A method for shipping clinical specimens lawfully, safely, cheaply, and easily without regard to some or all of the laws, rules, and regulations regarding samples that may contain infectious and/or etiologic agents. Optional method of direct analysis of shipped samples.

1. Field of the Invention
The present invention relates to a method for the simplified shipping of clinical specimens, especially specimens that may contain an etiologic agent. The present invention further relates to the laboratory analysis of the shipped specimen, preferably directly upon receipt and without further substantial sample preparation.
2. Background of the Invention
The laboratory analysis of human or animal material, including, but not limited, to excreta, secreta, blood and its components, tissue, and tissue fluids is a necessity of modern medicine for the purposes of diagnosis. Most if not all Americans are familiar with xe2x80x9cblood testsxe2x80x9d used to determine their cholesterol level, the presence or absence of various microorganisms, and, depending upon level of sophistication, phenotyping, genotyping, etc. Such analysis is also used in therapeutic drug monitoring (TDM), which determines the quantity of a drug in the blood. TDM is now routine for approximately 20 different drugs for which dosing level is an issue and for which immnunochemical assays have been commercialized. TDM is extremely important for individualized therapy, and it is a tool used to avoid both toxic and sub-therapeutic blood concentrations (and the drug resistance that sub-therapeutic levels can induce in, for example, the treatment of infectious diseases).
One problem encountered in the laboratory analysis of clinical specimens is that oftentimes the laboratory where analysis is conducted is located apart from where samples are collected. Thus, the clinical specimen must somehow be transported to the site of the laboratory. The transportation of a clinical and, especially, an infectious specimen is highly regulated, complicated and expensive because of safety issues, health concerns, Department of Transportation regulations, and various other laws, rules, and regulations of the States and the United States, and foreign countries. In fact, the packaging and shipping standards for infectious substances in the United States are higher than those for any other class of dangerous goods except high-activity radioactive materials.
For example, Title 49 of the Code of Federal Regulations (CFR) governs the shipping of hazardous materials, and essentially encompasses the International Air Transport Association regulations regarding dangerous materials shipping, including the shipment of infectious substances that can affect a human. 49 CFR 171.8, 172.101, and 173.134, as well as 42 CFR, particularly sections 72.1-72.5, all incorporated herein by reference (current as of the filing date of this application), govern the shipment of etiologic agents (a viable microorganism or its toxin that causes, or may cause, human disease). As noted in 42 CFR 72.2, it is unlawful to knowingly transport or cause to be transported specimens and products that one reasonably believes may contain an etiologic agent unless certain packaging standards and requirements are met. Under 42 CFR 72.3, an extensive, non-comprehensive list of such etiologic agents is provided (incorporated herein by reference), and strict packing requirements, etc. are specified, as is a particular label that must be placed on the outer shipping containers of all materials containing etiologic agents. Of course, any package that possesses special labeling commands a significant surcharge that is payable to the shipping company. What is more, the special packaging that is required has become an industry in and of itself, and it is now common to spend at least $39 to purchase a box for a single sample (see, for example, part numbers STP100, STP300, and STP370, all found at www.cargopak.com/saftpak.htm and at www.saftpak.com). Even when a shipper does not reasonably believe that a clinical specimen contains an etiologic agent, readying such a sample for transport remains burdensome, expensive, and requires staffing by individuals who are fully apprised of all shipping regulations and who possess documentation of ongoing participation in training programs.
Another problem caused by the transport or shipping of clinical specimens to a laboratory for analysis is the integrity of the sample being shipped. If the sample is not maintained at a proper temperature during transport it is possible that the sample when analyzed is different from that when it was obtained, and that the results provided by the laboratory do not reflect the true state of the patient""s condition. The incorporation of dry ice or cold packs in a package increases the weight and, hence the shipping cost. The convenience and timeliness of shipping temperature-controlled packages is low as well, since most receiving laboratories state that shipments should be made from Mondays to Thursdays only. What""s more, because carbon dioxide is toxic, the transport of dry ice by aircraft adds significant regulatory burden.
The inventor knows of three organizations that openly promote the fee-for-service measurement of antiviral drug concentrations in body fluids of HIV-infected individuals. Specifically, these organizations are University of Liverpool, National Jewish Medical and Research Center, and Specialty Laboratories. In each case, the support literature from these organizations ask that untreated, known infectious plasma or serum be shipped, in a legally proper manner, to the analysis facility. Hence, the burden of precise compliance to all shipping regulations regarding etiologic agents, dry ice, etc. rests squarely on the shipper. Further, the real cost of sample analysis is inflated because of the packaging material costs, shipping surcharges, staffing by highly-trained shipping specialists, etc.
The practical result of the difficulties encountered in shipping a clinical specimen to a laboratory for analysis (i.e., shipping requirements, increased cost, maintenance of sample integrity, etc.) is illustrated by the website for Specialty Laboratories (www.specialtylabs.com), a research-based clinical reference laboratory that provides diagnostic, prognostic, and monitoring services. On this website under xe2x80x9cDomestic and International Shipping Proceduresxe2x80x9d it is explained that the shipper of medical specimens is required to comply with the rules and guidelines for transport of such materials, and the shipper is ultimately responsible for all decisions that are made regarding packaging. Information is provided that outlines, with an intermediate level of detail, the various steps the shipper must go through in preparing a clinical specimen for shipment. Investigation into the shipment of such samples through overnight courier services, such as FedEx, has revealed that, beyond the normal fees based on weight and destination, substantially higher charges are incurred for samples labeled in accordance with the laws, rules and regulations that govern the shipping of clinical specimens that may contain etiologic agents.
It is one object of the invention to provide a method for the lawful shipment of clinical specimens that does not require compliance with U.S. laws, rules and regulations (including those of the States) regarding the shipment of samples or material that may contain an etiologic agent. (For applications in countries other than the U.S. the laws, rules and regulation are those of the examining country. All countries of the world are included such as Japan, the countries of Europe, South America, etc.)
It is a further object of the invention to provide a sample container useful for shipment of samples or material without the necessity of following the various laws, rules, and regulations regarding the shipment of etiologic materials.
It is a further object of the invention to provide method instructions and/or equipment to allow for the inactivation of clinical and etiologic specimens and their conversion from etiologic to non-etiologic or from biohazardous to non-biohazardous, the method equipment including a sample container for the shipment of the inactivated, non-etiologic sample in accordance with the invention method for shipment.
It is a further object of the invention to provide for the shipping of clinical specimens at ambient temperatures.
It is another object of the present invention to provide a process wherein biological, clinical, etc. samples that may be etiologic in nature are inactivated and made non-etiologic prior to shipping, lawfully shipped without compliance with at least one of the various laws, rules, and regulations regarding the shipping of etiologic materials, optionally received at an analysis laboratory, and optionally analyzed at said laboratory for example directly upon receipt and without further significant sample preparation.
These and other objects will become apparent as the invention is more thoroughly explained in the following detailed description.
In one embodiment the present invention relates to the shipment of a sample or material (hereinafter referred to as a clinical specimen) anywhere, including in interstate, intrastate, or international commerce. By xe2x80x9cclinical specimenxe2x80x9d the inventor means any human or animal material including, but not limited to, excreta, secreta, blood and its components, tissue, tissue fluids, and biological products that may or do contain an infectious or etiologic agent, excluding explanted medical devices and tissue, fluid, etc. adhering to an explanted medical device. A particularly preferred type of clinical specimen according to the invention is one that does contain an infectious or etiologic agent, where the term xe2x80x9cetiologic agentxe2x80x9d is defined herein as any microorganism or its toxin that causes, or may cause, human disease. The term xe2x80x9cshipmentxe2x80x9d as used herein means physical transport to a directed location, whether effected by mail, courier, vehicle, ship, airplane, etc. and includes all common forms of shipment well known to those of ordinary skill in the art such as the national mail system, commercial courier services such as FedEx, Airborne, Emery Worldwide, DHL, etc., UPS, trucking services, car delivery services, bicycle couriers, pedestrian foot delivery services, etc. xe2x80x9cShippingxe2x80x9d and xe2x80x9cshippedxe2x80x9d means the act of placing the thing to be physically transported in the hands of, the custody of, etc., a shipper such as the U.S. mail system, commercial courier services such as FedEx, Airborne, Emery Worldwide, DHL, etc., UPS, trucking services, car delivery services, bicycle couriers, pedestrian foot delivery services, etc. with delivery instructions and the subsequent shipment of the thing as received by the shipper. Excluded from the term xe2x80x9cshipmentxe2x80x9d is the movement of the thing within a building or within a campus, or within a complex of associated buildings. Excluded from the term xe2x80x9cshippingxe2x80x9d is the act of placing the thing to be physically transported in the hands of, custody of, etc. a shipper with delivery instructions limited to delivery within a building or within a campus, or within a complex of associated buildings. In a preferred embodiment, the clinical specimen is shipped to (transported to) a testing laboratory for the purpose of being subjected to a test offered by the laboratory. For examples of tests useful herein, Specialty Laboratories, mentioned above, lists hundreds of such tests at www.specialtylabs.com under the heading of xe2x80x9ctest menuxe2x80x9d, all of which are hereby incorporated by reference. Examples include amikacin (test #4900), epinephrine (test #3270), phenobarbital (test #4142), zidovudine (test #4959), etc. Another listing of tests useful herein is the Mayo Medical Laboratories 2000 Test Catalog, 1999, Mayo Press, Rochester, Minn., incorporated herein by reference.
In a highly preferred embodiment, the clinical specimen is subjected to pre-shipping treatment that renders the clinical specimen non-infectious and non-etiologic (i.e., converts the clinical specimen to a xe2x80x9csafe clinical samplexe2x80x9d) and that optionally also provides a sample that may be, and that preferably later is, capable of being directly subjected to the intended laboratory test without further significant sample pre-treatment.
Thus, a preferred embodiment of the present invention is a method for the shipping of clinical specimens lawfully without compliance with at least one of the various State, U.S., and, for countries other than the U.S., foreign national, as well as any applicable international, laws, rules, and regulations regarding shipment of materials that may contain etiologic agents, thereby avoiding the increased costs associated with shipping according to such laws, rules, and regulations and providing a safer, simpler, cost-effective method for the shipment of such samples. In a further preferred embodiment, the method includes receipt of the shipped clinical specimen (i.e., the safe clinical sample) by a laboratory, and in a highly preferred embodiment further includes the direct laboratory analysis of the sample as received (or after minimal preparation such as centrifigation, concentration, evaporation, and/or filtration). With the method of the present invention it is envisioned that the remote laboratory testing of a clinical specimen that has been converted into a safe clinical sample can be accomplished quickly (for example, within one day or less) and more cheaply than is the current state of the art with great efficiencies being realized in both the safer, simpler, easier, and cheaper method of shipping and, if laboratory testing is included in the method, with the cheaper and easier testing of the sample by either direct injection into the testing apparatus or direct subjection to the analysis method (or injection or subjection after minimal preparation such as centrifugation, concentration, evaporation, and /or filtration). It is envisioned that, with respect to TDM, the present method model will become a benchmark, allowing for relatively inexpensive, accurate, reproducible overnight turnaround for standard and even esoteric laboratory test results, thereby increasing the effectiveness of medical treatment and avoiding problems associated with sub-optimal therapy.
