Hyaluronidase Injection Research Articles

INTRAVITREAL INJECTION OF HYALURONIDASE CANNOT INDUCE POSTERIOR VITREOUS DETACHMENT IN THE RABBIT

To investigate whether intravitreal injection of hyaluronidase can induce posterior vitreous detachment (PVD) in the rabbit. One eye each of 12 New Zealand white rabbits received intravitreal injection via the pars plana of 20 IU of hyaluronidase (0.1 mL reconstituted in sterile balanced salt solution [BSS]) into the midvitreous cavity. The fellow eye of each rabbit received a vitreous injection of 0.1 mL of BSS. At 3 and 6 months after intravitreal injection, four and eight rabbits were killed, respectively, and the eyes were enucleated. After fixation, scanning electron microscopy was performed to study the vitreoretinal interface. At 3 and 6 months after injection, scanning electron microscopy showed that the retinal surfaces in eyes that received either hyaluronidase or BSS were covered with vitreous collagen fibers. No eyes, even those that received hyaluronidase over a period of 6 months, had the smooth retinal surface consistent with a bare internal limiting lamina that suggests the development of PVD. Hyaluronidase cannot induce PVD in the rabbit over a 6-month period after vitreous injection.

The use of betamethasone and hyaluronidase injections in the treatment of Peyronie's disease.

The aim of this study was to assess the effect of local injections of betamethasone, hyaluronidase and lidocaine in patients with Peyronie's disease. A total of 112 men who had a palpable plaque at the penis and suffered from painful erection and bending of penis was treated with a total of 12 injections containing betamethasone, hyaluronidase and lidocaine. Patients were classified into groups according to the duration of the disease (<6 months, 6-12 months or >12 months) as well as the size of the plaque (<10 mm, 10-20 mm or >20 mm). Pretreatment evaluation of patients and assessment of outcome were based on subjective criteria as well as measurement of the size of the plaque by means of ultrasound. Results were correlated to patients' characteristics. The overall response rate was 86%. Cure or improvement was noticed in 31% and 55% of patients respectively. Most of the patients (83%) had a duration of disease less than 12 months. Painful erection, bending of penis and plaque were absent in 97%, 32% and 31% of patients, respectively, after treatment. No severe complications were observed. The effect of treatment was strongly related to the duration of disease and the size of the plaque. The method is safe, well tolerated by patients and characterized by a high response rate in patients with a history of less than 12 months and a plaque not exceeding 20 mm.

Treatment of lumbosacral radiculopathy with epidural steroids.

Treatment of lumbosacral radiculopathy with epidural steroids.

A randomized controlled trial of local injections of hyaluronidase versus placebo in cancer patients receiving subcutaneous hydration

Most cancer patients develop reduced oral intake or dehydration before death. Subcutaneous hydration (SCH) can be safe and effective. SCH is frequently administered using hyaluronidase to improve fluid absorption. The objective of this study was to determine the effects of hyaluronidase on patient comfort during bolus SCH. Twenty-one cancer patients requiring parenteral hydration were administered a 500 cc bolus of two-thirds dextrose (5%) and one-third normal saline solution subcutaneously at 08:00 and 16:00 hours during day 1 and day 2. On day 1 patients were randomized on a double-blind basis to receive 150 units of hyaluronidase versus placebo as a bolus into the site of infusion immediately before starting each one-hour infusion. During day 2 patients were crossed over to receive the alternate treatment at a new infusion site. Visual analogue scales (0 = best, 100 = worst) for pain and swelling at the infusion site were completed by each patient. In addition, investigators blindly assessed the site of infusion for the presence of edema, rash, and leakage. No significant differences were observed for pain, swelling, edema, rash or leakage between the placebo and the hyaluronidase scores. After completion of the two days of the study, patients blindly chose hyaluronidase in 1 (5%) case, placebo in 5 (24%) cases, and no preference in 15 (71%) cases (P < 0.01). There was no treatment or interaction effect for pain, except for a period effect (P = 0.045) for the morning bolus administration. There were no treatment, period, or interaction effects for any of the other variables. Our results suggest that hyaluronidase is not necessary for routine bolus SCH. It may still be useful for a minority of patients who are not able to tolerate infusion well due to swelling or pain.

Hyaluronidase ameliorates rejection-induced edema.

