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Wednesday, August 6, 2025

Biologicals


Antitoxins and antivenins

Hematopoietic stem cell mobilizer

In vivo diagnostic biologicals

Miscellaneous erythropoiesis agents

Recombinant human erythropoietins


I. Biologicals: Antitoxins and Antivenins

Definition and Purpose
Antitoxins and antivenins are biologically derived immunoglobulin preparations or recombinant antibodies used to neutralize the harmful effects of toxins (produced by bacteria) or venoms (from snakes, spiders, or other venomous animals). These are essential in acute care settings, often representing life-saving interventions.

1. Mechanism of Action

  • Antitoxins: Bind to and neutralize bacterial exotoxins before they bind to cell receptors.

  • Antivenins (Antivenoms): Contain polyclonal or monoclonal antibodies that target venom proteins and enzymes, preventing their action on neuromuscular junctions, blood coagulation, or cellular membranes.

2. Examples

  • Botulism Antitoxin Heptavalent (Equine) – For botulinum neurotoxin types A–G

  • Diphtheria Antitoxin (Equine origin) – Now rare due to vaccination

  • Tetanus Immune Globulin (TIG) – For post-exposure prophylaxis or treatment

  • CroFab® (Crotalidae Polyvalent Immune Fab) – For North American rattlesnake envenomation

  • Anavip® (Crotalidae Immune F(ab')2) – For North and South American viper bites

  • Antivenin (Micrurus fulvius) – Coral snake antivenin

3. Pharmacokinetics

  • Administered intravenously or intramuscularly

  • Onset: Immediate neutralization; peak effects depend on venom/toxin levels

  • Elimination: Variable, immunoglobulin-based clearance

4. Adverse Effects

  • Hypersensitivity (including anaphylaxis)

  • Serum sickness (due to heterologous proteins)

  • Fever, rash, urticaria

  • Rare: nephrotoxicity, coagulopathies

5. Precautions

  • Pre-test for horse protein hypersensitivity (equine-derived)

  • Epinephrine availability for anaphylaxis

  • Monitor renal and hepatic function in severe envenomation

II. Hematopoietic Stem Cell Mobilizers

Definition
These are agents used to mobilize hematopoietic stem cells (HSCs) from the bone marrow into the peripheral blood, facilitating their collection for autologous or allogeneic transplantation.

1. Mechanism of Action

  • Most commonly, agents antagonize the CXCR4–SDF-1 interaction, disrupting the bone marrow niche and allowing CD34+ stem cells to migrate into circulation.

  • Used in conjunction with granulocyte-colony stimulating factor (G-CSF).

2. Approved Agents

  • Plerixafor (Mozobil®)

    • CXCR4 antagonist

    • Indicated for mobilization in patients with non-Hodgkin lymphoma or multiple myeloma

    • Administered SC before apheresis

  • Filgrastim (Neupogen®)

    • G-CSF that primes marrow to release stem cells

3. Pharmacokinetics

  • Plerixafor: SC, peak levels ~30–60 min; half-life ~3–5 hours

  • Combined with G-CSF for optimal mobilization

4. Adverse Effects

  • Diarrhea, injection site reactions

  • Leukocytosis

  • Splenic rupture (rare with G-CSF)

  • Headache, dizziness

5. Contraindications

  • Hypersensitivity

  • Leukemia (risk of mobilizing malignant cells)

III. In Vivo Diagnostic Biologicals

Definition
Biological products administered to humans to elicit a physiological response, aiding in the diagnosis or monitoring of disease or organ function.

1. Mechanism of Action

  • Mimic or provoke specific immune, endocrine, or metabolic responses.

  • Measured changes (e.g., hormonal levels, imaging signals) indicate pathology.

