does not show signs of peripheral toxicity." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A863. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0814.
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BackgroundOnly a fraction of cancer patients benefit from currently available immune checkpoint inhibitors (ICI). Attempts to improve efficacy of ICI by combining with costimulatory receptor agonists such as CD137 (4-1BB) have led to greater anti-tumor activity preclinically but have shown systemic toxicity in the clinic. MCLA-145 is a human CD137xPD-L1 bispecific common light chain antibody (bAb), identified through functional screening of agonist and ICI bAb combinations. Further, MCLA-145 can overcome Treg and macrophage suppression to potently activate T cells in these immune suppressive conditions. In two ICI insensitive xenograft models, MCLA-145 demonstrated good anti-tumor activity and CD8+ T cells were enriched in tumors post treatment (indicative of intratumor expansion and recruitment). No signs of GvHD were observed in mice following treatment with MCLA-145 in contrast to that seen in animals treated with other ICI mAbs.MethodsThe EC30 from an in vitro T cell transactivation assay based on IFNg was used as an estimate of the MABEL for MCLA-145. A 2 compartment PK model coupled to a target-mediated drug disposition component was generated based on the available cynomolgus monkey PK data.ResultsRepeated doses of MCLA-145 up to 100 mg/kg/wk in cynomolgus monkeys were well tolerated without major adverse effects, and dose-dependent increases in serum MCLA-145 concentrations were observed. Following allometric scaling, the model was used to predict exposure in humans following MCLA-145 IV given over 2-hours every 2 weeks, including the starting dose for the FIH trial.ConclusionsConditional activation of CD137 signaling by MCLA-145, triggered by a neighboring target cell expressing of PD-L1, may provide both improved efficacy and safety. MCLA-145 is currently undergoing clinical investigation (NCT03922204).
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Di Martino, Maria Teresa, Mariamena Arbitrio, Massimiliano Fonsi, Claudio Alberto Erratico, Francesca Scionti, Daniele Caracciolo, Pierosandro Tagliaferri, and Pierfrancesco Tassone. "Allometric Scaling Approaches for Predicting Human Pharmacokinetic of a Locked Nucleic Acid Oligonucleotide Targeting Cancer-Associated miR-221." Cancers 12, no. 1 (December 19, 2019): 27. http://dx.doi.org/10.3390/cancers12010027.
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LNA-i-miR-221 is a novel phosphorothioate backbone 13-mer locked nucleic acid oligonucleotide-targeting microRNA-221 designed for the treatment of human malignancies. To understand the pharmacokinetic properties of this new agent, including unbound/total clearance, we investigated the LNA-i-miR-221 protein binding in three different species, including rat (Sprague–Dawley), monkey (Cynomolgus), and human. To this end, we generated a suitable ultrafiltration method to study the binding of LNA-i-miR-221 to plasma proteins. We identified that the fraction of LNA-i-miR-221 (at concentration of 1 and 10 µM) bound to rat, monkey, and human plasma proteins was high and ranged from 98.2 to 99.05%. This high protein binding of LNA-i-miR-221 to plasma proteins in all the species tested translates into a pharmacokinetic advantage by preventing rapid renal clearance. The integration of these results into multiple allometric interspecies scaling methods was then used to draw inferences about LNA-i-miR-221 pharmacokinetics in humans, thereby providing a framework for definition of safe starting and escalation doses and moving towards a first human clinical trial of LNA-i-miR-221.
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Widrick, J. J., J. G. Romatowski, M. Karhanek, and R. H. Fitts. "Contractile properties of rat, rhesus monkey, and human type I muscle fibers." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 272, no. 1 (January 1, 1997): R34—R42. http://dx.doi.org/10.1152/ajpregu.1997.272.1.r34.
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It is well known that skeletal muscle intrinsic maximal shortening velocity is inversely related to species body mass. However, there is uncertainty regarding the relationship between the contractile properties of muscle fibers obtained from commonly studied laboratory animals and those obtained from humans. In this study we determined the contractile properties of single chemically skinned fibers prepared from rat, rhesus monkey, and human soleus and gastrocnemius muscle samples under identical experimental conditions. All fibers used for analysis expressed type I myosin heavy chain as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Allometric coefficients for type I fibers from each muscle indicated that there was little change in peak tension (force/fiber cross-sectional area) across species. In contrast, both soleus and gastrocnemius type I fiber maximal unloaded shortening velocity (Vo), the y-intercept of the force-velocity relationship (Vmax), peak power per unit fiber length, and peak power normalized for fiber length and cross-sectional area were all inversely related to species body mass. The present allometric coefficients for soleus fiber Vo (-0.18) and Vmax (-0.11) are in good agreement with published values for soleus fibers obtained from common laboratory and domesticated mammals. Taken together, these observations suggest that the Vo of slow fibers from quadrupeds and humans scale similarly and can be described by the same quantitative relationships. These findings have implications in the design and interpretation of experiments, especially those that use small laboratory mammals as a model of human muscle function.
