Intravesical chemotherapy of superficial bladder tumors in a controlled trial with cis-platinum versus cis-platinum plus hyaluronidase

Twenty-three patients with superficial transitional cell carcinoma of the urinary bladder were randomized for intravesical chemotherapy with either cis-platinum or cis-platinum plus hyaluronidase, an enzyme promoting diffusion factor. Treatment was administered at 3-week intervals and checked for efficacy by repeated cystoscopies after every three instillations. Hematologic and biochemical tests were repeated prior to each treatment and, these, in additional to the cystoscopic findings, served for final evaluation of results and toxicity. The complete response rate was found to be superior with cis-platinum than with cis-platinum plus hyaluronidase. The complete plus partial response rates were equal in both groups. We conclude that the addition of hyaluronidase to cis-platinum revealed no superiority to cis-platinum alone, and both modes of treatment showed similar clinical efficacy as other drugs previously used for intravesical chemotherapy.     

Use of intrathecal hyaluronidase in the management of tuberculous meningitis with hydrocephalus

A preliminary study to evaluate the efficacy of intrathecal hyaluronidase was carried out in nine children suffering from tuberculous meningitis with communicating hydrocephalus. This was followed by a randomized trial in which five cases were treated with intrathecal hyaluronidase, while six cases were treated by the insertion of a ventriculoperitoneal shunt. No untoward reaction of any significance was noted. The results were judged in terms of improvement in the sensorium and mentation, in specific neurological deficit (e.g., visual impairment and hemiparesis), and in overall functional performance. Although most of the patients receiving hyaluronidase showed some improvement in the sensorium, only one of the nine preliminary cases and one of the five cases in the randomized trial showed a total recovery of function. Two of the six shunted patients, however, showed complete recovery. Shunt insertion led to further improvement in two of the nine preliminary cases who had failed to respond to treatment with hyaluronidase. This preliminary study shows that intrathecal hyaluronidase does, in most cases, lead to an improvement in the sensorium but does not offer any particular advantage over shunt insertion in terms of regression of specific neurological deficit or overall functional improvement.     

Anti-Elastase and Anti-Hyaluronidase Activities of Saponins and Sapogenins from Hedera helix,Aesculus hippocastanum,and Ruscus aculeatus: Factors Contributing to their Efficacy in the Treatment of Venous Insufficiency

Triterpene and steroid saponins and sapogenins of medicinal plants (Aesculus hippocastanum L., Hedera helix L., Ruscus aculeatus L.) are claimed to be effective for the treatment/prevention of venous insufficiency. In this work we evaluated the inhibitory effects of these plant constituents on the activity of elastase and hyaluronidase, the enzyme systems involved in the turnover of the main components of the perivascular amorphous substance. The results evidence that for Hedera helix L., the sapogenins only non-competitively inhibit hyaluronidase activity in a dose-dependent fashion, showing comparable IC₅₀ values (hederagenin IC₅₀ = 280.4 μM; oleanolic acid IC₅₀ = 300.2 μM); both the saponins hederacoside C and α-hederin are very weak inhibitors. The same behaviour is observed for serine protease porcine pancreatic elastase: the glycosides are devoid of inhibitory action, while genins are potent competitive inhibitors (oleanolic acid IC₅₀ = 5.1 μM; hederagenin IC₅₀ = 40.6 μM). Constituents from Aesculus hippocastanum L. show inhibitory effects only on hyaluronidase, and this activity is mainly linked to the saponin escin (IC₅₀ = 149.9 μM), less to its genin escinol (IC₅₀ = 1.65 μM). By contrast, ruscogenins from Ruscus aculeatus L., ineffective on hyaluronidase activity, exhibit remarkable anti-elastase activity (IC₅₀ = 119.9 μM; competitive inhibition). The mechanism of elastase inhibition by triterpene and steroid aglycones, with a nitroanilide derivative as substrate, is discussed.     

Comparison of plain with pH-adjusted bupivacaine with hyaluronidase for peribulbar block

Fifty patients scheduled for cataract surgery under peribulbar block were randomised to receive either plain (pH 5.4) or pH-adjusted (pH 6.8 range 6.7-6.9) 0.75% bupivacaine. Hyaluronidase was added to both solutions prior to peribulbar block. The time of onset of akinesia of the globe and the need for supplementary injections were recorded by an independent observer. Patients who returned for surgery to the second eye received the alternative local anaesthetic solution for the second peribulbar block. The relative efficacy of the different anaesthetic solutions was compared in patients who underwent unilateral surgery (Group A, n = 50). In 12 patients (Group B) who underwent bilateral surgery, direct comparisons between eyes in the same patient were possible. In both groups of patients, eyes receiving peribulbar block with the pH-adjusted solution showed a shorter time to partial akinesia of the globe (P less than 0.05). However, there was no difference between the solutions in the time to complete akinesia of the globe, but the number of supplementary injections required for an effective block with the pH-adjusted solution was increased. Onset time to akinesia of the lateral and superior rectus muscles was shortened in patients receiving the pH-adjusted solution but there were minimal effects on the medial and inferior recti.     