A preferred present invention method for converting a clinical specimen into a safe clinical sample, thereby converting the clinical specimen from a very expensive and somewhat complicated sample to ship into a very simple, safe, easy, cheap sample to ship, is treatment of the clinical specimen with enough water-miscible organic solvent to render the specimen non-etiologic and non-infectious (e.g., contact, mixing, etc.). Those of ordinary skill in this art know how to determine if a sample may contain an etiologic or infectious agent, and they know how to determine whether a sample has been rendered non-infectious and non-etiologic. In a highly preferred embodiment, alchohol (preferably reagent ethanol, pure ethanol, reagent alcohol, or denatured alcohol) is mixed with the specimen to provide preferably at least 70% by volume alcohol. As an example, in order to prepare a non-infectious, non-etiologic safe clinical sample for shipping according to the present invention, a particular volume (for example 1.00 ml) of a body fluid such as urine, plasma, cerebral spinal fluid, whole blood, serum, etc. is mixed with sufficient alcohol to provide a 70 vol. % alcohol solution. Of course, higher and lower amounts of alcohol can be utilized (such as 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 and higher vol. %), but preferably 70 vol. % and above are used. In determining the amount of alcohol to add, one can assume that clinical specimens consisting of bodily fluids are essentially water. Thus, in the example above, 2.33 ml of anhydrous reagent alcohol would be added to the 1.00 ml of bodily fluid to provide at least a 70 vol. % alcohol solution. Of course, more or less alcohol could be added, if desired. In this way, method instructions and equipment may be provided that allows one to render a clinical specimen that may or does contain an etiologic and/or infectious agent non-infectious and non-etiologic and also, importantly, allow for lawful shipment of e.g., the safe clinical sample without compliance with at least one of the various laws, rules, and regulations regarding the shipment of specimens that may contain infectious or etiologic agents. If denatured alcohol is the solvent of choice, such a safe clinical sample may be subject to certain other rules and regulations regarding, for example, flammable samples, but the sample would not be subject to the significant and costly rules and regulations regarding shipment of, e.g., etiologic agents.
In addition to alcohol, other water-miscible organic solvents may be used for the invention purpose described above, including acetonitrile, methanol, and 2-propanol, among others. In a highly preferred embodiment, the solvent used does not affect the clinical specimen in a way that would affect the laboratory testing procedure intended for the specimen. It is particularly noteworthy that the invention method allows the user to avoid, if desired, the use of more hazardous and reactive chemicals that are often used for inactivation of etiologic agents, including chemicals such as formaldehyde, formalin, paraformaldehyde, glutaraldehyde, peroxygen-based compounds, and halogen-releasing compounds.
Another preferred present invention method for converting a clinical specimen into a safe clinical sample, thereby converting the clinical specimen from a very expensive and somewhat complicated sample to ship into a very simple, safe, easy, cheap sample to ship, is passage of the clinical specimen through a sterilizing filter to render the specimen non-etiologic and non-infectious. In a highly preferred embodiment, the clinical specimen is passed through a sterilizing filter that possesses pores preferably no greater than 0.2 microns in size. As an example, in order to prepare a non-infectious, non-etiologic safe clinical sample for shipping according to the present invention, a particular volume (for example 1.00 ml) of a body fluid such as urine, plasma, cerebral spinal fluid, whole blood, serum, etc. is passed through a 0.2 micron sterilizing filter. Of course, larger and smaller pore sizes can be utilized (such as 1.0 micron, 0.8 micron, 0.6 micron, 0.4 micron, 0.3 micron, 0.1 micron, 0.05 micron, 0.005 micron, and lower), but preferably 0.2 micron and smaller are used. In this way, method instructions and equipment may be provided that allows one to render a clinical specimen that may or does contain an etiologic and/or infectious agent non-infectious and non-etiologic and also, importantly, allow for lawful shipment of e.g., the safe clinical sample without regard to at least one of the various laws, rules, and regulations regarding the shipment of specimens that may contain infectious or etiologic agents.
Of course, the conversion methods noted above (filtration and solvent treatment) may be used in combination sequentially in any order or used together (e.g., the clinical specimen diluted with alcohol is passed through a filter).
Heat treatment of blood-derived samples at 56xc2x0 C. can inactivate the HIV virus, for example. A heat treatment period ranging from 0.5 hours to as much as 5 hours (Resnick, et al., JAMA (1986) 255, 1887-91) is recommended, however, and even the shortest 0.5 hour exposure can modify free drug concentrations (Dasgupta, et al., Ther. Drug Monit. (1999) 21, 421-5). Such conditions are too harsh for labile molecules, as hydrolysis and other unwanted reactions will occur. Although heating of known infectious plasma, serum, etc. prior to or after mixing with water-miscible organic solvents and/or filter sterilization is labor intensive and unnecessary, the combination of these steps is included herein.
Also included herein, alone or in any combination with the conversion techniques described above, is the inactivation of the clinical specimen with any other agent or treatment prior to shipping. Such agents include INACTINE(copyright) products and those described in U.S. Pat. No. 5,891,705, incorporated herein by reference.
An important benefit of the present invention method for rendering a clinical specimen safe (i.e., non-infectious and non-etiologic), in addition to the lessened costs and requirements regarding lawful shipping, is that the sample, once rendered safe according to the present invention method (by solvent addition, filter sterilization, use of some other agent, heating, etc.), may be shipped without temperature control, meaning that traditional cooling with dry ice, etc. is not required when shipping the invention safe clinical sample. In this regard, dual savings are realizedxe2x80x94the high cost and danger of shipping unsafe samples is avoided as is the high cost, regulatory burden, and difficulty of shipping samples that must be kept cold, for example with dry ice. Of course, temperature control may be used if desired, such as dry ice, ice packs, etc., and this is preferred for labile analytes.
In this sense, the present invention method of clinical specimen treatment (for example with a water-miscible organic solvent) so as to render the specimen safe followed by simple shipping lawfully without compliance with at least one of the various laws, rules and regulations regarding the shipment of, e.g., etiologic samples provides a new and useful method for shipping as well as a new and useful method that can capitalize on economies not previously recognized or utilized. In this way, the simple steps of adding, for example, alcohol to a clinical specimen, or filter sterilization, or a combination thereof, to render it safe followed by lawfully shipping the treated sample without regard to the laws, rules, and regulations that govern the shipment of, e.g., clinical specimens that may contain etiologic agents, provide a significant advance in the art not previously recognized. While it has previously been recognized that 70 vol. % denatured alcohol, heat, etc. can be used to inactivate etiologic agents and that filter sterilization can remove etiologic agents, it has not previously been recognized that if clinical specimens are so rendered prior to shipping they may then be shipped simply, lawfully, safely, cheaply, and easily without regard to the laws, rules, and regulations regarding shipment of etiologic specimens, and/or without regard to the maintenance of a certain temperature or general temperature control, such as cooling with dry ice, etc.
The xe2x80x9chardwarexe2x80x9d utilized in accomplishing what will be termed the xe2x80x9csample inactivation/shippingxe2x80x9d aspect of the present invention described above is not particularly limited. Practical considerations preferably include containment of the sample in a closed, preferably non-leaking container that is not damaged or leached by the water-miscible solvent. With regard to packaging for shipping, practical considerations should be borne in mind in view of the realities encountered by the various commercial and governmental shipping concerns. While no special accommodations are required, it is preferred that shipping occur in an envelope, box, etc. that will survive intact its transport to the ultimate destination.
Several sample collection containers and assemblies are known in the art, and all may be used herein. Examples include GB1,542,411, U.S. Pat. No. 1,594,370, 3,163,160, 3,915,806, 4,336,880, 4,311,792, 4,604,360, 4,732,850, 4,788,985, 4,813,432, 5,313,959, 5,266,266, 5,425,915, 5,658,531, 5,710,041, 5,726,062, 5,786,227, 5,786,228, 5,859,374, 5,879,635, 4,211,323, 4,150,950 and 5,511,558, all incorporated herein by reference. One particularly preferred embodiment for use in the sample inactivation/shipping embodiment of the present invention is a container that itself contains an inner container. The inner container holds the water-miscible solvent of the invention, for example, reagent alcohol. The volume of solvent held in the inner container (e.g., a frangible ampoule) may be pre-measured in accordance with the amount of clinical specimen that is directed to be placed in the container. In using this arrangement the clinical specimen is placed in the container, the container is optionally closed, and the inner container is manipulated such that the water-miscible organic solvent mixes with, contacts, etc. the clinical specimen such that it is rendered non-infectious and non-etiologic. If desired, this solution could then be passed through a sterilizing filter assembly. As noted above, it is preferred that the final volume percent of water-miscible organic solvent is at least 70%, including 75, 80, 85, 90 and greater than 90% by volume, and that the filter pores are less than 0.2 micron, including 0.1 micron, 0.05 micron, and 0.005 micron. Ethanol contents that are 70-75% by volume show excellent performance in HIV-inactivation assessments (van Bueren et al., J. Hosp. Infection (1994) 28, 137-148; Druce et al., J. Hosp. Infection (1995) 30, 167-180; both incorporated herein by reference). Filters with pore sizes of 0.2 micron and smaller are used to sterilize medicines, fluids, and blood-derived products that are meant for intravenous, intramuscular, etc. use (Brown et al., Dev. Biol. Stand., xe2x80x9cViral Safety and Evaluation of Viral Clearance from Biopharmaceutical Products.xe2x80x9d (1996) 88, 319-326; McKinnon et al., Am. J. Hosp. Pharm. (1993) 50, 1921-1936; Anonymous, PDA J. Pharm. Sci. Technol., xe2x80x9cParenteral Drug Association Technical Report No. 26, Sterilizing Filtration of Liquids.xe2x80x9d (1998) 52 (No. 3, Supplement), 1-31; all incorporated herein by reference). It is preferred that the container can be sealed such that it need only be placed in a high-quality plastic bag containing absorbent prior to placement in an envelope, box, etc. to be shipped and thus configured such that it can withstand such shipping without breakage, leakage, etc. Thus, and in accordance with the present invention, method equipment may include one or any combination of a clinical specimen container, a shipping container, method instructions, etc. The shipping container may be pre-addressed and is preferably configured such that the specimen container may be shipped therein. Optionally present in the method equipment, optionally located in the specimen container, is a certain volume of water-miscible organic solvent or instructions regarding the use of water-miscible organic solvents optionally with method equipment components. Also optionally present in the method equipment, optionally attached to the specimen container, is a sterilizing filter assembly and/or instructions regarding the use of a sterilizing filter assembly with other, e.g., method equipment components. The water-miscible organic solvent is preferably provided such that it can be contacted with the clinical specimen, sealed within the specimen container, and the specimen container shipped in the shipping container, for example to a testing laboratory, lawfully without regard to the various laws, rules, and regulations regarding the shipment of, e.g., etiologic agents and optionally without temperature controls such as packing on dry ice, etc. In a preferred embodiment, the water-miscible organic solvent itself, or the method equipment (or, if the method equipment does not contain solvent, the instructions regarding the solvent) may contain an internal standard (or instructions concerning the use of an internal standard) that allows a testing laboratory to quantitatively determine the amount of whatever is being tested for in the specimen.
Another embodiment of the present invention relates to the analysis of safe clinical samples, made safe (e.g., converted) according to the invention. In this further embodiment, a safe clinical sample is simply directly analyzed with minimal or no sample pre-treatment. For example, a clinical specimen that has been diluted to 70 vol. % reagent alcohol may be directly analyzed on an LC system or an LC-MS system, or analyzed after centrifugation, concentration, evaporation, and/or filtering. The system of analysis could not be more simple: the safe clinical sample containing, e.g., 70 % by volume reagent alcohol, is simply directly (or after centrifugation, concentration, evaporation, and/or filtering) injected into a laboratory instrument for analysis or subjected to the desired laboratory test. If one wishes to preserve the performance of the instrument, protective measures known in the art such as a in-line filter, a guard column, or a column-switching valve, etc. may be taken. Lab tests that do not depend upon specimen-associated enzyme activity and whose target (analyte) being tested for does not precipitate due to water-miscible organic solvent treatment, are preferred. Lab tests whose target (analyte) being tested for does pass through a sterilizing filter assembly are preferred. If an internal standard is not added to the clinical specimen at the point of origin or point of shipping, it may be added at the recipient laboratory prior to analysis. While it is known that some laboratories use water-miscible organic solvents, concentrated acids, and metal salts to precipitate proteins from samples prior to analysis, it is believed that 1) acetonitrile is used in the vast majority of cases and that 2) these methods have been used on an in-house basis only, and not on clinical specimens prior to shipping.
In a highly preferred embodiment, a further method is provided that combines the sample inactivation/shipping embodiment described above in combination with the direct analysis of the sample upon receipt at a laboratory. This model provides for highly effective and cost efficient shipping due to the non-etiologic and non-infectious nature of the sample and the lack of a requirement for temperature control (dry ice, etc.) while at the same time providing a sample that is xe2x80x9canalysis ready,xe2x80x9d meaning that no further sample preparation is required prior to laboratory testing. In this way, a method is described that provides extremely simple and quick turnaround of laboratory test results for clinical specimens.

