Enhancing Local Drug Delivery
Adjunct in local anesthesia
The first report of the synergistic effects of hyaluronidase with local anesthetic was reported in 1951 with procaine.13 Subsequently, several studies have demonstrated its surgical advantages in ophthalmologic and dermatologic surgery (Table 1).2,4,14 HA hydrolysis with hyaluronidase increases connective tissue permeability, decreasing HA’s viscosity and enabling greater dispersion of injected solutions.15 Example mixtures reported have included doses between 3–75IU.8 Diluent volume depends on the treated area and a range of 1–10ml has been reported.1
In all reported studies, addition of hyaluronidase led to faster onset of anesthetic effect and a greater anesthetized surface area due to increased dispersion of injected solutions.4,14,16-20 Additionally, there was decreased surface contour irregularities, which could particularly assist in anatomically sensitive areas prone to distortion, such as the lips and eyelids, which require precise alignment during surgery.4 A notable limitation of concomitant hyaluronidase use was the shorter duration of anesthesia though this did not seem to impact adversely on most procedures.
Distal nerve blocks
Using hyaluronidase and lidocaine could allow for distal nerve blocks, when regional nerve blocks have not dispersed to a large enough area.
A mixture of 0.5% Marcaine was used with 1:200,000 epinephrine and 1% lidocaine mixed with 1500IU of hyaluronidase (Hyalase®,CP pharmaceuticals), allowing for larger areas to be covered by the same amount of anesthetic, with one injection.20 Adding hyaluronidase might reduce pain associated with injections by decreasing tissue tension.20
Keloid and hypertrophic scars
Keloid scars are characterized by excessive collagen and ECM production with dysregulated expression of hyaluronidase mRNA compared to normal skin.21 HA has a fundamental part in wound-healing and ECM genesis and its disrupted expression in keloid disease is thought to be related to dysregulated hyaluronidase expression.22
A randomized controlled trial23 (n=100) in keloid and hypertrophic scars involved multiple treatment arms. Addition of hyaluronidase (1500IU/ml) to intralesional injection of triamcinolone (TAC) (40mg/ml) in a recombinant mixture appeared to have a lower side-effect profile (atrophy, depigmentation, telangiectasia, injection pain, ulceration, and infection) than intralesional TAC monotherapy, although had a marginally lower resolution rate of keloid scars at 21 weeks follow-up (69% resolution with combination versus 75% with TAC monotherapy).23 The main side-effects reported were atrophy, reported in 18.75% of the combination group compared with 31.25% of patients treated with TAC alone (P<0.001).23
In a separate study,24 a 1mL combination of 5-fluorouracil (5- FU) (250mg/5mL), TAC (40mg/mL), and hyaluronidase (1500U) recombinant mixture was injected into 20 patients with keloids or hypertrophic scars. Flattening of scars and resolution of pain and pruritus were reported effects of the treatment. Patients required an average of three treatments to produce flattening of keloids and symptom resolution.24 Triple therapy enabled the reduction in number of injections with a reduced side-effect profile compared to TAC monotherapy.24
Hyaluronidase has been shown to support the penetration of 5-FU and TAC.25 Two patients had a reduction of their scar size of 80% following treatment with a combination of intralesional cryosurgery, TAC (160mg/4mL), 5-fluorouracil (5- FU) (150mg/3mL), and hyaluronidase (100mg/mL).25
Taken together, the addition of hyaluronidase to TAC and 5-FU appears to enhance efficacy of treatment of intralesional therapy with reduced side-effects.
Kaposi’s sarcoma
Patients with Kaposi’s sarcoma (KS)26 were treated with intralesional vinblastine following prior treatment with 1% lidocaine with or without intralesional hyaluronidase every three weeks. Both vinblastine with and without intralesional hyaluronidase cleared the KS, although combination treatment with hyaluronidase proved more effective in treating tumor nodules. Relapse was reduced in patients treated with the hyaluronidase addition.26
Mucin deposition disorders
A major constituent of dermal mucin is glycosaminoglycans with HA being abundant.27 Hyaluronidase has been used successfully in several cutaneous conditions characterized by increased mucin deposition such as pretibial myxedema, scalp myxedema, scleredema, scleroderma, and cutis verticis gyrata.27
Pretibial myxedema
Pretibial myxedema is a rare condition in which glycosaminoglycans accumulate in pretibial skin and is associated with Grave’s disease and to a lesser degree Hashimoto’s thyroiditis.28 Normalization of thyroid levels rarely corrects this condition and treatment often proves challenging with topical and intralesional corticosteroids used in addition to systemic therapy.28
The rationale for hyaluronidase use in pretibial myxedema relates to hydrolysis of excessive HA and ECM reduction, with reported cases of its use in 1949 and 1950.29-30
Adjunct in local anesthesia
The first report of the synergistic effects of hyaluronidase with local anesthetic was reported in 1951 with procaine.13 Subsequently, several studies have demonstrated its surgical advantages in ophthalmologic and dermatologic surgery (Table 1).2,4,14 HA hydrolysis with hyaluronidase increases connective tissue permeability, decreasing HA’s viscosity and enabling greater dispersion of injected solutions.15 Example mixtures reported have included doses between 3–75IU.8 Diluent volume depends on the treated area and a range of 1–10ml has been reported.1
In all reported studies, addition of hyaluronidase led to faster onset of anesthetic effect and a greater anesthetized surface area due to increased dispersion of injected solutions.4,14,16-20 Additionally, there was decreased surface contour irregularities, which could particularly assist in anatomically sensitive areas prone to distortion, such as the lips and eyelids, which require precise alignment during surgery.4 A notable limitation of concomitant hyaluronidase use was the shorter duration of anesthesia though this did not seem to impact adversely on most procedures.