Hyaluronan, a glucosaminoglycan with unique water-binding capacity, is accumulated in the interstitial edematous tissue in rejecting organs. We here investigated whether the increased tissue content of water and hyaluronan seen during allograft rejection can be prevented by treatment with the hyaluronan-degrading enzyme hyaluronidase. Heterotopic heart transplantations between PVG and Wistar/Kyoto rats were performed. Recipient rats were treated with hyaluronidase prophylactically or therapeutically, either alone or in combination with cyclosporine. Daily intravenous injections of hyaluronidase induced a significant reduction of the cardiac content of both hyaluronan and water, as evaluated on day six after transplantation. Morphological examination revealed grafts with better preserved morphology and fewer infiltrating mononuclear cells, compared to untreated controls. Hyaluronidase therapy, alone or combined with cyclosporine, resulted in prolonged graft survival times. Hyaluronidase infusion for two hours also reduced already established edema five days after transplantation. This study confirms the hypothesis that hyaluronan accumulation plays a critical role in edema formation, and that hyaluronidase therapy can be used to reduce edema after organ transplantation.

Hyaluronidase ameliorates rejection-induced edema

Abstract Hyaluronan, a glucosaminoglycan with unique water-binding capacity, is accumulated in the interstitial edematous tissue in rejecting organs. We here investigated whether the increased tissue content of water and hyaluronan seen during allograft rejection can be prevented by treatment with the hyaluronan-degrading enzyme hyaluronidase. Heterotopic heart transplantations between PVG and Wistar/Kyoto rats were performed. Recipient rats were treated with hyaluronidase prophylactically or therapeutically, either alone or in combination with cyclosporine. Daily intravenous injections of hyaluronidase induced a significant reduction of the cardiac content of both hyaluronan and water, as evaluated on day six after transplantation. Morphological examination revealed grafts with better preserved morphology and fewer infiltrating mononuclear cells, compared to untreated controls. Hyaluronidase therapy, alone or combined with cyclosporine, resulted in prolonged graft survival times. Hyaluronidase infusion for two hours also reduced already established edema five days after transplantation. This study confirms the hypothesis that hyaluronan accumulation plays a critical role in edema formation, and that hyaluronidase therapy can be used to reduce edema after organ transplantation.

Reversal of intrinsic and acquired forms of drug resistance by hyaluronidase treatment of solid tumors

There are two broad categories of drug resistance encountered during cancer chemotherapy, i.e. intrinsic and acquired. They are observed in virtually every type of tumor with every known anticancer chemotherapeutic drug. As such there is an urgent need to develop innovative approaches of preventing or reversing these types of resistance. One strategy to do so is to develop completely new drugs which may be resistance free, such as direct acting angiogenesis inhibitors (T. Boehm, J. Folkman, T. Browder, M.S. O'Reilly, Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance, Nature 390 (1997) 404–407; R.S. Kerbel, Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents, BioEssays 13 (1991) 31–36; R.S. Kerbel, A cancer therapy resistant to resistance, Nature 390 (1997) 335–336). Another is to devise methods which will improve significantly the effectiveness of those conventional drugs already in use, such as adriamycin, cyclophosphamide and taxol. We have directed efforts towards the latter. They depend on the discovery of a new class of chemosensitizers which act as antiadhesive agents rendering solid tumors more susceptible to such conventional cytotoxic therapeutic drugs. Examples of this concept are illustrated with bovine testicular hyaluronidase and a mouse mammary tumor called EMT-6. When this enzyme preparation is used to treat intact multicellular spheroids of the EMT-6 tumor, the spheroids are substantially disaggregated. Dispersed spheroids are more susceptible to the cytotoxic effects of cyclophosphamide than intact spheroids. Moreover, this antiadhesive chemosensitizing effect can actually be reproduced in BALB/c mice when EMT-6 cells are grown intraperitoneally as an ascites tumor (consisting mostly of multicellular aggregates) and the mice are given injections of hyaluronidase and cyclophosphamide. In a similar fashion, the indifference of P-glycoprotein-positive multidrug-resistant EMT-6 spheroids to the P-glycoprotein reversal agent PSC-833 (a cyclosporin A analogue) can be reversed by disaggregation of the intact spheroids by hyaluronidase. This renders the treated cells highly sensitive to a combination of adriamycin and PSC-833 in a manner similar to the striking chemosensitization effects commonly observed in monolayer culture systems. Thus, hyaluronidase has the potential to reverse forms of both intrinsic and acquired drug resistance in solid tumors, such as EMT-6, which are sensitive to its antiadhesive effects.