Method for simplified shipping of clinical specimens and optional direct analysis


Disclosed are nucleic acid-based molecular switches that respond to changes in pH. The switches may be used in DNA nanodevices. The switches may also act as sensors for measuring the pH of a sample, including cells, regions thereof, and whole organisms. The switch includes an A-motif that forms at acidic pH. Also disclosed are compositions and methods for measuring the pH of cells or regions thereof, such as vesicles, the nucleus, mitochondrial matrix, or the Golgi lumen.

The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art.
One aim of biotechnology and nanotechnology is a rational approach to the construction of new biomaterials, including individual objects and nanomechanical devices. Intricate arrangements of atoms could serve many practical purposes. The informational macromolecules of biological systems, proteins and nucleic acids, are believed to have the potential to serve as building blocks for these constructions, because they are used for similar purposes in the cell. Structural DNA nanotechnology is an emerging field that uses DNA to create either rigid architectures or dynamic switches. Dynamic, DNA-based nanodevices may also be described as molecular switches. They are based on structural transitions between two well-defined conformations of DNA upon the application of a stimulus. For instance, nanometer-scale circuitry and robotics could accomplish many tasks that are impossible today. One can envision improvements in the storage and retrieval of information, understanding of the molecular basis of medical problems, and the assembly of very smart materials as possible end products of the ability to control the structure of matter on the nanometer scale.

DNA-based molecular switches and uses thereof


A bifurcated endoluminal prosthesis is provided that includes a valve or gate in one of the bifurcated branches. The valve or gate prevents flow of blood through the branch when it is closed and permits the flow of blood when it is open. In one variation, the valve comprises a spring member attached to a graft material substantially impermeable to the flow of blood. The spring member holds the graft material over the opening that forms a lumen in the bifurcated portion. The spring member may be flipped from a closed position in which it is initially deployed, to an open position whereby the graft material forms an opening continuous with lumen in the bifurcated portion permitting the flow of blood therethrough. The invention may be used in bifurcated or branched tubular grafts for endoluminal placement within a body lumen, including blood vessels, and for the treatment of abdominal and other aneurysms.

