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Biomedical subjects

E E Codd

Publications and source records attributed to E E Codd.

At least 19 recordsLinked to original sources
PubMed1995

Piperazinylalkyl heterocycles as potential antipsychotic agents.

We recently reported on a series of pyrrole Mannich bases orally active in inhibiting the conditioned avoidance response (CAR) in rats. These compounds exhibit affinity for both D2 and 5-HT1A receptors, and some are noncataleptogenic. Such a profile suggests that they may be potential antipsychotic agents which lack the propensity for causing extrapyramidal side effects and tardive dyskinesias in humans. One of these compounds, 1-[[1-methyl-5-[[4-[2-(1-methylethoxy)phenyl]- 1-piperazinyl]methyl]-1H-pyrrol-2-yl]methyl]-2-piperidinone (RWJ 25730, 1), was chosen for further development but found to be unstable in dilute acid. In order to improve stability, we replaced the pyrrole methylene linkage to the piperazine ring with ethylene, employed ethylene and dicarbonyl as linkers between the lactam and the pyrrole ring, placed electron-withdrawing groups on the pyrrole ring, and substituted acyclic amide for lactam. In addition, we replaced the pyrrole segment with other heterocycles including thiophene, furan, isoxazole, isoxazoline, and pyridine. Generally, replacement of the N-methylpyrrole segment with thiophene, furan, isoxazoline, or pyridine afforded compounds equipotent with 1 in CAR, which were more stable in dilute acid. In the case of side chain or lactam modifications, CAR activity was significantly decreased or abolished, with the exception of 6. For the most part, the modifications to 1 resulted in the decrease or loss of D2 receptor binding. However, within this series, 5-HT1A receptor binding was greatly increased, with thiophene 40 exhibiting an IC50 of 0.07 nM. The CAR activities of pyrroles 6 and 12, thiophene 40, furans 44-47, isoxazolines 49 and 50, and pyridine 54 coupled with their weak or nonexistent D2 binding and strong 5-HT1A binding suggest that they may be acting via a nondopaminergic mechanism or that dopaminergic active metabolites are responsible. Pyrrole 6 and furans 44 and 47 show promise as antipsychotic agents based on their CAR activity, receptor-binding profile, and solution stability.

Animals↗
PubMed1995

N-aryl-N'-benzylpiperazines as potential antipsychotic agents.

N1-(2-Alkoxyphenyl)piperazines additionally containing an N4-benzyl group bearing alcohol, amide, imide, or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response (CAR) test predictive of clinical antipsychotic activity and in in vitro receptor-binding assays. Certain of the compounds display high affinity for the D2, 5-HT1A, and alpha 1-adrenergic receptors. Structures bearing acyclic amide, lactam, and imide functionalities display good biological activity, with a preference for the 1,3-disubstituted phenyl ring relative to the 1,4- and 1,2-congeners (7 vs 10 and 12). Every possible position of hydantoin attachment was investigated (e.g., substitution at N1, N3, and C5). The hydantoin involving attachment to N1 (24) was found to have good biological activity, whereas those hydantoins with attachment to N3 or C5 (22, 23, and 25) were inactive. Several of the smaller acetylated derivatives (30 and 33) have fair in vivo activity, which was lost in the case of the larger benzoyl analog 31. Uracil congener 34 had modest affinity for the D2 receptor (65 nM) as well as excellent in vivo activity. Benzylamino compounds display (viz. 27 and 35-38) moderate CAR activity but have surprising receptor affinity, often greater than those of comparable structures bearing a carbonyl (36 vs 7). Benzyl and benzhydryl alcohol compounds 40-48 are more active than amino structures 27 and 35-38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and 5-HT1A receptor binding.

Animals↗
PubMed1995

Alpha 2-adrenoceptors vs. imidazoline receptors: implications for alpha 2-mediated analgesia and other non-cardiovascular therapeutic uses.

