Author: kodiac

  • GB-115

    Retrodipeptide cholecystokinin-1 (CCK-1) receptor antagonist with anxiolytic, anti-inflammatory, analgesic, and immunomodulatory activity

    A synthetic retrodipeptide analogue of cholecystokinin tetrapeptide (CCK-4) designed at the Zakusov Research Institute of Pharmacology, distinguished by selective central CCK-1 receptor antagonism, non-benzodiazepine anxiolytic activity, and a favorable safety profile confirmed through Phase 3 clinical evaluation under the trade name Ranquilon.

    Abstract

    GB-115 (N-(6-phenylhexanoyl)-glycyl-L-tryptophan amide; CAS 678996-63-9) is a synthetic retrodipeptide analogue of the endogenous anxiogenic tetrapeptide cholecystokinin-4 (CCK-4, Trp-Met-Asp-Phe-NH2), designed and synthesized at the V.V. Zakusov Research Institute of Pharmacology (Russian Academy of Medical Sciences) using the topochemical Shemyakin-Ovchinnikov-Ivanov principle for rational peptide drug design. The compound functions as a selective antagonist of the central cholecystokinin type 1 (CCK-1) receptor, producing anxiolytic activity in rodent and primate behavioral models at doses of 0.05 to 0.2 mg/kg without the sedation, tolerance, dependence, or cognitive impairment associated with benzodiazepine anxiolytics. The biologically active conformation of GB-115 has been identified by nuclear Overhauser effect NMR spectroscopy as a type II beta-turn, with the native spatial distance between the phenyl and indolyl hydrophobic pharmacophores critical for receptor interaction. Structure-activity relationship studies demonstrated that L-tryptophan-containing derivatives produce anxiolytic effects, while D-tryptophan-containing enantiomers produce anxiogenic effects mirroring CCK-4 itself, confirming the stereospecificity of the CCK-1 receptor interaction.

    Preclinical pharmacology extends beyond anxiolysis. GB-115 potentiates morphine-induced analgesia through supraspinal opioidergic mechanisms and produces independent antinociceptive activity in chemical and thermal pain models with a significant non-opioid component. Anti-inflammatory effects have been demonstrated in concanavalin A-induced and carrageenan-induced inflammation models and in experimental autoimmune encephalomyelitis in C57Bl/6 mice, where intraperitoneal administration at 1 mg/kg significantly alleviated pathological symptoms, promoted thymus weight recovery, and reduced perivascular edema and neutrophil infiltration of brain tissue. Immunomodulatory activity includes stimulation of phagocytic activity of peritoneal macrophages and humoral immune response in intact mice and immunocorrecting effects in animals with secondary immunodeficiency. The compound reverses antinociceptive tolerance to morphine on sub-chronic co-administration, a property consistent with its CCK-1 receptor antagonist mechanism given the established role of cholecystokinin in opioid tolerance.

    Pharmacokinetics are characterized by rapid oral absorption, low absolute bioavailability (approximately 4.65 percent in animal models), and a short elimination half-life of approximately 1.0 hour in humans. The amide bond confers greater peptidase resistance than native peptide bonds, extending plasma detection time relative to unmodified dipeptides. Acute toxicity is very low, with an oral LD50 exceeding 6000 mg/kg in rodents, providing a therapeutic index of approximately 30,000 to 60,000 relative to the effective anxiolytic dose range.

    Clinical evaluation has progressed through Phase 2 and Phase 3 trials. An open-label pilot study in 25 patients with generalized anxiety disorder demonstrated significant reduction in Hamilton Anxiety Rating Scale (HAM-A) total scores from a median of 22 at baseline to 5 at day 21 on 6 mg daily oral dosing (p < 0.001), with concurrent improvement in cognitive processing speed, attention, and reaction time, and no stimulation-related adverse events. A Phase 3 double-blind, randomized, placebo-controlled, multicenter trial (NCT05586789) in 220 patients with anxiety associated with neurasthenia and adjustment disorders confirmed superiority of Ranquilon 6 mg daily over placebo in reducing anxiety, with all recorded adverse events classified as mild and no serious adverse events or treatment discontinuations. A Phase 4 open-label comparative trial (NCT06843044) against fabomotizole (Afobazole) 30 mg daily is currently recruiting. This monograph reviews the chemistry, design rationale, and stereochemistry of GB-115; the CCK-1 receptor antagonist mechanism and downstream pharmacology; the preclinical evidence across anxiolytic, analgesic, anti-inflammatory, and immunomodulatory applications; the clinical evidence base including Phase 2 and Phase 3 data; pharmacokinetics across species; sourcing and quality verification; reconstitution and handling; stack interactions; adverse events and safety; and a comparative assessment of five anxiolytic or CCK-modulating alternatives against GB-115 on five competency standards.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • Thymalin

    Plain-language summaryIntrigue 58 / 100

    Thymalin is a Russian-developed bovine thymus peptide preparation used as an immunomodulator for elderly patients and immune disorders. Combined with epitalon in Khavinson’s longevity research. Not stocked by Kodiac. This monograph is provided for research and educational reference.

    Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

    Thymic polypeptide bioregulator complex with immunomodulatory and geroprotective activity

    A heterogeneous polypeptide complex isolated from calf thymus, developed at the Military Medical Academy in Leningrad as a thymic bioregulator for immune restoration, distinguished from other thymic peptide preparations by its multicomponent composition containing the immunomodulatory dipeptides L-glutamyl-L-tryptophan and L-lysyl-L-glutamic acid and the tripeptide L-glutamyl-L-aspartyl-L-proline.