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Pereira-Pedro, Ana Sofia, James K. Rilling, Xu Chen, Todd M. Preuss, and Emiliano Bruner. "Midsagittal Brain Variation among Non-Human Primates: Insights into Evolutionary Expansion of the Human Precuneus." Brain, Behavior and Evolution 90, no. 3 (2017): 255–63. http://dx.doi.org/10.1159/000481085.
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The precuneus is a major element of the superior parietal lobule, positioned on the medial side of the hemisphere and reaching the dorsal surface of the brain. It is a crucial functional region for visuospatial integration, visual imagery, and body coordination. Previously, we argued that the precuneus expanded in recent human evolution, based on a combination of paleontological, comparative, and intraspecific evidence from fossil and modern human endocasts as well as from human and chimpanzee brains. The longitudinal proportions of this region are a major source of anatomical variation among adult humans and, being much larger in Homo sapiens, is the main characteristic differentiating human midsagittal brain morphology from that of our closest living primate relative, the chimpanzee. In the current shape analysis, we examine precuneus variation in non-human primates through landmark-based models, to evaluate the general pattern of variability in non-human primates, and to test whether precuneus proportions are influenced by allometric effects of brain size. Results show that precuneus proportions do not covary with brain size, and that the main difference between monkeys and apes involves a vertical expansion of the frontal and occipital regions in apes. Such differences might reflect differences in brain proportions or differences in cranial architecture. In this sample, precuneus variation is apparently not influenced by phylogenetic or allometric factors, but does vary consistently within species, at least in chimpanzees and macaques. This result further supports the hypothesis that precuneus expansion in modern humans is not merely a consequence of increasing brain size or of allometric scaling, but rather represents a species-specific morphological change in our lineage.
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Laska, Matthias, and Alexandra Seibt. "Olfactory sensitivity for aliphatic alcohols in squirrel monkeys and pigtail macaques." Journal of Experimental Biology 205, no. 11 (June 1, 2002): 1633–43. http://dx.doi.org/10.1242/jeb.205.11.1633.
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SUMMARY The view that primates are microsmatic animals is based mainly on an interpretation of neuroanatomical features, whereas physiological evidence of a poorly developed sense of smell in this order of mammals is largely lacking. Using a conditioning paradigm, we therefore assessed the olfactory sensitivity of three squirrel monkeys (Saimiri sciureus) and of four pigtail macaques (Macaca nemestrina) for a homologous series of aliphatic alcohols (ethanol to 1-octanol) and isomeric forms of some of these substances. In the majority of cases, the animals of both species significantly discriminated concentrations below 1 part per million from the odourless solvent, and with 1-hexanol individual monkeys even demonstrated thresholds below 10 parts per billion. The results showed (i) that both primate species have a well-developed olfactory sensitivity for aliphatic alcohols, which for the majority of substances matches or even is better than that of species such as the rat, (ii) that both species generally show very similar olfactory detection thresholds for aliphatic alcohols, and (iii) that a significant negative correlation between perceptibility in terms of olfactory detection threshold and carbon chain length of both the aliphatic 1-and 2-alcohols exists in both species. These findings support the idea that across-species comparisons of neuroanatomical features are a poor predictor of olfactory performance and that general labels such as `microsmat' or`macrosmat', which are usually based on allometric comparisons of olfactory brain structures, are inadequate to describe the olfactory capabilities of a species. Further, our findings suggest that olfaction may play an important and hitherto underestimated role in the regulation of behaviour in the species tested.
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Mahmood, Iftekhar. "A Single Animal Species-Based Prediction of Human Clearance and First-in-Human Dose of Monoclonal Antibodies: Beyond Monkey." Antibodies 10, no. 3 (September 5, 2021): 35. http://dx.doi.org/10.3390/antib10030035.