The multiple clinical actions of clonidine have historically been linked to the same receptor (alpha 2-adrenoceptor) due to the belief that clonidine was a selective alpha 2-agonist. However, it is now recognized that clonidine binds with a similar affinity to alpha 2-adrenoceptors and to non-adrenergic imidazoline receptors. These two pharmacological targets (and subtypes of each alpha 2 and imidazoline receptors) provide the basis for a possible separation of cardiovascular and other targeted effects, such as analgesia. Consequently, the design of selective alpha 2-adrenoceptor (subtype) agonists as analgesics devoid of the cardiovascular effects associated with clonidine appears to be a rational approach to novel therapeutic agents. The present review focuses on alpha 2-adrenoceptor subtype/imidazoline diversity as a target for analgesic (and other CNS) drug discovery.

Adrenergic alpha-2 Receptor Agonists↗
PubMed1995

High affinity ibogaine binding to a mu opioid agonist site.

The naturally occurring indole alkaloid ibogaine is of interest because of its reported ability to block drug seeking behavior for extended periods. The compound also potentiates morphine-induced analgesia in mice and reduces certain naltrexone-precipitated withdrawal signs in morphine-dependent rats. Although these results might suggest ibogaine interaction with opioid receptors, previous receptor binding studies (Brain Res. 571:242-247, 1980) found that ibogaine had a Ki value of only 2 microM for the kappa opioid receptor and was virtually inactive in blocking mu and delta receptor binding (Ki > 100 microM). The present investigation of ibogaine interaction with the mu opioid receptor from mouse forebrain labeled with [3H]-naloxone, however, yielded significantly more potent mu opioid Ki values. LIGAND analysis indicated that the data were best fit by a two site binding model, with Ki values of about 130 nM and 4 microM, reflecting ibogaine recognition of different agonist affinity states of the receptor. Inclusion of 100 mM NaCl in the assay to induce the agonist low affinity state of the receptor, reduced ibogaine's inhibition of [3H]-naloxone binding. These results suggest that ibogaine is an agonist at the mu opioid receptor with a Ki value of about 130 nM, potentially explaining ibogaine's antinociceptive effects as well as its reported reduction of opioid withdrawal symptoms and attenuation of drug seeking behavior.

Animals↗
PubMed1995

LiCl uncouples signal transduction in morphine-induced supraspinal antinociception in mice.

1. The present study examined whether LiCl antagonism of morphine-induced antinociception in mice occurs at mu-opioid receptors. 2. The antinociceptive ED50 value of intracerebroventricular morphine was maximally increased compared to controls 18 hr after LiCl (10 mmol/kg, s.c.) and remained significantly less (P < 0.05) 7 and 14 days after once-daily LiCl treatment. 3. There was no significant difference in [3H]-[D-Ala2,N-MePhe4,Gly- ol5]enkephalin affinity or receptor density compared to controls (KD = 0.43 nM, Bmax = 54.8 +/- 9.3 pM). 4. These results suggest that LiCl's effect is not on mu-opioid receptors, but rather on some distal site.

Analgesics↗
PubMed1995

Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception.

Although it is well established that the analgesic effects of morphine are mediated by opioid receptors, previous studies have shown that some opioids additionally inhibit the uptake of serotonin and norepinephrine. The present investigation of a diverse group of opioids revealed that structurally identifiable subgroups inhibited the neuronal reuptake of these monoamines. Phenanthrene opioids with an oxygen bridge between C4 and C5, such as morphine and naloxone (group I), did not block norepinephrine or serotonin uptake, whereas phenanthrene opioids without the oxygen bridge and the C6-OH moiety, such as levorphanol and levomethorphan (group II), did inhibit uptake, as did nonphenanthrene opioids, such as d-propoxyphene and methadone (group III). Affinity at the mu opioid receptor correlated with antinociceptive potency (r = 0.87, P < .05). Although the antinociceptive activity of the "active enantiomers" of group II and III compounds also correlated with their affinity at the mu opioid receptor (r = 0.85, P = .007), additional consideration of serotonin uptake inhibiting activity (but not of norepinephrine uptake inhibiting activity) significantly improved the correlation between antinociceptive potency and the in vitro activity of these compounds (r = 0.915, P = .0017). Additionally, for group II and III (but not group I) compounds, smaller differences between enantiomers in antinociceptive potency than in mu receptor affinity were noted, presumably because of the contribution of uptake inhibition to the antinociceptive activity of group II and III compounds. Evidence also is provided suggesting a broader role for the combination of mu opioid affinity and 5-hydroxytryptamine uptake inhibition in the activity of other antinociceptive agents.