    Abstract

    Thymalin is a standardized polypeptide complex isolated from the thymus gland of calves by acid hydrolysis and ultrafiltration, containing peptide fractions in the 1,000 to 10,000 dalton molecular weight range. Developed at the Military Medical Academy in Leningrad (now Saint Petersburg) by Vladimir Khavinson and Vyacheslav Morozov in the 1970s, the preparation was registered as an immunomodulatory pharmaceutical in the Soviet Union in 1982 and has remained in clinical use in the Russian Federation for more than four decades. Unlike the structurally defined thymic peptides thymosin alpha-1 (a 28-amino-acid single-sequence peptide), thymulin (a zinc-dependent nonapeptide), and thymopentin (a synthetic pentapeptide fragment of thymopoietin), Thymalin is a multicomponent extract whose principal bioactive constituents have been identified by reversed-phase high-performance liquid chromatography as the dipeptide L-glutamyl-L-tryptophan (Glu-Trp, subsequently developed independently as Thymogen), the dipeptide L-lysyl-L-glutamic acid (Lys-Glu, developed as Vilon), and the tripeptide L-glutamyl-L-aspartyl-L-proline (Glu-Asp-Pro, developed as Crystagen). The molecular mechanism of the immunoprotective activity is attributed to the capacity of these short peptides to bind selectively to double-stranded DNA sequences and to histone proteins, thereby modulating chromatin conformation, gene expression, and the synthesis of immune system proteins including interleukins, interferons, heat-shock proteins, and components of the fibrinolytic system. In experimental systems, Thymalin stimulates the differentiation and functional activity of T-lymphocyte subpopulations (CD4+ and CD8+), normalizes the ratio of T-helper to T-suppressor cells, enhances natural killer cell activity and phagocytosis, and modulates the balance between pro-inflammatory and anti-inflammatory cytokines. The geroprotective properties of Thymalin are supported by a prospective clinical observation of 266 elderly subjects over 6 to 8 years conducted at the St. Petersburg Institute of Bioregulation and Gerontology and the Institute of Gerontology of the Ukrainian Academy of Medical Sciences, in which Thymalin-treated subjects exhibited 2.0- to 2.1-fold lower mortality compared to controls receiving standard geriatric care, with further reductions (4.1-fold lower mortality) observed in a subgroup receiving annual combined Thymalin and Epithalamin treatment for 6 years. More recently, a prospective randomized single-blind controlled trial of Thymalin (10 mg intramuscular daily for 10 days) in 80 elderly patients with severe COVID-19 reported a 92 percent increase in blood lymphocytes, 6.5-fold reduction in interleukin-6, halved in-hospital mortality (19.4 percent versus 40.9 percent in controls), and more rapid clinical improvement (80.5 percent versus 59 percent). In vitro studies have demonstrated that Thymalin reduces expression of the stem cell markers CD44 and CD117 by 2- to 3-fold while increasing expression of CD28 (a marker of mature T lymphocytes) by 6.8-fold, consistent with stimulation of hematopoietic stem cell differentiation into functional T cells. The compound is administered by intramuscular or subcutaneous injection in short cyclical courses of 5 to 10 days at doses of 5 to 10 mg daily, with clinical effect reported to persist for weeks to months following each treatment course. The safety record across more than 40 years of clinical use indicates minimal adverse events, principally limited to injection-site reactions. This monograph reviews the composition, extraction, and characterization of Thymalin; the molecular pharmacology of its constituent peptides at the level of DNA binding, histone interaction, and gene expression regulation; the pharmacokinetic properties; the preclinical evidence base across immune restoration, geroprotection, and oncology models; the clinical evidence in elderly immune decline, respiratory infections, perioperative immune suppression, and COVID-19; sourcing and quality verification considerations; reconstitution and handling protocols; stack interactions with other immunomodulatory agents; the adverse-event and safety profile; and a comparative assessment of five alternative thymic and immunomodulatory peptide preparations against Thymalin on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).

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  • Bronchogen

    Synthetic bronchopulmonary tetrapeptide bioregulator with epigenetic gene-regulatory and anti-inflammatory activity targeting bronchial epithelium

    A synthetic tetrapeptide (H-Ala-Asp-Glu-Leu-OH; ADEL) developed at the Saint Petersburg Institute of Bioregulation and Gerontology as an ultrashort peptide bioregulator with bronchopulmonary tissue-specific proliferative, anti-inflammatory, and epithelial-regenerative activity targeting bronchial epithelium, ciliated cell restoration, and respiratory mucosal barrier function.

