Category: Uncategorized

  • 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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  • CB-03-01

    Topical steroidal androgen receptor antagonist with peripherally selective antiandrogen activity

    A synthetic pregnane steroid developed by Cosmo Pharmaceuticals (Cassiopea) as a topically applied, peripherally selective androgen receptor antagonist for the treatment of acne vulgaris and androgenetic alopecia, distinguished from systemic antiandrogens by rapid local metabolism to inactive cortexolone and minimal systemic bioavailability.

    Abstract

    CB-03-01 (clascoterone; cortexolone 17alpha-propionate; 11-deoxycortisol 17alpha-propionate) is a synthetic pregnane steroid that functions as a competitive antagonist of the androgen receptor (AR) with submicromolar potency (IC50 approximately 0.4 to 1 micromolar in AR transactivation assays) and peripheral selectivity conferred by rapid enzymatic hydrolysis to the inactive parent compound cortexolone (11-deoxycortisol) in human skin, plasma, and hepatic tissue. The compound was identified from a structure-activity series of cortexolone 17alpha-monoesters screened for topical antiandrogen activity in the hamster flank organ test, in which CB-03-01 demonstrated potency approximately four times greater than progesterone, three times greater than flutamide, two times greater than finasteride, and approximately equivalent to cyproterone acetate, while lacking systemic antiandrogenic, antianabolic, or glucocorticoid activity after subcutaneous administration in rats. The molecular pharmacology centers on competitive displacement of dihydrotestosterone (DHT) from the androgen receptor in sebocytes and dermal papilla cells, resulting in suppression of androgen-responsive gene transcription, reduction of sebaceous lipid synthesis, inhibition of inflammatory cytokine production (including interleukin-6), and attenuation of androgen-driven miniaturization of scalp hair follicles. In human dermal papilla cell cultures, CB-03-01 demonstrated significantly greater inhibition of DHT-stimulated IL-6 synthesis than the direct AR antagonist enzalutamide.

    The compound received its first regulatory approval from the United States Food and Drug Administration in August 2020 as a 1% topical cream (Winlevi) for the treatment of acne vulgaris in patients aged 12 years and older, representing the first new mechanism of action approved for acne in approximately 40 years and the first topical antiandrogen approved for acne in any jurisdiction. Two pivotal Phase 3 randomized, double-blind, vehicle-controlled trials enrolling a total of 1440 patients with moderate to severe facial acne demonstrated statistically significant treatment success rates (Investigator Global Assessment score of 0 or 1 with at least a two-grade reduction) of approximately 18 to 20 percent for clascoterone versus 7 to 9 percent for vehicle at 12 weeks, with concurrent reductions in both inflammatory and noninflammatory lesion counts. Long-term safety data through 12 months demonstrated a favorable tolerability profile dominated by local application site reactions (erythema, dryness, pruritus) without clinically meaningful systemic antiandrogen effects.

    A second clinical program in androgenetic alopecia (AGA) has advanced through Phase 2 dose-ranging studies (2.5%, 5%, and 7.5% solutions applied twice daily) demonstrating statistically significant improvements in target area hair count (TAHC) at 6 and 12 months, and into Phase 3 registration trials (SCALP-1 and SCALP-2) using a 5% topical solution in 1465 male patients with mild to moderate AGA. The Phase 3 topline results reported statistically significant improvements in TAHC relative to vehicle, with a 5.39-fold relative improvement in one study and a 1.68-fold relative improvement in the second, the divergence attributable to baseline hair count differences rather than inconsistent drug performance. The safety profile in the AGA trials was comparable to vehicle, with no evidence of systemic androgen blockade.

    Pharmacokinetics following topical application are characterized by minimal systemic absorption. At maximal clinical use conditions (6 grams of 1% cream applied twice daily), steady-state plasma concentrations of clascoterone average 3.1 plus or minus 1.9 ng/mL with Cmax values of 4.5 plus or minus 2.9 ng/mL. The compound is rapidly hydrolyzed in plasma to cortexolone, which is detectable at concentrations generally near or below the lower limit of quantitation (0.5 ng/mL). Plasma protein binding is 84 to 89 percent. The principal safety signal is reversible hypothalamic-pituitary-adrenal (HPA) axis suppression, observed in approximately 7 percent of adolescent and adult subjects in maximal-use pharmacokinetic studies, with all cases resolving within 4 weeks of discontinuation. This monograph reviews the chemistry, synthesis, and structural pharmacology of CB-03-01; the competitive androgen receptor antagonist mechanism in molecular detail; the pharmacokinetic profile including systemic absorption, metabolism, and HPA axis considerations; the preclinical pharmacology in hamster, rat, and human tissue models; the clinical evidence base across acne and androgenetic alopecia indications; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event signal; and a comparative assessment of five alternative antiandrogen or androgen-modulating agents against CB-03-01 on five competency standards.

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  • Retinalamin

    Polypeptide bioregulator complex derived from bovine retinal tissue with retinoprotective and neurotrophic activity

    A tissue-derived polypeptide fraction developed at the St. Petersburg Institute of Bioregulation and Gerontology as a retinoprotective agent, distinguished from conventional neuroprotective ophthalmologics by its multi-peptide composition, tissue-specific gene expression regulation, and clinical application across glaucoma, diabetic retinopathy, and hereditary retinal dystrophies.