Analgesics, Opioid↗
PubMed1994

Lack of glibenclamide or TEA affinity for opioid receptors: further evidence for in vivo modulation of antinociception at K+ channels.

Radioligand binding of the opioid receptor subtype selective ligands, [3H][D-Ala2,N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) (mu), [3H][D-Pen2,D-Pen5]-enkephalin (DPDPE) (delta) and [3H]U-69,593 (kappa), to rat brain particulate preparations was virtually unaffected by 1-100 microM glibenclamide (Glib) or tetraethylammonium bromide (TEA). These results argue against opioid receptor antagonism by Glib or TEA and support the hypothesis that antagonism of opioid-induced antinociception by Glib or TEA occurs at the level of K+ (possibly ATP-sensitive KATP) channels.

Amino Acid Sequence↗
PubMed1994

Low affinity of FMRFamide and four FaRPs (FMRFamide-related peptides), including the mammalian-derived FaRPs F-8-Famide (NPFF) and A-18-Famide, for opioid mu, delta, kappa 1, kappa 2a, or kappa 2b receptors.

The binding affinities at opioid receptor subtypes in rat or guinea pig brain membranes were determined for the neuropeptide FMRFamide (Phe-Met-Arg-Phe-NH2), the two mammalian-derived FMRFamide-related peptides F-8-Famide (NPFF; Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe- NH2) and A-18-Famide (Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe -NH2), and the two other FMRFamide-related peptides Tyr-Phe-Met-Arg-Phe-NH2 (Tyr-FMRFamide) and Pro-Gln-Arg-Phe-NH2 (Pro-Gln-RFamide). The mu and delta sites were labeled in rat brain membranes using tritiated [D-Ala2, N-MePhe4,Gly-ol5] enkephalin ([3H]DAMGO) and [D-Ala2,D-Leu5]enkephalin ([3H]DADLE), respectively. The kappa sites were labeled in guinea pig brain using [3H]U-69,593 after treatment with BIT and FIT for kappa 1 and [3H]bremazocine after pretreatment with BIT and FIT for kappa 1 and [3H]bremazocine after pretreatment with BIT and FIT for kappa 2. The kappa 2a binding sites were assayed using [Leu5]enkephalin to block kappa 2b sites and the kappa 2b sites were assayed using (-)-(1S,2S)-U50,488 to block kappa 2a sites. Neither FMRFamide nor any of the FMRFamide-related peptides (up to 61.0 microM) displayed significant affinity at any of the subtypes of opioid receptor. Hence, the known ability of FMRFamide and FaRPs to interact with the opioid system does not appear to be related to direct binding to these opioid receptors.

Amino Acid Sequence↗
PubMed1993

Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol.

The explanation for the co-existence of opioid and nonopioid components of tramadol-induced antinociception appears to be related to the different, but complementary and interactive, pharmacologies of its enantiomers. The (+) enantiomer had Ki values of only 1.33, 62.4 and 54.0 microM at mu, delta and kappa receptors, respectively. The (-) enantiomer had even lower affinity at the mu and delta sites (Ki = 24.8, 213 and 53.5 microM, respectively. The (+) enantiomer was the most potent inhibitor of serotonin uptake (Ki = 0.53 microM) and the (-) enantiomer was the most potent inhibitor of norepinephrine uptake (Ki = 0.43 microM). Basal serotonin release was preferentially enhanced by the (+) enantiomer and stimulation-evoked norepinephrine release was preferentially enhanced by the (-) enantiomer. The (+) and (-) enantiomers each independently produced centrally mediated antinociception in the acetylcholine-induced abdominal constriction test (ED50 = 14.1 and 35.0 micrograms i.t., respectively). Racemic tramadol was significantly more potent (P < .05) than the theoretical additive effect of the enantiomers (antinociceptive synergy). Synergy was also demonstrated (P < .1) in the mouse 55 degrees C hot-plate test (i.p. route) and (P < .05) the rat Randall-Selitto yeast-induced inflammatory nociception model (i.v. and i.p. routes). Critically, the enantiomers interacted less than synergistically in two side-effects of inhibition of colonic propulsive motility and impairment of rotarod performance. The racemate and the (+) enantiomer were active in a chronic (arthritic) inflammatory pain model. Taken together, these findings provide a rational explanation for the coexistence of dual components to tramadol-induced antinociception and might form the basis for understanding its clinical profile.