    Abstract

    Bronchogen (H-Ala-Asp-Glu-Leu-OH; ADEL tetrapeptide; molecular formula C18H30N4O9; molecular weight 446.45 g/mol) is a synthetic tetrapeptide bioregulator developed by Vladimir Khavinson and colleagues at the Saint Petersburg Institute of Bioregulation and Gerontology as the bronchopulmonary-specific member of the Khavinson ultrashort peptide bioregulator family [1, 2]. The compound belongs to a class of synthetic two-to-seven-residue peptide sequences modeled on tissue-specific peptide fragments isolated from mammalian organ extracts, and is designated as the respiratory system bioregulator within this peptide family. Bronchogen is structurally related to but distinct from the other Khavinson tetrapeptides that share the Ala-Glu-Asp tripeptide core (Cardiogen, Cortagen, Epithalon); the ADEL sequence carries a different arrangement of the acidic residues (Asp at position two, Glu at position three) and a hydrophobic leucine residue at the C-terminus, a configuration that determines bronchial tissue specificity within the Khavinson classification system [3, 4]. The principal molecular mechanism of Bronchogen, characterized through molecular modeling, cell culture, organotypic bronchial tissue studies, and animal models of obstructive lung disease, is epigenetic regulation of gene expression through direct interaction of the tetrapeptide with double-stranded DNA and with histone proteins, producing chromatin remodeling and reactivation of transcriptional programs in bronchial epithelial cells [5, 6, 7]. The bronchopulmonary activity, characterized in organotypic lung tissue cultures from young and aged rats, human bronchial epithelial cell cultures across multiple passages, and nitrogen dioxide-induced chronic obstructive pulmonary disease (COPD) rat models, includes stimulation of bronchial epithelial cell proliferation and differentiation with upregulation of differentiation markers in aging cell cultures [8, 9], regulation of Ki67, Mcl-1, p53, CD79, and endothelial nitric oxide synthase (NOS-3) protein expression in human bronchial epithelium [5], restoration of normal ciliated epithelial architecture with reduction of goblet cell hyperplasia and squamous metaplasia in COPD models [10], normalization of proinflammatory cytokine profiles and neutrophilic inflammation in bronchoalveolar lavage fluid [10, 11], and enhancement of secretory immunoglobulin A and surfactant protein B production indicating recovery of respiratory mucosal barrier and surfactant function [11]. No formal pharmacokinetic studies have been published for Bronchogen as the isolated synthetic ADEL tetrapeptide. As a linear tetrapeptide with unprotected termini, the compound is expected to undergo rapid proteolytic degradation by aminopeptidases and carboxypeptidases in plasma and gastrointestinal fluid; however, molecular modeling studies have demonstrated that ultrashort peptides are substrates of the proton-coupled oligopeptide transporter (PEPT1/PEPT2) family carriers, supporting intestinal absorption and cellular uptake through active transport mechanisms [12, 13]. No human clinical trials have been published. The compound is not approved by the United States Food and Drug Administration, the European Medicines Agency, or any major Western regulatory authority. Bronchogen is registered in the Russian Federation as a biologically active additive and is commercially available there in capsule formulations. It is supplied internationally as a research-grade lyophilized peptide by multiple peptide synthesis vendors at greater than 95 percent purity by high-performance liquid chromatography. This monograph reviews the chemistry, synthesis, and structural characterization of Bronchogen; the discovery and development history within the Khavinson bioregulatory peptide program; the molecular pharmacology including peptide-DNA binding, histone interaction, and bronchial gene expression modulation; the pharmacokinetic considerations for ultrashort peptides; the preclinical pharmacology across bronchial, inflammatory, and aging cell models; the clinical evidence base (absent); sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety signal; and a comparative assessment of five bronchopulmonary or respiratory-protective peptide candidates (Chonluten, GHK-Cu, BPC-157, Thymalin, N-acetylcysteine) against Bronchogen on five competency standards.

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  • BPAP

    Tryptamine-derived synthetic monoaminergic activity enhancer (MAE) with catecholaminergic and serotonergic impulse-propagation-mediated release enhancement and TAAR1 agonism

    A benzofuran-containing synthetic enhancer substance developed by Knoll and colleagues as the most potent known monoaminergic activity enhancer, selectively amplifying impulse-dependent release of dopamine, norepinephrine, and serotonin in the brain without monoamine oxidase inhibition or amphetamine-like releasing activity.

    Abstract

    (-)1-(Benzofuran-2-yl)-2-propylaminopentane, designated (-)BPAP and also known by the developmental code FPFS-1169, is a synthetic monoaminergic activity enhancer (MAE) structurally derived from phenylpropylaminopentane (PPAP) through replacement of the phenyl ring with a benzofuran heterocycle. First described by Jozsef Knoll and colleagues in 1999, BPAP represents the most potent synthetic enhancer substance characterized to date, approximately 130-fold more potent than selegiline ((-)-deprenyl) in antagonizing tetrabenazine-induced performance inhibition in the rat shuttle box paradigm, and is the first enhancer substance to augment serotonergic neurotransmission in addition to the catecholaminergic enhancement shared with selegiline and PPAP. The compound selectively amplifies the quantity of dopamine, norepinephrine, and serotonin released per nerve impulse from monoaminergic neurons without inducing spontaneous (impulse-independent) neurotransmitter release, a pharmacological property that distinguishes it fundamentally from amphetamine-type releasing agents and from monoamine oxidase inhibitors. The mechanism of the enhancer effect has been attributed, on the basis of pharmacological antagonism studies using the selective antagonist EPPTB, to agonism at trace amine-associated receptor 1 (TAAR1), which triggers PKC-dependent phosphorylation of SNARE complex proteins and vesicular monoamine transporter 2 (VMAT2), thereby increasing vesicular monoamine accumulation and exocytotic release. At substantially higher concentrations, BPAP also inhibits monoamine reuptake (predominantly dopamine and norepinephrine), though this activity is not considered pharmacologically relevant at the low nanogram-per-milliliter concentrations that produce the enhancer effect. In preclinical pharmacology, BPAP has demonstrated neuroprotective activity against N-methyl(R)salsolinol-induced apoptosis in human dopaminergic SH-SY5Y neuroblastoma cells through stabilization of mitochondrial membrane potential and upregulation of anti-apoptotic Bcl-2 protein expression. The compound upregulates synthesis and secretion of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) in cultured mouse astrocytes, with NGF secretion increased up to 120-fold over control at optimal concentrations. In longevity studies conducted by Knoll and Miklya, subcutaneous administration of BPAP at 0.0001 mg/kg three times weekly from the 10th week of life significantly extended lifespan in male Wistar rats (P < 0.02) and suppressed spontaneous fibromyxosarcoma manifestation from 50 percent (saline controls) to 20 percent (P < 0.001). Pharmacokinetic characterization in rats indicates oral bioavailability with peak plasma levels at 30 to 60 minutes, a secondary peak at approximately 4 hours consistent with enterohepatic recirculation, a terminal elimination half-life of 5.5 to 5.8 hours, blood-brain barrier penetration with distribution to multiple brain regions, and predominantly urinary excretion with greater than 90 percent recovery in excreta within 72 hours. No human clinical trials have been conducted with BPAP as of the date of this monograph. The compound remains an investigational research tool with potential therapeutic relevance to neurodegenerative disease (Parkinson's disease, Alzheimer's disease), depression, and age-related cognitive decline. This monograph reviews the chemistry, synthesis, and stereochemistry of BPAP; the enhancer pharmacology in molecular and neurochemical detail including the TAAR1 mechanism; comprehensive preclinical pharmacokinetics; the neuroprotective, neurotrophic, and longevity evidence; sourcing and quality verification considerations; reconstitution and handling; stack-interaction considerations; adverse-event and safety signal; and a comparative assessment of five monoaminergic activity enhancer and related catecholaminergic compounds against BPAP on five competency standards.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • Urolithin-B

