ABSTRACT
The canine is the most important large animal model for testing novel hemophilia A (HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, different biological properties between cFVIII and human FVIII (hFVIII) indicated that the development of novel HA treatment may require careful characterization of non-human FVIII. To investigate whether the data obtained using cFVIII can translate to HA treatment in human, we analyzed the differential biological properties of canine heavy chain (cHC) and light chain (cLC) by comparing with human heavy chain (hHC) and light chain (hLC). The secretion of cHC was 5-30-fold higher than hHC, with or without light chains (LCs). cHC+hLC group exhibited ~18-fold increase in coagulation activity compared with hHC+hLC delivery by recombinant adeno-associated viral vectors. Unlike hHC, the secretion of cHC was independent of LCs. cLC improves the specific activity of FVIII by two- to threefold compared with hLC. Moreover, the cLC, but not cHC, contributes to the higher stability of cFVIII. Our results suggested that the cFVIII expression results in the canine model should be interpreted with caution as the cHC secreted more efficiently than hHC and cLC exhibited a more active and stable phenotype than hLC.
Subject(s)
Factor VIII/immunology , Genetic Therapy/adverse effects , Hemophilia A/therapy , Animals , Cricetinae , Dependovirus/genetics , Disease Models, Animal , Dogs , Factor VIII/genetics , Factor VIII/metabolism , Gene Transfer Techniques/adverse effects , Genetic Therapy/methods , HEK293 Cells , Humans , Immunoglobulins/immunology , Mice, Inbred BALB C , Mice, Inbred C57BL , Species SpecificityABSTRACT
BACKGROUND: Telomerase activation and an alternative lengthening of telomeres (ALT) mechanism are two telomere-lengthening cancer cell survival mechanisms elicited by both chemo- and/or radiotherapy. Telomere lengthening interferes with cell lethality and results in the immortalization of cancer cells. To counteract these mechanisms, we developed a drug delivery system (DDS) consisting of a polymeric implant that is inserted directly into tumors. The DDS releases, continuously and gradually, a cationic porphyrin (PdTMPyP4) for >30 days after a single application, and inhibits telomerase activation. METHODS: The PdTMPyP4 porphyrin is incorporated into a poly(co-glycolic lactic)acid (PLGA) polymer, solidified and cut into small rods. PdTMPyP4 release from the rods was measured spectrophotometrically over time. Uptake of Pd in the DNA of in L428 Hodgkins lymphoma cells was measured by ICP-MS, and telomerase activation by the TRAP assay. The rods were placed into the growth medium of cells whose growth rate was measured for 11 and 19 days. The cylinders were also inserted directly into KHJJ murine mammary tumors borne on the thighs of BALB/c mice and the tumor growth rate measured. RESULTS: In vitro, >10(9)Pd atoms were measured in the DNA of each L428 cell and telomerase activity was reduced by ~15% within 24 h. A one-time application of the rod in the cell medium induced a factor of >5 greater lethality compared to a blank rod or untreated controls. In vivo, a one-time insertion of the rod into tumors resulted in the retardation of the growth rate by factors of 3-5 compared to untreated controls. Systemic uptake after intratumoral insertion of the rod was negligible. CONCLUSION: The results suggest that the direct intratumoral insertion of a PdTMPyP4-containing polymeric rod would be of benefit as an adjuvant treatment for patients undergoing chemo- or radiotherapy. By preventing the lengthening of telomeres and therefore the unrestricted growth of cancer cells, our DDS will provide a significant therapeutic advantage to these treatments without affecting normal tissues.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Cell Proliferation/drug effects , Drug Delivery Systems , Hodgkin Disease/prevention & control , Mammary Neoplasms, Animal/prevention & control , Porphyrins/administration & dosage , Telomere/genetics , Angiogenesis Inhibitors/pharmacology , Animals , DNA, Neoplasm/genetics , Female , Hodgkin Disease/genetics , Hodgkin Disease/pathology , Humans , Lactic Acid/chemistry , Mammary Neoplasms, Animal/genetics , Mammary Neoplasms, Animal/pathology , Mice , Mice, Inbred BALB C , Palladium/chemistry , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Porphyrins/pharmacology , Telomerase/metabolism , Tumor Cells, CulturedABSTRACT