    Abstract

    Retinalamin is a complex of water-soluble polypeptide fractions with molecular weight not exceeding 10,000 daltons, isolated from bovine retinal tissue and developed as a retinoprotective peptide bioregulator by Vladimir Khavinson and colleagues at the St. Petersburg Institute of Bioregulation and Gerontology of the Russian Academy of Medical Sciences. The compound is registered in the Russian Federation and several Commonwealth of Independent States jurisdictions as a lyophilized preparation for parabulbar and intramuscular injection, manufactured by Geropharm LLC under the ATC code S01XA (other preparations for eye disease treatment). Retinalamin represents a distinct pharmacological class within ophthalmic neuroprotection: rather than a single molecular entity with a defined receptor target, it consists of a heterogeneous mixture of short-chain polypeptides (predominantly 2 to 7 amino acid residues in length) that act through tissue-specific modulation of gene expression, stimulation of intracellular protein synthesis, regulation of lipid peroxidation, and normalization of cellular membrane function in retinal photoreceptors, retinal pigment epithelium, and Mueller glial cells.

    The mechanistic basis of Retinalamin activity has been characterized through in vitro and in vivo models at the St. Petersburg Institute. In Xenopus laevis early gastrula ectoderm assays, Retinalamin demonstrated concentration-dependent induction of neuronal differentiation including brain, retinal, and pigment epithelium lineages, establishing the compound as a morphogenetic peptide regulator with tissue-specific inductive capacity. In cell culture, Retinalamin and the related synthetic tetrapeptide Epithalon stimulated proliferation of retinal and pigmented epithelial cells in a tissue-specific and concentration-dependent manner. The proposed molecular mechanism involves sequential binding of constituent short peptides to promoter regions of genes involved in retinal cell differentiation, survival, and metabolic homeostasis, thereby modulating transcriptional activity and downstream protein expression. Pharmacodynamic effects observed in preclinical and clinical settings include stimulation of photoreceptor and retinal cellular element function, improvement of functional interactions between retinal pigment epithelium and photoreceptor outer segments, enhancement of Mueller cell activity and glutamate inactivation, normalization of vascular permeability, and reduction of oxidative stress through regulation of lipid peroxide metabolism.

    Clinical evidence for Retinalamin spans multiple retinal pathologies. In compensated primary open-angle glaucoma, a 180-patient randomized controlled trial (Egorov et al. 2019) demonstrated that intramuscular Retinalamin produced significant retinoprotective effects, with improvement in mean deviation index from negative 5.52 to negative 4.82 decibels, stabilization of ganglion cell complex thickness (versus progressive thinning in controls), and preservation of pattern electroretinography amplitudes over the study period. A subsequent 147-patient randomized trial (Strakhov et al. 2020) demonstrated that biannual Retinalamin courses over 24 months arrested development of glaucomatous optic neuropathy, with retinal nerve fiber layer thickness remaining stable in treated patients versus declining from 83.5 to 76.7 micrometers in controls. In diabetic retinopathy, a 56-patient comparative study (Malakhova et al. 2024) provided objective structural and functional evidence of positive retinal changes with intramuscular Retinalamin in early-stage disease. In hereditary retinal dystrophies, long-term observational data (Razumovskiy et al.) demonstrated that a first course of Retinalamin improved visual acuity in 58.1 percent and visual fields in 64.5 percent of retinal degeneration patients, with repeated courses over 23 to 25 years preserving residual vision in 55.6 percent of patients and preserving object vision in 11.1 percent. In retinal abiotrophy, residual vision was preserved in 100 percent of treated cases. A 498-patient glaucoma study (Erichev et al. 2020) comparing intramuscular, retrobulbar, and combined administration routes demonstrated comparable efficacy across delivery methods, with total threshold retinal sensitivity increasing by 122 to 274 decibels across glaucoma stages.

    The safety profile of Retinalamin is characterized by low adverse event rates. The principal reported events are local injection site reactions (pain, redness, swelling) and rare hypersensitivity reactions including anaphylactic shock and angioneurotic laryngeal edema. The compound is contraindicated during pregnancy (absence of clinical safety data) and in pediatric populations under 18 years for most indications. Pharmacokinetic characterization in the conventional sense is not feasible owing to the multi-component polypeptide composition, which does not permit standard absorption, distribution, metabolism, and elimination analysis of individual constituents. The standard clinical regimen consists of 5 to 10 milligrams administered once daily by parabulbar or intramuscular injection for 5 to 10 days, with courses repeated every 3 to 6 months. Retinalamin is not approved by the United States Food and Drug Administration, the European Medicines Agency, or other major Western regulatory authorities. The clinical evidence base is derived predominantly from Russian-language literature published in Vestnik Oftalmologii and related journals. Investigators outside the Russian Federation should approach the compound as a research-grade peptide preparation requiring independent analytical verification and should interpret the clinical literature with attention to the methodological standards and reporting conventions of the source publications.

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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.

  • Superdrol

    Synthetic 17-alpha-alkylated anabolic-androgenic steroid derived from 5-alpha-dihydrotestosterone

    A potent orally active 2-alpha,17-alpha-dimethylated dihydrotestosterone derivative with a high anabolic-to-androgenic dissociation ratio, originally synthesized by Syntex in 1956, never marketed pharmaceutically, and classified as a Schedule III controlled substance following its illicit distribution as an over-the-counter designer steroid supplement beginning in 2005.