Hyaluronidase reduces the interstitial fluid pressure in solid tumours in a non-linear concentration-dependent manner

Hyaluronidase has gained increasing interest as an adjuvant in local and systemic cancer therapy, despite the incomplete knowledge of its physiological function. To this end, direct intratumoural injection of bovine testicular hyaluronidase (500, 1600 or 7500 U in 50 μl phosphate-buffered saline (PBS)) was performed in orthotopic (o.t.) osteosarcoma xenografts grown in the hind leg of nude mice. Control tumours received 50 μl PBS alone or supplemented with 10% bovine serum albumin (BSA). Central tumour interstitial fluid pressure (IFP) and mean arterial blood pressure (MABP) were measured using the wick-in-needle technique and after cannulation of the carotid artery, respectively. IFP was 32±8 mmHg ( n=44, mean±SD) in untreated tumours and there was a significant correlation between tumour IFP and volume ( P<0.01). The hyaluronidase injection reduced IFP to 63–84% after 1 h compared with controls ( P<0.05) and in a non-linear concentration-dependent manner. MABP was not affected significantly. In conclusion, an intratumoural hyaluronidase injection might reduce IFP temporally in solid osteosarcoma xenografts.

Pretreatment with intralesional hyaluronidase prior to excision of dermatofibrosarcoma protuberans

Dermatofibrosarcoma protuberans (DFSPs) are an uncommon malignancy that commonly recur, but rarely metastasize. The origin of DFSPs is controversial; however, they stain with the progenitor marker CD34. DFSPs usually show increased stromal mucin, mainly hyaluronic acid (HA). HA increases cellular proliferation, delays differentiation and increases cellular motion. We evaluated the pretreatment of DFSPs with intralesional injections of hyaluronidase (HD) prior to the surgical excision. Five of nine cases of DFSPs were pretreated with HD. In HD-pretreated cases the margins for excision of the residual tumor were reduced. HD pretreatment also decreased CD34 staining and increased polarizable collagen in the residual tumor.

Treatment of Carpal and Digital Ganglions by Simple Aspiration, or Aspiration and Injection of Corticosteroid And/Or Hyaluronidase

This retrospective study examined the treatment outcome of 178 carpal and digital ganglion cysts by simple aspiration or aspiration and injection of corticosteroid (triamcinolone acetonide 40 mg/mL) and/or hyaluronidase in 174 patients between 1987 and 1995. A total of 106 ganglions were treated with aspiration and triamcinolone acetonide injection; the cumulative cure rates were 45.3%, 50.0% and 53.8% following one, two or three treatments, respectively. The cure rates were similar in 23 ganglions in the hyaluronidase group: 43.5%, 52.2% and 56.5%, respectively. Seventeen of the 23 ganglions treated with a combination of triamcinolone acetonide and hyaluronidase recurred, yielding success rates of 17.4% and 26.1% following two or three treatments, respectively. Twenty-six ganglions were treated with simple aspiration. Of these, 23 were volar digital ganglions. The success rates were 61.5% and 69.2% following one or two treatments, respectively. The overall success rate was 94 of 178 (52.8%) after a maximum of three treatments, regardless of the type of treatment and the anatomical location of the ganglions. This study provided baseline data following nonoperative management of ganglions; the data can be compared with those from a planned prospective randomized clinical trial involving the use of rolitetracycline as a sclerosing agent, which is currently under review by the Ethics Committee at the authors’ institution.

Intraocular Pressure and Outflow Facility are Unchanged Following Acute and Chronic Intracameral Chondroitinase ABC and Hyaluronidase in Monkeys

We determined the effect of chronic and acute loss of glycosaminoglycans from the aqueous outflow pathway on intraocular pressure (IOP) and outflow facility in the subhuman primate eye. For the study of the chronic effects of the GAGases, cynomolgus monkeys received intracameral injections of hyaluronidase (Streptomyces, 5 or 50 units,n=2) or chondroitinase ABC (0.05 or 0.25 units,n=2) biweekly for 8 months (4 months for each dose). IOP was measured at 3, 7, 10 and 14 days after each injection. Outflow facility (2-level constant pressure) was determined at 2, 4, 6, and 8 months. Monkeys were killed 6 days after the last injection. The changes in the distribution of hyaluronic acid and sulfated proteoglycans in the outflow pathway were examined using substrate-specific histochemical techniques. The acute effects of these enzymes on outflow facilities (30 min or 2 hr after enzyme) were determined in another group of animals (n=4 for each time enzyme−1).IOP and outflow facility were unchanged compared to controls (heat inactivated enzyme) at any time in the chronically or acutely treated monkeys. Hyaluronic acid staining was absent in the outflow pathways of eyes treated chronically with hyaluronidase compared with control eyes, while collagen-associated sulfated proteoglycans were decreased but not completely removed by the chronic chondroitinase ABC treatment. Chronic loss of these glycosaminoglycans from the trabecular meshwork does not appear to contribute to the IOP elevation and decrease in outflow facility that accompanies open-angle glaucoma. Most importantly, no increase in outflow facility was found with acute hyaluronidase or chondroitinase treatment.