BACKGROUND: The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In this large phase 3 clinical trial, we sought to confirm the efficacy of telcagepant, the first orally bioavailable CGRP receptor antagonist. METHODS: Adults with migraine with or without aura (International Headache Society criteria) treated a moderate or severe attack with oral telcagepant 50 mg (n = 177), 150 mg (n = 381), 300 mg (n = 371), or placebo (n = 365) in a randomized, double-blind trial. The 5 co-primary endpoints were pain freedom, pain relief, and absence of photophobia, absence of phonophobia, and absence of nausea, all at 2 hours postdose. The key secondary endpoint was 2-24 hour sustained pain freedom. The prespecified primary efficacy analyses evaluated the 150 mg and 300 mg groups; the 50-mg group was included on an exploratory basis to further characterize the dose response but was not prespecified for analysis. Tolerability was assessed by adverse experience reports. RESULTS: Telcagepant 300 mg was more effective (p Subject(s)
Azepines/administration & dosage
, Calcitonin Gene-Related Peptide Receptor Antagonists
, Calcitonin Gene-Related Peptide/antagonists & inhibitors
, Imidazoles/administration & dosage
, Migraine Disorders/drug therapy
, Acute Disease
, Adult
, Azepines/adverse effects
, Calcitonin Gene-Related Peptide/metabolism
, Dose-Response Relationship, Drug
, Double-Blind Method
, Endpoint Determination
, Female
, Humans
, Hyperacusis/drug therapy
, Hyperacusis/etiology
, Imidazoles/adverse effects
, Male
, Middle Aged
, Migraine Disorders/metabolism
, Migraine Disorders/physiopathology
, Nausea/etiology
, Outcome Assessment, Health Care
, Pain Measurement
, Photophobia/drug therapy
, Photophobia/etiology
, Placebos
, Quality of Life
, Receptors, Calcitonin Gene-Related Peptide/metabolism
, Surveys and Questionnaires
, Treatment Outcome
ABSTRACT
Raltegravir is a human immunodeficiency virus-1 (HIV-1) integrase strand transfer inhibitor metabolized by glucuronidation via UDP-glucuronosyltransferase 1A1 (UGT1A1). In this study, 30 subjects with a UGT1A1*28/*28 genotype (associated with decreased activity of UGT1A1) and 27 UGT1A1*1/*1 control subjects (matched by race, age, gender, and body mass index) received a single 400-mg dose of raltegravir after fasting. No serious adverse experiences were reported, and there were no discontinuations due to adverse experiences. The geometric mean ratio (GMR) (UGT1A1*28/*28 to UGT1A1*1/*1) and 90% confidence interval (CI) were 1.41 (0.96, 2.09) for raltegravir area under the concentration-time curve (AUC(0-infinity)), 1.40 (0.86, 2.28) for maximum plasma concentration (C(max)), and 1.91 (1.43, 2.55) for concentration at the 12-h time point (C(12 h)). No clinically important differences in time to maximum concentration (T(max)) or half-life were observed. Plasma concentrations of raltegravir are modestly higher in individuals with the UGT1A1*28/*28 genotype than in those with the UGT1A1*1/*1 genotype. This increase is not clinically significant, and therefore no dose adjustment of raltegravir is required for individuals with the UGT1A1*28/*28 genotype.
Subject(s)
Glucuronosyltransferase/genetics , HIV Integrase Inhibitors/pharmacokinetics , Pyrrolidinones/pharmacokinetics , Adult , Area Under Curve , Female , Genotype , Glucuronosyltransferase/metabolism , Half-Life , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Raltegravir PotassiumABSTRACT
Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC(95) = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C(max) of approximately 20 muM raltegravir was attained, approximately 4-fold higher than the C(max) at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.
Subject(s)
Electrocardiography , HIV Integrase Inhibitors/adverse effects , Pyrrolidinones/adverse effects , Adult , Anti-Infective Agents/adverse effects , Aza Compounds/adverse effects , Cross-Over Studies , Double-Blind Method , Female , Fluoroquinolones , HIV Integrase Inhibitors/pharmacokinetics , Humans , Male , Middle Aged , Moxifloxacin , Pyrrolidinones/pharmacokinetics , Quinolines/adverse effects , Raltegravir Potassium , Time FactorsABSTRACT
Raltegravir is a novel human immunodeficiency virus-1 integrase inhibitor with potent in vitro activity (95% inhibitory concentration (IC95)=33 nM in 50% human serum). Three double-blind, randomized, placebo-controlled, pharmacokinetic, safety, and tolerability studies were conducted: (1) single-dose escalation study (10-1,600 mg), (2) multiple-dose escalation study (100-800 mg q12 h x 10 days), and (3) single-dose female study (400 mg). Raltegravir was rapidly absorbed with a terminal half-life (t1/2) approximately 7-12 h. Approximately 7-14% of raltegravir was excreted unchanged in urine. Area under the curve (AUC)(0-infinity) was similar between male and female subjects. After multiple-dose administration, steady state was achieved within 2 days; there was little to modest accumulation of raltegravir. Trough levels were >33 nM for dose levels of 100 mg and greater. Raltegravir is generally well tolerated at doses of up to 1,600 mg/day given for up to 10 days and exhibits a pharmacokinetic profile supportive of twice-daily dosing with multiple doses of 100 mg and greater achieving trough levels >33 nM.
