Author: kodiac

  • Turinabol

    4-chloro-substituted 17alpha-alkylated anabolic-androgenic steroid derived from metandienone with dissociated anabolic-to-androgenic activity ratio

    A 4-chloro-1,2-dehydro-17alpha-methyltestosterone developed at Jenapharm as a clinical anabolic agent for muscle wasting and bone density disorders, distinguished from its parent compound metandienone by the 4-chloro substitution that eliminates aromatase substrate activity and confers a markedly dissociated anabolic-to-androgenic ratio.

    Abstract

    Chlorodehydromethyltestosterone (CDMT), marketed as Oral Turinabol, is a synthetic anabolic-androgenic steroid (AAS) first synthesized by chemist Albert Stachowiak at Jenapharm in the German Democratic Republic and patented in 1961. The compound is the 4-chloro-substituted derivative of metandienone (Dianabol), combining structural elements of clostebol (4-chlorotestosterone) and metandienone (1,2-dehydro-17alpha-methyltestosterone). The 4-chloro substitution at the A-ring prevents aromatization to estrogenic metabolites, while the 1,2-dehydro modification and the 17alpha-methyl group confer oral bioavailability and a dissociated anabolic-to-androgenic ratio of approximately 54:6 relative to methyltestosterone. Introduced for clinical use in 1965 for the treatment of muscle wasting disorders, osteoporosis, and recovery from debilitating illness, CDMT was prescribed at therapeutic doses of 5 to 10 mg per day in adults and 1 to 2.5 mg per day in women and children [1, 2].

    The compound occupies a singular position in pharmacological and sporting history as the principal agent of State Plan Topic 14.25 (Staatsplanthema 14.25), the systematic doping program administered by the German Democratic Republic’s Sports Medical Service from 1974 through 1989, under which approximately ten thousand athletes received CDMT, frequently without informed consent and often described to recipients as vitamins [3, 4]. The program produced a generation of international athletic dominance and a subsequent generation of adverse health consequences in exposed athletes, including hepatotoxicity, endocrine disruption, virilization in female athletes, and cardiovascular morbidity. Production was discontinued by Jenapharm in 1994, and the compound holds no current marketing authorization in any jurisdiction.

    Pharmacokinetically, CDMT is characterized by complete oral absorption, hepatic first-pass metabolism through multiple cytochrome P450 pathways (principally CYP3A4 for 6beta-hydroxylation and mitochondrial CYP11A1, CYP11B1, and CYP11B2 for 11beta-hydroxylation and additional oxidative transformations), and a plasma elimination half-life of approximately 16 hours [5, 6, 7]. The compound produces extensive phase I and phase II metabolites, with approximately 50 urinary metabolites identified. Of particular significance to anti-doping science, the long-term metabolite 4-chloro-18-nor-17beta-hydroxymethyl,17alpha-methyl-5beta-androst-13-en-3alpha-ol, identified by Schanzer and colleagues and subsequently confirmed in controlled human administration studies, extends the urinary detection window to 40 to 50 days after a single dose and potentially longer with chronic administration, enabling retrospective detection of CDMT use in athletes [8, 9, 10].

    The pharmacology of CDMT is that of a moderate-affinity androgen receptor agonist with strong dissociation between anabolic (nitrogen-retentive, myotrophic) and androgenic (virilizing, sebotropic) activities. The compound does not undergo 5alpha-reduction to more potent androgens, does not serve as an aromatase substrate, and binds sex hormone-binding globulin (SHBG) with sufficient affinity to displace endogenous androgens and elevate free testosterone fractions in the presence of concurrent testosterone [11]. The principal adverse effects are dose-dependent hepatotoxicity (consistent with the 17alpha-alkylated steroid class), suppression of the hypothalamic-pituitary-gonadal axis with reduction of luteinizing hormone, follicle-stimulating hormone, and endogenous testosterone production, unfavorable alterations in serum lipid profiles (suppression of high-density lipoprotein cholesterol and elevation of low-density lipoprotein cholesterol), and, in female subjects, irreversible virilization at supratherapeutic doses [12, 13]. This monograph reviews the chemistry, synthesis, and structural pharmacology of CDMT; the receptor-level mechanism of action; the comprehensive metabolic and pharmacokinetic profile including anti-doping detection science; the preclinical pharmacology; the limited clinical evidence base; sourcing and quality considerations; reconstitution and handling; stack interactions; adverse events and safety signals; and a structured comparative assessment of five alternative oral anabolic-androgenic steroids against CDMT on five competency standards.