    Dibenzopyranone gut microbiota metabolite derived from ellagitannin catabolism with anabolic, anti-inflammatory, antioxidant, and neuroprotective activity

    A monohydroxylated dibenzo[b,d]pyran-6-one produced by colonic microflora from dietary ellagitannins and ellagic acid, distinguished from the structurally related urolithin A by selective promotion of skeletal muscle protein synthesis via androgen receptor and mTORC1 signaling, and by protective activity against islet amyloid polypeptide proteotoxicity.

    Abstract

    Urolithin B (3-hydroxy-6H-dibenzo[b,d]pyran-6-one; CAS 1139-83-9) is one of the two principal terminal metabolites generated by human colonic microflora from dietary ellagitannins and ellagic acid, polyphenolic compounds abundant in pomegranates, walnuts, raspberries, strawberries, and certain tree nuts. Unlike its dihydroxylated isomer urolithin A (3,8-dihydroxyurolithin), which has advanced into human clinical trials primarily on the basis of mitophagy induction and mitochondrial quality control, urolithin B is distinguished by a pharmacological profile centered on skeletal muscle anabolism, neuroprotection through PI3K/Akt survival signaling, anti-inflammatory activity through NF-kappaB and NLRP3 inflammasome suppression, and a unique capacity to attenuate islet amyloid polypeptide (IAPP) proteotoxicity relevant to type 2 diabetes pathogenesis. The skeletal muscle activity, formally characterized by Rodriguez et al. (2017), demonstrated that urolithin B at 15 micromolar enhanced C2C12 myotube protein synthesis by 96.1 percent, increased myotube diameter and fusion index, suppressed the ubiquitin-proteasome degradation pathway, and operated through an androgen receptor to mTORC1 signaling axis independent of Akt phosphorylation. In vivo, 28-day subcutaneous delivery at 10 micrograms per day produced 11.9 percent increases in tibialis anterior muscle fiber cross-sectional area and significant preservation of muscle mass in denervation-induced atrophy models. The neuroprotective profile, characterized by Chen et al. (2021) in D-galactose-induced aging mice, demonstrated dose-dependent rescue of spatial and working memory deficits at oral doses of 50 to 150 mg/kg/day for 8 weeks, mediated by PI3K/Akt pathway activation, inhibition of JNK/p38 apoptotic signaling, suppression of cytochrome c mitochondrial release, and restoration of hippocampal synaptic density markers PSD95 and synapsin I. Anti-inflammatory mechanisms, characterized in BV2 microglial cells by Lee et al. (2019), include suppression of NF-kappaB activation through reduced IkappaBalpha phosphorylation and degradation, attenuation of JNK, ERK, and Akt phosphorylation, enhancement of AMPK phosphorylation, and upregulation of heme oxygenase-1 through Nrf2/ARE signaling. Anticancer activity has been demonstrated in hepatocellular carcinoma (through Wnt/beta-catenin inactivation), osteosarcoma (G2/M arrest and MMP-2/-9 targeting), bladder cancer, leukemia, triple-negative breast cancer, and esophageal cancer cell lines. Bone-protective activity was reported in ovariectomy-induced osteoporosis models through inhibition of osteoclast formation via ERK/NF-kappaB suppression. The compound is produced endogenously only by individuals with the urolithin metabotype B (UM-B) gut microbiota profile, estimated at approximately 10 to 50 percent of the population depending on ethnicity and dietary pattern. Urolithin B undergoes extensive hepatic phase II conjugation to glucuronide and sulfate metabolites; circulating total urolithin concentrations in UM-B individuals following ellagitannin consumption range from 0.003 to 5.2 micromolar, with urinary excretion reaching up to 50 micromolar. No human clinical trials of exogenous urolithin B supplementation have been completed as of monograph preparation. The compound is available as a research-grade preparation from multiple chemical suppliers at greater than 95 percent purity. This monograph reviews the chemistry, biosynthesis, and structural class of urolithin B; the molecular pharmacology across muscle, neuronal, inflammatory, metabolic, and oncologic systems; the preclinical evidence base; the pharmacokinetic and metabotype considerations; sourcing and quality verification; reconstitution and handling; stack interactions; adverse events and safety signals; and a comparative assessment of five structurally or functionally related compounds against urolithin B on five competency standards.