Acetylcholine↗
PubMed1992

1,3-Di(2-[5-3H]tolyl)guanidine labels more than one site in rat forebrain.

Studies of 1,3-di-(2-[5-3H]tolyl)guanidine ([3H]DTG) binding to rat brain membranes revealed that [3H]DTG binds to a high and a low affinity site with Kd values of 19.8 nM and 1.31 microM (corresponding Bmax values 291 fmol/mg protein and 8.68 pmol/mg protein). The order of potency of competitors for [3H]DTG binding revealed a binding profile typical of sigma site ligands. Several sigma ligands such as the enantiomers of 3-PPP (3-(3-hydroxyphenyl)-N- (n-propyl)piperidine) and (+/-)-pentazocine exhibited biphasic competition profiles for [3H]DTG binding, whereas other sigma ligands such as haloperidol displayed monotonic competition curves. Neither phenytoin nor carbamazepine were observed to enhance [3H]DTG binding. These data support the hypothesis that multiple sigma binding sites exist. The lack of phenytoin and carbamazepine modulation of [3H]DTG binding are in agreement with the proposed greater density of sigma site 2 in the rat, since allosteric modulation has been ascribed to the DM1/sigma 1 site.

Animals↗
PubMed1992

Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic.

Tramadol hydrochloride produced dose-related antinociception in mouse abdominal constriction [ED50 = 1.9 (1.2-2.6) mg/kg i.p.], hot-plate [48 degrees C, ED50 = 21.4 (18.4-25.3) mg/kg s.c.; 55 degrees C, ED50 = 33.1 (28.2-39.1) mg/kg s.c.] and tail-flick [ED50 = 22.8 (19.2-30.1) mg/kg s.c.] tests. Tramadol also displayed antinociceptive activity in the rat air-induced abdominal constriction [ED50 = 1.7 (0.7-3.2) mg/kg p.o.] and hot-plate [51 degrees C, ED50 = 19.5 (10.3-27.5) mg/kg i.p.] tests. The antinociceptive activity of tramadol in the mouse tail-flick test was completely antagonized by naloxone, suggesting an opioid mechanism of action. Consistent with this, tramadol bound with modest affinity to opioid mu receptors and with weak affinity to delta and kappa receptors, with Ki values of 2.1, 57.6 and 42.7 microM, respectively. The pA2 value for naloxone obtained with tramadol in the mouse tail-flick test was 7.76 and was not statistically different from that obtained with morphine (7.94). In CXBK mice, tramadol, like morphine, was devoid of antinociceptive activity after intracerebroventricular administration, suggesting that the opioid component of tramadol-induced antinociception is mediated by the mu-opioid receptor. In contrast to the mouse tail-flick test and unlike morphine or codeine, tramadol-induced antinociception in the mouse abdominal constriction, mouse hot-plate (48 degrees or 55 degrees C) or rat hot-plate tests was only partially antagonized by naloxone, implicating a nonopioid component. Further examination of the neurochemical profile of tramadol revealed that, unlike morphine, it also inhibited the uptake of norepinephrine (Ki = 0.79 microM) and serotonin (0.99 microM). The possibility that this additional activity contributes to the antinociceptive activity of tramadol was supported by the finding that systemically administered yohimbine or ritanserin blocked the antinociception produced by intrathecal administration of tramadol, but not morphine, in the rat tail-flick test. These results suggest that tramadol-induced antinociception is mediated by opioid (mu) and nonopioid (inhibition of monoamine uptake) mechanisms. This hypothesis is consistent with the clinical experience of a wide separation between analgesia and typical opioid side effects.

Animals↗
PubMed1991

Intranasal activity of the growth hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in conscious dogs.

