Pharmcokinetic and pharmacodynamic considerations for the anticholinergic burden scale of drugs.

Older adults frequently have many systemic diseases that require treatment with multiple drugs, and thus anticholinergic adverse effect by polypharmacy is a significant concern in the management of older adults. The accuracy of the anticholinergic burden rating may be increased by considering pharmacokinetic and pharmacodynamic factors such as biophase drug concentrations, the pharmacologically active metabolites formed after drug administration, and muscarinic receptor-mediated effects. Therefore, a pharmacological evidence-based burden scale that considers pharmacokinetic and pharmacodynamic factors is expected to be a more optimal tool for precisely assessing the anticholinergic burden, specifically risk reductions in anticholinergic adverse events in the poly-medicated elderly. Geriatr Gerontol Int 2023; ••: ••-••.

Carbon, nitrogen, and oxygen stable isotope ratios of striped dolphins and short-finned pilot whales stranded in Hokkaido, northern Japan, compared with those of other cetaceans stranded and hunted in Japan.

Strandings of striped dolphins (SD) and short-finned pilot whales (PW) in Hokkaido, northern Japan, are rare but have recently increased, probably due to global warming. We quantified δ13C, δ15N, and δ18O in muscles of SD (n = 7) and PW (n = 3) stranded in Hokkaido and compared these values with those in muscles (red meat products) of hunted SD and PW in three areas of central and southern Japan. δ18O in stranded SD, except for the calf, decreased with increasing body length (BL), whereas δ13C increased, with no BL-related changes in δ15N. The variability of δ18O (range of maximum and minimum) was larger in the stranded SD (7.5 ‰) than of the hunted SD in three areas (0.9, 1.9, and 1.4 ‰), whereas that of δ15N was smaller in the stranded SD than in the hunted SD. Similarly, the variability of δ18O was larger in the stranded PW in Hokkaido (3.3 ‰) than in the hunted PW in central Japan (1.4 ‰). The larger variability of δ18O and smaller variability of δ15N in stranded SD imply long-term sojourning in coastal waters and feeding on small amounts of limited prey species at low trophic levels before death.

Profiles and determinants of dicofol, endosulfans, mirex, and toxaphenes in breast milk samples from 10 prefectures in Japan.

Human exposure to persistent organic pollutants (POPs) is reflected by POP concentrations in breast milk. Many studies of POPs in breast milk have been performed in Japan, but insufficient information is available about some legacy POPs (e.g., mirex and toxaphenes, included in the Stockholm Convention in 2001) and novel POPs (e.g., dicofol and endosulfans, included in the Stockholm Convention in 2019 and 2011, respectively). In this study, dicofol, endosulfan, mirex, and toxaphene concentrations in breast milk from 10 prefectures in Japan were determined. The samples were collected between 2005 and 2010, before Stockholm Convention restrictions on endosulfans and mirex were implemented. Common POPs (e.g., polychlorinated biphenyls) were also analyzed to allow the contamination statuses to be compared. The α-endosulfan and ß-endosulfan concentrations were 0.26-13 and 0.012-0.82 ng/g lipid, respectively. The toxaphene #26 and #50 concentrations were <0.08-5.6 and < 0.1-8.5 ng/g lipid, respectively. The dicofol concentrations were <0.01-4.8 ng/g lipid. The mirex concentrations were <0.2-3.5 ng/g lipid. The α- and ß-endosulfan concentrations on a lipid weight basis negatively correlated with the lipid contents of the milk samples (ρ = -0.65, p < 0.01 for α-endosulfan; ρ = -0.58, p < 0.01 for ß-endosulfan). The toxaphene concentrations positively correlated with the lipid contents. The mirex concentrations positively correlated with the maternal age but negatively correlated with the maternal body mass index. No correlations between the dicofol concentrations and the factors were found. Principal component analysis divided the data into four groups, (1) chlordanes, dichlorodiphenyltrichloroethanes and related compounds, hexachlorobenzene, hexachlorocyclohexanes, hexachloroethane, and polychlorinated biphenyls, (2) endosulfans, (3) dicofol, dieldrin, and toxaphenes, and (4) bromodiphenyl ether 47. This indicated that bromodiphenyl ether 47, dicofol, endosulfans, and toxaphenes have different exposure routes or different kinetics to the other legacy POPs.