The present invention relates to tubular prostheses such as grafts and endoluminal prostheses including, for example, stent-grafts and aneurysm exclusion devices, and methods for placement of such grafts and endoluminal structures. Further, the present invention relates to a stent graft and deployment method.
A wide range of medical treatments have been previously developed using xe2x80x9cendoluminal prostheses,xe2x80x9d which terms are herein intended to mean medical devices which are adapted for temporary or permanent implantation within a body lumen, including both naturally occurring or artificially made lumens. Examples of lumens in which endoluminal prostheses may be implanted include, without limitation: arteries such as those located within coronary, mesentery, peripheral, or cerebral vasculature; veins; gastrointestinal tract; biliary tract; urethra; trachea; hepatic shunts; and fallopian tubes. Various types of endoluminal prostheses have also been developed, each providing a uniquely beneficial structure to modify the mechanics of the targeted luminal wall.
A number of vascular devices have been developed for replacing, supplementing or excluding portions of blood vessels. These vascular grafts may include but are not limited to endoluminal vascular prostheses and stent grafts, for example, aneurysm exclusion devices such as abdominal aortic aneurysm (xe2x80x9cAAAxe2x80x9d) devices that are used to exclude aneurysms and provide a prosthetic lumen for the flow of blood.
One very significant use for endoluminal or vascular prostheses is in treating aneurysms. Vascular aneurysms are the result of abnormal dilation of a blood vessel, usually resulting from disease or a genetic predisposition, which can weaken the arterial wall and allow it to expand. While aneurysms can occur in any blood vessel, most occur in the aorta and peripheral arteries, with the majority of aneurysms occurring in the abdominal aorta. Typically an abdominal aneurysm will begin below the renal arteries and may extend into one or both of the iliac arteries.
Aneurysms, especially abdominal aortic aneurysms, have been treated in open surgery procedures where the diseased vessel segment is bypassed and repaired with an artificial vascular graft. While considered to be an effective surgical technique in view of the alternative of a fatal ruptured abdominal aortic aneurysm, the open surgical technique suffers from a number of disadvantages. The surgical procedure is complex and requires long hospital stays due to serious complications and long recovery times and has high mortality rates. In order to reduce the mortality rates, complications and duration of hospital stays, less invasive devices and techniques have been developed. The improved devices include tubular prostheses that provide a lumen or lumens for blood flow while excluding blood flow to the aneurysm site. They are introduced into the blood vessel using a catheter in a less or minimally invasive technique. Although frequently referred to as stent-grafts, these devices differ from covered stents in that they are not used to mechanically prop open natural blood vessels. Rather, they are used to secure an artificial lumen in a sealing engagement with the vessel wall without further opening the natural blood vessel that is already abnormally dilated.
Typically these endoluminal prostheses or stent grafts are constructed of graft materials such as woven polymer materials (e.g., Dacron,) or polytetrafluoroethylene (xe2x80x9cPTFExe2x80x9d) and a support structure. The stent-grafts typically have graft material secured onto the inner diameter or outer diameter of a support structure that supports the graft material and/or holds it in place against a luminal wall. The prostheses are typically secured to a vessel wall above and below the aneurysm site with at least one attached expandable annular spring member that provides sufficient radial force so that the prosthesis engages the inner lumen wall of the body lumen to seal the prosthetic lumen from the aneurysm
Abdominal Aortic Aneurysms are frequently treated with bifurcated devices that provide an artificial lumen for flow of blood past the aneurysm and into the iliac vessels that branch off from the aorta. One such commonly used device comprises a bifurcated device having one branch portion longer than the other branch portion. This enables deployment of the main body through one of the iliac arteries where the longer branch is deployed. An extension leg is then deployed through the second iliac artery and is connected with the shorter branch portion.
Iliac vessels associated with abdominal aneurysms frequently have tortuous and twisted anatomies and other structural abnormalities that can prevent effect introduction of an extension leg through an iliac vessel. Often it must be decided prior to deployment whether to use a single lumen prosthesis through one iliac vessel and join the vessels with a shunt further down in the anatomy, or to use a bifurcated prosthesis with an extension. Often a surgeon may not be able to determine the appropriate course of action until the prosthesis is in place or after attempts have been made to deploy an extension graft through a tortuous iliac artery. It would be desirable to provide a device that would enable the decision to be made during the deployment procedure. Devices have been proposed in U.S. Pat. No. 6,102,938, incorporated herein by reference, that provide for sealing off a bifurcated portion of a bifurcated AAA device before or after deployment. Such device is designed for situations where a determination is made during a procedure that it would not be possible to introduce an extension leg into the shorter bifurcated portion to provide blood flow through one of the iliac vessels. It would be desirable to provide an improved or alternative device for accomplishing such task.
Frequently, the AAA procedures are performed in emergency situations where the aorta has ruptured or is extremely fragile and about to rupture. In these situations, frequently a single leg device is deployed through the aorta and one of the iliac vessels occluding the second iliac vessel. This may be done because of the importance of reestablishing blood flow through the aorta and iliac vessel and stopping the loss of blood through the ruptured or rupturing vessel. Such situations may not permit deployment of the second (extension) leg. During this crucial time, in using an existing bifurcated device, blood would be able to flow through the shorter bifurcated portion of the prosthesis into the area of the aneurysm. Accordingly it would be desirable to provide an improved or alternative device that allows for deployment of a bifurcated device in emergency situations that would prevent further blood flow into the area of the aneurysm.
Accordingly one embodiment according to the present invention provides a novel device and method that include providing a bifurcated device with one leg initially in an occluded position preventing flow of blood through that portion into the aorta. Once the implant is in place and blood is excluded from the aneurysm site, an extension may be introduced and the occluded side opened to blood flow through the extension.
An embodiment of the endoluminal prosthesis comprises a bifurcated tubular member constructed of a graft material and at least one annular support member. The tubular graft is formed of a woven fiber for conducting fluid. The tubular member includes, a proximal opening and distal openings though the bifurcated portions providing a lumen or lumens through which body fluids may flow. When deployed, annular support members support the tubular graft and/or maintain the lumen in a conformed, sealing arrangement with the inner wall of a body lumen. One of the bifurcated portions is provided with a valve that can open or close to permit or prevent the flow of blood through the bifurcated portion. Various embodiments of the valve includes a member that move a section of graft or other material over or away from the opening into the short iliac leg of the bifurcated prosthesis to close or open the short leg to the flow of blood.
The annular support members of an embodiment of the prosthesis each comprise an annular expandable member formed by a series of connected compressible diamond structures. Alternatively, the expandable member may be formed of an undulating or sinusoidal patterned wire ring or other compressible spring member. Preferably the annular support members are radially compressible springs biased in a radially outward direction, which when released, bias the prosthesis into conforming fixed engagement with an interior surface of the vessel. Annular support members are used to create a seal between the prosthesis and the inner wall of a body lumen as well as to support the tubular graft structure. The annular springs are preferably constructed of Nitinol. Examples of such annular support structures are described, for example, in U.S. Pat. Nos. 5,713,917 and 5,824,041 incorporated herein by reference. When used in an aneurysm exclusion device, the support structures have sufficient radial spring force and flexibility to conformingly engage the prosthesis with the body lumen inner wall, to avoid excessive leakage, and prevent pressurization of the aneurysm, i.e., to provide a leak resistant seal. Although some leakage of blood or other body fluid may occur into the aneurysm isolated by the prosthesis, an optimal seal will reduce the chances of aneurysm pressurization and resulting rupture.
The annular support members are attached or mechanically coupled to the graft material along the tubular graft by various means, such as, for example, by stitching onto either the inside or outside of the tubular graft.
An embodiment according to the present invention provides such a tubular graft for endoluminal placement within a blood vessel for the treatment of abdominal and other aneurysms. In this embodiment, the endoluminal prosthesis is an aneurysm exclusion device forming a lumen for the flow of body fluids excluding the flow at the aneurysm site. The aneurysm exclusion device may be used for example, to exclude an aneurysm in the aorta (Abdominal Aortic Aneurysm (xe2x80x9cAAAxe2x80x9d) device) in which the prosthesis is bifurcated.
The generally Y-shaped bifurcated tubular prosthesis has a trunk joining at a graft junction with a pair of lateral limbs, namely an ipsilateral limb and a contralateral limb. In a bifurcated prosthesis, the proximal portion of the prosthesis comprises a trunk with a proximal opening and the distal portion is branched into at least two branches with distal openings. Preferably the ipsilateral limb is longer so that when deployed, it extends into the common iliac. The contralateral limb includes a valve located therein that is initially in a closed position in which body fluids flow from the proximal opening through the distal opening of the ipsalateral limb while the flow of body fluid through the contralateral limb is prevented by the valve. A single limb extension member is provided having a mating portion for coupling with a lateral limb of a bifurcated member and an adjustable length portion extending along an axis from a distal end of the mating portion. The insertion of the limb extension into the contralateral portion of the main prosthesis opens the valve which is then in part maintained open by the extension limb, permitting blood flow from the proximal opening in the main prosthesis through the distal opening in the contralateral and extension limbs.
The valve in one embodiment comprises a plurality of support members coupled to a section of graft material. One of the support members is an annular member forming an opening for the flow of body fluids. A proximal support member is a semicircular member which has an closed position in which the section of graft material forms a cover over the opening formed by the annular member, and an open position in which the section of graft material is held is a position against the wall of the prosthesis so that the opening formed by the annular member is in fluid communication with the flow of body fluid through the prosthesis.
In another embodiment the valve comprises a plurality of annular support members coupled to a section of graft material where at least one of the annular support members is configured to be folded to form a semicircular member engaged to an inner circumference of the bifurcated prosthesis. When the valve is in an open position, the support members are in an open configuration whereby the annular members and a section of graft material form a lumen through which blood may flow. When the valve is in a closed position, one of the annular support members is folded to that the graft material attached to the folded annular member is drawn across the opening through the short leg in which the valve is located.
In another embodiment the valve comprises a graft material sewn in part on an inner circumference of the bifurcated prosthesis and forming a pocket when the valve is closed. A portion of an annular member is sewn on to at least a portion of the section of graft material not sewn on to the prosthesis. When the valve is in a closed position, the annular member holds section of the graft material in a position over the opening in the short leg of the prosthesis. The annular member in this position is across from the location where the opposite side of the section of graft material is sewn on to the prosthesis. When the valve is in a closed position, the annular member holds the pocket formed by the section of graft material closed. The annular member in this position is against the location where the section of graft material is sewn on to the prosthesis so that the opening in the short leg provides a lumen through which blood may flow from the proximal end of the prosthesis to the distal end of the short leg.
The compressed profile of the prosthesis, including the valve, is sufficiently low to allow the endoluminal graft to be placed into the vasculature using a low profile delivery catheter. The prosthesis can be placed within a diseased vessel via deployment means at the location of an aneurysm. Various means for deliver of the device through the vasculature to the site for deployment, are well known in the art and may be found for example is U.S. Pat. Nos. 5,713,917 and 5,824,041. In general, the endoluminal prosthesis is radially compressed and loaded in a catheter for delivery to the deployment site. The aneurysm site is located using an imaging technique such as fluoroscopy and is guided through a femoral iliac artery with the use of a guide wire to the aneurysm site. Once appropriately located, a sheath restraining the tubular graft may be retracted to release the annular springs to expand and attach or engage the tubular member to the inner wall of the body lumen. The iliac extension is also loaded into a catheter and is then located into the main body of the stent graft and within the iliac vessel and is placed through an opened valve where it is deployed. According to an embodiment, when deployed, the iliac has proximal annular springs which when located within the inner lumen of the main body hold or maintain the valve open. The distal portion of the extension extends into one of the iliac vessels.

