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FDA-cleared application: medicinal leech therapy to relieve venous congestion in compromised tissue flaps awaiting vascular ingrowth.

FDA-cleared application: post-replantation venous decompression in digits, ears, scalp, and partial avulsion injuries.

FDA-cleared application: venous decompression of compromised DIEP, TRAM, and latissimus dorsi flaps in post-mastectomy reconstruction.

Off-label use with three RCTs showing pain and function improvement comparable to NSAID gel at 3 months in mild-to-moderate symptomatic knee OA.

Off-label use with RCT evidence: single-session leech therapy reduces pain and improves function in CMC-1 (basal thumb) OA at 8 weeks.

Off-label use with two RCTs showing significant pain reduction at 7-12 weeks compared to topical NSAID and conventional physiotherapy.

Off-label use with one RCT showing significant heel pain reduction at 6 weeks compared to conservative care.

Off-label use with controlled trial evidence for symptomatic improvement in venous claudication, leg heaviness, and edema in CEAP C3-C5 stages.

Off-label adjunct to compression therapy with case-series evidence for accelerated healing in compression-resistant venous ulcers.

Off-label use with case-series evidence for symptomatic relief of leg pain, heaviness, and ulceration in PTS following deep vein thrombosis.

Off-label use with one RCT showing symptom and SNOT-22 score improvement at 4 weeks in non-polypoid chronic sinusitis.

Off-label use with one RCT (Michalsen 2018) showing significant pain reduction at 7 days in cervical radiculopathy without surgical indication.

Off-label use with controlled trial evidence (n=80) showing leg pain and Oswestry score improvement at 4-12 weeks in non-surgical lumbar disc disease.

Investigational use with case-series evidence for reduction of migraine frequency and intensity; mechanism plausible via reduction of cervico-cranial venous congestion.

Investigational use with small case series suggesting frequency reduction in chronic tension headache via reduction of pericranial muscle tension and venous congestion.

Investigational adjunctive use; mechanism includes mild diuresis from blood-volume removal and hirudin-mediated vascular endothelial effects. Not a substitute for pharmacotherapy.

Investigational use for symptomatic relief of varicose tributary discomfort and inflammation; does not eliminate underlying venous reflux.

Investigational use for symptomatic relief of grade II-III internal/external hemorrhoidal disease; does not address anatomic prolapse.

Investigational adjunctive use in primary open-angle glaucoma; weak case-series evidence. Not a substitute for IOP-lowering eye drops or surgery.

Investigational use for dry eye disease; mechanism via reduction of meibomian gland inflammation. Weak case-series evidence.

Investigational adjunctive use for non-suppurative lactational mastitis; case-series evidence for resolution of induration and reduced antibiotic days.

Investigational adjunctive use; one small pilot suggests transient improvement in tender-point and quality-of-life scores. Not a primary treatment.

Investigational use for non-discogenic sciatica including piriformis syndrome; case-series evidence for pain reduction.

Investigational use for primary Raynaud's phenomenon; mechanism via local vasodilation and rheologic improvement. No RCT evidence.

Investigational use for primary livedo reticularis; very limited evidence. Secondary causes (lupus, APLAS) require rheumatology referral.

Investigational use for chronic lipodermatosclerosis; small case series suggest softening of fibrotic gaiter-area skin changes.

Investigational use to soften and remodel insulin injection-related lipohypertrophy nodules; very limited evidence.

Investigational use for androgenic alopecia; mechanism via local scalp perfusion improvement. Single-arm series only.

Investigational use for erythematotelangiectatic rosacea; case-series evidence for reduction in facial erythema.

Investigational use for localized stable plaque psoriasis; small case series suggest plaque thinning. Not a primary treatment.

Investigational use for localized refractory atopic dermatitis; very limited case-series evidence.

Investigational use for stable keloid and hypertrophic scars; case-series evidence for softening and flattening.

Investigational use for chronic recurrent (non-acute) cellulitis with underlying lymphedema or venous insufficiency.

Investigational adjunctive use; case-series evidence for limb-volume reduction when combined with complete decongestive therapy.

Investigational adjunctive use following breast cancer treatment with axillary node dissection; case-series evidence for arm volume reduction.

Investigational use for acute monoarticular gout when NSAIDs and colchicine are contraindicated; small case series.

Investigational use for chronic mid-substance Achilles tendinopathy; case-series evidence for pain and VISA-A score improvement.

Investigational use for non-surgical rotator cuff tendinopathy and chronic shoulder impingement; case-series evidence for pain reduction.

Investigational use for stenosing tenosynovitis of the digital flexor pulleys; small case series.

Investigational use for early-stage Dupuytren's nodules; case-series evidence for nodule softening, not for established contracture.

Investigational use for plantar fascia nodules in early Ledderhose disease; case-series evidence for symptomatic improvement.

Investigational use for stable-phase Peyronie's disease; case-report-level evidence only. Standard treatments (verapamil, collagenase, surgery) remain first-line.

Investigational use for category III CP/CPPS; small case series suggest symptom reduction. Multimodal therapy remains standard.

Investigational adjunctive use for chronic endometriosis-related pelvic pain; very limited evidence. Not a substitute for hormonal or surgical management.

Investigational use for primary dysmenorrhea refractory to NSAIDs and hormonal contraception; small case series.

Investigational use for non-specific chronic pelvic pain syndrome; case-series evidence for symptom reduction within multimodal management.

Investigational use for chronic subjective tinnitus; case-series evidence for THI score improvement. Mechanism speculative.

Investigational adjunctive use for Ménière's disease; very limited evidence. Standard management (diet, betahistine, intratympanic therapy) remains primary.

Investigational use for residual symptoms in the post-acute phase of DVT (>6 weeks); contraindicated in acute DVT.

Investigational adjunctive use for Hurley stage I-II hidradenitis suppurativa in quiescent phase between flares.

The most potent natural thrombin inhibitor — and the molecular template for three FDA-approved direct thrombin inhibitor drugs.

Factor Xa inhibitor — prototype molecule that inspired the entire DOAC drug class (rivaroxaban, apixaban).

First-generation recombinant hirudin — FDA-approved 1998 for heparin-induced thrombocytopenia (HIT). Withdrawn 2012 by Bayer for commercial reasons.

Recombinant hirudin variant — FDA-approved 2003 for prophylaxis of DVT after hip replacement surgery.

Histamine-receptor-acting compound — contributes to local vasodilation at feeding site.