Chemistry: analytical and immunological testing – Metal or metal containing – Organometallic compound determined
Reexamination Certificate
1999-06-24
2002-12-10
Brusca, John S. (Department: 1623)
Chemistry: analytical and immunological testing
Metal or metal containing
Organometallic compound determined
C436S076000, C548S543000, C424S449000
Reexamination Certificate
active
06492180
ABSTRACT:
FIELD OF THE INVENTION
This is generally in the area of non-invasive methods and apparatus for sampling of analytes present in body fluids, including sweat, such as glucose, heavy metals, and compounds of abuse.
BACKGROUND OF THE INVENTION
The development of transdermal methods of delivering drugs through the skin has been made possible by the optimization of solvent conditions of individual drugs so that they solubilize and partition into the stratum corneum skin layer (Brown, L. and Langer, R., “Transdermal Delivery of Drugs,”
Ann. Rev. Med.
39: 221-229, 1988). In addition, transdermal diffusion of drug compounds has been also enhanced using iontophoresis, electroporation and ultrasound. These observations have lead to the further investigation of using the transdermal route to detect metabolites in the skin. Virtually all of the work in the scientific literature has been focused in the area of glucose detection in the treatment of diabetes mellitus. However, large fluctuations in glucose concentrations can occur within minutes after the ingestion of a carbohydrate loaded meal. In contrast, glucose diffusion through the stratum corneum skin layer is relatively slow and lags behind these glycemic variations. Thus, there is a significant “lag time” between the skin measurement of glucose concentration through the stratum corneum skin layer and the actual blood concentration.
Previous attempts restricted to the detection of glucose have not and can not be extended to heavy metals. A more useful and uninvestigated application of transdermal diffusion is to non-invasively detect analytes whose concentration does not vary significantly over short time periods. This is especially important for the detection of chemicals such as heavy metals. For example, a heavy metal such as lithium used to treat manic depressives could be detected by psychiatrists to easily determine patient compliance. The detection of iron would be useful for the detection of iron overload diseases.
Lead (Pb) is an example of a heavy metal which is also a toxic substance. Public health organizations in the United States require all children to be tested several times before beginning school and during their early education. It is required for kindergarten grade entry in many school districts in the United States. Studies indicate that nearly 10% of the children in the United States ages six and under, or 1.7 million children, are victims of lead poisoning (Carolina Environment, Inc. Aug. 8, 1996). The United States Public Health Service estimates one out of six children under the age of six has enough lead in their blood to place them in what scientists consider the risky zone. Childhood lead poisoning has no predilection for socioeconomics or geography.
Although adults are susceptible to lead poisoning, children remain at the highest risk due to the natural instinct to introduce non-food items into their bodies. The effects of lead poisoning include learning disabilities, delinquent behavior, hyperactivity, decreased growth, kidney and heart disease, and even brain damage. Common potential lead-contaminated areas include older play equipment and chipping paint from window and door trim, and even walls.
The symptoms of lead poisoning include headaches, irritability, abdominal pain, vomiting, anemia, weight loss, poor attention span, noticeable learning difficulty, slowed speech development, and hyperactivity. The effects of lead poisoning include reading and learning disabilities, speech and language handicaps, lowered I.Q., neurological deficits, behavior problems, mental retardation, kidney disease, heart disease, stroke, and death.
Current test procedures for lead are traumatic for young children as they require venipuncture and extraction of a blood sample. The scientific literature does not describe non-invasive methodologies for detecting heavy metals via the dermal route.
There are numerous descriptions of the toxicology of Pb absorbed through the skin and then found to result in toxic effects or elevated levels in other tissues. This is especially true in the use of lead for topical cosmetic applications (Moore et al.,
Food Cosmet. Toxicol.
18(4) :399-405(1980)) and in industrial applications (Hine et al.,
J. Occup. Med.
11(11):568-75 (1969)). In one citation in the scientific literature, sweat is used to assess the absorption of lead through the skin, but not from systemic blood supply and organs to the skin (Lilley et al.,
Science Total Environ.
76(2-3):267-78 (1988)).
Other examples of plasma heavy metal concentrations caused by skin absorption include zinc (Morgan et al.,
Br. J. Dermatol.
102(5):579-83 (1980)). Cadmium, chromium, and arsenic have also been detected in male reproductive organs (Danielsson et al.,
Arch. Toxicol. Suppl.
7:177-80 (1984)).
Sweat lead detection was well studied by an Australian group at CSIRO, Menai, Australia. Stauber and colleagues worked on sweat lead detection for occupational lead absorption through skin. They found that even inorganic lead can be absorbed through skin and rapidly distributed through the body (Stauber et al.,
Science Total Environ.
145:55-70 (1994)). In one of their experiments (Lilley et al.,
Science Total Environ.
76:267-278 (1988)), lead powder was placed on the left arm of a healthy adult male volunteer, and a certain region of skin of the right arm was induced to sweat for lead detection. The placing of 6 mg of lead as 0.5 M lead nitrate to the left arm resulted in the increase in lead concentration in pilocarpine-induced iontophoresis samples in the right arm. No changes were found in the blood or urine samples. However, Omokhodion and Crockford,
Science Total Environ.
103:113-122 (1991)) found that there is a good relationship between blood and sweat lead levels among non-occupationally exposed persons.
Many other substances must be measured on a frequent basis, resulting in trauma and pain to the patient. Examples include measuring blood glucose in diabetics and sampling drugs of abuse in cocaine addicts. Efforts for the non-invasive detection of glucose have focused on transdermal extraction of glucose using solvents, iontophoresis or using the penetration of infrared light through the skin. None of these glucose efforts have been commercialized. Among the scientific difficulties associated with glucose detection are that glucose concentrations change transiently and quickly throughout the day, and often do so at rates which exceed the permeability rate of the glucose molecule through the skin. Therefore the iontophoretic or solvent extraction routes have proven to yield irreproducible data. The use of infrared light has been plagued with interference from other substances of similar structure found in vivo and the inability to calibrate these devices reproducibly.
Transdermal detection of substrates other than lead from sweat has been applied to non-invasive devices. Several transdermal alcohol detection devices have been developed by Dermal Systems International to detect alcohol from sweat (Swift,
Addiction
88:1037-1039 (1993)). One of those methods is an alcohol dosimeter or “sweat patch” which is a portable, wearable, non-invasive, occlusive patch applied to the skin surface. However, it requires a 7-10 day period for the detection. Another alcohol “Band-Aid®” is a small strip applied to the skin that utilized enzymatic calorimetric detection to estimate blood ethanol concentration over several minutes (Roizman et al.,
Anesthesiology
73(3A):A512, (1990)). However, estimating concentration of a drug (e.g. alcohol) across pharmacokinetic compartments (blood and skin) is not always straightforward. Sweat detection also involves the complexity of both passive diffusion through the skin (Scheuplein and Blank,
Physiological Rev.
51(4):702-747 (1971)) and active secretion by eccrine glands, primarily sweat glands (Brusilow and Gordis,
Amer. J. Dis. Child
112:328-333 (1966)).
“Band-Aid®” sweat patches have also been tested in a human clinical study to monitor drug use, for example with cocaine (Burns and Baselt,
J. A
Brown Larry R.
Edelman Elazer
Tseng David
Becker Daniel M.
Brusca John S.
Fish & Neave
Moran Marjorie A.
Pisano Nicola A.
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