Stent graft with integrated valve device and method


An implantable prosthetic device adapted for use in repairing a hernia defect includes at least one body made from a biocompatible textile material. The body is provided with a first section and a second section inverted into the first section such that the second section is radially surrounded by the first section. The second section is movably connected to the first section such that the body is expandable or collapsible in a radial direction so as to conform to the size and shape of a hernia defect.

The present invention relates to a hernia repair device and, more particularly, to a hernia repair device adapted to be implanted in a patient.
Various prosthetic mesh devices have been proposed for use in repairing hernia defects (e.g., an opening in or the thinning of the tranversalis fascia through which the abdominal viscera can extrude). Some of these mesh devices are adapted for anterior-side hernia repair (i.e., repairing a hernia defect from an anterior side of the fascia proximate to the surgeon). For instance, a hernia defect can be repaired exclusively from the anterior side of the fascia by dissecting the sac from the surrounding structures, inverting the sac into an abdominal cavity and then closing the defect with the use of an overlay patch or with the use of a space-filling prosthesis having an overlay patch.
One type of prosthesis adapted for anterior-side hernia repair is made from a sheet of surgical mesh fabric folded into a multi-layered cone. In order to repair a hernia defect, the prosthesis is inserted into the defect to occlude the void. Because the prosthesis is stiff, it does not readily conform to the contour of the defect, forming gaps between the prosthesis and the interior wall of the defect and hence potentially causing recurrent herniation. The stiff, multi-layered prosthesis is also susceptible to kinking and buckling during its placement into the defect.
Additional examples of prostheses adapted for anterior-side hernia repair include the xe2x80x9cPERFIX(copyright) Plugxe2x80x9d and xe2x80x9cMARLEX(copyright) Mesh Dartxe2x80x9d devices marketed by C. R. Bard, Inc., Murray Hill, N.J. The xe2x80x9cMARLEX(copyright) Mesh Dartxe2x80x9d devices are implantable mesh prostheses which are hot-molded into a conical, non-compressible configuration and hence are not readily compliant to irregularities in muscle or tissue walls of hernia defects.
An implantable prosthesis similar to the xe2x80x9cPERFIX(copyright) Plugxe2x80x9d devices is disclosed in U.S. Pat. No. 5,356,432. More particularly, the implantable prosthesis is in the form of a conical plug made from a polypropylene mesh. Longitudinally extending pleats are hot-molded into the mesh to enhance the flexibility of the conical plug for the purpose of allowing the prosthesis to conform more readily to the contour of a herniated opening. Because of its conical shape, the prosthesis has a relatively large vertical length or profile. As a result, when the prosthesis is implanted into a hernia defect, its tip tends to press into and/or against a visceral sac, causing discomfort to the patient and/or impeding proper hernia repair. In one embodiment, the prosthesis is provided with filler layers incorporated into the interior of the prosthesis in order to minimize its contraction while the hernia defect is healed. These layers make the manufacturing of the prosthesis rather complicated.
Hernia defects can also be repaired from the posterior side of the fascia (i.e., the side of the fascia remote from the surgeon) by implanting prostheses in pre-peritoneal spaces to prevent peritonea from passing through the fascia defect. These prostheses are, in some instances, implanted with the use of laparoscopic techniques and, in other instances, require deployment from remote locations within the pre-peritoneal space. Examples of these prostheses are disclosed in U.S. Pat. Nos. 5,116,357, 5,254,133 and 5,916,225. The devices disclosed in these patents will be discussed in greater detail hereinbelow.
U.S. Pat. No. 5,116,357 discloses a hernia repair device having a plug positionable in an opening formed in the abdominal fascia, as well as a patch positionable over weakened portions of the abdominal fascia adjacent to the opening. A central extent of the patch is coupled to a proximal end of the plug. Resilient means is coupled to the patch and provided with memory to assume an extended shape for the proper positioning of the patch with respect to the weakened portions for the abdominal fascia. While this device provides a means of plugging and patching a circular defect, it does not conform to the shape of the naturally occurring defect. Additionally, it requires general anesthesia and additional instrumentation for its deployment at the site of a hernia defect with the use of a laparoscopic surgery.
U.S. Pat. No. 5,254,133 discloses a surgical implantation device for closing an enlarged, generally circular opening in a patient""s body. The surgical implantation device includes a pair of generally planar portions interconnected by a connecting segment. While this device can reduce the amount of post-operative discomfort experienced by patients, it requires general anesthesia and additional instrumentation for its deployment at the site of a hernia defect with the use of a laparoscopic surgery.
U.S. Pat. No. 5,916,225 relates to a hernia mesh patch adapted for posterior-side hernia repair. More particularly, the patch includes a first layer sized and shaped so as to extend across and beyond a hernia defect. A second layer overlies the first layer to create a generally planar configuration for the patch. The first and second layers are joined together by a seam defining a periphery of a pouch formed between the first and second layers. An access slit is formed in one of the layers for insertion of a finger of a surgeon into the pouch to allow the surgeon to deform the planar configuration of the patch to facilitate insertion of the patch into the patient and to position the patch across the hernia. A resilient loop is located within the pouch for urging the patch to conform to the generally planar configuration across the hernia defect as the surgeon withdraws his or her finger. Due to the construction and deployment method of the patch, the surgeon needs to have proper dexterity in order to implant the patch at the site of a hernia defect. Moreover, while the resilient loop expands the device into a planar configuration, anatomical structures surrounding a hernia defect are typically non-planar. In such circumstances, the device may not readily conform to such anatomical structures.
Accordingly, there is a need for an implantable hernia repair device that has enhanced compliancy to the irregular shapes of hernia defects, that is simple to install without requiring general anesthesia and that has a reduced length or profile when implanted.
It is an object of the present invention to provide a prosthesis adapted for easy insertion into a hernia defect from an anterior-side thereof and capable of either expanding or collapsing radially so as to occlude and conform to the fascia wall of the hernia defect.
A further object of the present invention is to provide an implantable hernia repair device having a reduced length/profile when deployed in a hernia defect.
Yet another object of the present invention is to provide a prosthesis adapted for use in repairing hernia defects having varying sizes and shapes and adapted to be anchored to surrounding tissues such that it extends beyond the edge of a hernia defect on the anterior-side thereof to prevent migration.
The present invention overcomes the disadvantages and shortcomings of the prior art discussed above and achieves the aforementioned objects by providing a new and improved implantable prosthesis having at least one body made from a biocompatible textile material. The body is provided with a first section and a second section inverted into the first section such that the second section is radially surrounded by the first section. The second section is movably connected to the first section such that the body is expandable or collapsible in a radial direction so as to conform to the size and shape of a hernia defect. In one embodiment, a single, radially collapsible body is provided for use in repairing a hernia defect. In another embodiment, two identical bodies are connected to one another so as to form an implantable plug adapted to be radially expanded into position after its insertion into a hernia defect.


This invention relates to the use of potent potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which leads to elevated intraoccular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans.

Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma.
Many of the drugs formerly used to treat glaucoma proved unsatisfactory. The early methods of treating glaucoma employed pilocarpine and produced undesirable local effects that made this drug, though valuable, unsatisfactory as a first line drug. More recently, clinicians have noted that many xcex2-adrenergic antagonists are effective in reducing intraocular pressure. While many of these agents are effective for this purpose, there exist some patients with whom this treatment is not effective or not sufficiently effective. Many of these agents also have other characteristics, e.g., membrane stabilizing activity, that become more apparent with increased doses and render them unacceptable for chronic ocular use and can also cause cardiovascular effects.
Although pilocarpine and xcex2-adrenergic antagonists reduce intraocular pressure, none of these drugs manifests its action by inhibiting the enzyme carbonic anhydrase, and thus they do not take advantage of reducing the contribution to aqueous humor formation made by the carbonic anhydrase pathway.
Agents referred to as carbonic anhydrase inhibitors decrease the formation of aqueous humor by inhibiting the enzyme carbonic anhydrase. While such carbonic anhydrase inhibitors are now used to treat intraocular pressure by systemic and topical routes, current therapies using these agents, particularly those using systemic routes are still not without undesirable effects. Because carbonic anhydrase inhibitors have a profound effect in altering basic physiological processes, the avoidance of a systemic route of administation serves to diminish, if not entirely eliminate, those side effects caused by inhibition of carbonic anhydrase such as metabolic acidosis, vomiting, numbness, tingling, general malaise and the like. Topically effective carbonic anhydrase inhibitors are disclosed in U.S. Pat. Nos. 4,386,098; 4,416,890; 4,426,388; 4,668,697; 4,863,922; 4,797,413; 5,378,703, 5,240,923 and 5,153,192.
Prostaglandins and prostaglandin derivatives are also known to lower intraocular pressure. U.S. Pat. No. 4,883,819 to Bito descibes the use and synthesis of PGAs, PGBs and PGCs in reducing intraocular pressure. U.S. Pat. No. 4,824,857 to Goh et al. describes the use and synthesis of PGD2 and derivatives thereof in lowering intraocular pressure including derivatives wherein C-10 is replaced with nitrogen. U.S. Pat. No. 5,001,153 to Ueno et al. describes the use and synthesis of 13,14-dihydro-15-keto prostaglandins and prostaglandin derivatives to lower intraocular pressure. U.S. Pat. No. 4,599,353 describes the use of eicosanoids and eicosanoid derivatives including prostaglandins and prostaglandin inhibitors in lowering intraocular pressure.
Prostaglandin and prostaglandin derivatives lower intraocular pressure by increasing uveoscleral outflow. This is true for both the F type and A type of Pgs and hence presumably also for the B, C, D, E and J types of prostaglandins and derivatives thereof. A problem with using prostaglandin derivatives to lower intraocular pressure is that these compounds often induce an initial increase in intraocular pressure, can change the color of eye pigmentation and cause proliferation of some tissues surrounding the eye.
As can be seen, there are several current therapies for treating glaucoma and elevated intraocular pressure, but the efficacy and the side effect profiles of these agents are not ideal. Recently potassium channel blockers were found to reduce intraocular pressure in the eye and therefore provide yet one more approach to the treatment of ocular hypertension and the degenerative ocular conditions related thereto. Blockage of potassium channels can diminish fluid secretion, and under some circumstances, increase smooth muscle contraction and would be expected to lower IOP and have neuroprotective effects in the eye. (see U.S. Pat. Nos. 5,573,758 and 5,925,342; Moore, et al., Invest. Ophthalmol. Vis. Sci 38, 1997; WO 89/10757, WO94/28900, and WO 96/33719).
This invention relates to the use of potent potassium channel blockers or a formulation thereof in the treatment of glaucoma and other conditions which are related to elevated intraocular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans. More particularly this invention relates to the treatment of glaucoma and/or ocular hypertension (elevated intraocular pressure) using indole compounds having the structural formula I:
or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof: wherein,
R1 represents hydrogen or C1-6 alkyl;
R2, R3a and R3b independently represent hydrogen, alkylsilyl, C1-10 alkyl, C1-10 cycloalkyl, C4-10 heterocycloalkyl, C4-10 heteroaryl, NH2, or C6-10 aryl said alkyl, aryl or heteraryl optionally substituted with 1-3 groups of Rx;
Rx represents C1-6 alkyl, halogen, CF3, C1-6 alkoxy, NR1R1, or NO2, or NH2;
R4 represents hydrogen, C1-6 alkoxy, C1-6 alkyl, CF3, or halogen;
R5 represents hydrogen, C1-6 alkoxy, C1-6 alkyl, CF3, nitro, amino, cyano, C1-6 alkylamino, or halogen and
R6 represents hydrogen, halogen or C1-6 alkyl.
This and other aspects of the invention will be realized upon inspection of the invention as a whole.
The present invention is directed to a method for decreasing elevated intraocular pressure or treating glaucoma by administration, preferably topical or intra-camaral administration, of a composition containing a potassium channel blocker of Formula I and a pharmaceutically acceptable carrier.
One embodiment of this invention is realized when R2 is C1-6 alkyl, C6-10 aryl, alkylsily, or C3-10 cycloalkyl and all other variables are as originally described.
Another embodiment of this invention is realized when R3b is C1-6 alkyl, C6-10 aryl, alkylsilyl or C3-10 cycloalkyl and all other variables are as originally described.
A preferred embodiment of this invention is realized when R1 is C1-6 alkyl, R2 and R3b independently are C1-6 alkyl, C6-10 aryl, alkylsilyl or C3-10 cycloalkyl, R4 is hydrogen, R5 is C1-6 alkoxy, C1-6 alkyl, R3a is hydrogen and R6 is halogen or C1-6 alkyl.
A more preferred embodiment of this invention is realized when R1 is C1-3 alkyl, R2 and R3b independently are C1-4 alkyl, C6-10 aryl, alkylsilyl or C5-10 cycloalkyl, R4 is hydrogen, R5 is C1-3 alkoxy, and R6 is halogen.
Preferred compounds to be used in this invention are:
The invention is described herein in detail using the terms defined below unless otherwise specified.
The term xe2x80x9calkylxe2x80x9d refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with xe2x80x9cbranched alkyl groupxe2x80x9d.
Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 rings which are fused.
Alkoxy refers to C1-C6 alkyl-Oxe2x80x94, with the alkyl group optionally substituted as described herein. Said groups are those groups of the designated length in either a straight or branched configuration and if two or more carbon atoms in length, they may include a double or a triple bond. Exemplary of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, and the like.
Halogen (halo) refers to chlorine, fluorine, iodine or bromine.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by hetero atoms.
The term xe2x80x9cheteroatomxe2x80x9d means O, S or N, selected on an independent basis.
The term xe2x80x9cheteroarylxe2x80x9d refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole.
The term alkylsilyl refers to t-butyldimethylsilyl (TBDMS), triethylsilyl (TES), tribenzylsilyl, tributylsilyl, triisobutylsilyl, trimethylsilyl and the like.
This invention is also concerned with a method of treating ocular hypertension or glaucoma by administering to a patient in need thereof one of the compounds of formula I in combination with a xcex2-adrenergic blocking agent such as timolol, a parasympathomimetic agent such as pilocarpine, carbonic anhydrase inhibitor such as dorzolamide, acetazolamide, metazolamide or brinzolamide, a prostaglandin such as latanoprost, rescula, S1033 or a prostaglandin derivative such as a hypotensive lipid derived from PGF2xcex1 prostaglandins. An example of a hypotensive lipid (the carboxylic acid group on the xcex1-chain link of the basic prostaglandin structure is replaced with electrochemically neutral substituents) is that in which the carboxylic acid group is replaced with a C1-6 alkoxy group such as OCH3 (PGF2a 1-OCH3), or a hydroxy group (PGF2a 1-OH).
Preferred potassium channel blockers are calcium activated potassium channel blockers. More preferred potassium channel blockers are high conductance, calcium activated potassium (Maxi-K) channel blockers. Maxi-K channels are a family of ion channels that are prevalent in neuronal, smooth muscle and epithelial tissues and which are gated by membrane potential and intracellular Ca2+.
Intraocular pressure (IOP) is controlled by aqueous humor dynamics. Aqueous humor is produced at the level of the non-pigmented ciliary epithelium and is cleared primarily via outflow through the trabecular meshwork. Aqueous humor inflow is controlled by ion transport processes. It is thought that maxi-K channels in non-pigmented ciliary epithelial cells indirectly control chloride secretion by two mechanisms; these channels maintain a hyperpolarized membrane potential (interior negative) which provides a driving force for chloride efflux from the cell, and they also provide a counter ion (K+) for chloride ion movement. Water moves passively with KCl allowing production of aqueous humor. Inhibition of maxi-K channels in this tissue would diminish inflow. Maxi-K channels have also been shown to control the contractility of certain smooth muscle tissues, and, in some cases, channel blockers can contract quiescent muscle, or increase the myogenic activity of spontaneously active tissue. Contraction of ciliary muscle would open the trabecular meshwork and stimulate aqueous humor outflow, as occurs with pilocarpine. Therefore maxi-K channels could profoundly influence aqueous humor dynamics in several ways; blocking this channel would decrease IOP by affecting inflow or outflow processes or by a combination of affecting both inflow/outflow processes.
The present invention is based upon the finding that maxi-K channels, if blocked, inhibit aqueous humor production by inhibiting net solute and H2O efflux and therefore lower IOP. This finding suggests that maxi-K channel blockers are useful for treating other ophthamological dysfunctions such as macular edema and macular degeneration. It is known that lowering IOP promotes blood flow to the retina and optic nerve. Accordingly, the compounds of this invention are useful for treating macular edema and/or macular degeneration.
Macular edema is swelling within the retina within the critically important central visual zone at the posterior pole of the eye. An accumulation of fluid within the retina tends to detach the neural elements from one another and from their local blood supply, creating a dormancy of visual function in the area.
Glaucoma is characterized by progressive atrophy of the optic nerve and is frequently associated with elevated intraocular pressure (IOP). It is possible to treat glaucoma, however, without necessarily affecting IOP by using drugs that impart a neuroprotective effect. See Arch. Ophthalmol. Vol. 112, January 1994, pp. 37-44; Investigative Ophthamol. and Visual Science, 32, Apr. 5, 1991, pp. 1593-99. It is believed that maxi-K channel blockers which lower IOP are useful for providing a neuroprotective effect. They are also believed to be effective for increasing retinal and optic nerve head blood velocity and increasing retinal and optic nerve oxygen by lowering IOP, which when coupled together benefits optic nerve health. As a result, this invention further relates to a method for increasing retinal and optic nerve head blood velocity, increasing retinal and optic nerve oxygen tension as well as providing a neuroprotective effect or a combination thereof.