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  • Bacteriostatic-Water

    Preserved sterile aqueous vehicle for parenteral reconstitution and dilution

    A sterile, nonpyrogenic preparation of Water for Injection preserved with 0.9 percent benzyl alcohol, serving as the standard multi-dose diluent and reconstitution vehicle for lyophilized peptides, proteins, and small-molecule injectables in pharmaceutical, compounding, and research applications.

    Abstract

    Bacteriostatic Water for Injection, USP is a sterile, nonpyrogenic aqueous preparation containing 0.9 percent (9 mg/mL) benzyl alcohol as a bacteriostatic preservative, manufactured to the United States Pharmacopeia monograph specification and distributed under FDA oversight as a pharmaceutical-grade parenteral vehicle. Unlike Sterile Water for Injection, which contains no antimicrobial agent and is designated for single-use applications, Bacteriostatic Water for Injection is formulated specifically for multi-dose access, permitting repeated aseptic puncture of a single vial over a period of up to 28 days while maintaining microbiological integrity. The preparation is classified as a pharmaceutical vehicle rather than an active pharmaceutical ingredient; it carries no intrinsic therapeutic activity and is indicated exclusively as a diluent or solvent for drugs intended for intravenous, intramuscular, or subcutaneous injection, according to the labeling of the drug to be administered.

    The bacteriostatic property of the formulation derives entirely from the benzyl alcohol excipient, a simple aromatic primary alcohol (C6H5CH2OH; CAS 100-51-6; molecular weight 108.14 g/mol) that exerts its antimicrobial effect principally through disruption of bacterial cell membrane phospholipid bilayer integrity and interference with cellular metabolic processes. The mechanism is bacteriostatic rather than bactericidal: at 0.9 percent concentration, benzyl alcohol inhibits the reproduction of common environmental contaminants (including Staphylococcus aureus and Pseudomonas aeruginosa) without achieving immediate sterilization of the solution. This distinction is operationally important, as the formulation depends on initial sterility at the point of manufacture and on aseptic technique during use to maintain the sterile state; the preservative serves as a secondary barrier against microbial proliferation following vial puncture.

    Benzyl alcohol is metabolized in adult humans through a well-characterized hepatic oxidation pathway: alcohol dehydrogenase converts benzyl alcohol to benzaldehyde, aldehyde dehydrogenase converts benzaldehyde to benzoic acid, and benzoic acid is conjugated with glycine in the liver to form hippuric acid, which is excreted renally. Within six hours of oral administration of 1.5 g of benzyl alcohol, adult subjects excreted 75 to 85 percent of the dose as urinary hippuric acid, reflecting the efficiency of this metabolic pathway in mature individuals. However, in neonates (particularly premature infants), the enzymatic capacity for benzoic acid metabolism is developmentally immature, and repeated parenteral exposure to benzyl alcohol at cumulative doses of 100 to 240 mg/kg/day has been associated with a severe toxicity syndrome characterized by metabolic acidosis, gasping respirations, central nervous system depression, intraventricular hemorrhage, and cardiovascular collapse, termed the “gasping syndrome.” This association, first reported in 1982 in the New England Journal of Medicine and subsequently confirmed by the FDA, resulted in a regulatory contraindication against the use of benzyl alcohol-containing preparations in neonatal patients.

    The preparation is supplied in multi-dose glass or plastic flip-top vials, most commonly in a 30 mL presentation. The principal FDA-listed manufacturer is Hospira, Inc. (a Pfizer subsidiary), with the product distributed under NDC codes including 0409-3977. The USP monograph specifies a pH range of 4.5 to 7.0, a bacterial endotoxin limit of less than 0.5 USP Endotoxin Units per mL, and compliance with USP particulate matter, sterility, and container-closure integrity requirements. The preparation is isotonically and osmotically insufficient on its own and is not suitable for direct intravenous administration without prior dilution or reconstitution with the intended drug product; the tonicity of the final solution depends on the solute.

    This monograph reviews the compound identification, history, molecular pharmacology (of the benzyl alcohol preservative), pharmacokinetics of benzyl alcohol, the preclinical and clinical evidence base for safety and toxicology, sourcing and quality verification considerations, reconstitution and handling protocols, interactions with peptide and protein solutes, the adverse event and safety signal profile (including neonatal contraindication), and a comparative assessment of five alternative parenteral vehicles against Bacteriostatic Water for Injection on five competency standards.

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  • Emodin

    Natural anthraquinone derivative with multi-target anti-inflammatory, antitumor, and metabolic regulatory activity

    A 1,3,8-trihydroxy-6-methylanthraquinone isolated from Rheum palmatum and related Polygonaceae species, characterized by pleiotropic pharmacology spanning NF-kappaB inhibition, AMPK activation, kinase modulation, and broad-spectrum antimicrobial activity, with longstanding traditional use and emerging preclinical validation across oncology, metabolic disease, and inflammatory indications.