This series of experiments was conducted to evaluate the growth hormone (GH) releasing activity of intranasally administered His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6, SK&F 110679) in conscious dogs. Intranasal administration of GHRP-6 increased plasma growth hormone levels in the conscious dog in a dose-related manner. Doses of 0.25 and 0.5 mg/kg produced GH levels of 11.3 +/- 4.8 ng/ml and 28.6 +/- 8.0 ng/ml, respectively. Peak levels were observed 15 minutes after dosing and GH levels were elevated for up to 105 minutes after intranasal dosing. Intranasal administration of isotonic saline did not produce any change in basal (negligable) GH levels. When GHRP-6 was given by the intravenous route, a maximal dose of 0.5 mg/kg, produced a peak plasma GH concentration of 60.8 +/- 10.5 ng/ml. Saline had no effect on GH levels when given intravenously. Using the intravenous and intranasal GH response data (i.e., area under the time-response curves), the intranasal bioavailability of GHRP-6 was estimated to be 34.4 to 44.9%. The results of these studies suggest that significant activity and excellent bioavailability can be achieved when GHRP-6 is administered by the intranasal route to conscious dogs. Based on these results, the intranasal activity of GHRP-6 should be evaluated in man. The successful intranasal administration of this peptide in man should provide GH therapy with reduced patient discomfort and better patient compliance when compared to presently available parenterally administered remedies.

Administration, Intranasal↗
PubMed1990

Oral activity of the growth hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in rats, dogs and monkeys.

The purpose of this study was to evaluate the growth hormone (GH) releasing activity of orally administered His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GHRP-6, SK&F 110679) in rats, dogs and monkeys. Rats were administered GHRP-6 orally by gavage or parenterally through femoral artery catheters. Blood was collected before and after GHRP-6 administration for estimation of plasma GH and comparison of GH changes resulting from enteral and parenteral administration of the peptide. GHRP-6 was administered to dogs intravenously (i.v.) through cephalic vein catheters, intragastrically (i.g.) through esophagostomy tubes or intraduodenally (i.d.) through vascular access ports, and blood was collected before and after peptide administration for estimation of plasma GH. Cynomolgus monkeys were administered GHRP-6 i.g., and blood was collected from abdominal aorta for estimation of changes in plasma GH. Enteral activity of GHRP-6 was observed in all 3 species tested. In rats, ED50's for enteral and parenteral administration of GHRP-6 were 4 mg/kg and 28 micrograms/kg, respectively. Thus in rats, enterally administered GHRP-6 was 0.7% as bioactive as the parenterally administered peptide. In dogs GHRP-6 was slightly less potent than in rats, with ED50's for i.g. and i.v. administration approximately 15 mg/kg and 125 micrograms/kg, respectively. However, enteral potency of GHRP-6 in dogs was 0.8% of parenteral potency, and thus, comparable to that in rats. Additionally, comparison of plasma GH levels following i.g. vs i.d. administration in dogs suggested greater activity by the i.d. route. Monkeys were the species most sensitive to enterally administered GHRP-6, with plasma GH increased in those receiving i.g. doses as low as 0.3 mg/kg and an ED50 of 0.75 mg/kg compared to 4 and 15 mg/kg in rats and dogs, respectively. The results of this study demonstrate that GHRP-6 releases GH when administered directly into the gastrointestinal tract. Although enteral activity is approximately 1% of parenteral activity, GHRP-6 is potent, especially in primates which require relatively low doses to provoke GH release. These data suggest that orally active GHRP-6 may provide a practical therapeutic alternative to parenterally administered peptides such as GHRH, especially if enteral activity is enhanced with appropriate formulation.

Administration, Oral↗
PubMed1990

A non-opioid pattern characterizes inhibition of growth hormone releasing peptide binding by dynorphin-related peptides.

GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-LysNH2; SK&F 110679) is a hexapeptide that specifically releases growth hormone. Although derived from methionine enkephalin, 3H-SK&F 110679 binding profiles suggest that it retains little mu or delta opioid activity. In the present study, dynorphin A was a potent inhibitor of SK&F 110679 binding. However, detailed structure-activity studies using dynorphin-related compounds suggest that the interaction between SK&F 110679 and dynorphin was non-opioid in nature. The non-opioid peptide des-Tyr-dynorphin was virtually as potent an inhibitor of 3H-SK&F 110679 binding as the intact dynorphin peptide. Additionally, the non-peptide, kappa selective ligand U-50,488 was a very weak inhibitor of 3H-SK&F 110679 binding. Since dynorphin but not U-50,488 has been reported to release growth hormone, the present results suggest that a non-opioid dynorphin site participates in SK&F 110679's growth hormone releasing action.