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  • 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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  • Topilitumide

    Topical nonsteroidal antiandrogen of the perfluoroacylamido-arylpropanamide class with rapid serum hydrolysis and local androgen receptor suppression

    A rationally designed, serum-labile topical antiandrogen engineered from the flutamide scaffold for androgen receptor suppression in dermal tissue without systemic absorption, developed by Biophysica Inc. and marketed as Eucapil for androgenetic alopecia in Central European jurisdictions.

    Abstract

    Topilutamide (International Nonproprietary Name; also known as fluridil and by the development code BP-766) is a nonsteroidal antiandrogen of the perfluoroacylamido-arylpropanamide structural class, rationally designed for topical application in the treatment of androgenetic alopecia. The compound represents a deliberate medicinal chemistry solution to the principal limitation of systemic nonsteroidal antiandrogens such as flutamide, bicalutamide, and enzalutamide: hepatotoxicity and sexual adverse effects arising from systemic androgen receptor blockade. The design strategy incorporated perfluoroalkyl moieties into the flutamide analog BP-34 to produce a molecule that retains high-affinity androgen receptor antagonism and androgen receptor protein downregulation in dermal tissue while undergoing rapid hydrolytic decomposition upon contact with human serum (half-life approximately 6 hours at 37 degrees Celsius; undetectable after 48 hours), yielding the inactive fragments BP-34 and trifluoroacetic acid. Neither parent compound nor metabolites have been detected in human serum following chronic topical application at the marketed 2 percent concentration, establishing a pharmacokinetic profile that functionally eliminates systemic antiandrogenic exposure.

    In vitro pharmacology in LNCaP human prostate cancer cells demonstrates concentration-dependent suppression of androgen receptor protein expression: approximately 40 percent reduction at 3 micromolar and up to 95 percent reduction at 10 micromolar following 48-hour incubation [1, 2]. Comparative binding studies suggest that topilutamide binds the androgen receptor with approximately 9- to 15-fold greater affinity than bicalutamide and hydroxyflutamide, though these findings require further validation with rigorous competitive binding assays [2]. The mechanism appears to involve both direct receptor antagonism and receptor protein downregulation, distinguishing topilutamide from pure competitive antagonists that stabilize the receptor in an inactive conformation.

    The clinical evidence base is limited to two published trials comprising 53 total participants. The pivotal randomized, double-blind, placebo-controlled trial in 43 men with androgenetic alopecia demonstrated significant promotion of anagen-phase hair growth: anagen percentage increased from 75.7 percent to 85.1 percent at 3 months and 87 percent at 9 months with daily topical application of 2 percent fluridil in isopropanol vehicle [3]. Sexual function, libido, hematology, and blood chemistry values remained within normal limits throughout the study period, and no systemic absorption of the parent compound or its metabolites was detectable. A second open-label study in 11 women with female pattern hair loss demonstrated significant increases in hair shaft diameter at 6 and 9 months but did not achieve statistical significance on anagen-telogen ratio endpoints [4]. The compound was introduced for cosmetic use in 2003 and is marketed exclusively in the Czech Republic and Slovakia by Interpharma Praha (a subsidiary of Otsuka Pharmaceutical) under the brand name Eucapil. It is not approved by the United States Food and Drug Administration, the European Medicines Agency, or any other major regulatory authority for pharmaceutical use. The patent expired in 2020. This monograph reviews the chemistry, synthesis, rational design strategy, androgen receptor pharmacology, pharmacokinetics and serum lability, preclinical toxicology, the clinical evidence base, sourcing and handling considerations, comparator assessment against five alternative androgenetic alopecia agents, and the safety profile of topilutamide.

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  • 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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  • Paraxanthine

    Dimethylxanthine adenosine receptor antagonist and selective cGMP-preferring phosphodiesterase (PDE9) inhibitor

    The principal dimethylxanthine metabolite of caffeine in humans, distinguished from the parent compound and from other methylxanthines by selective inhibition of cGMP-preferring phosphodiesterase 9, potentiation of nitric oxide signaling, ryanodine receptor channel activation, and a favorable safety profile relative to caffeine.