    Abstract

    Superdrol (methasterone; 2-alpha,17-alpha-dimethyl-5-alpha-androstan-17-beta-ol-3-one) is a synthetic, orally active anabolic-androgenic steroid (AAS) of the 5-alpha-dihydrotestosterone (DHT) structural class. The compound was first synthesized by researchers at Syntex Corporation in 1956 and characterized in a 1959 publication as a potent orally active anabolic agent exhibiting only weak androgenic activity. Despite this favorable preclinical dissociation profile, methasterone was never advanced to clinical development or marketed as a prescription pharmaceutical. The compound resurfaced in 2005 when it was introduced to the United States consumer market under the trade name Superdrol, sold as an over-the-counter dietary supplement and marketed deceptively as a prohormone to circumvent the Anabolic Steroid Control Act of 1990. In preclinical rat bioassays using methyltestosterone as the reference standard, methasterone demonstrated approximately 400 percent anabolic potency and 20 percent androgenic potency, yielding a Q-ratio (anabolic-to-androgenic dissociation index) of 20, among the highest reported for any oral AAS. The compound’s oral bioavailability (approximately 50 percent) is conferred by the 17-alpha-methyl group, which protects the steroid nucleus from hepatic first-pass metabolism but simultaneously renders the compound hepatotoxic through a mechanism common to all C17-alpha-alkylated androgens. Methasterone is non-aromatizable owing to its 5-alpha-reduced A-ring saturation, and therefore does not produce estrogenic effects such as gynecomastia or water retention. Hepatotoxicity is the principal and most serious adverse effect: a distinctive pattern of bland cholestatic liver injury, characterized by severe hyperbilirubinemia with only modest aminotransferase elevation, has been documented in multiple case series and case reports. A comprehensive literature review of 52 reported cases identified a median presentation bilirubin of 314 micromol/L, peak bilirubin of 705 micromol/L occurring approximately 28 days after cessation, and resolution over a median of 90 days with supportive care alone; no deaths or liver transplantations were reported in the published literature. Acute kidney injury occurred in 43 percent of cases, with peak creatinine correlating with peak bilirubin. The World Anti-Doping Agency placed methasterone on its prohibited list in 2006. The United States Drug Enforcement Administration classified methasterone as a Schedule III controlled substance in January 2012 under the Controlled Substances Act, and the Designer Anabolic Steroid Control Act of 2014 further expanded regulatory authority over designer steroids of this class. Methasterone has no approved medical indication in any jurisdiction. This monograph documents the complete chemistry, synthesis, pharmacology, pharmacokinetics, hepatotoxicity profile, clinical case evidence, sourcing considerations, handling, combination interactions, adverse event signal, and a comparative assessment against five alternative oral anabolic-androgenic steroids (oxandrolone, oxymetholone, stanozolol, methyltestosterone, and epistane) on five competency standards.

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  • 1,3-DMAA

    Synthetic aliphatic sympathomimetic amine with indirect adrenergic and dopaminergic activity

    A branched-chain aliphatic amine originally developed by Eli Lilly as the inhaled nasal decongestant Forthane, subsequently repurposed as an ergogenic dietary supplement ingredient, and characterized pharmacologically as an indirect sympathomimetic acting principally through norepinephrine and dopamine release with substrate-like dopamine transporter regulation.

    Abstract

    1,3-Dimethylamylamine (1,3-DMAA; 4-methylhexan-2-amine; methylhexanamine) is a synthetic aliphatic sympathomimetic amine first introduced by Eli Lilly and Company in 1944 under the trade name Forthane as an inhaled nasal decongestant and voluntarily withdrawn from the market in 1983. The compound re-entered commercial circulation in 2006 when it was marketed as an ergogenic dietary supplement ingredient under the name Geranamine, following the regulatory removal of ephedrine alkaloids from the United States supplement market in 2004. The pharmacology of 1,3-DMAA is that of an indirect sympathomimetic: the compound acts as a norepinephrine and dopamine releasing agent, inhibits the norepinephrine transporter (NET) at low micromolar concentrations, and exhibits substrate-like regulation of the dopamine transporter (DAT) including competitive inhibition of dopamine uptake, binding at the S1 substrate site, induction of outward-facing-open to outward-facing-closed conformational transitions, and stimulation of DAT endocytosis through cocaine- and protein kinase A-sensitive mechanisms. These monoaminergic actions produce dose-dependent cardiovascular stimulation (vasoconstriction, elevation of systolic and diastolic blood pressure, tachycardia), central nervous system arousal, and thermogenic effects consistent with the broader sympathomimetic amine class that includes ephedrine, amphetamine, and phenylpropanolamine.

