Effect of Hyaluronidase on the Subcutaneous Absorption of Electrolytes in Humans

Forbes, Gilbert B.; Deisher, Robert W.; Perley, Anne M.; Hartmann, Alexis F.

doi:10.1126/science.111.2877.177

Cited by 38 publications

(7 citation statements)

References 6 publications

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“…Since its discovery as a ''spreading factor'' in testes extracts, purified preparations of hyaluronidase have been studied extensively and used to facilitate the subcutaneous absorption of fluids (hypodermoclysis) and substances (35)(36)(37)(38)(39) and also administered intravenously to deplete intracardiac HA and reduce myocardial ischemic injury (40)(41)(42). Although extremely effective in these capacities, the animal-sourced enzyme can induce hypersensitivity reactions and has a very short circulatory half-life.…”

Section: Substrate Specificity Of a Modified Recombinant Enzymementioning

confidence: 99%

Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase

DuFort

DelGiorno

Carlson

et al. 2016

Biophysical Journal

142

132

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Elevated interstitial fluid pressure can present a substantial barrier to drug delivery in solid tumors. This is particularly true of pancreatic ductal adenocarcinoma, a highly lethal disease characterized by a robust fibroinflammatory response, widespread vascular collapse, and hypoperfusion that together serve as primary mechanisms of treatment resistance. Free-fluid pressures, however, are relatively low in pancreatic ductal adenocarcinoma and cannot account for the vascular collapse. Indeed, we have shown that the overexpression and deposition in the interstitium of high-molecular-weight hyaluronan (HA) is principally responsible for generating pressures that can reach 100 mmHg through the creation of a large gel-fluid phase. By interrogating a variety of tissues, tumor types, and experimental model systems, we show that an HA-dependent fluid phase contributes substantially to pressures in many solid tumors and has been largely unappreciated heretofore. We investigated the relative contributions of both freely mobile fluid and gel fluid to interstitial fluid pressure by performing simultaneous, real-time fluid-pressure measurements with both the classical wick-in-needle method (to estimate free-fluid pressure) and a piezoelectric pressure catheter transducer (which is capable of capturing pressures associated with either phase). We demonstrate further that systemic treatment with pegylated recombinant hyaluronidase (PEGPH20) depletes interstitial HA and eliminates the gel-fluid phase. This significantly reduces interstitial pressures and leaves primarily free fluid behind, relieving the barrier to drug delivery. These findings argue that quantifying the contributions of free- and gel-fluid phases to hydraulically transmitted pressures in a given cancer will be essential to designing the most appropriate and effective strategies to overcome this important and frequently underestimated resistance mechanism.

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Section: Substrate Specificity Of a Modified Recombinant Enzymementioning

confidence: 99%

Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase

DuFort

DelGiorno

Carlson

et al. 2016

Biophysical Journal

142

132

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“…10,23,[39][40][41][42] Clinical history demonstrates the increased dispersion and faster absorption of a broad range of drugs and fluids administered with hyaluronidase products. 10,23,[38][39][40][41][42][43][44] With rHuPH20, for example, Thomas and colleagues 45,46 have demonstrated an accelerated PK profile of SC morphine coadministered with rHuPH20 compared with SC morphine alone, with earlier and greater peak exposure and comparable total bioavailability. Similarly, administration of rHuPH20 significantly enhanced gravity-driven SC infusion flow rates of fluid and electrolytes compared with placebo, leading the authors to suggest the possibility of using hyaluronidaseenabled SC infusions as replacements for pump-driven intravenous fluid therapy.…”

Section: History Of Hyaluronidase Administrationmentioning

confidence: 99%

Review of the Mechanism of Action and Clinical Efficacy of Recombinant Human Hyaluronidase Coadministration with Current Prandial Insulin Formulations

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Vaughn

2010

Journal of Diabetes Science and Technology

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Abbreviations: (A1C) derived average glucose, (C max ) peak plasma concentration, (PK) pharmacokinetics, (PPG) postprandial plasma glucose, (rHuPH20) recombinant human hyaluronidase, (SC) subcutaneous, (t max ) time to peak plasma concentration Keywords: diabetes, glycemic control, hyaluronidase, rHuPH20, ultrafast insulin AbstractFor patients with type 1 or type 2 diabetes, achieving good glycemic control is critical for successful treatment outcomes. As many patients remain unable to reach glycemic goals with currently available rapid-acting analog insulins, ultrafast insulin products are being developed that provide an even faster pharmacokinetic profile compared with current rapid prandial insulin products. The overall strategy of these ultrafast insulin products is to better mimic the normal physiologic response to insulin that occurs in healthy individuals to further improve glycemic control. Recombinant human hyaluronidase (rHuPH20) is a genetically engineered soluble hyaluronidase approved by the U.S. Food and Drug Administration as an adjuvant to increase the absorption and dispersion of other injected drugs; mammalian hyaluronidases as a class have over 6 decades of clinical use supporting the safety and/or efficacy of hyaluronidase coadministration. Clinical findings have demonstrated that coadministration of rHuPH20 with insulin or an insulin analog achieved faster systemic absorption, reduced inter-and intrapatient variability of insulin absorption, and achieved faster metabolic effects compared with injection of either insulin formulation alone. The magnitude of this acceleration is similar to the incrementally faster absorption of prandial insulin analogs as compared with regular insulin. In addition, coadministration of rHuPH20 with regular insulin or insulin analog also improved the achievement of prandial glycemic targets. Thus, rHuPH20 coadministration shows promise as a method of establishing a more rapid insulin profile to prandial insulin in patients with diabetes and has the potential to yield substantial improvements in postprandial glycemic excursion.

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“…However, any dehydrated patient may benefit, regardless of age. The original descriptions of clysis were concerned with its use in pediatric medicine 4–8 …”

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confidence: 99%

Nutrition by Hypodermoclysis

Berger

1984

J American Geriatrics Society

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It is possible to administer fluid subcutaneously at a rate so slow that the forces of diffusion and perfusion are able to transfer that fluid to the circulation at a rate equal to the rate of its delivery. In clinical practice, fluid can be delivered subcutaneously in the presence of hyaluronidase at about 1 ml per minute without the accumulation of edema. Thus, 1500 ml can be delivered in 24 hours at a single site, and 3000 ml of fluid can be delivered at two sites in 24 hours. This procedure, called hypodermoclysis, is used for hydration. It is particularly useful for the aged patient in the long-term care institution when it will save the patient from the dangers of hospitalization and save society from its costs.

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Effect of Hyaluronidase on the Subcutaneous Absorption of Electrolytes in Humans

Cited by 38 publications

References 6 publications

Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase

Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase

Review of the Mechanism of Action and Clinical Efficacy of Recombinant Human Hyaluronidase Coadministration with Current Prandial Insulin Formulations

Nutrition by Hypodermoclysis

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