Subject(s)
HIV Integrase Inhibitors/administration & dosage , Organic Chemicals/administration & dosage , Administration, Oral , Adult , Area Under Curve , Double-Blind Method , Drug Administration Schedule , Female , HIV Integrase Inhibitors/adverse effects , HIV Integrase Inhibitors/pharmacokinetics , Half-Life , Humans , Male , Metabolic Clearance Rate , Organic Chemicals/adverse effects , Organic Chemicals/pharmacokinetics , Pyrrolidinones , Raltegravir Potassium , Reference ValuesABSTRACT
A number of issues have remained unanswered in the design of "thorough QT"(TQT) studies. In this randomized, placebo-controlled, two-period crossover study in 20 healthy subjects, replicate electrocardiograms (ECGs) were recorded on a digital 12-lead Holter recorder, extracted in a core ECG laboratory, and interpreted manually by a cardiologist. The observed within-subject variability was slightly greater when time-matched baselines were employed than when predose baselines were employed, whereas the magnitude of the increase in QTc was similar for both. Moxifloxacin 400 mg was associated with an observed 7.5-12.5 ms increase in the mean placebo- and baseline-corrected QTc interval. A PK-QTc model estimated a 3.9 ms increase in the QTc interval for every 1,000 ng/ml increase in moxifloxacin concentration. The QTc increases associated with moxifloxacin support the appropriateness of its use as a positive control in TQT studies. This crossover study failed to justify the use of time-matched baselines rather than the less resource-intensive predose definition of baseline.
Subject(s)
Anti-Infective Agents/adverse effects , Aza Compounds/adverse effects , Long QT Syndrome/chemically induced , Quinolines/adverse effects , Research Design , Adult , Anti-Infective Agents/administration & dosage , Aza Compounds/administration & dosage , Cross-Over Studies , Dose-Response Relationship, Drug , Electrocardiography , Female , Fluoroquinolones , Humans , Long QT Syndrome/physiopathology , Male , Moxifloxacin , Pilot Projects , Quinolines/administration & dosageABSTRACT
The Paced Serial Addition Test (PSAT) presents a series of digits at different speeds with the requirement that the two most recent numbers be added together. Although the PSAT is a relatively difficult test, its level of difficulty may be decreased by changing the number list to make the answers simpler and by presenting the digits visually rather than aurally. In view of this, the present experiment varied both task difficulty (easy vs. hard) and mode of presentation (visual vs. auditory). Task difficulty was manipulated by using two different lists composed of single digits whose answers ranged between 2 and 10 (easy) or 2 and 18 (hard). All stimuli were presented by computer which permitted measurement of response latencies, as well as correctness of responding. The results showed that mode of presentation, but not task difficulty, produced highly significant effects. Additional evidence showed that the ability to compute answers to simple addition problems must be considered as a modulator variable. However, an individual's basic arithmetic ability is not as critical as the modality in which a stimulus is presented. The lower performance associated with the auditory version (i.e., PASAT) was interpreted as an interference effect caused by both the stimulus and the response occurring in a single auditory information processing channel. This interpretation suggests that the PASAT's well documented sensitivity to traumatic brain injury (TBI) may be due, at least in part, to an increased susceptibility to interference effects rather than attributable solely to a decreased rate of information processing.