    The sole formal human pharmacokinetic study (Schilling et al., 2013; n = 7 healthy men; single oral dose of 25 mg) reported a peak plasma concentration of approximately 70 ng/mL, time to peak of 3.57 hours, terminal elimination half-life of 8.45 hours, oral clearance of 20.02 L/hr, and volume of distribution of 236 L, indicating extensive tissue partitioning. Physiological monitoring in that study documented modest increases in heart rate and diastolic blood pressure that remained within normal clinical ranges at the 25 mg dose. However, case reports and postmarketing surveillance have associated substantially higher doses of 1,3-DMAA (often in combination with caffeine and other stimulants in multi-ingredient pre-workout and weight-loss supplements) with serious cardiovascular events including cerebral hemorrhage, myocardial infarction, cardiac arrest, hepatotoxicity, and death. The United States Food and Drug Administration has received at least 86 reports of illness and death associated with DMAA-containing supplements and has determined that 1,3-DMAA is not a dietary ingredient; its inclusion in products marketed as dietary supplements is unlawful under United States federal law. Preclinical abuse liability assessment (Dolan and Gatch, 2015) demonstrated that 1,3-DMAA fully substituted for cocaine and partially substituted for methamphetamine in drug discrimination assays, produced conditioned place preference in mice at intermediate doses, and generated dose-dependent locomotor depression, indicating psychostimulant-like abuse potential.

    The compound is banned or restricted in the United States, Canada, Australia, New Zealand, the United Kingdom, Brazil, Sweden, Finland, and Switzerland, and is listed as a prohibited substance by the World Anti-Doping Agency. It is not approved as a medicine in any jurisdiction as of the date of this monograph. This monograph reviews the chemistry, synthesis, and structural classification of 1,3-DMAA; the historical development and regulatory trajectory; the molecular pharmacology at monoamine transporters and adrenergic receptors; the limited human pharmacokinetic record; preclinical pharmacology including abuse liability; the clinical and adverse-event evidence base; sourcing and analytical verification considerations; reconstitution and handling; stack interaction and combination risks; the comprehensive adverse-event and safety signal; and a comparative assessment of five sympathomimetic amine stimulants against 1,3-DMAA on five competency standards (novelty, effect size, promising potential, side-effect profile, 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.

  • Alpha-Klotho

    Type I transmembrane protein and circulating endocrine factor of the glycosyl hydrolase family 1 superfamily with obligate FGF23 co-receptor and pleiotropic anti-aging functions

    A kidney-derived transmembrane glycoprotein and its shed soluble ectodomain, identified through insertional mutagenesis in 1997 as a suppressor of aging phenotypes in mice, functioning both as an obligate co-receptor for fibroblast growth factor 23 in mineral metabolism and as a circulating endocrine factor that inhibits insulin/IGF-1, Wnt, TGF-beta, and NF-kappaB signaling pathways with demonstrated neuroprotective, cardioprotective, and renoprotective activity in preclinical models.

    Abstract

    Alpha-Klotho (alpha-KL) is a 130 kDa type I single-pass transmembrane protein encoded by the KL gene on human chromosome 13q13.1, first identified in 1997 by Kuro-o et al. through characterization of an insertional mutation in mice that produced a syndrome of accelerated aging encompassing soft tissue calcification, arteriosclerosis, skin atrophy, osteoporosis, emphysema, gonadal dysplasia, and dramatically shortened lifespan [1]. The protein comprises a short intracellular domain, a single transmembrane helix, and a large extracellular region containing two tandem glycosyl hydrolase family 1 (GH1) domains, designated KL1 and KL2, which share sequence homology with family 1 beta-glucosidases but lack catalytic activity against conventional substrates due to substitutions in the active-site residues. The extracellular domain undergoes proteolytic shedding by ADAM10, ADAM17, and BACE1, generating a soluble ectodomain (sKL) comprising KL1 and KL2 that circulates as an endocrine factor detectable in plasma, cerebrospinal fluid, and urine. A shorter secreted isoform containing only KL1 is produced by alternative mRNA splicing.

    In its membrane-bound form, alpha-Klotho functions as an obligate co-receptor for fibroblast growth factor 23 (FGF23), forming a ternary complex with FGF receptor 1c (FGFR1c) that is essential for phosphaturic signaling in the renal proximal tubule and for suppression of 1,25-dihydroxyvitamin D3 (calcitriol) synthesis. The crystal structure of the alpha-Klotho/FGFR1c/FGF23 ternary complex, resolved by Chen et al. (2018) at 3.0 angstrom resolution, demonstrated that the KL2 domain of alpha-Klotho cradles FGF23 with a receptor-binding arm extending from the KL1-KL2 interdomain cleft, creating a composite binding surface for FGF23 engagement [2]. Loss of this co-receptor function produces the hyperphosphatemia, hypervitaminosis D, and ectopic calcification that characterize the kl/kl mouse phenotype and that are recapitulated in FGF23 knockout mice.

    Independent of the FGF23 co-receptor function, soluble alpha-Klotho acts as a circulating endocrine factor with pleiotropic anti-aging activity. Characterized signaling activities include inhibition of the insulin/insulin-like growth factor 1 (IGF-1) pathway through suppression of receptor autophosphorylation; suppression of Wnt/beta-catenin signaling through direct binding to Wnt ligands; inhibition of transforming growth factor beta (TGF-beta) type II receptor signaling and downstream Smad phosphorylation; suppression of NF-kappaB-driven inflammatory transcription; and regulation of ion channel and transporter activity in the renal tubule, including TRPV5, TRPV6, ROMK1, and the Na+/K+-ATPase [3, 4, 5]. These FGF23-independent activities are the molecular basis for the broader anti-aging, neuroprotective, cardioprotective, and anti-fibrotic effects observed in gain-of-function and supplementation studies.