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These days, there is a lot of emphasis on the prediction of human clearance (CL) from a single species for monoclonal antibodies (mabs). Many studies indicate that monkey is the most suitable species for the prediction of human clearance for mabs. However, it is not well established if rodents (mouse or rat) can also be used to predict human CL for mabs. The objectives of this study were to predict and compare human CL as well as first-in-human dose of mabs from mouse or rat, ormonkey. Four methods were used for the prediction of human CL of mabs. These methods were: use of four allometric exponents (0.75, 0.80, 0.85, and 0.90), a minimal physiologically based pharmacokinetics method (mPBPK), lymph flow rate, and liver blood flow rate. Based on the predicted CL, first-in-human dose of mabs was projected using either exponent 1.0 (linear scaling) or exponent 0.85, and human-equivalent dose (HED) from each of these species. The results of the study indicated that rat or mouse could provide a reasonably accurate prediction of human CL as well as first-in-human dose of mabs. When exponent 0.85 was used for CL prediction, there were 78%, 95%, and 92% observations within a 2-fold prediction error for mouse, rat, and monkey, respectively. Predicted human dose fell within the observed human dose range (administered to humans) for 10 out of 13 mabs for mouse, 11 out of 12 mabs for rat, and 12 out of 15 mabs for monkey. Overall, the clearance and first-in-human dose of mabs were predicted reasonably well by all three species (a single species). On average, monkey may be the best species for the prediction of human clearance and human dose but mouse or rat especially; rat can be a very useful species for conducting the aforementioned studies.
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King, Anthony H., and Emet D. Schneiderman. "Differential Growth among Components of the Palate in Rhesus Monkeys (Macaca mulatta)." Cleft Palate-Craniofacial Journal 30, no. 3 (May 1993): 302–8. http://dx.doi.org/10.1597/1545-1569_1993_030_0302_dgacot_2.3.co_2.
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To understand the etiology of maxillary hypoplasia better, which is common in individuals with cleft palate and other cranlofacial anomalies, the relative growth and contribution of the maxillary and palatine segments to enlargement of the hard palate was examined in rhesus monkeys. The purpose of the study was to identify and evaluate sites of differential growth of the palatine and maxillary segments as they contribute to the development of the midface and facial prognathism. One hundred and eight male and 107 female skulls ranging from 1.0 to 7.0 years of age were examined. Measurements of the maxillary and palatine lengths, palatal width, midface depth, canine length, and molar surface areas in the ontogenetic sample were collected. Univariate and bivariate statistics were used to describe dimensional changes and evaluate region-specific sex differences. The relative growth of palatal dimensions was evaluated using allometric analysis methods. Significant sex differences were observed (t-test, p ≤ .05) for all palatal dimensions by 4 years of age. However, proportions of the maxillary and palatine segments to overall palate length appeared to be similar throughout growth for both sexes. The results suggest that sutures of the midface, in particular the transverse palatine suture, may be important in the bony development of the palate during growth. These sutures may contribute to the overall modulation of palatal development. These findings suggest that the greater midfacial prognathism seen in adult rhesus males than in females may be associated with increased relative growth of the palatine segment during puberty, and that small growth differentials in the transverse palatine suture region can have a significant effect on the overall sagittal dimensions of the midface.
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Clarke, A. H. "On the vestibular labyrinth of Brachiosaurus brancai." Journal of Vestibular Research 15, no. 2 (April 1, 2005): 65–71. http://dx.doi.org/10.3233/ves-2005-15202.
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The extensive remains of large sauropods, excavated in the Upper Jurassic layers of the Tendaguru region of Tanzania, East Africa by Janensch [15], include an intact fossil cast of a vestibular labyrinth and an endocast of the large Brachiosaurus brancai. The approximately 150 million year old labyrinth cast demonstrates clearly a form and organisation congruent in detail to those of extant vertebrate species. Besides the near-orthogonal arrangement of semicircular canals (SCCs), the superior and inferior branches of the vestibulo-acoustic nerve, the endolymphatic duct, the oval and round windows, and the cochlea can be identified. The orientation of the labyrinth in the temporal bone is also equivalent to that of many extant vertebrates. Furthermore, the existence of the twelve cranial nerves can be identified from the endocast. The present study was initiated after the photogrammetric measurement of the skeleton volume of B. brancai [13] yielded a realistic estimate of body mass (74.42 metric tons). Dimensional analysis shows that body mass and average SCC dimensions of B. brancai generally fit with the allometric relationship found in previous studies of extant species. However, the anterior SCC is significantly larger than the allometric relationship would predict. This would indicate greater sensitivity, supporting the idea that the behavioural repertoire must have included much slower pitch movements of the head. These slower movements would most likely have involved flexion of the neck, rather than head pitching about the atlas joint. Pursuing the relationship between body mass and SCC dimensions further, the SCC frequency response is estimated by scaling up from the SCC dimensions of the rhesus monkey; this yields a range between 0.008–26 Hz, approximately one octave lower than for humans.