As indicated above, potassium channel antagonists are useful for a number of physiological disorders in mammals, including humans. Ion channels, including potassium channels, are found in all mammalian cells and are involved in the modulation of various physiological processes and normal cellular homeostasis. Potassium ions generally control the resting membrane potential, and the efflux of potassium ions causes repolarization of the plasma membrane after cell depolarization. Potassium channel antagonists prevent repolarization and enable the cell to stay in the depolarized, excited state.
There are a number of different potassium channel subtypes. Physiologically, one of the most important potassium channel subtypes is the Maxi-K channel which is present in neuronal tissue, smooth muscle and epithelial tissue. Intracellular calcium concentration (Ca2+i) and membrane potential gate these channels. For example, Maxi-K channels are opened to enable efflux of potassium ions by an increase in the intracellular Ca2+ concentration or by membrane depolarization (change in potential). Elevation of intracellular calcium concentration is required for neurotransmitter release. Modulation of Maxi-K channel activity therefore affects transmitter release from the nerve terminal by controlling membrane potential, which in turn affects the influx of extracellular Ca2+ through voltage-gated calcium channels. The compounds of the present invention are therefore useful in the treatment of neurological disorders in which neurotransmitter release is impaired.
A number of marketed drugs function as potassium channel antagonists. The most important of these include the compounds Glyburide, Glipizide and Tolbutamide. These potassium channel antagonists are useful as antidiabetic agents. The compounds of this invention may be combined with one or more of these compounds to treat diabetes.
Potassium channel antagonists are also utilized as Class 3 antiarrhythmic agents and to treat acute infarctions in humans. A number of naturally occuring toxins are known to block potassium channels including Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, and xcex2-Bungarotoxin (xcex2-BTX). The compounds of this invention may be combined with one or more of these compounds to treat arrhythmias.
Depression is related to a decrease in neurotransmitter release. Current treatments of depression include blockers of neurotransmitter uptake, and inhibitors of enzymes involved in neurotransmitter degradation which act to prolong the lifetime of neurotransmitters.
Alzheimer""s disease is also characterized by a diminished neurotransmitter release. Alzheimer""s disease is a neurodegenerative disease of the brain leading to severely impaired cognition and functionality. This disease leads to progressive regression of memory and learned functions. Alzheimer""s disease is a complex disease that affects cholinergic neurons, as well as serotonergic, noradrenergic and other central neurotransmitter systems. Manifestations of Alzheimer""s disease extend beyond memory loss and include personality changes, neuromuscular changes, seizures, and occasionally psychotic features.
Alzheimer""s disease is the most common type of dementia in the United States. Some estimates suggest that up to 47% of those older than 85 years have Alzheimer""s disease. Since the average age of the population is on the increase, the frequency of Alzheimer""s disease is increasing and requires urgent attention. Alzheimer""s is a difficult medical problem because there are presently no adequate methods available for its prevention or treatment.
Three classes of drugs are being investigated for the treatment of Alzheimer""s disease. The first class consists of compounds that augment acetylcholine neurotransmitter function. Currently, cholinergic potentiators such as the anticholinesterase drugs are being used in the treatment of Alzheimer""s disease. In particular, physostigmine (eserine), an inhibitor of acetylcholinesterase, has been used in its treatment. The administration of physostigmine has the drawback of being considerably limited by its short half-life of effect, poor oral bioavailability, and severe dose-limiting side-effects, particularly towards the digestive system. Tacrine (tetrahydroaminocridine) is another cholinesterase inhibitor that has been employed; however, this compound may cause hepatotoxicity.
A second class of drugs that are being investigated for the treatment of Alzheimer""s disease is nootropics that affect neuron metabolism with little effect elsewhere. These drugs improve nerve cell function by increasing neuron metabolic activity. Piracetam is a nootropic that may be useful in combination with acetylcholine precursors and may benefit Alzheimer""s patients who retain some quantity of functional acetylcholine release in neurons. Oxiracetam is another related drug that has been investigated for Alzheimer treatment.
A third class of drugs is those drugs that affect brain vasculature. A mixture of ergoloid mesylates is used for the treatment of dementia. Ergoloid mesylates decrease vascular resistance and thereby increase cerebral blood flow. Also employed are calcium channel blocking drugs including Nimodipine which is a selective calcium channel blocker that affects primarily brain vasculature.
Other miscellaneous drugs are targeted to modify other defects found in Alzheimer""s disease. Selegiline, a monoamine oxidase B inhibitor which increases brain dopamine and norepinephrine has reportedly caused mild improvement in some Alzheimer""s patients. Aluminum chelating agents have been of interest to those who believe Alzheimer""s disease is due to aluminum toxicity. Drugs that affect behavior, including neuroleptics, and anxiolytics have been employed. Side effects of neuroleptics range from drowsiness and anti cholinergic effects to extrapyramidal side effects; other side effects of these drugs include seizures, inappropriate secretion of antidiuretic hormone, jaundice, weight gain and increased confusion. Anxiolytics, which are mild tranquilizers, are less effective than neuroleptics, but also have milder side effects. Use of these behavior-affecting drugs, however, remains controversial. The present invention is related to novel compounds which are useful as potassium channel antagonists. It is believed that certain diseases such as depression, memory disorders and Alzheimers disease are the result of an impairment in neurotransmitter release. The potassium channel antagonists of the present invention may therefore be utilized as cell excitants which should stimulate an unspecific release of neurotransmitters such as acetylcholine, serotonin and dopamine. Enhanced neurotransmitter release should reverse the symptoms associated with depression and Alzheimers disease.
The compounds within the scope of the present invention exhibit potassium channel antagonist activity and thus are useful in disorders associated with potassium channel malfunction. A number of cognitive disorders such as Alzheimer""s Disease, memory loss or depression may benefit from enhanced release of neurotransmitters such as serotonin, dopamine or acetylcholine and the like. Blockage of Maxi-K channels maintains cellular depolarization and therefore enhances secretion of these vital neurotransmitters.
The compounds of this invention may be combined with anticholinesterase drugs such as physostigmine (eserine) and Tacrine (tetrahydroaminocridine), nootropics such as Piracetam, Oxiracetam, ergoloid mesylates, selective calcium channel blockers such as Nimodipine, or monoamine oxidase B inhibitors such as Selegiline, in the treatment of Alzheimer""s disease. The compounds of this invention may also be combined with Apamin, Iberiotoxin, Charybdotoxin, Noxiustoxin, Kaliotoxin, Dendrotoxin(s), mast cell degranuating (MCD) peptide, xcex2-Bungarotoxin (xcex2-BTX) or a combination thereof in treating arrythmias. The compounds of this invention may further be combined with Glyburide, Glipizide, Tolbutamide or a combination thereof to treat diabetes.
The herein examples illustrate but do not limit the claimed invention. Each of the claimed compounds are potassium channel antagonists and are thus useful in the decribed neurological disorders in which it is desirable to maintain the cell in a depolarized state to achieve maximal neurotransmitter release. The compounds produced in the present invention are readily combined with suitable and known pharmaceutically acceptable excipients to produce compositions which may be administered to mammals, including humans, to achieve effective potassium channel blockage.
The maxi-K channel blockers used can be administered in a therapeutically effective amount intravaneously, subcutaneously, topically, transdermally, parenterally or any other method known to those skilled in the art. Ophthalmic pharmaceutical compositions are preferably adapted for topical administration to the eye in the form of solutions, suspensions, ointments, creams or as a solid insert. Ophthalmic formulations of this compound may contain from 0.01 to 5% and especially 0.5 to 2% of medicament. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing intraocular pressure, treating glaucoma, increasing blood flow velocity or oxygen tension. For a single dose, from between 0.001 to 5.0 mg, preferably 0.005 to 2.0 mg, and especially 0.005 to 1.0 mg of the compound can be applied to the human eye.
The pharmaceutical preparation which contains the compound may be conveniently admixed with a non-toxic pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethyl-cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like. Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like. The pharmaceutical preparation may also be in the form of a microparticle formulation. The pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament. The polymer used to form the insert may be any water soluble non-toxic polymer, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, (hydroxyloweralkyl cellulose), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; acrylates such as polyacrylic acid salts, ethylacrylates, polyactylamides; natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia; the starch derivatives such as starch acetate, hydroxymethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum, gellan gum, and mixtures of said polymer.
Suitable subjects for the administration of the formulation of the present invention include primates, man and other animals, particularly man and domesticated animals such as cats and dogs.
The pharmaceutical preparation may contain non-toxic auxiliary substances such as antibacterial components which are non-injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic acid, and the like.
The ophthalmic solution or suspension may be administered as often as necessary to maintain an acceptable IOP level in the eye. It is contemplated that administration to the mamalian eye will be about once or twice daily.
For topical ocular administration the novel formulations of this invention may take the form of solutions, gels, ointments, suspensions or solid inserts, formulated so that a unit dosage comprises a therapeutically effective amount of the active component or some multiple thereof in the case of a combination therapy.
The following examples given by way of illustration is demonstrative of the present invention.