    Abstract

    Emodin (1,3,8-trihydroxy-6-methylanthraquinone; CAS 518-82-1) is a naturally occurring anthraquinone derivative present in the roots and rhizomes of multiple medicinal plant species, most notably Rheum palmatum L. (Chinese rhubarb), Polygonum cuspidatum (Japanese knotweed), Polygonum multiflorum (He Shou Wu), Cassia obtusifolia, and Aloe vera. The compound has been a constituent of traditional Chinese medicine preparations for over two millennia, with rhubarb first recorded in the Shen Nong Ben Cao Jing, the earliest systematic pharmacopoeia of traditional Chinese medicine. Modern pharmacological investigation has revealed emodin to be a pleiotropic bioactive molecule operating through multiple convergent signaling pathways, including inhibition of nuclear factor kappa B (NF-kappaB) transcriptional activity, activation of AMP-activated protein kinase (AMPK), suppression of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) axis, modulation of peroxisome proliferator-activated receptor gamma (PPARgamma), and direct inhibition of casein kinase II (CKII) and the protein tyrosine kinase p56lck. These molecular activities produce a composite pharmacological profile encompassing anti-inflammatory, antitumor, antiviral, antibacterial, antifibrotic, hepatoprotective (at low doses), antidiabetic, and immunomodulatory effects demonstrated across extensive in vitro and in vivo preclinical models.

    The antitumor activity of emodin has been characterized in cell culture and rodent xenograft models against pancreatic, hepatocellular, breast, lung, colorectal, and prostate carcinomas, with mechanisms including induction of caspase-dependent apoptosis, cell cycle arrest at the G2/M checkpoint, suppression of matrix metalloproteinase-mediated invasion, inhibition of angiogenesis through vascular endothelial growth factor downregulation, and reversal of gemcitabine resistance through IKKbeta/NF-kappaB pathway suppression. The anti-inflammatory profile operates primarily through suppression of NF-kappaB-driven proinflammatory cytokine release (tumor necrosis factor alpha, interleukin-1 beta, interleukin-6) and through NLRP3 inflammasome inhibition. Antiviral activity has been demonstrated against more than ten viral species in vitro and in vivo, including herpes simplex virus types 1 and 2, influenza A virus, coxsackievirus B3, hepatitis B virus, and SARS-CoV. Antibacterial activity is notable against Gram-positive organisms, with minimum inhibitory concentrations against Staphylococcus aureus and Mycobacterium tuberculosis in the low-micromolar range.

    The principal pharmacokinetic limitation of emodin is extremely poor oral bioavailability, approximately 3 percent in rodent models, attributable to rapid and extensive phase II glucuronidation by UDP-glucuronosyltransferases (UGT1A1, UGT1A9, UGT2B7) in both intestinal epithelium and hepatocytes, with additional contributions from CYP1A2 and CYP2E1 oxidative metabolism. Approximately 56 percent of an oral dose is unabsorbed and excreted in feces as parent compound. This pharmacokinetic barrier has substantially limited clinical translation despite extensive preclinical efficacy data. Strategies to overcome poor bioavailability include co-administration with the glucuronidation inhibitor piperine (which produces a 221 percent increase in area under the curve in rodent models), nanoparticle encapsulation, liposomal formulation, polymeric lipid hybrid nanoparticles, and solid lipid nanoparticle delivery systems.

    Toxicological evaluation has identified dose-dependent hepatotoxicity, nephrotoxicity, and reproductive toxicity at sustained high doses. Hepatotoxicity is mediated in part through inhibition of hepatocyte nuclear factor 4 alpha expression and consequent downregulation of UGT2B7, creating a paradoxical positive feedback loop in which high-dose emodin impairs its own principal detoxification pathway. Nephrotoxicity occurs through induction of apoptosis in proximal tubular epithelial cells via PPARgamma-related mitochondrial pathways. Reproductive toxicity includes disruption of testicular gene expression and inhibition of human sperm calcium signaling and tyrosine phosphorylation in vitro. The compound is not approved as a pharmaceutical agent by any major regulatory authority. It is classified as a dietary supplement ingredient and research compound. This monograph reviews the chemistry, natural sourcing, and structural characterization of emodin; the multi-pathway molecular pharmacology; the comprehensive pharmacokinetic record including glucuronidation-dominated metabolism; the preclinical evidence base across oncology, inflammatory, metabolic, infectious disease, and fibrotic indications; the limited clinical evidence; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; the adverse-event and toxicity profile; and a structured comparative assessment of five anthraquinone derivatives (chrysophanol, rhein, aloe-emodin, diacerein, physcion) against emodin on five competency standards.

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  • 1,4-DMAA

    Aliphatic alkylamine sympathomimetic stimulant and putative monoamine releasing agent

    A branched-chain aliphatic amine structurally related to methylhexanamine (1,3-DMAA), identified in geranium plant material and in dietary supplements, with presumed sympathomimetic and catecholamine-releasing activity but no approved pharmaceutical application and a minimal primary pharmacological literature.