Teratogenic Effects of Organohalogen Contaminants Extracted from Whale Bacon in a Whole-Rat-Embryo Culture System.

Marine foods can be contaminated with organochlorines and the risk to human beings who consume these foods needs to be evaluated. We examined the teratogenic effects of contaminants extracted from whale bacon on rat embryos using a whole-embryo culture system. Embryonic day 11.5 embryos were cultured for 48 h with organohalogens extracted from whale bacon at low (polychlorinated biphenyls (PCBs): 0.32 ppm, dichlorodiphenyltrichloroethanes (DDTs): 0.16 ppm, chlordanes (CHLs): 0.02 ppm) and high (PCBs: 2.15 ppm, DDTs: 1.99 ppm, CHLs: 0.20 ppm) doses. The levels of organohalogen compounds in cultured embryos were determined. The organochlorine contaminants extracted from whale products were readily transferred to the cultured rat embryos. The number of heartbeats, yolk sac circulation score, and embryonic body circulation score of embryos did not change during the culture period in either exposure group. Cultured embryos treated with the low-dose contaminated medium for 48 h showed abnormalities of the mandible, and craniofacial or forelimb hematomas with an incidence of 50%. All embryos treated with the high-dose medium showed craniofacial abnormalities and cleft lip, and limb abnormalities and hematomas. These results indicate that the organohalogen contaminants in whale bacon may be teratogenic in a dose-dependent manner. Further studies are necessary to determine the dose-effect relationship.

Effects of saw palmetto extract on the vanilloid receptor TRPV1.

OBJECTIVE: Transient receptor potential vanilloid subtype 1 (TRPV1) may play a significant role in the pathophysiology of the bladder. The present study investigated the effects of the herbal product, saw palmetto extract (SPE) on TRPV1-mediated Ca2+ influx and specific [3 H]resiniferatoxin ([3 H]RTX) binding to TRPV1 in HEK293 cells expressing TRPV1 (HEK293VR11 cells). METHODS: Ca2+ influx induced by and the direct binding activity of TRPV1 were measured using a method with Fura 2-AM, a cytoplasmic calcium indicator, and a radioligand binding assay using a [3 H]RTX, respectively. RESULTS: SPE did not markedly affect Ca2+ influx in HEK293VR11 cells; however, it significantly inhibited capsaicin-induced increases in Ca2+ influx in these cells. The specific binding of [3 H]RTX in HEK293VR11 cells was saturable with Kd value of 120 ± 7 pM and Bmax of 1.07 ± 0.10 fmol/mg protein, and was inhibited by low concentrations of non-labeled RTX with Ki of 60.1 ± 7.6 nM. These results confirmed the pharmacological specificity of specific binding sites of [3 H]RTX to TRPV1 in HEK293VR11 cells. SPE inhibited the specific binding of [3 H]RTX in a concentration-dependent manner, with Ki of 24.2 ± 1.4 µg/mL. CONCLUSIONS: The present study demonstrated for the first time, that SPE inhibited capsaicin-induced Ca2+ influx with binding to TRPV1 in HEL293VR11 cells. These results will contribute to a more detailed understanding of the pharmacological effects of SPE on urinary dysfunction.

Comparative characterization of ß-adrenoceptors in the bladder, heart, and lungs of rats: Alterations in spontaneously hypertensive rats.

The present study aimed to characterize and compare ß-adrenoceptors in the rat bladder with those in the heart and lungs of SD rats (8-10 weeks old) using subtype-selective agonists and antagonists in a radioligand binding assay with (-)-[125I]cyanopindolol ([125I]CYP), and also to clarify alterations in ß-adrenoceptors in the bladder of spontaneously hypertensive rats (SHR) at 14 weeks old, from those of Wistar-Kyoto rats (WKY) and Wistar rats at the same age. A radioligand binding assay with [125I]CYP was used to measure ß-adrenoceptor binding activity in rat tissues. Metoprolol exhibited the highest affinity to specific binding sites of [125I]CYP in the rat heart, indicating the dominance of ß1-adrenoceptors. ß3-selective agonists (BRL37344 and CL316243) and antagonist (SR59230A) exhibited higher affinity to specific binding sites of [125I]CYP in the bladder than in the heart and lungs. Furthermore, the binding affinity of the ß2-selective antagonist, ICI118551 was the highest in the bladder. The Bmax of specific [125]CYP binding in the bladder was significantly lower in WKY and SHR than in Wistar rats. The present study provides further evidence for the coexistence of ß2-and ß3-adrenoceptors in the rat bladder, and indicates that ß-adrenoceptor density is lower in the bladders of WKY and SHR.