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Rajagopalan, P., F. D. Boudinot, C. K. Chu, B. C. Tennant, B. H. Baldwin, and R. F. Schinazi. "Pharmacokinetics of (-)-2'-3'-dideoxy-3'-thiacytidine in woodchucks." Antimicrobial Agents and Chemotherapy 40, no. 3 (March 1996): 642–45. http://dx.doi.org/10.1128/aac.40.3.642.
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The woodchuck (Marmota monax) has proven to be a suitable animal model for studying hepatitis B virus (HBV) infection owing to similarities in the course of infection between woodchuck hepatitis virus (WHV) in woodchucks and HBV in humans. (-)-beta-L-2',3'-Dideoxy-3'-thiacytidine (3TC; lamivudine) is a nucleoside analog which has demonstrated antiviral activity against HBV as well as human immunodeficiency virus (HIV). The purpose of the present investigation was to characterize the pharmacokinetics of 3TC following intravenous and oral administration of 20 mg of 3TC per kg of body weight to woodchucks. Following intravenous administration, the concentrations of 3TC in plasma declined, with a terminal half-life of 2.84 +/- 0.85 h (mean +/- standard deviation). The systemic clearance and steady-state volume of distribution of 3TC were 0.22 +/- 0.078 liters/h/kg and 0.75 +/- 0.13 liters/kg, respectively. The renal clearance of the nucleoside analog was 0.063 +/- 0.016 liters/h/kg. The oral bioavailability of 3TC ranged from 18 to 54%. Allometric relationships between pharmacokinetic parameters and body weight developed by Hussey et al. (E.K. Hussey, K.H. Donn, M.J. Daniel, S.T. Hall, A.J. Harker, and G.L. Evans, J. Clin. Pharmacol. 34:975-977, 1994) were augmented by including data from woodchucks, monkeys (S.M. Blaney, M.J. Daniel, A.J. Harker, K. Godwin, and F.M. Balis, Antimicrob. Agents Chemother. 39:2779-2782, 1995), and additional data from rats (P. Rajagopalan, L. Moore, C.K. Chu, R.F. Schinazi, and F.D. Boudinot, submitted for publication). Interspecies scaling of the pharmacokinetic parameters of 3TC demonstrated a good correlation between clearance (0.74 . W0.76 [where W is body weight]; r = 0.93; P < 0.025), apparent volume of distribution (1.62 . W0.81; r = 0.98; P < 0.005), and steady-state volume of distribution (1.09 . W0.94; r = 0.99; P < 0.05) and species body weight. The allometric relationships for clearance and volume of distribution at steady state predicted the observed pharmacokinetic parameters in humans quite well; however, the apparent volume of distribution was underestimated in humans. Thus, the pharmacokinetic data obtained with the woodchuck HBV animal model should be useful for designing clinical trials.
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Nagilla, Rakesh, and Keith W. Ward. "A comprehensive analysis of the role of correction factors in the allometric predictivity of clearance from rat, dog, and monkey to humans." Journal of Pharmaceutical Sciences 93, no. 10 (October 2004): 2522–34. http://dx.doi.org/10.1002/jps.20169.
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Toyn, Jeremy H., Lorin A. Thompson, Kimberley A. Lentz, Jere E. Meredith, Catherine R. Burton, Sethu Sankaranararyanan, Valerie Guss, et al. "Identification and Preclinical Pharmacology of theγ-Secretase Modulator BMS-869780." International Journal of Alzheimer's Disease 2014 (2014): 1–22. http://dx.doi.org/10.1155/2014/431858.
