1 Department of Physiological
Sciences, College of Veterinary Medicine, University of Florida,
Gainesville, Florida 32606; and
2 Allergy, Schering-Plough
Research Institute, Kenilworth, New Jersey ...07033
The present study was conducted to determine the
effects of administration of centrally active antitussive drugs on the
cough motor pattern. Electromyograms of diaphragm and rectus abdominis muscles were recorded in anesthetized, spontaneously breathing cats.
Cough was produced by mechanical stimulation of the intrathoracic trachea. Centrally acting drugs administered included codeine, morphine, dextromethorphan, baclofen, CP-99,994, and SR-48,968. Intravertebral artery administration of all drugs reduced cough number
(number of coughs per stimulus trial) and rectus abdominis burst
amplitude in a dose-dependent manner. Codeine, dextromethorphan, CP-99,994, SR-48,968, and baclofen had no effect on cough cycle timing
(CT tot ) or diaphragm amplitude
during cough, even at doses that inhibited cough number by
80-90%. Morphine lengthened
CT tot and inhibited diaphragm
amplitude during cough, but these effects were not dose dependent. Only
CP-99,994 altered the eupneic respiratory pattern. Central antitussive
drugs primarily suppress cough by inhibition of expiratory motor drive
and cough number. CT tot and inspiratory motor drive are relatively insensitive to the effects of
these drugs. CT tot can be
controlled independently from cough number.
diaphragm; abdominal; rectus abdominis; brain stem; control of
breathing
We describe the pharmacological and pharmacokinetic profiles of SCH 486757, a nociceptin/orphanin FQ peptide (NOP) receptor agonist that has recently entered human clinical trials for cough. SCH ...486757 selectively binds human NOP receptor (
K
i
=
4.6
±
0.61
nM) over classical opioid receptors. In a guinea pig capsaicin cough model, SCH 486757 (0.01–1
mg/kg) suppressed cough at 2, 4, and 6
h post oral administration with a maximum efficacy occurring at 4
h equivalent to codeine, hydrocodone, dextromethorphan and baclofen. The antitussive effects of SCH 486757 (3.0
mg/kg, p.o.) was blocked by the NOP receptor antagonist J113397 (12
mg/kg, i.p.) but not by naltrexone (10
mg/kg, p.o.). SCH 486757 does not produce tolerance to its antitussive activity after a 5-day BID dosing regimen. After acute and chronic dosing paradigms, SCH 486757 (1
mg/kg) inhibited capsaicin-evoked coughing by 46
±
9% and 40
±
11%, respectively. In a feline mechanically-evoked cough model, SCH 486757 produces a maximum inhibition of cough and expiratory abdominal electromyogram amplitude of 59 and 61%, respectively. SCH 486757 did not significantly affect inspiratory electromyogram amplitude. We examined the abuse potential of SCH 486757 (10
mg/kg, p.o.) in a rat conditioned place preference procedure which is sensitive to classical drugs of abuse, such as amphetamine and morphine. SCH 486757 was without effect in this model. Finally, SCH 486757 displays a good oral pharmacokinetic profile in the guinea pig, rat and dog. We conclude that SCH 486757 has a favorable antitussive profile in preclinical animal models.
Background
ALZ‐801 is an oral inhibitor of amyloid oligomer formation in development as a disease‐modifying Alzheimer’s treatment, including a Phase 3 trial in APOE4/4 homozygotes and a Phase 2 ...biomarker study in APOE4 carriers. We analyzed correlations between brain volume and cognitive effects of ALZ‐801 after 1 year in the Phase 2 study. We previously reported that at 1‐year timepoint, plasma p‐tau181 (primary outcome) was significantly reduced by 41% from baseline, and hippocampal volume (HV) showed ∼20% less atrophy compared to external matched controls.