Subject(s)
Diagnosis, Computer-Assisted , Memory, Short-Term/physiology , Mental Processes/physiology , Neuropsychological Tests , Acoustic Stimulation/methods , Adolescent , Adult , Female , Humans , Male , Neuropsychological Tests/statistics & numerical data , Photic Stimulation/methods , Problem Solving , Random Allocation , Reference ValuesABSTRACT
Sonophoresis at a frequency of 20 kHz has been shown to enhance transdermal drug delivery, a phenomenon referred to as low-frequency sonophoresis. This study provides an investigation of the dependence of low-frequency sonophoresis on various ultrasound parameters, including the distance of the horn from the skin, intensity, and frequency. We performed in vitro experiments with full thickness pig skin to measure enhancements of skin conductivity and drug permeability. Ultrasound was applied to pretreat the skin using a sonicator operating at a frequency of either 20 or 40 kHz. We also measured pitting of aluminum foil to measure cavitation, which is the principal mechanism of low-frequency sonophoresis. The skin conductivity enhancement was found to be inversely proportional to the distance of the horn from the skin. As the intensity increased, skin conductivity enhancement also increased up to a certain threshold, and then dropped off. The intensities (I(max)) at which maximum enhancement occur are about 14 W/cm2 for 20 kHz and 17 W/cm2 for 40 kHz. These findings may be useful in optimizing low-frequency sonophoresis. Overall, the dependence of transport on ultrasound parameters is similar to that of aluminum foil pitting. These results support the role of cavitation in low-frequency sonophoresis.
Subject(s)
Phonophoresis/methods , Ultrasonics , Administration, Cutaneous , Animals , Diuretics, Osmotic/administration & dosage , Diuretics, Osmotic/pharmacokinetics , Mannitol/administration & dosage , Mannitol/pharmacokinetics , Phonophoresis/instrumentation , Skin/diagnostic imaging , Skin/drug effects , Skin/metabolism , Swine , UltrasonographyABSTRACT
UNLABELLED: PURPOSE. Heparin and low-molecular weight heparin (LMWH) are the most commonly used anticoagulants and are administered by intravenous or subcutaneous injections. However, injections of heparin have the potential risk of bleeding complications and the requirement of close monitoring in some cases. We hypothesized that transdermal delivery of heparin may provide an attractive alternative to injections. However, the dose of transdermally delivered heparin is limited by low skin permeability. METHODS: We increased skin permeability to heparin and LMWH using low-frequency (20 kHz) ultrasound. Biologic activity of transdermally delivered heparin was measured by using activated clotting time assays and by using anti-Xa (aXa) activity. Structural integrity of heparin was also assessed by using gel electrophoresis. RESULTS: Low-frequency ultrasound increased permeability of pigskin in vitro and rat skin in vivo and allowed delivery of biologically active doses of heparin and low-molecular weight heparin transdermally. A prolonged contact of transdermally delivered heparin with pigskin was found to reduce the biologic activity of heparin, although no such deactivation was observed during short exposures. Transdermally delivered LMWH resulted in sustained aXa levels in the blood. This result was in strong contrast to subcutaneous or intravenous injections of LMWH, which resulted in only temporary elevations of aXa level. CONCLUSIONS: Transdermal delivery of low-molecular weight heparin is a potential alternative to injections.
Subject(s)
Anticoagulants/administration & dosage , Heparin, Low-Molecular-Weight/administration & dosage , Heparin/administration & dosage , Skin Absorption/physiology , Administration, Cutaneous , Animals , Anticoagulants/pharmacokinetics , Blood Coagulation/drug effects , Electric Conductivity , Electrophoresis, Polyacrylamide Gel , Female , Heparin/pharmacokinetics , Heparin/pharmacology , Heparin, Low-Molecular-Weight/pharmacokinetics , Heparin, Low-Molecular-Weight/pharmacology , In Vitro Techniques , Inulin , Male , Rats , Rats, Sprague-Dawley , Swine , UltrasonicsABSTRACT
OBJECTIVES: Bladder hyperpermeability should result in elevated blood levels of intravesically administered agents. Reabsorption from a hyperpermeable bladder should result in prolonged urinary excretion of an agent after parenteral administration. To test these hypotheses, urinary clearance and plasma levels of sodium fluorescein (NaF) were measured in mice before and during cyclophosphamide (CYP) and protamine-induced hemorrhagic cystitis. METHODS: To measure the plasma uptake of NaF from the bladder, 10 mg/mL NaF was instilled, either by catheter or retrograde urethral infusion, 15 minutes before retro-orbital or ventricular sampling. The plasma levels were measured 24 hours and 14 days after exposure to CYP 300 mg/kg or 15 minutes after instillation of protamine 10 mg/mL. Hourly urine concentrations were measured immediately after intraperitoneal administration of 10 mg/kg NaF. Pretreatment samples were compared with those obtained 24 hours after intraperitoneal administration of 300 mg/kg CYP. RESULTS: Urinary NaF excretion was delayed in CYP-exposed mice. A bi-exponential model provided an appropriate fit of the data, both before and after CYP administration. The plasma levels of NaF were significantly elevated at 24 hours and 14 days after CYP exposure when sampled by ventricular nick or retro-orbitally. The median concentration of fluorescein in the protamine-treated mice was significantly higher than in the control mice. CONCLUSIONS: Fluorescein can be used to measure alterations in bladder permeability after bladder mucosal injury in mice. Urinary excretion of NaF is a bi-exponential process that is delayed after bladder mucosal injury, presumably because of increased mucosal permeability and resorption from the urine into the bloodstream.