    Abstract

    1,4-Dimethylamylamine (1,4-DMAA), systematically named 5-methylhexan-2-amine, is a branched-chain aliphatic amine of the alkylamine stimulant class. It is a positional isomer of the better-characterized 1,3-dimethylamylamine (1,3-DMAA, methylhexanamine), differing in the placement of the methyl branch along the carbon backbone: in 1,3-DMAA the branch is at carbon 4 (producing 4-methylhexan-2-amine), whereas in 1,4-DMAA the branch is at carbon 5 (producing 5-methylhexan-2-amine). The compound has never been developed or marketed as a pharmaceutical agent, in contrast to 1,3-DMAA, which was introduced by Eli Lilly as an inhaled nasal decongestant (Forthane) in 1948 and voluntarily withdrawn in 1983. 1,4-DMAA came to regulatory and scientific attention through its identification in dietary supplements marketed for pre-workout stimulation and weight loss, where it was detected at doses of 21 to 94 mg per serving alongside other undeclared stimulants including 1,3-DMAA, octodrine, and 1,3-dimethylbutylamine, as reported by Cohen et al. (2018) in Clinical Toxicology. The compound has also been detected at trace concentrations (13 to 162 ng/g) in Pelargonium graveolens (geranium) plant material from the Changzhou region of China, as documented by Fleming et al. (2012), though these concentrations are insufficient to account for the milligram-scale quantities found in commercial supplement formulations. The pharmacology of 1,4-DMAA has not been independently characterized in published receptor-binding, transporter-interaction, or in vivo behavioral studies. Its mechanism of action is inferred by structural analogy to 1,3-DMAA and to the broader class of aliphatic alkylamine sympathomimetics. 1,3-DMAA has been characterized as an indirect sympathomimetic agent that competitively inhibits dopamine uptake at the human dopamine transporter (DAT) with an IC50 of approximately 29.4 micromolar (roughly 60-fold less potent than amphetamine) and that induces DAT endocytosis through cocaine- and protein kinase A-sensitive mechanisms, as reported by Bhatt et al. (2023). By structural analogy, 1,4-DMAA is presumed to function as a catecholamine releasing agent with sympathomimetic properties, producing vasoconstriction, elevated blood pressure, increased heart rate, and central nervous system stimulation, though the potency and selectivity of these effects relative to 1,3-DMAA remain unquantified. No human pharmacokinetic data specific to 1,4-DMAA have been published. The pharmacokinetic profile of 1,3-DMAA, characterized by Bloomer et al. (2013) in seven healthy men receiving a single 25 mg oral dose, provides the closest available analog: peak plasma concentration of approximately 70 ng/mL at 3.6 hours, terminal elimination half-life of 8.5 hours, oral clearance of 20 L/hr, and volume of distribution of 236 L. Whether these parameters translate to the 1,4-isomer is unknown. The safety of 1,4-DMAA in humans is unknown. The compound has not been studied in controlled clinical trials at any dose. Cardiovascular adverse events (hypertension, tachycardia, and theoretical risk of hemorrhagic stroke and sudden cardiac death) are inferred from the pharmacology of structurally related sympathomimetic amines and from case reports associated with 1,3-DMAA-containing products. The United States Food and Drug Administration considers 1,4-DMAA to be an illegal ingredient in dietary supplements and has stated that products containing it should not be consumed. The World Anti-Doping Agency includes 1,4-dimethylamylamine on the Prohibited List under category S6 (stimulants, prohibited in competition). This monograph reviews the chemistry, structural classification, inferred mechanism of action, pharmacokinetic analogy data, detection in plant material and supplements, regulatory status, adverse-event signal, sourcing and handling considerations, and a comparative assessment of five structurally or functionally related alkylamine stimulants against 1,4-DMAA on five competency standards: novelty, effect size, side-effect profile, regulatory status, and overall validation.

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    FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

  • Nortadalafil

    Synthetic phosphodiesterase type 5 (PDE5) inhibitor; N-desmethyl analogue of tadalafil

    An unapproved, demethylated structural analogue of tadalafil with retained nanomolar PDE5 inhibitory potency, identified principally as a synthetic adulterant in dietary supplements marketed for sexual enhancement and as a reference standard for forensic and analytical chemistry.

    Abstract

    Nortadalafil (demethyl tadalafil, CAS 171596-36-4) is a synthetic analogue of the clinically approved phosphodiesterase type 5 (PDE5) inhibitor tadalafil, distinguished from the parent compound by the absence of the N-methyl substituent on the piperazinedione ring of the hexahydropyrazinopyridoindole scaffold. The compound retains nanomolar inhibitory potency against PDE5 (IC50 approximately 11 to 12 nM against bovine PDE5, compared to approximately 5 nM for tadalafil) and produces cGMP-mediated smooth muscle relaxation with EC50 values of 300 to 600 nM in rat aortic preparations. Despite this pharmacological activity, nortadalafil has never been submitted for regulatory approval in any jurisdiction and has not been the subject of controlled clinical trials in human subjects. The compound first entered the scientific literature through its detection as an undeclared adulterant in herbal and dietary supplements marketed for erectile dysfunction, a context in which it represents one member of a large and expanding family of synthetic PDE5 inhibitor analogues (including aminotadalafil, N-octylnortadalafil, chloropretadalafil, and others) introduced into the unregulated supplement market to evade analytical screening for the approved parent compounds. Analytical characterization of nortadalafil in adulterated products relies on high-performance liquid chromatography with diode-array and mass spectrometric detection, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy. The pharmacokinetic profile of nortadalafil diverges substantially from tadalafil: the reported elimination half-life is approximately 5.9 to 6.2 hours after single oral doses of 40 to 120 mg, compared to the 17.5-hour half-life of tadalafil, a difference attributable to the loss of the N-methyl group and the resulting alteration of hepatic metabolic clearance. No systematic toxicology, no formal pharmacokinetic characterization in healthy volunteers under regulatory oversight, and no controlled efficacy data exist for the compound. Safety concerns are inferred from the PDE5 inhibitor class and include the absolute contraindication of concurrent nitrate administration (risk of severe, potentially fatal hypotension), the interaction with alpha-adrenergic receptor antagonists and potent CYP3A4 inhibitors, and the unknown dose-response and adverse-event profile of a compound consumed without medical supervision at uncharacterized doses in adulterated supplements. This monograph reviews the chemistry, synthesis, and structural relationship of nortadalafil to tadalafil; the molecular pharmacology of PDE5 inhibition and the cGMP-nitric oxide signaling cascade; the limited pharmacokinetic data; the forensic and regulatory context of dietary supplement adulteration; sourcing and quality verification for research applications; handling and reconstitution; stack-interaction considerations; the adverse-event and safety signal inferred from the PDE5 inhibitor class; and a comparative assessment of five PDE5 inhibitor compounds against nortadalafil on five competency standards. The compound is not approved by any regulatory authority. It is available as a research-grade reference standard; investigators should obtain analytical confirmation of identity and purity on every lot.