    Abstract

    Paraxanthine (1,7-dimethylxanthine) is the primary metabolite of caffeine in humans, accounting for approximately 80 percent of caffeine biotransformation through hepatic cytochrome P450 1A2 (CYP1A2) catalyzed N3-demethylation. Although structurally an isomer of the naturally occurring dimethylxanthines theophylline (1,3-dimethylxanthine) and theobromine (3,7-dimethylxanthine), paraxanthine is not produced by plants and is encountered in human plasma exclusively as a product of caffeine metabolism. The compound has received escalating research attention since the mid-2000s as a pharmacologically distinct entity rather than a mere intermediate metabolite, with a mechanism of action profile that diverges meaningfully from caffeine at several molecular targets.

    The principal pharmacological activities of paraxanthine are competitive antagonism at adenosine A1 and A2A receptors (with binding affinities comparable to or modestly greater than caffeine), selective inhibition of the cGMP-preferring phosphodiesterase PDE9 (an activity not shared by caffeine, theophylline, or theobromine), potentiation of nitric oxide neurotransmission (a unique property among the naturally occurring methylxanthines), and activation of ryanodine receptor calcium release channels (the mechanism underlying its neuroprotective activity in dopaminergic cell models). The composite pharmacology produces psychostimulant, procognitive, neuroprotective, lipolytic, and ergogenic effects that are quantitatively and qualitatively distinguishable from those of caffeine in both preclinical and clinical studies.

    Pharmacokinetically, paraxanthine is generated in the liver from caffeine with a formation half-life determined by CYP1A2 activity and reaches plasma concentrations that exceed those of the parent compound approximately 8 to 10 hours after caffeine ingestion. When administered exogenously as pure paraxanthine, the compound exhibits an elimination half-life of approximately 3.1 hours (shorter than caffeine at 4.1 hours, theophylline at 6.2 hours, and theobromine at 7.2 hours), rapid oral absorption, and dose-proportional pharmacokinetics across the studied range of 100 to 400 mg. The shorter half-life contributes to a cleaner offset of stimulant effects and reduced sleep disruption relative to caffeine at equimolar doses.

    Clinical evidence from double-blind, placebo-controlled crossover trials demonstrates that acute oral paraxanthine at 100 to 200 mg improves sustained attention, working memory, executive function, reaction time, and psychomotor vigilance in healthy adults, with effects comparable to or exceeding those of caffeine on several cognitive endpoints and with fewer reported adverse events. A 2024 study demonstrated superior cognitive maintenance after a 10-kilometer run compared to caffeine, with caffeine-treated subjects committing 31 percent more errors while paraxanthine-treated subjects improved correct responses by approximately 6.8 percent. Preclinical studies in rodents have demonstrated that paraxanthine supplementation increases muscle mass by 14 to 41 percent, forelimb grip strength by 17 percent, and treadmill endurance by 39 percent relative to control. Paraxanthine has also been shown to enhance brain-derived neurotrophic factor (BDNF) levels, elevate hippocampal acetylcholine and dopamine, and provide neuroprotection against MPTP-induced dopaminergic cell death through ryanodine receptor channel activation.

    The safety profile of paraxanthine is favorable relative to caffeine. In 90-day repeat-dose oral toxicity studies in rats, the no-observed-adverse-effect level (NOAEL) for paraxanthine was established at 185 mg/kg body weight compared to 150 mg/kg for caffeine; mortality was observed in two rats receiving caffeine at 185 mg/kg but in none receiving paraxanthine at the same dose. The acute oral LD50 in rats is 829.20 mg/kg. In vitro genotoxicity and mutagenicity studies are negative. In human clinical studies, acute and 7-day daily ingestion of paraxanthine at doses up to 300 mg has not been associated with clinically significant adverse events, changes in blood pressure, or anxiogenic effects at the magnitude observed with equivalent caffeine doses. The ingredient has achieved self-affirmed Generally Recognized as Safe (GRAS) status for use in food and beverages in the United States at levels up to 300 mg per serving. This monograph reviews the chemistry, synthesis, and structural relationships of paraxanthine; the multi-target mechanism of action; the comprehensive pharmacokinetic record; preclinical pharmacology across cognitive, neuroprotective, ergogenic, and metabolic endpoints; the clinical evidence base; sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety; and a comparative assessment of five methylxanthine and stimulant alternatives against paraxanthine on five competency standards.