Subject(s)
Fluorescein/pharmacokinetics , Urinary Bladder Diseases/blood , Urinary Bladder Diseases/urine , Urinary Bladder/metabolism , Analysis of Variance , Animals , Cyclophosphamide , Cystitis/chemically induced , Cystitis/metabolism , Hematuria/chemically induced , Hematuria/metabolism , Injections, Intraperitoneal , Mice , Mucous Membrane/metabolism , Permeability , Protamines , Urinary Bladder Diseases/chemically induced , Urothelium/metabolismSubject(s)
Contrast Media/pharmacokinetics , Cystitis/metabolism , Fluorescein/pharmacokinetics , Urinary Bladder/metabolism , Animals , Cyclophosphamide , Cystitis/chemically induced , Heparin Antagonists , Mice , Mucous Membrane/drug effects , Mucous Membrane/metabolism , Permeability , Protamines , Urinary Bladder/drug effectsSubject(s)
Mercury Poisoning, Nervous System/epidemiology , Seafood , Animals , Child , Denmark/epidemiology , Developmental Disabilities/chemically induced , Environmental Pollutants , Female , Fishes , Humans , Male , Methylmercury Compounds/adverse effects , Pregnancy , Prenatal Exposure Delayed Effects , Regression Analysis , Seafood/poisoning , Seychelles/epidemiology , WhalesABSTRACT
This paper discusses the state of the art in a relatively new approach in the field of controlled drug delivery-responsive polymeric drug delivery systems. Such systems are capable of adjusting drug release rates in response to a physiological need. The fundamental principles of externally and self-regulated delivery systems are examined. Special attention is paid to specific clinical settings such as diabetes, presenting the advantages and disadvantages of different approaches.
Subject(s)
Drug Delivery Systems , Excipients/chemistry , Polymers/chemistry , Animals , HumansABSTRACT
Transdermal extraction of clinically relevant analytes offers a potentially noninvasive method of diagnostics. However, development of such a method is limited by the low permeability of skin. In this paper, we present a potential method for noninvasive diagnostics based on ultrasonic skin permeabilization and subsequent extraction of interstitial fluid (ISF) across the skin using vacuum. ISF extracted by this method was collected and analyzed for glucose and other analytes. Glucose concentration in the extracted fluid correlates well with blood glucose concentration over a range of 50-250 mg/dl. A mathematical model describing vacuum-induced transport of ISF through ultrasonically permeabilized skin is presented as well. The model accounts for convective, as well as diffusive, transport processes across blood capillaries, epidermis, and the stratum corneum. The overall predictions of the model compare favorably with the experimental observations.
Subject(s)
Blood Glucose/analysis , Extracellular Space/metabolism , Skin/diagnostic imaging , Skin/metabolism , Specimen Handling/methods , Animals , Forecasting , Glucose/metabolism , Models, Biological , Permeability , Rats , Rats, Sprague-Dawley , UltrasonographyABSTRACT
We studied the glucose-responsive insulin controlled release system based on the hydrogel poly(2-hydroxyethyl methacrylate-co-N,N-dimethylaminoethyl methacrylate), also called poly(HEMA-co-DMAEMA), with entrapped glucose oxidase, catalase and insulin. When exposed to physiological fluids, glucose diffuses into the hydrogel, glucose oxidase catalyzes the glucose conversion to gluconic acid, causing swelling of the pH-sensitive hydrogel and subsequently increased insulin release. The higher the glucose concentration in the medium, the higher and faster the swelling and release rates. The effects of polymer morphology and oxygen availability on hydrogel swelling and on insulin release kinetics were tested. Polymer morphology was modified by changing the crosslinking agent (tetraethylene glycol dimethacrylate) concentration (0-0.95 vol%). Oxygen availability was modified by changing the immobilized catalase concentration (0-15 units catalase per unit glucose oxidase) and by bubbling oxygen through the medium. The results indicated that: (i) Hydrogels without crosslinking agent were found to be stable in water, and their sensitivity to pH and glucose was higher than the chemically crosslinked hydrogels. (ii) Immobilization of catalase in addition to glucose oxidase in hydrogels prepared without crosslinking agent, resulted in enhanced swelling kinetic. In addition, we carried out primary in vivo experiments on rats, which demonstrated that at least some of the entrapped insulin retains its active form and is effective in reducing blood glucose levels. Moreover, no tissue encapsulation was observed around matrices implanted in the peritoneum. In conclusion, the pH-sensitive hydrogel poly(HEMA-co-DMAEMA) can be manipulated to produce glucose-responsive insulin release system that is effective in reducing blood glucose levels.