Ophthalmic compositions for treating ocular hypertension


A filter, particularly suitable for radio frequency applications comprises a first filter which, in turn, comprises at least a pair of intercoupled resonators (RES1, RES2), and a SAW filter (SAW) which is coupled between the two intercoupled resonators so that a signal input to the filter at its input (IN) is coupled through the SAW filter to provide an output signal at its output (OUT). This provides a filter with all the advantages of a SAW filter, but with the ability to withstand the high power requirements of radio frequency applications. If three or more resonators are present in the first filter, then an amplifier can also be integrated in the filter. The SAW filter (and the amplifier if present) are inductively or capacitively coupled to the resonators depending upon the type of filter that is required.

Generally speaking, a radio transmitter-receiver (transceiver), for example, as in a radio telephone requires a duplex filter when the same antenna is used for both transmission and reception. It is well known to persons skilled in the art to employ duplex filters, comprising resonators, in radio transceivers to prevent the transmission signal from travelling into the receiver and, likewise, the received signal from travelling into the transmitter. A duplex filter usually consists of two separate bandpass filters, one of which is connected to the receiver section of the transceiver, the mean frequency and bandwidth thereof corresponding to the reception frequency band, and the other filter being connected to the transmitter section of the transceiver, the mean frequency and bandwidth thereof being equivalent to the transmission frequency band. The other ends of the filters are frequently connected to a common antenna line via a transmission line that matches the impedance of the common antenna line.
Duplex filter designs are commercially available for a plurality of different transceiver circuit designs and are usually composed of helical filters, dielectric filters, or the like. As the size and price of radio telephones goes down, there is a need to provide, not only smaller and less expensive circuit elements, such as semiconductors, but also to implement smaller and less expensive duplex filters. The helical and dielectric filters take up most of the space within a radio transceiver although attempts have been made to make them more and more compact.
In radio telephone technology, filters based on surface acoustic wave resonators have been in use for some time. These are often called surface acoustic wave or SAW filters. An advantage of these SAW filters is not only their small size but also the precision with which they can be reproduced in manufacture. The part of the component accommodating the surface wave phenomenon, in itself, is an interdigital converter, consisting of interdigital electrodes arranged in comb-like fashion on a piezoelectric substrate. An electrical voltage between the electrodes generates acoustic waves in the substrate, propagating on the surface thereof, in a direction perpendicular to the interdigital comb electrodes. These surface acoustic waves can be detected by an interdigital converter which converts the acoustic surface waves propagating on the surface of the substrate back into an electrical voltage. In comparison with electromagnetic waves, the propagation velocity of an acoustic surface wave on a piezoelectric substrate is slower by about 1/100,000 times. Using surface acoustic wave technology, many circuits, such as filters, delay lines, resonators, oscillators, etc. can be produced, for example, such as a notch filter disclosed in US patent U.S. Pat. No. 4,694,266.
However, the use of SAW filters in duplex filters does involve certain problems. A received signal at the reception frequency entering the receiver through the reception branch of a duplex filter, is required to withstand high levels of power, since, for example, in a cellular radio telephone system the maximum output power of a base station is of the order 2 to 300 W. Respectively, the maximum output power of a conventional radio telephone is of the order 2 to 20 W, and the standard output power range varies from a few hundreds of milliWatts to several Watts. At these power levels the SAW filter becomes overheated and burns, as it withstands voltages poorly, this being due to its small-sized electrode structure. Commercially available SAW filters are typically bandpass filters with a low attenuation capacity in the proximity of the mean frequency, though it will grow rapidly outside the pass band. The stop band attenuation of the SAW filter, being of the order 20 dB, is insufficient for a duplex filter. For example, in ceramic filters the attenuation of the stop band is of the order 30 dB. The attenuation of the pass band in a SAW filter (which is about 3-4 dB) suffices, although it is worse than for example, in ceramic filters (which is about 2 dB).
U.S. Pat. No. 4,509,165 describes a duplex filter comprising SAW resonators and is described below with reference to FIG. 1. FIG. 1 is a schematic block diagram of part of a radio telephone having a common antenna 1 for both transmitting and receiving signals. The receiver branch of a duplex filter is a bandpass filter 2 which is coupled, in the receiver section of the transceiver to the antenna 1 to receive signals therefrom. The transmitter section (TX) of the transceiver is also coupled to the antenna 1 via a transmitter branch of the duplex filter (not shown) for coupling a transmission signal thereto. This bandpass filter 2 comprises a dielectric or helical filter 3 (which is a bandpass filter) coupled to the antenna 1 at one end and, at its other end, to a SAW filter 4. By providing a dielectric or helical filter 3 at the antenna end to receive the power from the antenna 1, attempts have been made to avoid the breaking down of the SAW filter 4 caused by far too high a voltage. In U.S. Pat. No. 4,509,165 a method of connecting the SAW filter 4 in series with the bandpass filter 3 is disclosed. Normally, the resistivity of a commercially available SAW filter is 200 ohms, and since in the systems in which filters are in use, the impedance is usually 50 ohms, the SAW filter has to be matched to 50 ohms. By means of the coupling disclosed in U.S. Pat. No. 4,509,165, the need of matching circuits can be minimized, but in such instances the performance, i.e., the attenuation of the pass band and the stop band is not as good as is possible. For a higher performance, the first end of the filter 2, i.e., the dielectric or helical filter 3 and the SAW filter 4 should be coupled separately, which means more components are necessary in the filter 2, which also means an increases in the size of the filter. Another problem with this design is that the attenuations of the pass band of the series-connected SAW filter 4 and the dielectric/helical filter 3 are summed, and, as a result, the attenuation of the pass band increases.
As is well known to persons skilled in the art, filters having the desired properties can be realised by the appropriate interconnection of a number of resonators. The resonators are in the form of a transmission line resonator corresponding to the parallel connection of an inductance and a capacitance. It is also well known in the art in high frequency technology to use different types of resonators for different applications according to the conditions and the desired properties. Known resonator types include dielectric, helical, strip line and air-insulated rod resonators each having a relevant range of a uses. For example, dielectric resonators and filters constructed therefrom are commonly used in high frequency technology and are useful in a number of applications because of their small size and weight, stability and power resistance. For instance, a dielectric filter, for use in a duplex filter, can be constructed from separate ceramic blocks or from one block provided with a number of resonators in which the coupling therebetween is accomplished electromagnetically within the ceramic material. A dielectric stop band filter is usually composed of separate blocks, with coupling between the resonators via the dielectric material being prevented completely. A filter described above and used in the first end of the duplex filter may equally be constructed from helical, strip line or coaxial resonators. All of these are filter designs well known to a person skilled in the art, and therefore, they are not described herein any further detail except as is relevant to the present invention.
FIG. 2 is a schematic circuit diagram of a stop filter having two resonators RES1, RES2. To each resonator RES1 and RES2, a capacitance C1, C2 respectively, is coupled galvanically in an appropriate point A,B. The coupling point A,B determines the impedance level of the resonator, and by selecting the coupling point A,B appropriately, the resonator can be matched into the circuit. This coupling, wherein the coupling point A,B, forms a tap output from the resonators RES1, RES2 respectively is called tapping, and the coupling point A,B, the tapping point. When using helical resonators, they are also coupled by tapping, whereby, for example, a connection line is soldered to a given point in the helical resonator coil, usually in the first round of the coil. A filter is realised by coupling the resonators RES1, RES2 together. This coupling can be accomplished either capacitively or inductively according to what kind of filter is desired. By coupling the resonators together inductively L, as shown in FIG. 2, a bandstop filter is produced (in this case a high-pass filter). By replacing the capacitances C1,C2 with transmission lines, a low-pass filter is produced, and furthermore, by coupling the resonators RES1, RES2 together capacitively at the upper ends, a bandpass filter is produced. The input IN and output OUT of the filter is provided in the example in FIG. 2 at the other ends of the capacitances C1,C2 from those ends coupled to the resonators RES1,RES2.

Filter having resonators coupled by a saw filter and a duplex filter formed therefrom