Pilot Study of Human Recombinant Hyaluronidase–Enhanced Subcutaneous Hydration and Opioid Administration for Sickle Cell Disease Acute Pain Episodes

ABSTRACT

The objective of this study was to determine the feasibility of protocol-driven human recombinant hyaluronidase (rHuPH20)-enhanced subcutaneous (SC) hydration and opioid administration in adults presenting to the emergency department (ED) with sickle cell disease acute pain episodes (SCDAPE). Adults with SCDAPE were given 150 U of rHuPH20 and normal saline subcutaneously. Opioids were administered SC every 15 minutes for 4 hours until numerical rating scale (NRS) pain intensity scores fell to <5, or Ramsay Sedation Scores were >4. Pain intensity and pain relief were recorded hourly. Total morphine equivalents and fluid volume, total pain relief (TOTPAR), patient- and physician-perceived global efficacy, patient-perceived global SC needle discomfort, physician-rated ease of needle placement, and adverse effects were noted. Ten patients (6 males, 4 females), mean age 32.9 years (23–56 years) completed the trial. Mean pain intensity scores fell 25% (from 9.2 to 6.9) from baseline and mean 4-hour TOTPAR score was 4 (maximum: 16). A mean total of 119 mg (70–170 mg) morphine equivalents and 846 mL (200–1650 mL) normal saline were administered. Mean patient and physician global perceived efficacy ratings were 3.4 and 4.2 (of 5). Patient global discomfort of SC needle presence was 2.7 (of 10), and ease of needle placement was physician rated at 4 (of 4; easiest). Patients experienced mild swelling and stinging at the SC site, and no infusion required discontinuation. The authors conclude that rHuPH20-enhanced subcutaneous hydration and opioid administration appear feasible from this pilot study. These results need confirmation in a controlled clinical trial.     

Effect of microplasmin on the clearance of vitreous haemorrhage from an experimental model in rabbits

Purpose: Microplasmin is known to alter the structure of the vitreous gel. The current experiments were designed to assess its ability to enhance clearance of an experimentally induced vitreous haemorrhage, and to compare it to ovine hyaluronidase. Methods: Twenty‐five rabbits were used for this experiment, divided into five groups; groups 1–3 are microplasmin‐treated eyes with 25, 75 and 125 μg, respectively. Group 4 treated with 55 IU of hyaluronidase, while group 5 was treated with normal saline (control). Eyes were injected in the mid‐vitreous with 0.05 ml of autologous blood obtained from the marginal ear vein. One week later, all the groups were injected with the test solution injected in mid‐vitreous as stated above. Clearance of the vitreous haemorrhage was assessed weekly indirect ophthalmoscopy for 8 weeks. Results: Microplasmin‐treated eyes showed a significant clearance of the vitreous haemorrhage in a dose‐dependent fashion, where group 3 (125 μg) had the highest clearance rate in comparison with control eyes. Hyaluronidase‐treated eyes showed a similar clearance rate as group 3. In addition, group 3 showed a complete posterior vitreous detachment, which did not develop in hyaluronidase‐treated eyes. Conclusion: Microplasmin may be a useful agent to accelerate the clearance of vitreous haemorrhage.     

Delayed Hypersensitivity Reaction to Restylane® SubQ

Purpose: To report on 4 patients who developed delayed hypersensitivity reactions to Restylane^® SubQ and their management. To our knowledge, no cases of delayed hypersensitivity to Restylane^® SubQ have been previously reported.

Methods: A retrospective case series of 4 patients who were treated with preperiosteal Restylane^® SubQ to their cheeks, for facial volume augmentation. All 4 patients were subsequently referred with delayed hypersensitivity reactions over a 4-month period.

Results: The hypersensitivity reactions occurred from 1 week to 4 months’ post-cheek augmentation using Restylane^® SubQ. All patients had previously (and some since) been treated with other non-animal stabilized hyaluronic acid (NASHA) products without adverse effect. Hyaluronidase led to fast and effective resolution in all cases, although 2 of the patients required repeat treatment.

Conclusion: Hyaluronidase was effective at treating the inflammatory reaction and breaking up the retained Restylane^® SubQ in all patients. Although Restylane^® SubQ should be avoided in these patients, in our experience this does not preclude them from using other similar NASHA products.     

Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2

Failure of remyelination is largely responsible for sustained neurologic symptoms in multiple sclerosis (MS). MS lesions contain hyaluronan deposits that inhibit oligodendrocyte precursor cell (OPC) maturation. However, the mechanism behind this inhibition is unclear. We report here that Toll-like receptor 2 (TLR2) is expressed by oligodendrocytes and is up-regulated in MS lesions. Pathogen-derived TLR2 agonists, but not agonists for other TLRs, inhibit OPC maturation in vitro. Hyaluronan-mediated inhibition of OPC maturation requires TLR2 and MyD88, a TLR2 adaptor molecule. Ablated expression of TLR2 also enhances remyelination in a lysolecithin animal model. Hyaluronidases expressed by OPCs degrade hyaluronan to hyaluronan oligomers, a requirement for hyaluronan/TLR2 signaling. MS lesions contain both TLR2⁺ oligodendrocytes and low-molecular-weight hyaluronan, consistent with their importance to remyelination in MS. We thus have defined a mechanism controlling remyelination failure in MS where hyaluronan is degraded by hyaluronidases into hyaluronan oligomers that block OPC maturation and remyelination through TLR2-MyD88 signaling.