Method
The study is conducted at 7 European sites and enrolled 84 APOE4 carriers (MMSE 22‐30) with positive amyloid/tau biomarkers who receive ALZ‐801 265 mg BID for 104 weeks. Primary outcome is plasma p‐tau181 at 104 weeks, and primary imaging outcome is hippocampal volume (HV) atrophy. Volumetric vMRI measures (baseline, 52 and 104 weeks) are performed by Clario, and MMSE conducted. A PK sub‐study was conducted at 65 weeks (n = 23) with bioanalysis at DDS (UK) and non‐compartmental PK analyzed by WinNonlin. Pearson correlations of MMSE changes to BSI changes of HV and lateral ventricle volume (LVV) were conducted, with two‐sided p‐values reported.
Result
At 52 and 65 weeks, changes of MMSE from baseline showed significant correlations to HV (r = 0.32 and 0.34; p<0.01, n = 66) and LVV changes (r = ‐0.42 and ‐0.44; p<0.001, n = 65). Correlations between DMMSE and DLVV were significant for both genders (range r = ‐0.54 to ‐0.42, p<0.02); correlations were observed for DHV in females (range r = 0.39‐0.47; p<0.05) and males (range r = 0.26‐0.23; p<0.18, ns). PK/PD analysis in 23 subjects showed trends (r = 0.21‐0.16, ns) between decreased HV atrophy/LVV expansion and plasma AUC24h of tramiprosate+3‐SPA (active and primary metabolite). ALZ‐801 exhibited favorable safety; main treatment‐related adverse event was mild nausea. No ARIA‐E was observed.
Conclusion
Early AD subjects treated with ALZ‐801 for 65 weeks in the Phase 2 biomarker study showed strong correlations between MMSE stability, HV reduction, and decreased ventricular enlargement in overall group, and by genders. The significant correlations between cognitive and brain volume effects support the clinical benefits of ALZ‐801 in APOE4 carriers with early AD. Oral ALZ‐801 showed favorable safety and no brain edema/ARIA‐E.
A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure–activity relationship was explored. These benzimidazolone analogs demonstrate potent ...H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9μMh.
Histamine release from mast cells is a primary mediator of rhinorrhea, nasal mucosal swelling, increased secretion, sneezing, pruritus and congestion that occur in allergic rhinitis. It is well known ...that histamine H(1) receptor antagonists inhibit the itch and rhinorhea, but do not block the allergic nasal congestion. A growing body of evidence shows that in addition to histamine H(1) receptors, activation of H(3) receptors may contribute to the procongestant nasal actions of histamine. Activation of the prejunctional histamine H(3) receptor modulates sympathetic control of nasal vascular tone and resistance. The present study was conducted to further characterize the role of histamine H(3) receptors on neurogenic sympathetic vascular contractile responses in isolated porcine nasal turbinate mucosa. We presently found that the histamine H(3) receptor agonist, (R)-alpha-methylhistamine (10-1000 nM), inhibited electrical field stimulation-induced sympathetic vasomotor contractions in a concentration-dependent fashion. Pretreatment with either of the selective histamine H(3) receptor antagonists, thioperamide and clobenpropit, blocked the sympathoinhibitory effect of (R)-alpha-methylhistamine in porcine turbinate mucosa. The effect of compound 48/80, an agent that elicits the release of endogenous histamine from mast cells on nasal sympathetic contractile responses, was also tested. The action of compound 48/80 to release mast cell-derived histamine in the nose mimics many of the nasal responses associated with allergic rhinitis, extravascular leakage and decreased nasal patency. We presently found that compound 48/80 also inhibited the electrical field stimulation-induced sympathetic response. Pretreatment with the H(3) receptor antagonist clobenpropit blocked the sympathoinhibitory action of compound 48/80 on sympathetic contractile responses in nasal mucosa. Taken together, these studies indicate that histamine H(3) receptors modulate vascular contractile responses by inhibition of noradrenaline release from sympathetic nerve terminals in nasal mucosa. It is further suggested that histamine H(3) receptors may play a role in the regulation of vascular tone and nasal patency in allergic nasal congestive disease.