    Circulating soluble alpha-Klotho levels decline with age in humans, beginning approximately in the fourth decade of life, and are markedly reduced in chronic kidney disease, where loss of renal alpha-Klotho expression precedes and contributes to the mineral and bone disorder, cardiovascular calcification, and accelerated aging phenotype of uremia [6]. Epidemiological studies have identified inverse associations between circulating soluble alpha-Klotho concentrations and all-cause mortality, cardiovascular events, and cognitive decline in community-dwelling older adults [7]. The KL-VS haplotype (defined by the F352V and C370S variants, rs9536314 and rs9527025) has been associated in some cohorts with altered klotho secretion, cortical brain volume, and cognitive resilience in aging, though replication across large cohorts remains inconsistent [8, 9].

    Preclinical studies have demonstrated that recombinant alpha-Klotho protein administration, adeno-associated virus-mediated KL gene transfer, and transgenic KL overexpression produce renoprotection in ischemia-reperfusion injury and unilateral ureteral obstruction models; cardioprotection with attenuation of left ventricular hypertrophy and fibrosis; suppression of vascular calcification; and cognitive enhancement in aged, young, and alpha-synuclein transgenic mice through NMDA receptor-dependent glutamatergic mechanisms [10, 11, 12, 13]. A 2023 study in aged nonhuman primates demonstrated that a single subcutaneous injection of a klotho protein fragment enhanced spatial and working memory, representing the first primate cognitive enhancement data for the compound [14].

    As of 2026, alpha-Klotho is in early clinical development. Klothea Bio launched a Phase 1b randomized, double-blind, placebo-controlled trial of AKL003, an alpha-Klotho mRNA therapeutic administered intravenously, in healthy adult volunteers in February 2026. Klotho Neurosciences is advancing KLTO-202, a KL gene therapy, toward first-in-human studies for amyotrophic lateral sclerosis. No alpha-Klotho protein or gene therapy product has received regulatory approval in any jurisdiction. Recombinant human alpha-Klotho protein is available from multiple research suppliers (R&D Systems, Abcam, Sino Biological, Thermo Fisher) for in vitro and preclinical applications. This monograph reviews the molecular identification, structural biology, receptor pharmacology, preclinical pharmacology across organ systems, the emerging clinical evidence base, sourcing and handling considerations, stack interactions, safety signal, and a comparative assessment of five anti-aging intervention candidates against alpha-Klotho 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.

  • Aminotadalafil

    Synthetic phosphodiesterase type 5 (PDE5) inhibitor analog; tadalafil N-methyl-to-amino substituted derivative

    A synthetic structural analog of tadalafil in which the piperazinedione N-methyl group is replaced by a primary amine, yielding an unapproved phosphodiesterase type 5 inhibitor principally encountered as an undeclared adulterant in dietary supplements marketed for erectile dysfunction.

    Abstract

    Aminotadalafil, formally (6R,12aR)-2-amino-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione (CAS 385769-84-6), is a synthetic structural analog of tadalafil, the selective cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) inhibitor marketed as Cialis for the treatment of erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. The single structural modification that distinguishes aminotadalafil from the parent drug is the replacement of the N-methyl substituent on the 2-position of the piperazinedione (diketopiperazine) ring with a primary amino group (NH2), a change that alters hydrogen-bonding capacity, basicity, and physicochemical properties while preserving the core beta-carboline-fused diketopiperazine scaffold responsible for PDE5 active-site recognition. Aminotadalafil retains inhibitory activity at PDE5 and exhibits greater than 100 percent cross-reactivity with anti-tadalafil polyclonal antibodies, confirming close structural and immunochemical homology with the parent compound [1]. The compound has not undergone formal preclinical toxicology, human pharmacokinetic characterization, or clinical efficacy evaluation in any regulatory jurisdiction, and it is not approved for human use by any national medicines authority. Its principal significance in the biomedical literature arises from its repeated identification as an undeclared adulterant in dietary supplements, herbal products, and electronic cigarette liquids marketed for sexual enhancement, where it poses uncharacterized risks to consumers who are unaware of its presence and who may be concurrently taking nitrate-containing medications or other agents that interact with the cGMP-nitric oxide signaling pathway [2, 3, 4, 5].

    The analytical chemistry literature on aminotadalafil is substantial. The compound has been identified and structurally characterized by proton and carbon-13 nuclear magnetic resonance spectroscopy, electrospray ionization mass spectrometry, Fourier transform infrared spectroscopy, and ultraviolet spectrophotometry in dietary supplement matrices across multiple continents, including reports from Latin America, Asia, Europe, and North America [2, 6, 7]. Validated high-performance liquid chromatography with diode array detection (HPLC-DAD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods permit simultaneous identification and quantification of aminotadalafil alongside other PDE5 inhibitor analogs (hydroxythiohomosildenafil, thiosildenafil, dimethylsildenafil, thiodimethylsildenafil) in complex supplement matrices [3, 8]. A dimeric interaction product of aminotadalafil has also been isolated from adulterated health food products, suggesting that the compound undergoes degradation or condensation reactions under storage conditions encountered in supplement manufacture [9].