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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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  • 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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  • Telmisartan

    Non-peptide angiotensin II type 1 receptor antagonist with selective partial peroxisome proliferator-activated receptor gamma agonism

    A biphenyl-benzimidazole angiotensin II receptor blocker developed at Boehringer Ingelheim, distinguished from other sartans by intrinsic partial agonist activity at the nuclear peroxisome proliferator-activated receptor gamma and downstream metabolic, anti-inflammatory, and neuroprotective activity.

    Abstract

    Telmisartan is a non-peptide, orally active antagonist of the angiotensin II type 1 receptor (AT1R) and a selective partial agonist of the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma), approved by the United States Food and Drug Administration in 1998 for the treatment of hypertension and subsequently for cardiovascular risk reduction in patients intolerant to angiotensin-converting enzyme inhibitors. The compound is marketed as Micardis (Boehringer Ingelheim) and is available in extensive generic competition worldwide. Among the eight clinically marketed angiotensin II receptor blockers (ARBs), telmisartan is distinguished by three pharmacological and pharmacokinetic features: the longest terminal elimination half-life (approximately 24 hours), the largest volume of distribution (approximately 500 liters), and a structurally defined partial agonist interaction with PPARgamma that is not shared at clinically meaningful potency by any other marketed sartan. The PPARgamma partial agonism, first formally characterized by Benson et al. (2004) in a systematic screen of ARBs against nuclear receptor panels, produces downstream modulation of carbohydrate and lipid metabolism gene expression, reduction of insulin resistance markers, suppression of NF-kappaB-driven proinflammatory cytokine release, and enhancement of adiponectin secretion, all at concentrations achieved by the registered 80 mg oral dose [1]. These pleiotropic activities extend the pharmacological profile of telmisartan substantially beyond the hemodynamic consequences of AT1R blockade and have driven a preclinical and clinical research literature encompassing metabolic syndrome, type 2 diabetes prevention, neuroprotection, renoprotection, and anti-inflammatory applications.

    The clinical evidence base for telmisartan is anchored by two landmark randomized controlled trials. The ONTARGET trial (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; N = 25,620) demonstrated that telmisartan 80 mg daily was non-inferior to ramipril 10 mg daily on a composite cardiovascular endpoint of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure in high-risk patients, with superior tolerability and fewer treatment discontinuations [2]. The TRANSCEND trial (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease; N = 5,926) demonstrated that telmisartan modestly reduced the composite of cardiovascular death, myocardial infarction, or stroke compared with placebo in ACE-inhibitor-intolerant patients, leading to the 2009 FDA supplemental indication for cardiovascular risk reduction [3]. Additional large-scale trials include PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes; N = 20,332), which evaluated telmisartan for secondary stroke prevention, and DETAIL (Diabetics Exposed to Telmisartan and Enalapril; N = 250), which demonstrated renoprotective non-inferiority to enalapril in type 2 diabetic patients with early nephropathy.

    Pharmacokinetics are characterized by dose-dependent oral bioavailability (42 percent at 40 mg, 58 percent at 160 mg), negligible cytochrome P450-mediated metabolism (less than 3 percent of the dose is glucuronidated; the remainder is excreted unchanged in bile and feces), a terminal elimination half-life of approximately 24 hours supporting once-daily dosing, and greater than 99.5 percent plasma protein binding. The compound is poorly soluble in water but freely soluble in dimethyl sulfoxide and dimethylformamide. Telmisartan does not require dose adjustment for renal impairment but should be used with caution in severe hepatic impairment owing to the predominantly biliary elimination pathway.