The treatment of carpal and digital ganglions by simple aspiration, or aspiration and injection of corticosteroid and/or hyaluronidase

The treatment of carpal and digital ganglions by simple aspiration, or aspiration and injection of corticosteroid and/or hyaluronidase

Clinical course and management of paclitaxel extravasation

Four case reports describing our experience with clinical course and management of paclitaxel extravasation are presented. Local reactions included swelling, mild pain, erythema, induration and hyperpigmentation, but no ulceration. Two patients were treated with cooling only while two further patients received additional hyaluronidase injections subcutaneously. The latter patients suffered longer from symptoms. Local reaction resolved within two weeks and paclitaxel treatment was continued in 3 of 4 patients without further complications. Overall, paclitaxel extravasation induced only mild soft tissue reaction and cooling should be considered standard treatment.

Skin ulceration potential of paclitaxel in a mouse skin model in vivo.

THe antimitotic agent paclitaxel is highly active in the therapy of several tumor types, including ovarian and breast cancer. The commercial formulation (Taxol) is supplied in a vehicle containing alcohol and the surfactant Cremophor EL (polyethoxylated castor oil). Whereas Phase I studies did not describe extravasation necrosis, more recent case reports have suggested that paclitaxel can cause soft tissue necrosis if inadvertently extravasated. The efficacy of various antidotal maneuvers, if any, was not known. Dehaired, BALB/c mice were given intradermal (ID) injections of paclitaxel 0.3 mg, 0.6 mg, or 1.2 mg, or Cremophor EL, 0.1 mL, into the dorsal skin. The sites were observed thrice weekly for evidence of ulceration. Perpendicular widths of skin ulcers were measured by caliper and multiplied to yield a lesion area in cm2. The lesion area multiplied by time in days was integrated by computer to yield cumulative ulceration areas in (cm2 x days). Potential pharmacologic adjuvants were injected ID after paclitaxel. These included saline (0.05 mL), albumin (0.05 mL), hyaluronidase (15 Units), and hydrocortisone (2.5 mg). Topical adjuvants included dimethylsulfoxide solution, (0.1 mL), cooling to 8-10 degrees C or heating to 43-44 degrees C for 30 minutes after ID paclitaxel. Dose-dependent skin ulcers that lasted 12-17 days were created with the 3 ID paclitaxel doses. The two higher paclitaxel dose levels, 0.6 mg and 1.2 mg, were selected for antidote studies. Hyaluronidase and saline were effective ID antidotes for lesions induced by the 0.6-mg paclitaxel dose, but not for the higher paclitaxel dose of 1.2 mg (P<0.05 by analysis of variance). None of the topical adjuvants or other ID adjuvants significantly reduced paclitaxel-induced skin ulcers in the mice. Paclitaxel has experimental vesicant potential in the ID mouse skin model. Clinical extravasations of paclitaxel may be treated by subcutaneous injections of hyaluronidase diluted in saline.

Posttraumatic Macroglossia Complicated by Hyaluronidase Injection

A patient with posttraumatic macroglossia has been presented. A literature review reveals that this is a rare sequela of tongue injury and is usually of acute onset. The delayed symptom of swelling in this patient and the exacerbation of swelling in association with hyaluronidase suggest a causal relationship between the two events. Macroglossia has not been reported in association with hyaluronidase injection, and it is recommended that the drug not be used to treat swelling after tongue injury.

Posttraumatic macroglossia complicated by hyaluronidase injection

A patient with posttraumatic macroglossia has been presented. A literature review reveals that this is a rare sequela of tongue injury and is usually of acute onset. The delayed symptom of swelling in this patient and the exacerbation of swelling in association with hyaluronidase suggest a causal relationship between the two events. Macroglossia has not been reported in association with hyaluronidase injection, and it is recommended that the drug not be used to treat swelling after tongue injury.