Anti-Allergic Effects of the Subcritical Water Extract Powder of Citrus unshiu in Mouse and Guinea Pig Models.

We evaluated the effects of unripe mandarin orange (Citrus unshiu) extract powder (unripe mandarin extract powder [UMEP]) treated with subcritical water on allergic diseases by using animal models. High performance liquid chromatography (HPLC) analysis revealed that subcritical water is a more effective solvent than alcohol and hot water, as it quickly extracted approximately 90% of the functional compounds narirutin (1) and hesperidin (2) from whole fruits. Repeated oral administration of UMEP significantly reversed the peripheral blood flow decline observed during the promotion of allergies after sensitization with the antigen, hen egg-white lysozyme (HEL). UMEP also significantly inhibited compound 48/80-induced scratching behavior in HEL-sensitized mice, which are more sensitive to itching stimuli than are normal mice, without suppressing locomotor activity. In addition, repeated oral administration of UMEP in ovalbumin-challenged guinea pigs significantly suppressed the late phase of nasal airway resistance. This study provides evidence that the subcritical water extract powder of unripe C. unshiu fruit is an effective anti-allergic functional food.

Effects of perfluoroalkyl carboxylic acids on the uptake of sulfobromophthalein via organic anion transporting polypeptides in human intestinal Caco-2 cells.

We performed a detailed investigation of the uptake of sulfobromophthalein (BSP) from the apical membrane of Caco-2 cells, which is a substrate for organic anion transporting polypeptides (OATPs), and calculated the kinetic parameters of BSP uptake as follows: Km = 13.9 ± 1.3 µM, Vmax = 1.15 ± 0.07 nmol (mg protein)-1 (5 min)-1, and kd = 38.2 ± 0.53 µL (mg protein)-1 (5 min)-1. Coincubation with medium-chain (C7-C11) perfluoroalkyl carboxylic acids (PFCAs), such as perfluoroheptanoic acid (PFHpA, C7), perfluorooctanoic acid (PFOA, C8), perfluorononanoic acid (PFNA, C9), perfluorodecanoic acid (PFDA, C10) and perfluoroundecanoic acid (PFUnDA, C11), significantly decreased BSP uptake by 27-55%, while coincubation with short- (C3-C6) and long-chain (C12-C14) PFCAs decreased the uptake only slightly. Dixon plotting suggested that PFOA, PFNA and PFDA competitively inhibited the BSP uptake with inhibition constant (Ki) values of 62.2 ± 1.3 µM, 35.3 ± 0.1 µM and 43.2 ± 0.3 µM, respectively. PFCAs with medium-chains could be substrates for OATPs, probably OATP2B1, which is the most abundantly expressed OATP isoform in Caco-2 cells.

Kanechlor 500-mediated changes in serum and hepatic thyroxine levels primarily occur in a transthyretin-unrelated manner.

The effects of Kanechlor-500 (KC500) on the levels of serum total thyroxine (T4 ) and hepatic T4 in wild-type C57BL/6 (WT) and its transthyretin (TTR)-deficient (TTR-null) mice were comparatively examined. Four days after a single intraperitoneal injection with KC500 (100 mg/kg body weight), serum total T4 levels were significantly decreased in both WT and TTR-null mice. The KC500 pretreatment also promoted serum [125 I]T4 clearance in both strains of mice administrated with [125 I]T4 , and the promotion of serum [125 I]T4 clearance in WT mice occurred without inhibition of the [125 I]T4 -TTR complex formation. Furthermore, the KC500 pretreatment led to significant increases in liver weight, steady-state distribution volume of [125 I]T4 , hepatic accumulation level of [125 I]T4 , and concentration ratio of the liver to serum in both strains of mice. The present findings indicate that the KC500-mediated decrease in serum T4 level occurs in a TTR-unrelated manner and further suggest that KC500-promoted T4 accumulation in the liver occurs through the development of liver hypertrophy and the promotion of T4 transportation from serum to liver.

Muscarinic receptor binding of fesoterodine, 5-hydroxymethyl tolterodine, and tolterodine in rat tissues after the oral, intravenous, or intravesical administration.