Animals↗
PubMed1989

Binding of a growth hormone releasing hexapeptide to specific hypothalamic and pituitary binding sites.

The drug SK&F 110679 (His-D-Trp-Ala-Trp-D-Phe-LysNH2), is an enkephalin-derived hexapeptide, which specifically releases growth hormone in a wide variety of species in vivo and in vitro. Previous binding studies, using ligands which are specific for mu and delta opioid binding sites, demonstrated an inverse relationship between the opioid binding potency and the potency in releasing growth hormone of a series of peptides related to SK&F 110679. In an attempt to understand its mode of action better, a binding assay for the peptide was established using a ligand which had been tritium labelled at the D-Trp2 residue. Membrane fragments from both the hypothalamus and anterior pituitary tissue were found to contain sites to which [3H]SK&F 110679 reversibly and saturably bound. The binding curves for [3H]SK&F 110679 to membrane fragments of both hypothalamus and anterior pituitary were resolved into two binding components with the computer program LIGAND. The Kd's obtained were in the 10(-8) M and 10(-5) M range. The relationship of these binding sites to the growth hormone-releasing activity of the peptide was explored by examining the relationship between the binding and potency in releasing growth hormone of a series of peptides related to SK&F 110679. For sites in both the hypothalamus and pituitary, a significant correlation between binding and the release of growth hormone was obtained. Thus, these binding sites appeared to be involved in the release of growth hormone by SK&F 110679-related peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Cyclic enkephalin analogues containing alpha-amino-beta-mercapto-beta,beta-pentamethylenepropionic acid at positions 2 or 5.

Analogues of the highly potent and delta-receptor-selective enkephalins 1-4 were prepared with alpha-amino-beta-mercapto-beta,beta-pentamethylenepropionic acid (Apmp) replacing the beta,beta-dimethylcysteine (Pen) at positions 2 or 5. The peptides 5-8 were prepared by employing D,L-Apmp and, following oxidative cyclization, the resulting diastereomeric peptides were separated and purified by preparative high performance liquid chromatography. Compounds 7 and 8, with D- or L-Apmp substituted at position 5 are approximately 5 orders of magnitude more potent in the MVD assay than analogues 5 or 6 with D- or L-Apmp at position 2. While displaying less delta-receptor selectivity than the corresponding Pen-containing compounds, 7 and 8 are an order of magnitude more potent. All the analogues showed diminished delta-receptor selectivity in the rat brain binding assay. Compounds 7 and 8 displayed delta-receptor affinity comparable to the corresponding Pen-containing analogues.

Amino Acids, Sulfur↗
PubMed1988

Factors affecting serotonin uptake into human platelets.

Because of complexities in platelet serotonin uptake dynamics, we studied the influence on the time of day and year as well as the subject's age on uptake parameters. While the assay itself was quite reproducible, and the kinetic parameters of 5 HT uptake were stable over a few days, at a given time, within an individual, the variance was quite large when samples from different times of the day or year or from different individuals were compared. An inverse relationship between Vmax (moles/cell number/time) and platelet number was found in data from a group of individuals, suggesting regulation of Vmax not at the level of uptake capacity per cell, but in a manner that somehow takes into consideration the number of platelets in the subject's plasma. Indeed, expressing Vmax in a new way (called "total Vmax"), not based on Vmax "per cell" or "per 10(7) cells" but for the total number of platelets in the volume of PRP used, greatly reduced the scatter in the between-individuals and across-time data. While Vmax (moles/cell number/time) exhibited only a trend toward reduction with age, for example, the decline in total Vmax with subject age was statistically significant. It is suggested that total Vmax (moles/time) may be a more physiologically relevant expression for an uptake function than Vmax (moles/time/cell number).

Adult↗