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Alzheimer’s disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-βpeptide (Aβ), particularly the 42-amino acid Aβ1-42, in the brain. Aβ1-42 levels can be decreased byγ-secretase modulators (GSM), which are small molecules that modulateγ-secretase, an enzyme essential for Aβproduction. BMS-869780 is a potent GSM that decreased Aβ1-42 and Aβ1-40 and increased Aβ1-37 and Aβ1-38, without inhibiting overall levels of Aβpeptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing byγ-secretase and lowered brain Aβ1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aβ1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aβ1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aβ1-42 without Notch-related side effects.
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Nagilla, Rakesh, and Keith W. Ward. "Erratum: A Comprehensive Analysis of the Role of Correction Factors in the Allometric Predictivity of Clearance from Rat, Dog, and Monkey to Humans." Journal of Pharmaceutical Sciences 94, no. 1 (January 2005): 231–32. http://dx.doi.org/10.1002/jps.20277.
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Sim, Derek S., Alan Brooks, Cornell Mallari, Yifan Xu, Rick I. Feldman, Doug Schneider, Chandra Patel, et al. "Glycopegylated Factor IX Enables Prolonged Efficacy After Subcutaneous Injection But Requires a Higher Than Expected Plasma Activity To Prevent Bleeding In Hemophilia B Mice." Blood 122, no. 21 (November 15, 2013): 1104. http://dx.doi.org/10.1182/blood.v122.21.1104.1104.
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Abstract Background Reduced frequency of administration as well as subcutaneous (s.c.) injection would improve the treatment of Hemophilia B. Conjugation to polyethylene glycol (PEG) has been shown to increase the half-life of i.v. dosed Factor IX (FIX), but s.c. dosing of PEGylated FIX was not previously evaluated. Because s.c. dosing is limited by volume and bioavailability, we evaluated the combination of PEGylation with the increased specific activity variant R338A to reduce the amount of protein needed to provide therapeutic levels of FIX. Methods FIX-R338A was PEGylated on N-linked glycans in the activation peptide by periodate oxidation of sialic acid residues followed by conjugation to amino-oxy functionalized PEG. Pharmacokinetic (PK) profiles were determined in hemophilia B mice and cynomologous monkeys. Allometric scaling was used to predict dose regimens in humans. Prophylactic efficacy was determined in a Hemophilia B mouse tail bleeding model. Results 60kDaPEG-R338A had prolonged terminal half-life in mice (3-fold) and monkeys (5-fold) and the s.c. bioavailability was 44% and 35%, respectively. The volume of distribution was reduced 5-fold. To achieve a trough level of 3% FIX activity, s.c. dosing at weekly, bi-monthly and monthly intervals was predicted to require doses of 7, 25 and 220 IU/kg in patients. However, in a tail vein transection injury model, approximately 10-fold higher plasma FIX activity levels of PEGylated proteins were found to be needed to protect hemophilia B mice against bleeding than was required for i.v. dosed un-PEGylated recombinant FIX. This difference was observed for PEGylated wild-type and R338A proteins, dosed i.v or s.c. We hypothesize that this is related to the reduced distribution of PEGylated FIX to the extravascular compartment. Trough levels of 30% FIX activity were predicted to be achievable in humans after weekly and bi-monthly s.c. dosing at 70 and 260 IU/kg. Conclusions The PEGylation of FIX led to a significant improvement in both i.v. and s.c. PK. Unexpectedly, a 10-fold higher plasma activity was needed for PEGylated FIX to provide protection against bleeding in Hemophilia B mice, suggesting that trough levels of 10 to 30% of PEGylated FIX activity may be needed in patients to provide efficacy equivalent to current therapy of recombinant or plasma derived FIX. Nevertheless, 60kDaPEG-R338A has the potential to treat hemophilia B patients with once weekly or twice monthly subcutaneous injection. Disclosures: Sim: Bayer HealthCare: Employment. Brooks:Bayer HealthCare: Employment. Mallari:Bayer HealthCare: Employment. Xu:Bayer HealthCare: Employment. Feldman:Bayer HealthCare: Employment. Schneider:Bayer HealthCare: Employment. Patel:Bayer HealthCare: Employment. Blasko:Bayer HealthCare: Employment. Ho:Bayer HealthCare: Employment. Su:Bayer HealthCare: Employment. Liu:Bayer HealthCare: Employment. Laux:Bayer HealthCare: Employment. Murphy:Bayer HealthCare: Employment.