The present study aimed to characterize muscarinic receptor binding of fesoterodine, 5-hydroxymethyl tolterodine (5-HMT), and tolterodine in bladder and other tissues of rats after their oral, intravenous, or intravesical administration. Muscarinic receptors in tissues were measured by using [N-methyl-3H]scopolamine methyl chloride ([3H]NMS). The in vitro binding affinity for muscarinic receptors was the highest by 5-HMT, followed by tolterodine and fesoterodine. Fesoterodine exhibited lower affinity in rat submaxillary gland than in detrusor muscle and urothelium. Muscarinic binding affinities of 5-HMT and tolterodine were similar among tissues. The duration of binding of oral fesoterodine to muscarinic receptors was longer in bladder than in submaxillary gland, heart, and lung, and its binding was little observed in colon and cerebral cortex. Binding activity of intravenous 5-HMT to muscarinic receptors was significantly observed in all tissues, except cerebral cortex, with a longer duration in bladder. Significant binding of bladder detrusor and urothelial muscarinic receptors was observed following intravesical instillation of 5-HMT. This selectivity may be attributed to the direct blockade of bladder receptors by excreted urinary 5-HMT. Thus, fesoterodine may be efficacious as a treatment for patients with overactive bladder.

Levels and profiles of long-chain perfluoroalkyl carboxylic acids in Pacific cod from 14 sites in the North Pacific Ocean.

We investigated the profiles and levels of perfluoroalkyl carboxylic acid (PFCA) contamination in Pacific cod (Gadus macrocephalus) from the North Pacific Ocean. The mean concentrations of PFCAs containing 8 to 14 carbon atoms (C8-C14) in edible Pacific cod muscle ranged from 216 to 670 pg g-1 wet weight in the Northeast Pacific Ocean (Seattle, Vancouver, Alaska, and Russia), from 819 to 1710 pg g-1 wet weight in Japanese coastal waters (Hokkaido, Aomori, Iwate, Miyagi, Tottori, and Shimane), and from 288 to 892 pg g-1 wet weight in Korean waters (Sokcho, Busan, and Yeosu). These results indicate there are geographical differences in the distribution of PFCAs. The long-chain PFCAs (C9-C14) contributed 96% of the total PFCA concentration across Japan, whereas they contributed only 33% of the total PFCA concentration in the USA and Canada. Long-chain PFCA concentrations in cod samples collected in Japanese and Korean waters were about three to four times those in samples from the USA, Canada, and Russia. Because seafood is considered an important dietary source of PFCAs, high concentrations of long-chain PFCAs in Pacific cod from Japanese and Korean waters may affect human dietary exposure and blood concentrations of long-chain PFCAs.

Different profiles of naturally produced and anthropogenic organohalogens in the livers of cetaceans from the Sea of Japan and the North Pacific Ocean.

Levels and profiles of naturally produced halogenated bipyrroles (Br4Cl2-DBP and Cl7-MBP), methoxylated tetrabromodiphenyl ethers (6-MeO-BDE47), anthropogenic perfluoroalkyl substances (PFASs) and legacy persistent organic pollutants (POPs) were investigated in the livers of 14 cetaceans from the Sea of Japan and the North Pacific Ocean. The concentrations of Br4Cl2-DBP (4 to 4900 ng/g-wet), Cl7-MBP (16 to 3960 ng/g-wet) and 6-MeO-BDE47 (7 to 190 ng/g-wet) were higher in the order of killer whales > toothed whales > baleen whales. Profiles of PFASs were dominated by perfluoroundecanoic and perfluorotridecanoic acids (10 to 540 ng/g-wet), sum of which accounted for 70% of total measured PFASs. Regional difference was observed for Cl7-MBP and PFASs, which were higher in the Sea of Japan, whereas Br4Cl2-DBP was in the North Pacific Ocean. Specific accumulation pattern of these natural contaminants in cetaceans around northern Japan could help compare the exposure profile of PFASs and POPs among other geographic regions.

Data on COA-Cl administration to the APP/PS2 double-transgenic mouse model of Alzheimer׳s disease: Improved hippocampus-dependent learning and unchanged spontaneous physical activity.