Distal nerve blocks
Using hyaluronidase and lidocaine could allow for distal nerve blocks, when regional nerve blocks have not dispersed to a large enough area.
A mixture of 0.5% Marcaine was used with 1:200,000 epinephrine and 1% lidocaine mixed with 1500IU of hyaluronidase (Hyalase®,CP pharmaceuticals), allowing for larger areas to be covered by the same amount of anesthetic, with one injection.20 Adding hyaluronidase might reduce pain associated with injections by decreasing tissue tension.20
Keloid and hypertrophic scars
Keloid scars are characterized by excessive collagen and ECM production with dysregulated expression of hyaluronidase mRNA compared to normal skin.21 HA has a fundamental part in wound-healing and ECM genesis and its disrupted expression in keloid disease is thought to be related to dysregulated hyaluronidase expression.22
A randomized controlled trial23 (n=100) in keloid and hypertrophic scars involved multiple treatment arms. Addition of hyaluronidase (1500IU/ml) to intralesional injection of triamcinolone (TAC) (40mg/ml) in a recombinant mixture appeared to have a lower side-effect profile (atrophy, depigmentation, telangiectasia, injection pain, ulceration, and infection) than intralesional TAC monotherapy, although had a marginally lower resolution rate of keloid scars at 21 weeks follow-up (69% resolution with combination versus 75% with TAC monotherapy).23 The main side-effects reported were atrophy, reported in 18.75% of the combination group compared with 31.25% of patients treated with TAC alone (P<0.001).23
In a separate study,24 a 1mL combination of 5-fluorouracil (5- FU) (250mg/5mL), TAC (40mg/mL), and hyaluronidase (1500U) recombinant mixture was injected into 20 patients with keloids or hypertrophic scars. Flattening of scars and resolution of pain and pruritus were reported effects of the treatment. Patients required an average of three treatments to produce flattening of keloids and symptom resolution.24 Triple therapy enabled the reduction in number of injections with a reduced side-effect profile compared to TAC monotherapy.24
Hyaluronidase has been shown to support the penetration of 5-FU and TAC.25 Two patients had a reduction of their scar size of 80% following treatment with a combination of intralesional cryosurgery, TAC (160mg/4mL), 5-fluorouracil (5- FU) (150mg/3mL), and hyaluronidase (100mg/mL).25
Taken together, the addition of hyaluronidase to TAC and 5-FU appears to enhance efficacy of treatment of intralesional therapy with reduced side-effects.
Kaposi’s sarcoma
Patients with Kaposi’s sarcoma (KS)26 were treated with intralesional vinblastine following prior treatment with 1% lidocaine with or without intralesional hyaluronidase every three weeks. Both vinblastine with and without intralesional hyaluronidase cleared the KS, although combination treatment with hyaluronidase proved more effective in treating tumor nodules. Relapse was reduced in patients treated with the hyaluronidase addition.26
Mucin deposition disorders
A major constituent of dermal mucin is glycosaminoglycans with HA being abundant.27 Hyaluronidase has been used successfully in several cutaneous conditions characterized by increased mucin deposition such as pretibial myxedema, scalp myxedema, scleredema, scleroderma, and cutis verticis gyrata.27
Pretibial myxedema
Pretibial myxedema is a rare condition in which glycosaminoglycans accumulate in pretibial skin and is associated with Grave’s disease and to a lesser degree Hashimoto’s thyroiditis.28 Normalization of thyroid levels rarely corrects this condition and treatment often proves challenging with topical and intralesional corticosteroids used in addition to systemic therapy.28
The rationale for hyaluronidase use in pretibial myxedema relates to hydrolysis of excessive HA and ECM reduction, with reported cases of its use in 1949 and 1950.29-30