2. Examples

  • Tuberculin Purified Protein Derivative (PPD) – Mantoux Test

    • Used to assess prior exposure to Mycobacterium tuberculosis

  • Corticotropin (Acthar® Gel)

    • Stimulates adrenal cortisol release; used in adrenal function testing

  • Cyanocobalamin (Vitamin B12) – Schilling Test (obsolete)

    • Assesses intrinsic factor-mediated B12 absorption

  • C-14 or C-13 Urea Breath Test

    • Diagnoses Helicobacter pylori infection

3. Administration

  • SC or intradermal for immune tests

  • Oral or IV for metabolic or absorption studies

4. Adverse Effects

  • Hypersensitivity

  • Injection site reactions

  • False positives/negatives due to concurrent conditions

5. Contraindications

  • Immunosuppression (may blunt immune-based diagnostics)

  • Active skin conditions (for intradermal tests)

IV. Miscellaneous Erythropoiesis Agents

Definition
Erythropoiesis-stimulating agents (ESAs) that do not fall under the standard recombinant erythropoietin formulations, including novel small molecules or non-erythropoietin pathway stimulants.

1. Mechanism of Action

  • Promote red blood cell production through pathways other than erythropoietin receptor stimulation.

  • May involve HIF (hypoxia-inducible factor) stabilization or other transcriptional activators.

2. Agents

  • Roxadustat (not yet approved in all jurisdictions)

    • HIF prolyl hydroxylase inhibitor (HIF-PHI)

    • Increases endogenous EPO, iron absorption, and reduces hepcidin

  • Luspatercept (Reblozyl®)

    • TGF-β superfamily ligand trap

    • Enhances late-stage erythroid maturation

    • Approved for:

      • β-thalassemia

      • Myelodysplastic syndromes (MDS)

  • Sotatercept (under development)

    • Similar mechanism to luspatercept

    • Targeting anemia of chronic disease

3. Adverse Effects

  • Hypertension

  • Thrombosis

  • Diarrhea

  • Hyperkalemia

  • Increased cancer risk (hypothetical for HIF agents)

4. Contraindications

  • Uncontrolled hypertension

  • Active malignancy (for ESAs)

V. Recombinant Human Erythropoietins

Definition
Biotechnologically derived analogs of endogenous erythropoietin (EPO), used to stimulate red blood cell production in various anemic conditions.

1. Mechanism of Action

  • Bind to erythropoietin receptors on erythroid progenitor cells in bone marrow.

  • Stimulate proliferation and differentiation → ↑ RBC production

2. Agents

  • Epoetin alfa (Epogen®, Procrit®)

    • Short-acting

    • Used in CKD, chemotherapy-induced anemia

  • Darbepoetin alfa (Aranesp®)

    • Longer half-life (addition of sialic acid)

    • Less frequent dosing

  • Epoetin beta (NeoRecormon®)

    • Similar to epoetin alfa

    • Available in select markets

  • Methoxy polyethylene glycol-epoetin beta (Mircera®)

    • Continuous erythropoietin receptor activator (CERA)

    • Ultra-long-acting (dosing every 2–4 weeks)

3. Indications

  • Anemia in chronic kidney disease (CKD)

  • Anemia secondary to chemotherapy

  • HIV-associated anemia (zidovudine-induced)

  • Preoperative anemia (selected cases)

4. Pharmacokinetics

  • SC or IV administration

  • Half-life: Epoetin alfa ~4–13 h; Darbepoetin ~25–49 h; Mircera >130 h

  • Dose titration based on hemoglobin targets

5. Adverse Effects

  • Hypertension

  • Thrombosis

  • Pure red cell aplasia (PRCA – rare, antibody-mediated)

  • Tumor progression (potential in some cancers)

6. Contraindications

  • Uncontrolled hypertension

  • Hypersensitivity to mammalian cell products

  • PRCA with anti-EPO antibodies

7. Black Box Warning

  • Increased risk of cardiovascular events, stroke, and death when used to target hemoglobin >11 g/dL in CKD

  • ESA use in oncology linked to shorter survival and tumor progression





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