    The pharmacological characterization of aminotadalafil is limited. No peer-reviewed study has reported a direct IC50 determination for aminotadalafil against recombinant human PDE5, and no selectivity panel across the eleven mammalian phosphodiesterase families has been published. The compound’s activity is inferred from its structural homology to tadalafil (IC50 approximately 1.8 to 5.0 nanomolar against PDE5) and from the immunochemical cross-reactivity data. Structure-activity relationship studies of the broader tadalafil analog series indicate that modifications at the 2-position of the diketopiperazine ring modulate PDE5 affinity, and that the (6R,12aR) stereochemistry derived from L-tryptophan is essential for potent inhibition [10, 11]. Aminotadalafil preserves this stereochemistry. No human pharmacokinetic, dose-response, or safety data exist; toxicological risk assessment must therefore rely on extrapolation from tadalafil and on the general pharmacology of the PDE5 inhibitor class. This monograph reviews the chemistry, structural pharmacology, inferred pharmacokinetics, regulatory history, detection methodology, sourcing considerations, and comparative assessment of aminotadalafil against five alternative PDE5 inhibitor analogs encountered in the adulterated supplement landscape.

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  • Tuftsin

    Endogenous immunostimulatory tetrapeptide derived from the CH2 domain of immunoglobulin G

    A spleen-dependent, IgG-derived tetrapeptide that activates phagocytic cells through neuropilin-1 receptor binding, stimulating macrophage phagocytosis, chemotaxis, and tumoricidal activity, and serving as the structural parent of the anxiolytic heptapeptide Selank.

    Abstract

    Tuftsin (L-threonyl-L-lysyl-L-prolyl-L-arginine) is an endogenous tetrapeptide corresponding to residues 289 through 292 of the CH2 domain of the immunoglobulin G (IgG) heavy chain. First identified in 1970 by Victor A. Najjar and Keisuke Nishioka at the Tufts University School of Medicine during investigations of phagocytosis by polymorphonuclear granulocytes, the peptide derives its name from its institutional origin and has since become the prototype endogenous immunostimulatory peptide. Tuftsin is not synthesized de novo but is liberated from a larger IgG-associated polypeptide termed leukokinin through the sequential action of two proteases: tuftsin-endocarboxypeptidase, a splenic enzyme that cleaves the C-terminal bond of the tetrapeptide within the intact immunoglobulin, and leukokinase, a serine protease on the outer membrane of phagocytic cells that releases the active N-terminal tetrapeptide from the partially processed fragment. This two-step enzymatic liberation places the spleen as an obligate organ in tuftsin physiology and accounts for the well-documented tuftsin deficiency, impaired phagocytic function, and increased susceptibility to overwhelming bacterial infection observed following splenectomy.

    The molecular pharmacology of tuftsin centers on its binding to neuropilin-1 (NRP1), a single-pass transmembrane glycoprotein that also serves as a co-receptor for vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta). Tuftsin binds the b1 domain of neuropilin-1 through a motif similar to the C-terminal sequence encoded by exon 8 of VEGF165, and signals through TGF-beta receptor 1 (a co-receptor of NRP1) via the canonical Smad3 phosphorylation pathway, with concurrent reduction in Akt phosphorylation. At the cellular level, tuftsin binding stimulates phagocytosis, pinocytosis, chemotaxis, respiratory burst (superoxide anion and hydrogen peroxide generation), antigen presentation, and tumoricidal activity in monocytes, macrophages, neutrophils, microglia, and Kupffer cells. Intracellular calcium serves as a critical second messenger in tuftsin-mediated phagocyte activation. In neuroinflammatory models, tuftsin promotes an anti-inflammatory M2 microglial phenotype shift, suppresses pro-inflammatory Th1 responses, upregulates Th2 responses, and expands regulatory T cell populations.

    Pharmacokinetically, tuftsin is an extremely labile peptide in vivo, with a plasma half-life of approximately 16 minutes owing to rapid degradation by serum aminopeptidases and carboxypeptidases. Oral bioavailability is negligible because of gastric peptidase destruction. The rapid enzymatic clearance has been the principal barrier to clinical development. Initial clinical studies conducted at the Weizmann Institute of Science demonstrated that tuftsin is nontoxic in humans when administered intravenously at doses up to 5 mg per injection in patients with advanced malignancy; a Phase II study in 25 patients with various advanced cancers reported leucocytosis and increased natural killer activity with two partial responses among 16 evaluable patients, confirming biological activity but insufficient monotherapy efficacy.

    The most significant translational legacy of tuftsin is the development of Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), a synthetic heptapeptide analog in which the tuftsin sequence is extended at the C-terminus with a Pro-Gly-Pro tripeptide motif that confers resistance to enzymatic degradation and facilitates blood-brain barrier penetration. Selank was developed at the Institute of Molecular Genetics of the Russian Academy of Sciences and is approved in Russia as a nasal spray for generalized anxiety disorder and neurasthenia. Selank exhibits pronounced anxiolytic, nootropic, and immunomodulatory activity through mechanisms including allosteric modulation of GABA-A receptors and modulation of monoamine neurotransmitter metabolism, and does so without the sedation, tolerance, or dependence associated with benzodiazepines.

    Beyond Selank, tuftsin has been developed as a targeting ligand for liposomal and nanoparticle drug delivery systems. Palmitoyl tuftsin grafted onto liposome surfaces enables selective binding to phagocytic cells and has demonstrated augmented antitumor efficacy of encapsulated cytotoxic agents (etoposide, doxorubicin, curcumin) against fibrosarcoma and Ehrlich ascites carcinoma in murine models. Tuftsin-bearing liposomes have also been used to deliver antimicrobial agents to macrophage-resident intracellular pathogens including Leishmania and Plasmodium species.