    This monograph reviews the chemistry, synthesis, and structural pharmacology of telmisartan; the dual AT1R antagonist and PPARgamma partial agonist mechanism in molecular detail; the comprehensive human pharmacokinetic record; the preclinical pharmacology across cardiovascular, metabolic, neuroprotective, and renoprotective models; the clinical evidence base across all studied indications; sourcing and quality verification considerations; reconstitution and handling for laboratory use; stack-interaction implications; adverse-event signal; and a structured comparative assessment of five alternative ARBs (losartan, valsartan, irbesartan, olmesartan, candesartan) against telmisartan 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.

  • Vesugen

    Synthetic tripeptide bioregulator (Lys-Glu-Asp) targeting vascular endothelial gene expression through epigenetic modulation

    A Khavinson-class synthetic tripeptide bioregulator derived from vascular wall protein sequences, characterized by epigenetic modulation of endothelial proliferation markers, endothelin-1 normalization, sirtuin-1 upregulation, and neuroprotective gene regulation in preclinical aging and Alzheimer’s disease models.

    Abstract

    Vesugen (Lys-Glu-Asp; KED) is a synthetic tripeptide bioregulator developed at the Saint Petersburg Institute of Bioregulation and Gerontology under the direction of Professor Vladimir Khavinson as part of a decades-long program investigating short-chain peptide regulation of age-associated tissue decline. The compound belongs to the Khavinson class of ultrashort (two to four amino acid residue) bioregulatory peptides, a family of synthetic sequences derived from organ-specific protein fractions that are proposed to penetrate cell nuclei and modulate gene expression through direct interactions with DNA promoter regions and epigenetic regulatory mechanisms. Vesugen is the synthetic analog corresponding to the vascular-wall-derived peptide fraction originally isolated as the active component of Ventfort, a polypeptide complex extracted from bovine aortic tissue. The tripeptide sequence Lys-Glu-Asp was identified as the minimal bioactive motif responsible for the vasoprotective activity of the parent extract.

    The molecular pharmacology of Vesugen is characterized by epigenetic modulation of vascular endothelial cell function. In dissociated human endothelial cell cultures, Vesugen stimulates synthesis of the proliferation-associated protein Ki-67, the expression of which declines during cellular aging [1]. Molecular docking studies demonstrate that Vesugen binds to the promoter region of the MKI67 gene, making contact through the CATC sequence at the core promoter located between positions -14 and +12 relative to the transcription initiation site [1]. In models of atherosclerotic and restenotic endothelium in vitro, Vesugen normalizes the expression of endothelin-1, restores connexin (Cx37, Cx43) expression for intercellular communication, and increases sirtuin-1 (SIRT1) expression, implicating the compound in DNA repair and cellular longevity pathways [2, 3]. The compound also modulates expression of vascular endothelial growth factor (VEGF) and the apoptosis marker p53, contributing to a net pro-proliferative and anti-apoptotic phenotype in aged vascular endothelial cells.

    Beyond its primary vascular target, Vesugen has demonstrated neuroprotective activity in several preclinical models. The tripeptide regulates expression of cell aging and apoptosis genes (p16, p21), neuronal differentiation genes and proteins (NES, GAP43, nestin), and genes implicated in Alzheimer’s disease pathogenesis (SUMO, APOE, IGF1) [4]. In hippocampal neuron cultures exposed to amyloid-beta synaptotoxicity, Vesugen increased the number of mushroom-type dendritic spines by 20 percent [5]. Oral administration of Vesugen improved memory and attention in elderly individuals with functional central nervous system disorders in a small clinical cohort [4]. In a 32-patient clinical study of elderly individuals with chronic polymorbidity and organic brain syndrome, Vesugen demonstrated anabolic properties and improved central nervous system activity, slowing the rate of aging as measured by biological age indicators [6].

    The compound is not approved by any national regulatory authority as a pharmaceutical product. It is supplied as a research-grade synthetic peptide and as a dietary supplement (capsule form) in certain jurisdictions. The primary literature on Vesugen originates predominantly from Russian research institutions, principally the Saint Petersburg Institute of Bioregulation and Gerontology and affiliated laboratories. Independent replication by Western laboratories using contemporary structural biology and pharmacology methodologies remains limited. This monograph reviews the chemistry, proposed mechanism of action, preclinical pharmacology, limited clinical evidence, sourcing and handling considerations, and a comparative assessment against five alternative vasoprotective and geroprotective peptide candidates.

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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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