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Day, W. W., M. C. Allen, E. S. Hamanaka, R. J. Aiello, J. T. Mayne, and T. S. Shah. "2.P.28 Preclinical drug metabolism studies in rat, mouse, dog and monkey with allometric scaling for CP-340,868, a novel squalene synthetase inhibitor." Atherosclerosis 134, no. 1-2 (October 1997): 122. http://dx.doi.org/10.1016/s0021-9150(97)88665-0.
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Choi, Suein, Seunghoon Han, Sangil Jeon, and Dong-Seok Yim. "Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP)." Pharmaceutics 11, no. 7 (July 15, 2019): 336. http://dx.doi.org/10.3390/pharmaceutics11070336.
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CKD519, a selective inhibitor of cholesteryl ester transfer protein(CETP), is undergoing development as an oral agent for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. The aim of this study was to predict the appropriate efficacious dose of CKD519 for humans in terms of the inhibition of CETP activity by developing a CKD519 pharmacokinetic/pharmacodynamic (PK/PD) model based on data from preclinical studies. CKD519 was intravenously and orally administered to hamsters, rats, and monkeys for PK assessment. Animal PK models of all dose levels in each species were developed using mixed effect modeling analysis for exploration, and an interspecies model where allometric scaling was applied was developed based on the integrated animal PK data to predict the human PK profile. PD parameters and profile were predicted using in vitro potency and same-in-class drug information. The two-compartment first-order elimination model with Weibull-type absorption and bioavailability following the sigmoid Emax model was selected as the final PK model. The PK/PD model was developed by linking the interspecies PK model with the Emax model of the same-in-class drug. The predicted PK/PD profile and parameters were used to simulate the human PK/PD profiles for different dose levels, and based on the simulation result, the appropriate efficacious dose was estimated as 25 mg in a 60 kg human. However, there were some discrepancies between the predicted and observed human PK/PD profiles compared to the phase I clinical data. The huge difference between the observed and predicted bioavailability suggests that there is a hurdle in predicting the absorption parameter only from animal PK data.
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Davis, Victor. "Types, Tokens, and Hapaxes: A New Heap’s Law." Glottotheory 9, no. 2 (October 25, 2019): 113–29. http://dx.doi.org/10.1515/glot-2018-0014.
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Abstract Heap’s Law https://dl.acm.org/citation.cfm?id=539986 Heaps, H S 1978 Information Retrieval: Computational and Theoretical Aspects (Academic Press). states that in a large enough text corpus, the number of types as a function of tokens grows as N = K{M^\beta } for some free parameters K, \beta . Much has been written http://iopscience.iop.org/article/10.1088/1367-2630/15/9/093033 Font-Clos, Francesc 2013 A scaling law beyond Zipf’s law and its relation to Heaps’ law (New Journal of Physics 15 093033)., http://iopscience.iop.org/article/10.1088/1367-2630/11/12/123015 Bernhardsson S, da Rocha L E C and Minnhagen P 2009 The meta book and size-dependent properties of written language (New Journal of Physics 11 123015)., http://iopscience.iop.org/article/10.1088/1742-5468/2011/07/P07013 Bernhardsson S, Ki Baek and Minnhagen 2011 A paradoxical property of the monkey book (Journal of Statistical Mechanics: Theory and Experiment, Volume 2011)., http://milicka.cz/kestazeni/type-token_relation.pdf Milička, Jiří 2009 Type-token & Hapax-token Relation: A Combinatorial Model (Glottotheory. International Journal of Theoretical Linguistics 2 (1), 99–110)., https://www.nature.com/articles/srep00943 Petersen, Alexander 2012 Languages cool as they expand: Allometric scaling and the decreasing need for new words (Scientific Reports volume 2, Article number: 943). about how this result and various generalizations can be derived from Zipf’s Law. http://dx.doi.org/10.1037/h0052442 Zipf, George 1949 Human behavior and the principle of least effort (Reading: Addison-Wesley). Here we derive from first principles a completely novel expression of the type-token curve and prove its superior accuracy on real text. This expression naturally generalizes to equally accurate estimates for counting hapaxes and higher n-legomena.
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Le Moigne, Ronan, Paul Pearson, Veronique Lauriault, Nan Hyung Hong, Peter Virsik, Han-Jie Zhou, and Alessandra Cesano. "Preclinical and clinical pharmacology of EPI-7386, an androgen receptor N-terminal domain inhibitor for castration-resistant prostate cancer." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 119. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.119.