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  • L-Carnitine

    Endogenous quaternary ammonium compound functioning as an obligate cofactor in mitochondrial long-chain fatty acid beta-oxidation via the carnitine palmitoyltransferase shuttle system

    A conditionally essential nutrient and FDA-approved pharmaceutical (levocarnitine) that mediates the translocation of long-chain fatty acyl groups across the inner mitochondrial membrane, with clinical applications spanning primary and secondary carnitine deficiency, cardiovascular secondary prevention, hemodialysis support, exercise performance, male reproductive health, and neuroprotection.

    Abstract

    L-Carnitine (levocarnitine) is a naturally occurring, water-soluble quaternary ammonium compound biosynthesized from the amino acids lysine and methionine in liver, kidney, and brain, and obtained exogenously from dietary sources (principally red meat and dairy products) and from pharmaceutical or nutraceutical supplementation. The compound is an obligate cofactor for the carnitine palmitoyltransferase (CPT) shuttle system, the sole mechanism by which long-chain fatty acyl-coenzyme A esters cross the inner mitochondrial membrane to undergo beta-oxidation. In the absence of adequate carnitine, mitochondrial long-chain fatty acid oxidation is impaired, producing the metabolic phenotype of primary systemic carnitine deficiency: hypoketotic hypoglycemia, cardiomyopathy, skeletal myopathy, and hepatic encephalopathy. The compound was first isolated from vertebrate muscle extract by Gulewitsch and Krimberg in 1905, structurally characterized as beta-hydroxy-gamma-trimethylaminobutyric acid by Tomita and Sendju in 1927, identified as the insect growth factor vitamin BT by Fraenkel and colleagues in the 1950s, and functionally linked to fatty acid oxidation by Fritz in 1955. Its obligate role in mitochondrial bioenergetics was established through the subsequent characterization of the CPT I, carnitine-acylcarnitine translocase (CACT), and CPT II enzyme system by McGarry, Foster, Ramsay, and colleagues in the 1970s and 1980s.

    L-Carnitine is approved by the United States Food and Drug Administration as levocarnitine (Carnitor, Leadiant Biosciences) for the treatment of primary systemic carnitine deficiency and for the prevention and treatment of carnitine deficiency in patients with end-stage renal disease undergoing maintenance hemodialysis. Pharmacokinetics are characterized by carrier-mediated intestinal absorption via the organic cation/carnitine transporter OCTN2 (SLC22A5), with oral bioavailability of 54 to 87 percent from dietary sources but only 14 to 18 percent from high-dose oral supplements owing to saturation of active transport. Renal handling is dominated by efficient tubular reabsorption (90 to 99 percent of filtered load) via OCTN2 at physiological plasma concentrations, with saturable reabsorption kinetics producing rapid urinary clearance of supraphysiological doses. Plasma elimination half-life is approximately 2 to 6 hours for exogenous doses; the endogenous total body pool (approximately 20 to 25 grams in a 70-kilogram adult) turns over slowly with an estimated whole-body half-life of 40 to 100 hours.

    Clinical evidence for supplemental L-carnitine spans multiple therapeutic domains. In cardiovascular secondary prevention, a 2013 meta-analysis of 13 controlled trials (N = 3,629) by DiNicolantonio et al. in Mayo Clinic Proceedings reported a 27 percent reduction in all-cause mortality (OR 0.73, 95% CI 0.54 to 0.99), a 65 percent reduction in ventricular arrhythmias, and a 40 percent reduction in angina development in patients following acute myocardial infarction. In chronic heart failure, a 2017 meta-analysis of 17 trials (N = 1,625) reported significant improvements in left ventricular ejection fraction (+4.14%), stroke volume (+8.21 mL), and cardiac output (+0.88 L/min). In hemodialysis populations, Cochrane and systematic reviews have reported potential benefits for anemia, C-reactive protein reduction, and intradialytic hypotension, though evidence quality remains low to moderate. In exercise physiology, systematic reviews report benefits of 1 to 4 grams daily on VO2max, peak power output, and lactate reduction, with effect sizes dependent on dosing duration and exercise modality. In male reproductive health, meta-analyses report significant improvements in sperm motility and morphology with 1 to 3 grams daily for 3 to 6 months, though pregnancy rate improvements have not been consistently demonstrated. Acetyl-L-carnitine, a physiological ester derivative, has demonstrated efficacy in randomized controlled trials for diabetic peripheral neuropathy, with significant pain reduction and nerve fiber regeneration.

    A safety consideration of growing importance is the gut microbial conversion of L-carnitine to trimethylamine (TMA), which undergoes hepatic oxidation by flavin-containing monooxygenase 3 (FMO3) to trimethylamine N-oxide (TMAO), a metabolite epidemiologically associated with increased atherosclerotic cardiovascular disease risk. The TMAO pathway is diet-dependent and microbiome-dependent, with omnivorous individuals producing substantially more TMAO from carnitine challenge than vegetarians or vegans. This monograph reviews the chemistry, biosynthesis, and transport of L-carnitine; the carnitine shuttle mechanism in molecular detail; the comprehensive pharmacokinetic record; the clinical evidence base across all studied indications; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event signal including the TMAO pathway; and a comparative assessment of five mitochondrial bioenergetic support compounds against L-carnitine on five competency standards.

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