Background
Plaque clearing amyloid antibodies show an increased risk of amyloid‐related imaging abnormalities with edema or hemorrhages (ARIA‐E or ARIA‐H). ARIA risk increases with number of APOE4 ...alleles, with APOE4/4 homozygotes showing the highest risk related to high burden of Aβ plaque in microvessels (cerebral amyloid angiopathy, CAA). To decrease the risk of ARIA, amyloid antibody trials exclude subjects with CAA‐related lesions such as >4 microhemorrhages (MH) or superficial siderosis. ALZ‐801 (valiltramiprosate), an oral drug that inhibits formation of neurotoxic Aβ oligomers, shows promising efficacy in APOE4 carriers with no observed ARIA‐E (Abushakra 2017, 2022). Two ALZ‐801 trials are currently ongoing in APOE4 carriers with Early AD. A Phase 2 study enrolled APOE4 carriers, and a Phase 3 trial enrolled APOE4/4 patients. Both studies allow >10 MH and/or some siderosis lesions at baseline.
Method
The fully‐enrolled Phase 3 trial (APOLLOE4) included 325 homozygotes with Early AD (MMSE ≥22). We evaluated prevalence of microhemorrhages (MH), macrohemorrhages and superificial siderosis (CAA lesions). Baseline MRIs acquired from 1.5T/3T scanners were centrally evaluated by Clario, and the number/location of these CAA lesions is reported.
Result
Subjects had mean age 69 years, 51% female, MMSE 26, 82% white, 65% with MCI. Of 325 subjects, 313 had baseline MRIs that showed > 1 MH in 32%, including 9% with > 4 MH. A total of 9% had ≥ 1 superficial siderosis, and 2 subjects had macrohemorrahages. Occipital and frontal lobes were most common locations of CAA lesions. Most subjects had white matter disease (Fazekas = 1).
Conclusion
APOE4/4 homozygotes show high prevalence of CAA lesions with 32% and 9% having lobar microhemorrhages and superificial siderosis respectively. This high burden of CAA lesions most likely underlies the high incidence of ARIA in APOE4/4 patients treated with the approved amyloid antibodies (30%‐60%). ARIA‐E is also reported in APOE4/4 patients treated with placebo in lecanemab & gantenerumab trials (4%‐6%). This background ARIA likely reflects spontaneous CAA‐related inflammation commonly reported in APOE4 carriers (CAA‐RI, Regendhardt 2020). Oral ALZ‐801 in the ongoing studies has not shown increased ARIA risk, and has safety advantage over amyloid antibodies especially for APOE4/4 homozygous patients.
A gene encoding a novel transmembrane protein was identified by DNA sequence analysis within the insulin-dependent diabetes mellitus (IDDM) locus
IDDM4 on chromosome 11q13. Based on its chromosomal ...position, this gene is a candidate for conferring susceptibility to diabetes. The gene, termed low-density lipoprotein receptor related protein 5 (
LRP5), encodes a protein of 1615 amino acids that contains conserved modules which are characteristic of the low-density lipoprotein (LDL) receptor family. These modules include a putative signal peptide for protein export, four epidermal growth factor (EGF) repeats with associated spacer domains, three LDL-receptor (LDLR) repeats, a single transmembrane spanning domain, and a cytoplasmic domain. The encoded protein has a unique organization of EGF and LDLR repeats; therefore,
LRP5 likely represents a new category of the LDLR family. Both human and mouse
LRP5 cDNAs have been isolated and the encoded mature proteins are 95% identical, indicating a high degree of evolutionary conservation.