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119 Background: EPI-7386 is the newest of the “anitens”, a new class of compounds designed to inhibit androgen receptor activity by binding to the N-terminal domain (NTD) of the AR. Through this novel method of AR inhibition, anitens can block AR transcription even in the presence of AR ligand-binding domain (LBD) resistance mechanisms including point mutations and splice variants. Compared to the first generation aniten, EPI-506, which showed poor pharmacokinetic properties in patients, EPI-7386 is metabolically stable in vitro and in vivo. A Phase 1 clinical trial of EPI-7386 in metastatic castration-resistant prostate cancer patients failing standard of care therapies is ongoing and the pharmacokinetic properties of the drug in preclinical models as well as in the initial cohort of patients are presented. Methods: The metabolic stability of EPI-7386 was evaluated in vitro in mouse, rat, dog, monkey, and human hepatocytes. Projected PK parameters in humans were estimated from in vitro and in vivo clearance correlation (IVIVC). Induction of CYP isoforms was evaluated in human hepatocyte cultures. In patients, plasma concentrations of EPI-7386 were determined by LC-MS-MS, and 4-beta-hydroxycholesterol levels in plasma were followed over time as an indirect indicator of CYP3A induction. Results: In vitro hepatocyte studies demonstrated good metabolic stability for EPI-7386 with an in vitro half-life > 360 min. In animal PK studies, the terminal half-life of EPI-7386 was approximately 5.8 hours in mouse, 4.9 hours in rat, 13.4 hours in dog and the plasma clearance was low across species. The oral bioavailability of EPI-7386 ranged from 33–112% in mouse to > 100% in rat and dog. Using IVIVC, a predicted human clearance of 0.16–0.39 mL/min/kg was calculated for EPI-7386, which was in line with allometric scaling from animal PK parameters. Human PK profiles of different doses of EPI-7386 were simulated using predicted oral bioavailability, clearance, and volume of distribution. Cmax and AUC0–24h for the Phase 1 first-in-human study (NCT04421222) starting dose of 200 mg dose were predicted to be 6,915 ng/mL and 137,278 ng•h/mL respectively. A comparison between estimated PK parameters and actual values observed in the first patient cohort will be presented. Human hepatocyte CYP induction studies showed that EPI-7386 is not an inducer of CYP1A2 but may have the potential to induce CYP2B6 and CYP3A4. A comparison of 4-beta-hydroxy cholesterol levels measured during the phase 1 will be presented along with a comparison drawn from in vitro models. Conclusions: Pre-clinical characterization predicts that EPI-7386 has the appropriate PK and metabolic properties to afford exposure in patients at potentially efficacious levels following once-daily oral administration. PK measurements in the initial cohort of patients treated in the Phase 1 study will be presented. Clinical trial information: NCT04421222.
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Hutchaleelaha, Athiwat, Mira Patel, Abel Silva, Donna Oksenberg, and Brian Metcalf. "GBT440 Demonstrates High Specificity for Red Blood Cells in Nonclinical Species." Blood 126, no. 23 (December 3, 2015): 2172. http://dx.doi.org/10.1182/blood.v126.23.2172.2172.