    This monograph reviews the chemistry, enzymatic biogenesis, and structural biology of tuftsin; the neuropilin-1 receptor pharmacology and downstream signaling; the pharmacokinetic constraints and stabilization strategies; the preclinical pharmacology across immunostimulatory, anti-inflammatory, antitumor, and anti-infective applications; the clinical evidence base; sourcing and quality verification; reconstitution and handling; stack interactions; adverse events and safety; and a comparative assessment of five immunostimulatory peptide candidates (Selank, thymosin alpha-1, muramyl dipeptide, GM-CSF, and thymopentin) against tuftsin on five competency standards.

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  • NSI-189

    Plain-language summaryIntrigue 45 / 100

    NSI-189 is a small molecule developed at Neuralstem to stimulate hippocampal neurogenesis (the birth of new neurons in the dentate gyrus). Preclinical rodent studies showed proliferation of neural progenitor cells, hippocampal volume increase, and antidepressant-like behavior in chronic stress models, generating considerable hope that this could be a fundamentally new class of antidepressant. Phase 1 trials were uneventful. Phase 2 trials in major depression in 2014 and 2017 failed to beat placebo on the primary endpoints, and Neuralstem ended development. It briefly became popular in nootropic communities sourced as a research chemical, on the strength of secondary cognitive endpoints in the failed trials. The clinical case is essentially closed. 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.

    Benzylpiperazine-aminopyridine neurogenic compound with indirect brain-derived neurotrophic factor modulation and hippocampal neurogenesis stimulation

    A first-in-class small molecule neurogenic agent discovered through phenotypic screening of human hippocampal neural stem cells, developed for major depressive disorder and under investigation for cognitive impairment, diabetic neuropathy, and post-traumatic stress disorder.

    Abstract

    NSI-189 (amdiglurax; ALTO-100) is a benzylpiperazine-aminopyridine small molecule identified through a phenotypic screen of approximately 10,000 compounds against human hippocampal neural stem cells and advanced as a first-in-class hippocampal neurogenesis stimulator for the treatment of major depressive disorder (MDD). The compound was discovered by Karl Johe and colleagues at Neuralstem, Inc. (Germantown, Maryland) and is now under development by Alto Neuroscience (Mountain View, California) under the designation ALTO-100. NSI-189 is mechanistically distinct from all marketed antidepressants: it has no detectable activity at serotonin, norepinephrine, or dopamine transporters, no binding at 52 standard neurotransmitter receptor and ion channel targets, and no activity across a panel of 900 kinases. Instead, the compound stimulates proliferation and neurogenic differentiation of hippocampal neural stem cells in vitro with low-micromolar potency and, on oral administration to rodents at 10 to 30 mg/kg/day, produces dose-dependent increases in hippocampal volume (up to 66 percent at 30 mg/kg in mice), upregulation of brain-derived neurotrophic factor (BDNF), stem cell factor (SCF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF), and activation of the TrkB/Akt signaling pathway. The morphological effects are confined to the dentate gyrus of the hippocampus and the subventricular zone; no structural changes have been observed elsewhere in the brain. A bell-shaped dose-response relationship is observed in preclinical hippocampal volume endpoints, with 100 mg/kg producing less effect than 30 mg/kg, suggesting an optimal range for neurogenic stimulation.

    Clinical development has proceeded through Phase 1 (41 healthy volunteers, 2011), Phase 1b (24 MDD patients, Fava et al. 2016, published in Molecular Psychiatry), and Phase 2 (220 MDD outpatients, Papakostas et al. 2020, published in Molecular Psychiatry). The Phase 1b trial demonstrated safety and tolerability at 40, 80, and 120 mg daily for 28 days, with medium-to-large effect sizes on the Symptoms of Depression Questionnaire (SDQ) and the Cognitive and Physical Functioning Questionnaire (CPFQ). The Phase 2 trial, conducted using a sequential-parallel comparison design across 12 weeks, did not meet its primary endpoint (change from baseline on the Montgomery-Asberg Depression Rating Scale, MADRS) at either 40 mg or 80 mg daily. However, 40 mg daily produced statistically significant improvements on the SDQ (pooled mean difference -8.2; Cohen’s d = -0.64 in Stage 2; p = 0.04), the CPFQ (pooled mean difference -1.9; p = 0.03), and several objective cognitive measures on the CogScreen battery (Cohen’s d ranging from 0.12 to 1.12 for significant measures). Hippocampal volume was not significantly changed in MDD patients at the studied doses and duration, despite the robust preclinical volumetric signal.

    Alto Neuroscience acquired the NSI-189 program in October 2021 and redesignated the compound ALTO-100. A Phase 2b trial (301 adults with MDD, 34 U.S. sites, 6 weeks, biomarker-enriched design using a cognitive memory test) reported topline results in 2024: ALTO-100 did not demonstrate statistically significant improvement in MADRS versus placebo in the biomarker-defined population and did not meet secondary endpoints. The compound was well tolerated, with headache, nausea, and abnormal dreams as the most common adverse events at rates similar to placebo. A Phase 2b trial in bipolar depression is expected to report in 2026, and the compound remains under investigation for post-traumatic stress disorder.