Optical difference spectroscopy was used to identify and quantify human adrenal microsomal and mitochondrial cytochrome P450 enzyme interactions with the histamine H(3) receptor antagonists ...thioperamide, clobenpropit and ciproxifan. Addition of these structurally diverse imidazole H(3) receptor antagonists to cytochrome-P450-containing human adrenal microsomal and mitochondrial preparations resulted in concentration-dependent type II optical difference spectra. Respective spectral dissociation constants (K(S)) for the drug interactions with human adrenal microsomal and mitochondrial cytochrome P450 were 1.5 and 1.6 micromol/l for thioperamide, 3.1 and 0.28 micromol/l for clobenpropit and 0.10 and 0.11 micromol/l for ciproxifan. The three compounds demonstrated a similar activity profile in cytochrome-P450-containing bovine adrenal microsomal and mitochondrial preparations. Findings indicate direct coordination of these imidazole-containing H(3) receptor antagonists with the heme moiety of human adrenal cytochrome P450 isozymes.
The peripheral histamine H3 receptor is a presynaptic heterologous receptor located on postganglionic sympathetic nerve fibers innervating sympathetic effector systems such as blood vessels and the ...heart. An extensive body of evidence shows that activation of the histamine H3 receptor attenuates sympathetic tone by presynaptic inhibition of noradrenaline release. It is proposed that this sympathoinhibitory action, in vivo, leads to reduced vasoconstriction, thereby eliciting a vasodilatory effect. In humans, the peripheral histamine H3 receptor has also been shown to exert a sympathoinhibitory function on specific peripheral autonomic effector systems. For example, human saphenous vein and heart possess functional presynaptic histamine H3 receptors on the sympathetic nerve terminals that upon activation decrease the sympathetic tone to these respective organs. The present studies were conducted to define the role of histamine H3 receptors on neurogenic sympathetic vasoconstrictor responses in human nasal turbinate mucosa. Contractility studies were conducted to evaluate the effect of histamine H3 receptor activation on sympathetic vasoconstriction in surgically isolated human nasal turbinate mucosa. We found that the histamine H3 receptor agonist, (R)-alpha-methylhistamine (30 and 300 nM), inhibited electrical field stimulation-induced (neurogenic) sympathetic vasoconstriction in a concentration-dependent fashion. Pretreatment with the selective histamine H3 receptor antagonist, clobenpropit (100 nM), blocked the sympathoinhibitory effect of (R)-alpha-methylhistamine on the neurogenic sympathetic vasoconstriction. In addition, analysis of Taqman mRNA expression studies showed a specific, high level of distribution of the histamine H3 receptor localized in the human nasal mucosa. Taken together, these studies indicate that histamine H3 receptors modulate vascular contractile responses in human nasal mucosa most likely by inhibiting noradrenaline release from sympathetic nerve terminals in nasal mucosa. It is further suggested that histamine H3 receptors may play a role in the regulation of vascular tone and nasal patency in histamine-dependent allergic nasal congestive disease.
It has been suggested that the rat is relatively more susceptible to toxicity induced by inhibitors for type 4 cAMP-specific phosphodiesterase (PDE4). In this study designed to elucidate possible ...biochemical basis for the higher susceptibility, we compared PDE4 expression levels and their functional relevance among rats, monkeys and humans. In several toxicologically relevant tissues and blood leukocytes, the mRNA expression levels of PDEs 4A, 4B, 4C and 4D were significantly higher in rats than in humans. We confirmed that higher PDE4 expression levels were correlated with a higher enzyme activity level in rat leukocytes. The PDE4 enzyme activity level of leukocytes in monkeys fell between that of rats and humans. Functionally, the potencies of the PDE4 inhibitors rolipram, SB 207499 and SCH 351591 in inhibiting tumor necrosis factor production from leukocytes were in the following order: rat > monkey > human. In addition, rolipram was about 10-fold more potent in rats than in humans in inhibiting phenylephrine-induced contraction of renal artery. These inhibitors were confirmed to be highly selective for PDE4 in comparison to all other PDE families, and to inhibit rat and human PDE4s with identical potencies. Taken together, these results suggest that the higher susceptibility of rats to PDE4 inhibitor-induced toxicity might be due to their higher expression levels of PDE4, and that PDE4 inhibitors may be safer in humans than in monkeys and, particularly, rats.
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