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Abstract Sickle cell disease (SCD) is caused by a point mutation in the β-globin gene leading to production of hemoglobin S (HbS) that polymerizes upon deoxygenation with subsequent formation of sickled red blood cells (RBCs). GBT440 modulates O2 affinity of hemoglobin (Hb) by binding to the N-terminal α chain of Hb via a reversible Schiff base. We previously demonstrated that GBT440 preventedsickling of RBCs from sickle cell patients, in vitro. Also, in a murine model of sickle cell disease (Townes SS mice), GBT440 prevented ex vivo sickling of RBCs and prolonged RBC half-life. Pharmacokinetic (PK) studies of GBT440 were conducted in mouse, rat, dog and monkey following IV and oral administration. Both blood and plasma samples were collected and assayed for GBT440 concentration using LCMS. Following IV and oral administrations, GBT440 quickly partitions into the RBC with a high blood/plasma ratio of ~70:1 which corresponded to a RBC/plasma ratio of ~150:1. Volume of distribution (Vss) was small in whole blood (0.041-0.171 L/kg) but much larger in plasma (1.44-8.45 L/kg) indicating that RBCs are a reservoir of GBT440. Systemic clearance (CLs) was low in both blood (0.016-0.113 mL/min/kg) and plasma (0.943-3.16 mL/min/kg) indicating that GBT440 was mostly bound to hemoglobin and only a small fraction of unbound GBT440 re-distributed into the plasma and was available for clearance. Terminal elimination half-life (t1/2) was similar between whole blood and plasma for each species and was long, ranging from 6.4 hours in mouse plasma to 93.5 hours in dog plasma. GBT440 was well absorbed and absolute oral bioavailability ranged from 33% to 70% in four species. A quantitative whole body autoradiography study to determine tissue distribution of GBT440 was conducted in male rats following an oral dose of 14C-GBT440 (10 mg/kg; 150 µCi/kg PO). The data showed that GBT440 is co-located in hematopoietic tissues as expected for a molecule whose target is hemoglobin, including blood, spleen, liver and bone marrow. A mass balance study of 14C-GBT440 (10 mg/kg; 150 µCi/kg PO) was conducted in rats to determine route of elimination of GBT440. The 14C-GBT440-derived radioactivity was well absorbed and rapidly excreted after oral administration. By 240 hours postdose, mean values of 79.0 ± 3.86 and 9.74 ± 3.02% of the administered radioactivity were excreted in feces and urine, respectively. The mean overall recovery of radioactivity was 92.4 ± 0.875%. Metabolism via both Phase I and Phase II pathways was the major route of elimination of GBT440. These data indicate that despite its high affinity binding toward Hb, GBT440 could be released from the hemoglobin complex and completely eliminated from the body. To further correlate PK to pharmacological activity (hemoglobin modification based on changes in the oxygen equilibrium curve), mice were given an oral dose of 30, 50 and 100 mg/kg and blood were collected at 4 and 6 hr postdose for hemoximetry analysis. Data showed good correlation between blood concentrations and changes in p50. Blood concentrations following 30, 50 and 100 mg/kg at 4 hr were 243, 446, and 806 µM, which resulted in changes in p50 of 11%, 25% and 55%, respectively, indicating that GBT440 elicits an ex vivo dose dependent increase in Hb-O2 affinity following increasing dosage to mice. Based on PK data from 4 animal species, PK profile of GBT440 in human was predicted using a simple allometric scaling technique. The predicted PK profile following an oral administration was highly concordant with actual data from healthy subjects for Cmax, AUC and T½, which suggested that the disposition kinetics of GBT440 in humans were consistent to that in animals. In summary, nonclinical PK studies support previous findings that GBT440 partitions to RBCs, binds specifically to Hb with a slow off rate, modulates Hb-O2 affinity, and is completely eliminated from the body. GBT440 is in clinical trials for the treatment of SCD. Disclosures Hutchaleelaha: Global Blood Therapeutics: Employment, Equity Ownership. Patel:Global Blood Therapeutics: Employment, Equity Ownership. Silva:Global Blood Therapeutics: Employment, Equity Ownership. Oksenberg:Global Blood Therapeutics: Employment, Equity Ownership. Metcalf:Global Blood Therapeutics: Consultancy, Equity Ownership.
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Cheng, Luqi, Yuanchao Zhang, Gang Li, Jiaojian Wang, Chet Sherwood, Gaolang Gong, Lingzhong Fan, and Tianzi Jiang. "Connectional asymmetry of the inferior parietal lobule shapes hemispheric specialization in humans, chimpanzees, and rhesus macaques." eLife 10 (July 2, 2021). http://dx.doi.org/10.7554/elife.67600.
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The inferior parietal lobule (IPL) is one of the most expanded cortical regions in humans relative to other primates. It is also among the most structurally and functionally asymmetric regions in the human cerebral cortex. Whether the structural and connectional asymmetries of IPL subdivisions differ across primate species and how this relates to functional asymmetries remain unclear. We identified IPL subregions that exhibited positive allometric in both hemispheres, scaling across rhesus macaque monkeys, chimpanzees, and humans. The patterns of IPL subregions asymmetry were similar in chimpanzees and humans, but no IPL asymmetries were evident in macaques. Among the comparative sample of primates, humans showed the most widespread asymmetric connections in the frontal, parietal, and temporal cortices, constituting leftward asymmetric networks that may provide an anatomical basis for language and tool use. Unique human asymmetric connectivity between the IPL and primary motor cortex might be related to handedness. These findings suggest that structural and connectional asymmetries may underlie hemispheric specialization of the human brain.