Doxorubicin chemomyectomy in orbicularis oculi: increasing drug infiltration at the injection site.

Doxorubicin is an effective agent for chemomyectomy of the orbicularis oculi muscle when injected directly into the eyelid. However, the amount of muscle loss often differs throughout the medial to lateral extent of the eyelid. In order to increase uniform muscle loss in rabbit eyelids, doxorubicin was injected together with agents known to increase the spread of drugs at their injection site in an attempt to increase infiltration of the doxorubicin in the plane of the orbicularis oculi muscle. Three agents were injected, singly or in combination, 20 min prior to doxorubicin administration. Drugs included: collagenase, hyaluronidase, bupivacaine, and hyaluronidase and bupivacaine together. Doxorubicin was injected at a dose of either 0.5 mg, 1 mg or 2 mg. Muscle loss from the co-treatments was compared with that seen with doxorubicin alone as assessed by light microscopic morphometric analysis of the treated eyelids one month after treatment. Injection of doxorubicin alone resulted in a dose-related muscle loss. Injections of either collagenase or hyaluronidase prior to doxorubicin treatment did not alter muscle loss compared with doxorubicin alone. The combination of hyaluronidase and bupivacaine slightly increased muscle loss over doxorubicin alone at the lower doses of doxorubicin. Muscle loss was increased further after doubling the dose of hyaluronidase. Collagenase pretreatment exacerbated eyelid skin injury. Hyaluronidase did not influence the skin toxicity of doxorubicin at doses of 1 or 2 mg, but did result in a delayed onset and a shorter duration of skin injury at the 0.5 mg dose of doxorubicin. Only hyaluronidase combined with bupivacaine increased doxorubicin induced myotoxicity in the orbicularis oculi muscle, presumably by increasing doxorubicin infiltration at the intramuscular injection site throughout the length of the muscle fibers. Thus, the combined injection of hyaluronidase and bupivacaine prior to doxorubicin treatment improves doxorubicin chemomyectomy by increasing drug infiltration throughout the full extent of the orbicularis oculi muscle. Future studies will be directed at achieving better penetration of the drug into individual muscle cells.

Cardiopulmonary Arrest After Retrobulbar Anesthesia in a Patient With an Orbital Roof Defect

Cardiopulmonary arrest developed after injection of bupivacaine hydrochloride, lidocaine, and hyaluronidase in a 78-year-old woman who had previously undergone ipsilateral transcranial orbital surgery with removal of the bone of the orbital roof. The patient required immediate cardiopulmonary resuscitation and intubation. Mechanical ventilation was necessary for 18 hours before spontaneous respirations resumed. The patient improved and was discharged on the fifth postanesthetic day. There were several possible mechanisms by which the local anesthetic could have entered the central nervous system. In patients with orbital roof defects, we recommend that retrobulbar anesthetic agents be used with caution.

Delayed Tarsal Eversion Following Periorbital Trauma

Delayed onset of upper lid edema with exuberant chemosis developed in a 3-year-old girl following blunt periorbital trauma. Examination under anesthesia demonstrated a tightly everted upper tarsus that focally compressed the underlying conjunctiva at the superior tarsal border. Injection of subconjunctival hyaluronidase followed by local compression and temporary tarsorrhaphy resulted in rapid resolution of the chemosis and restoration of the normal lid position.

Induction of vitreolysis and vitreous detachment with hyaluronidase and perfluoropropane gas.

To simulate the posterior vitreous detachment (PVD) in the rabbit, 1 IU hyaluronidase and/or 0.2 ml of perfluoropropane gas was intravitreally injected. Ophthalmoscopic, light microscopic examination prepared by cryotechnique, electron microscopic examination, and electroretinogram were done on the 3rd and 28th postoperative days. As a result, the eyes undergone simultaneous intravitreal injection of 1 IU hyaluronidase and 0.2 ml perfluoropropane gas showed membranous structure split from the internal limiting membrane of the superior retina in 3 days after injection. The eyes also demonstrated membranous structure separated from the superior retina after 28 days, simulating vitreous detachment. On the contrary, neither agent alone induced vitreous detachment. No toxic retinal changes associated with simultaneous intravitreal injection of 1 IU hyaluronidase and 0.2 ml perfluoropropane gas were observed. Therefore, with a future support by histologic examination other than cryotechnique and by immunohistochemical analysis, the simultaneous intravitreal injection of perfluoropropane gas and hyaluronidase would be a promising method to induce vitreous detachment in non-vitrectomized eye.