    Preclinical pharmacology extends beyond depression. NSI-189 reverses cognitive and motor deficits in a rat model of ischemic stroke (30 mg/kg oral), ameliorates central and peripheral neuropathy in mouse models of type 1 and type 2 diabetes (10 to 30 mg/kg oral), enhances synaptic plasticity and reverses motor and cognitive impairments in a mouse model of Angelman syndrome through TrkB/Akt pathway activation, and enhances long-term potentiation in hippocampal slice preparations in vitro. The compound has linear pharmacokinetics across the 40 to 120 mg/day clinical dose range, an oral Tmax of 1 to 2 hours, a plasma elimination half-life of 17.4 to 20.5 hours supporting once-daily dosing, and achieves steady state within 4 to 5 days.

    This monograph reviews the chemical identity and synthesis of NSI-189; the discovery through phenotypic screening; the molecular pharmacology and neurotrophic factor cascade; the comprehensive pharmacokinetic profile; the preclinical evidence base across depression, stroke, neuropathy, and Angelman syndrome models; the clinical evidence base from Phase 1 through Phase 2b; sourcing, reconstitution, and handling considerations; stack interactions; the adverse-event and safety signal; and a structured comparative assessment of five neurogenesis-associated compounds (fluoxetine, ketamine, agomelatine, psilocybin, and 7,8-dihydroxyflavone) against NSI-189 on five competency standards. The compound is not approved by any regulatory authority for any indication. It is sold as a research-grade preparation; investigators should obtain analytical confirmation of identity and purity on every lot.

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  • Anadrol

    17-alpha-alkylated anabolic-androgenic steroid; synthetic dihydrotestosterone derivative with potent erythropoietic and anabolic activity

    A 17-alpha-alkylated oral anabolic-androgenic steroid derived from dihydrotestosterone, developed at Syntex in the late 1950s for the treatment of anemias characterized by deficient red blood cell production, distinguished by potent erythropoietic stimulation, marked nitrogen retention, and significant hepatotoxic liability.

    Abstract

    Oxymetholone, marketed as Anadrol-50 (Syntex, later Unimed Pharmaceuticals, now Alaven Pharmaceutical) and Anapolon (Imperial Chemical Industries and generics), is a synthetic 17-alpha-alkylated derivative of dihydrotestosterone first described by Ringold et al. at Syntex in 1959 and introduced into clinical medicine in the early 1960s for the treatment of anemias, osteoporosis, and catabolic wasting states. The compound is the 2-hydroxymethylene analog of 17-alpha-methyl-dihydrotestosterone (mestanolone), bearing an unusual hydroxymethylene substituent at the C2 position that confers oral bioavailability through resistance to first-pass hepatic inactivation and that can be metabolically cleaved to yield mestanolone as an active metabolite. Oxymetholone is one of the most potent oral anabolic-androgenic steroids in clinical use, exhibiting a high ratio of anabolic to androgenic activity in classical levator ani and ventral prostate bioassays while paradoxically demonstrating low direct binding affinity for the androgen receptor in competitive displacement studies. The principal pharmacodynamic effects are stimulation of erythropoiesis through increased renal erythropoietin production (with urinary erythropoietin levels elevated up to fivefold at therapeutic doses), promotion of positive nitrogen balance and skeletal muscle protein synthesis, and a poorly characterized but clinically significant estrogenic activity that occurs despite the compound’s structural inability to undergo aromatization, possibly through direct activation of estrogen receptor alpha. The compound received approval from the United States Food and Drug Administration for the treatment of anemias caused by deficient red blood cell production, including acquired aplastic anemia, congenital aplastic anemia, myelofibrosis, and hypoplastic anemias due to the administration of myelotoxic drugs. In the mid-1970s, the FDA restricted the approved indication exclusively to anemias characterized by deficient erythropoiesis, withdrawing prior approvals for osteoporosis and general catabolic states. Clinical investigation has subsequently extended to HIV/AIDS-associated wasting (Hengge et al. 2003 Phase III trial demonstrating 3.0 to 3.5 kg weight gain over 16 weeks at 100 to 150 mg daily), antithrombin III deficiency, and pediatric growth failure, with varying degrees of success. The hepatotoxic liability of the 17-alpha-alkylated structure is the principal safety concern: cholestatic jaundice occurs in approximately 1 percent of treated patients, typically within 1 to 4 months of initiation; peliosis hepatis (blood-filled sinusoidal cysts) develops with prolonged administration and has resulted in fatal hepatic rupture and hemorrhage in case reports; and hepatocellular carcinoma and hepatic adenoma have been reported after 2 to 15 years of continuous use, predominantly in patients with Fanconi anemia and aplastic anemia receiving chronic androgen therapy. The compound is classified as a Schedule III controlled substance in the United States under the Controlled Substances Act and is subject to equivalent regulatory controls in most jurisdictions. This monograph reviews the chemistry, synthesis, and structure-activity relationships of oxymetholone; the androgen receptor, erythropoietic, and estrogenic pharmacology; the limited but clinically relevant pharmacokinetic record; the preclinical pharmacology in animal models of anemia and wasting; the clinical evidence base across anemia, HIV wasting, and ancillary indications; sourcing and quality verification for research applications; reconstitution and handling; stack interactions and combinations with other anabolic and therapeutic agents; the adverse-event and safety signal including detailed hepatotoxicity characterization; and a comparative assessment of five alternative anabolic-androgenic agents (oxandrolone, nandrolone decanoate, stanozolol, testosterone enanthate, danazol) against oxymetholone on five competency standards.

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