We herein present behavioral data regarding whether COA-Cl, a novel adenosine-like nucleic acid analog that promotes angiogenesis and features neuroprotective roles, improves cognitive and behavioral deficits in a murine model for Alzheimer׳s disease (AD). COA-Cl induced significant spatial memory improvement in the amyloid precursor protein/presenilin 2 double-transgenic mouse model of AD (PS2Tg2576 mice). Correspondingly, non-spatial novel object cognition test performance also significantly improved in COA-Cl-treated PS2Tg2576 mice; however, these mice demonstrated no significant changes in physical activity or motor performance. COA-Cl did not change the spontaneous activities and cognitive ability in the wild-type mice.

Contamination trends and factors affecting the transfer of hexabromocyclododecane diastereomers, tetrabromobisphenol A, and 2,4,6-tribromophenol to breast milk in Japan.

This study investigated contamination trends and factors affecting the levels of brominated flame retardants (BFRs), including hexabromocyclododecane (HBCD) diastereomers, tetrabromobisphenol A (TBBP-A), and 2,4,6-tribromophenol (2,4,6-TBP), in breast milk in Japan. Breast milk samples (n = 64) were collected from mothers living in six prefectures in Japan. The mean concentrations were 2.2, 0.19, 0.29, 3.0, and 0.59 ng/g lipid weight for α-HBCD, ß-HBCD, γ-HBCD, TBBP-A, and 2,4,6-TBP, respectively. Based on the previous studies, the levels of ΣHBCD in Japanese women's milk appear to be increasing, and the levels of TBBP-A are higher than those in other Asian countries. Although ΣHBCD were not correlated to phenolic BFRs, the concentration of ß-HBCD was significantly correlated to the concentrations of TBBP-A (r = 0.440, p < 0.01) and 2,4,6-TBP (r = 0.320, p < 0.01). The concentration of γ-HBCD increased significantly with maternal age (r = 0.378, p < 0.01), but the concentrations of the other analytes were not dependent on age. The concentration of α-HBCD was higher in primiparae than in multiparae (p < 0.05), while TBBP-A was higher in multiparae. No significant correlation was found between the phenolic BFR levels in milk and mothers' age, working place, and drinking/smoking habits. These results suggest that exposure to α- and γ-HBCD diastereomers could be affected by maternal age and parity, respectively, because of their different kinetics and sources. Therefore, these factors should be considered when conducting infant risk assessments.

A Real-Time Ultraviolet Radiation Imaging System Using an Organic Photoconductive Image Sensor.

We have developed a real time ultraviolet (UV) imaging system that can visualize both invisible UV light and a visible (VIS) background scene in an outdoor environment. As a UV/VIS image sensor, an organic photoconductive film (OPF) imager is employed. The OPF has an intrinsically higher sensitivity in the UV wavelength region than those of conventional consumer Complementary Metal Oxide Semiconductor (CMOS) image sensors (CIS) or Charge Coupled Devices (CCD). As particular examples, imaging of hydrogen flame and of corona discharge is demonstrated. UV images overlapped on background scenes are simply made by on-board background subtraction. The system is capable of imaging weaker UV signals by four orders of magnitude than that of VIS background. It is applicable not only to future hydrogen supply stations but also to other UV/VIS monitor systems requiring UV sensitivity under strong visible radiation environment such as power supply substations.

Tissue-specific bioaccumulation of long-chain perfluorinated carboxylic acids and halogenated methylbipyrroles in Dall's porpoises (Phocoenoides dalli) and harbor porpoises (Phocoena phocoena) stranded in northern Japan.