Subject(s)
Glucose/chemistry , Insulin/administration & dosage , Animals , Catalase/chemistry , Enzymes, Immobilized/chemistry , Glucose Oxidase/chemistry , Hydrogels , Hydrogen-Ion Concentration , Insulin/chemistry , Kinetics , Polymethacrylic Acids/chemistry , Rats , Scattering, RadiationABSTRACT
Transdermal drug delivery offers an attractive alternative to injections and oral medications. However, applications of transdermal drug delivery are limited to only a few drugs as a result of low skin permeability. Application of low-frequency ultrasound enhances skin permeability, a phenomenon referred to as low-frequency sonophoresis. In this method, a short application of ultrasound is used to permeabilize skin for a prolonged period of time. During this period, ultrasonically permeabilized skin may be utilized for drug delivery. In addition, a sample of interstitial fluid or its components may be extracted through permeabilized skin for diagnostic applications. In this paper, we report our in vivo studies that demonstrate the principles of both of these concepts. Detailed studies on drug delivery are performed using inulin and mannitol as model drugs. Studies on diagnostics are performed using glucose as a model analyte. Applications of this technology to drug delivery and diagnostics are discussed.
Subject(s)
Administration, Cutaneous , Diagnostic Techniques and Procedures , Drug Delivery Systems , Animals , Glucose/metabolism , Rats , Rats, Sprague-Dawley , Skin Absorption , UltrasonicsABSTRACT
PURPOSE: Transdermal extraction of clinically relevant analytes offers a potentially non-invasive method of diagnostics. However, development of such a method is limited by the low skin permeability. In this paper, we report a potential method for non-invasive diagnostics based on ultrasonic skin permeabilization and subsequent extraction of interstitial fluid (ISF) across the skin. METHODS: In vivo experiments were performed using Sprague Dawley rats to assess ultrasound-induced skin permeabilization and subsequent extraction of various analytes. Serum and ISF concentrations of various analytes were measured. RESULTS: Application of low-frequency ultrasound rapidly increased skin permeability. Skin remained in a state of high permeability for at least three hours. During this period, application of vacuum extracted ISF across rat skin in vivo at a rate of 25.7 microl/cm2/hr. We measured concentrations of various analytes including glucose, albumin, calcium, urea, triglycerides, lactate, and dextran in transdermally extracted fluid. The composition of the fluid extracted transdermally is similar to that of ISF. CONCLUSIONS: Application of low-frequency ultrasound allows skin permeabilization and extraction of ISF across the skin.
Subject(s)
Permeability , Skin/metabolism , Ultrasonics , Animals , Glucose/pharmacokinetics , Rats , Rats, Sprague-DawleyABSTRACT
Application of low-frequency ultrasound has been shown to enhance transdermal transport of drugs (low-frequency sonophoresis). In this paper, we show that the efficacy of low-frequency ultrasound in enhancing transdermal transport can be further increased by its combination with sodium lauryl sulfate (SLS), a well-known surfactant. The dependence of the ultrasound-SLS-mediated transport on ultrasound parameters, including intensity, net exposure time, and duty cycle, is discussed. The transdermal transport enhancement is proportional to ultrasound intensity as well as to exposure time, and is independent of duty cycle as long as the net exposure time is the same. The synergistic effect of SLS and ultrasound on transdermal transport increases linearly with SLS concentration. The enhancement is also proportional to the ultrasound energy density beyond a threshold value, which suggests that a certain minimum amount of energy density is required before noticeable changes in skin permeability occur. A similar dependence of the transdermal transport enhancement on energy density is observed in the case of the enhancement induced by ultrasound alone. Although the threshold energy density value in the presence of SLS is about 10 times lower than that in the case of ultrasound alone, the relationship between enhancement and energy density in the presence and in the absence of SLS is otherwise similar. Possible mechanisms for the synergistic effect of ultrasound and SLS are also discussed.