This study investigated accumulation of perfluoroalkyl substances (PFASs), persistent organochlorines (OCs), and naturally produced halogenated compounds (NHCs), including brominated methylbipyrroles and methoxylated bromodiphenyl ethers, in liver, blood, and blubber from Dall's porpoises (Phocoenoides dalli) and harbor porpoises (Phocoena phocoena) stranded in Hokkaido, northern Japan. Profiles of the PFASs were dominated by perfluoroundecanoic acid and perfluorotridecanoic acid, both of which accounted for 70% of the total measured PFAS concentrations in both porpoise species. The mean concentrations of the ∑PFCA were 573ng/g wet weight (ng/g-wet) in liver, 62ng/g-wet in whole blood, and 28ng/g-wet in blubber from the Dall's porpoises, and were significantly higher (p<0.05) than those in the harbor porpoises. The hepatic concentrations of perfluorooctane sulfonate (PFOS) were <14ng/g-wet, and accounted for only 3% of the total measured PFASs. The profiles of PFASs in the porpoises resembled those in fish species in this area, implying a common source of exposure to PFASs in East Asia. On the other hand, in the blubber of Dall's porpoises, NHCs were dominated by 2,3,3',4,4',5,5'-heptachloro-1'-methyl-1,2'-bipyrrole (867ng/g-wet), 5,5'-dichloro-1,1'-dimethyl-3,3',4,4'-tetrabromo-2,2'-bipyrrole (481ng/g-wet), and 6-methoxy-2,2',4,4'-tetrabromodiphenyl ether (30ng/g-wet), which were present at higher concentrations than in harbor porpoises. Factor analysis with varimax rotation revealed that factor 1 had higher eigenvectors (element in eigenvalues) for long-chain PFCAs and PFOS, which was found in the highest concentrations in the liver, whereas factor 2 was mainly associated with lipid soluble NHCs and OCs in both species. No correlations were observed between long-chain PFCAs and NHCs in the porpoises, probably because of the different sources and accumulation kinetics. Future research should assess the temporal trends and long-term effects of PFASs and NHCs in the tissues of mammals from the Asia-Pacific region.

Possible mechanism for the polychlorinated bipheny-linduced liver-selective accumulation of thyroxine in rats.

We have previously reported that decrease in level of serum thyroxine T4 by Kanechor 500 (KC500) in rats would occur through the increase in hepatic T4 accumulation rather than the increase in hepatic T4-glucuronyl transferase activity. In the present study, to understand the mechanism underlying the KC500-mediated increase in hepatic T4 accumulation, we examined the relationship between the KC500-mediated changes in hepatic T4 accumulation and the expression levels of mRNAs of hepatic transporters including T4 transporters. [125I]T4 was intravenously injected into KC500-pretreated and control (KC500-untreated) Wistar rats, and [125I]T4 uptake levels of liver parenchymal cells were comparatively examined. The amount of [125I]T4 uptake by hepatic cells increased in a time-dependent manner up to 96 hr after KC500 treatment. Following KC500 treatment, a time-dependent increase in the mRNA level of hepatic T4 influx transporter LAT1 was observed up to 96 hr later, while a significant increase in hepatic T4 influx transporter Oatp2 mRNA occurred only at 96 hr later. No KC500-mediated increases in the mRNAs of other hepatic transporters (Oatp1, Oatp3, Oatp4, Ntcp, LAT2, and Mrp2) were observed at any timepoints, although the mRNA expression of the T4 conjugate(s) efflux transporter Mrp3 significantly increased in a time-dependent manner 24-96 hr following KC500 treatment. The present findings suggest that KC500-mediated increase in hepatic T4 accumulation occurs, at least in part, through the increase in the expression of hepatic T4-transporters, such as LAT1 and Oatp2.

Growth-related changes in non-essential and essential metals in the liver of star-spotted smooth-hounds (dogfish) Mustelus manazo from the northern region of Japan.

We analyzed Cd, Hg, Zn, Cu, Mn and Fe concentrations in liver samples from male and female star-spotted smooth-hounds at various life stages. Male sharks of this species are known to reach their maximum body length (BL) more quickly than females, while females are known to mature later and live longer than males. Hepatic Cd and Hg concentrations in males and females markedly increased after maturation, but these increases proceeded earlier in males than in females. Hepatic Zn and Cu concentrations decreased during the growth stage of males and females, and thereafter increased concomitantly with increases of Cd and Hg burdens, forming a U-shaped curve over their lifespan, and the BL at which the lowest concentrations of Zn and Cu were observed was smaller in males than in females. These gender-related differences in those metals could reflect the faster growth and earlier cessation of growth in males.

Synthesis and Evaluation of Novel Cyclopropane Nucleoside as Potential Tube Formation Agents.

Five novel nucleoside analogs with mono or bis-hydroxymethylated cyclopropane rings at the N9-position of the 2-chloroadenine moiety (2-chloro-carbocyclic oxetanocin A [COA-Cl] analog) were synthesized and evaluated using human umbilical vein endothelial cells. All the prepared compounds (2a-e) showed good to moderate activity with angiogenic potency. cis-2'-(Hydroxymethyl)cycloprop-1'-yl derivative (2b) at 100 µM had greater angiogenic activity than the other compounds did, with relative tube areas of 2.71±0.45 (mean±standard deviation (S.D.)), which was superior to the potency of COA-Cl (2.30±0.59).