This invention describes novel formulations containing a water soluble disulfide, 2,2'-dithio-bis-ethane sulfonate, with or without cis-diammine dichloro platinum present in the same formulation, wherein the parenteral or oral administration of 2,2'-dithio-bis-ethane sulfonate is used to reduce the risk or prevent or retard the development of cisplatin induced nephrotoxicity, myelosuppression, and neurotoxicity, and wherein the parenteral or oral administration of 2,2'-dithio-bis-ethane sulfonate potentiates the antitumor activity of cisplatin when treating human patients with cancer. This invention also teaches novel formulations containing 2,2'-dithio-bis-ethane sulfonate alone or in combination with cisplatin in lyophilized or dissolved in an aqueous formulations which can be administered to patients with cancer who are being treated with cisplatin. The invention also teaches methods of preparing said formulations and their use in preventing cisplatin related toxicities and potentiation of cisplatin antitumor activity.

1. Field of the Invention
This invention teaches novel compositions and methods of use thereof, of a water soluble disulfide, 2,2'-dithio-bis-ethane sulfonate (also known as "disodium 2,2'-dithio-bis-ethane sulfonate", "dimesna" or "BNP7787") in human patients who are being treated for cancer with cis-diammine dichloro platinum (also known as "cisplatin" or "CDDP") and wherein cis-diammine dichloro platinum and 2,2'-dithio-bis-ethane sulfonate compositions are administered prior to, simultaneously or following the administration of cisplatin to reduce the risk of cisplatin induced nephrotoxicity when treating human patients with cancer. This invention also teaches the use of said compositions containing 2,2'-dithio-bis-ethane sulfonate as a key ingredient for the purposes of potentiating the antitumor activity of cisplatin in human subjects with cancer, and protecting against cisplatin related neurotoxicity and myelosuppression. In its preferred aspect, this invention involves the preparation and administration of a sterile, aqueous composition of 2,2'-dithio-bis-ethane sulfonate to human patients with cancer who are being treated with cisplatin. In another preferred form, this invention involves the preparation and administration of a lyophilized composition of 2,2'-dithio-bis-ethane sulfonate, which is reconstituted with aqueous media prior to administration to human patients with cancer who are being treated with cisplatin. This invention also teaches methods of administration of the claimed 2,2'-dithio-bis-ethane sulfonate compositions lacking cisplatin that can be carried out within 24 hours preceding and within 24 hours following the administration of cisplatin. Yet another aspect of this invention is the methods of simultaneous administration of cis-diammine dichloro platinum and 2,2'-dithio-bis-ethane sulfonate wherein the 2,2'-dithio-bis-ethane sulfonate is administered simultaneously with the administration of cis-diammine dichloro platinum. This simultaneous administration can be carried out by administering aqueous or lyophilized and reconstituted compositions containing 2,2'-dithio-bis-ethane sulfonate and cisplatin or by the simultaneous administration of each drug via separate routes of administration. Another aspect of this invention is a method of reducing cis-diammine dichloro platinum induced nephrotoxicity, neurotoxicity, and myelosuppression and also potentiating cisplatin antitumor activity in human patients whose cancer is optimally treated with cis-diammine dichloro platinum.
This invention describes novel aqueous and lyophilized compositions and methods of use thereof of a water soluble disulfide, 2,2'-dithio-bis-ethane sulfonate and disodium 2,2'-dithio-bis-ethane sulfonate, which has been discovered by the inventors to protect against cisplatin induced nephrotoxicity. The inventors also teach the use of 2,2'-dithio-bis-ethane sulfonate as a key ingredient of the claimed compositions for the purposes of preventing or retarding the development of cisplatin induced neurotoxicity and myelosuppression. The inventors have made the unexpected discovery that 2,2'-dithio-bis-ethane sulfonate also appears to potentiate (increase) the antitumor activity of cisplatin in vivo and accordingly claim the use of 2,2'-dithio-bis-ethane sulfonate for the purpose of increasing the antitumor activity of cisplatin. The novel lyophilized and aqueous compositions contain 2,2'-dithio-bis-ethane sulfonate or disodium 2,2'-dithio-bis-ethane sulfonate, with or without cis-diammine dichloro platinum and the invention teaches that 2,2'-dithio-bis-ethane sulfonate, and pharmaceutically acceptable salts thereof, may be administered simultaneously with or separately from cisplatin to reduce the risk of cisplatin induced toxicities when treating human patients with cancer.
2. Description of the Related Art
A. Introduction
The use of cytotoxic anticancer drugs pose an increased risk of certain drug related toxic side effects in human subjects undergoing cancer treatment. Drug toxicity associated with the use of anticancer drugs greatly limits their clinical utility and safety in human subjects. For example, drug-induced impairment of cellular and/or organ functions may result in organ-specific toxicities in human subjects being treated for cancer. Additionally, the drugs themselves or their metabolites may accumulate or damage certain cellular components or impair certain biochemical reactions in specific organs. The toxicities observed due to the administration of anticancer drugs are usually dose dependent (e.g., busulfan induced myelosuppression), are often related to cumulative dosages administered (e.g., BCNU induced pulmonary toxicity; anthracycline induced cardiac toxicity), and idiosyncratic drug toxicities are noted with some frequency with certain anticancer drugs (e.g., mitomycin-C induced hemolytic uremic syndrome). By impairing or damaging normal cellular function in specific organs the anticancer drug is causally connected with the drug-induced organ damage.
As a result of drug induced toxicity associated with the administration of anticancer drugs to humans, clinicians attempt to prevent or reduce the risk of drug toxicity by certain pharmacologic maneuvers. Such clinical maneuvers can impose risk of additional side effects, or result in a dose reduction of the anticancer drug which in turn may adversely affect the likelihood of achieving control of the patient's tumor. If the major dose-limiting organ toxicity of a particular anticancer drug is eliminated or substantially reduced, the result is that the safety and efficacy of the primary anticancer drug is greatly increased. A significant reduction in drug toxicity in cancer treatment generally results in greater ability to administer higher doses of the drug, prevents or reduces the number of treatment delays, and increases the safety and the quality of life for patients. An example of this approach is the use of G-CSF to reduce the duration and magnitude of drug induced myelosuppression resulting from the administration of several different types of anticancer drugs. Therefore, an important area of drug research and treatment is aimed at developing new methods to prevent or reduce drug induced dose limiting toxicities in human cancer patients.
This invention teaches new art which uses 2,2'-dithio-bis-ethane sulfonate or pharmaceutically acceptable salts thereof (including disodium 2,2'-dithio-bis-ethane sulfonate) contained in compositions which can be administered to human subjects with cancer being treated with cis-diammine dichloro platinum. For the purposes hereof, the useful composition of matter defined by this invention includes 2,2'-dithio-bis-ethane sulfonate, pharmaceutically acceptable salts of 2,2'-dithio-bis-ethane sulfonate, dimesna and BNP7787. The inventors have made an unexpected discovery that the use of compositions containing 2,2'-dithio-bis-ethane sulfonate are effective and safe in protecting against cis-diammine dichloro platinum induced nephrotoxicity (impairment of normal renal function). The inventors have also discovered that the administration of 2,2'-dithio-bis-ethane sulfonate compositions is safe and non-toxic and appears to provide protection against cisplatin induced myelosuppression, neurotoxicity and further appears to potentiate the antitumor activity of cisplatin. Myelosuppression is defined as the suppression of the production of blood cells from the bone marrow. Cisplatin neurotoxicity can manifest as the impairment of peripheral sensory neural function (paresthesias, numbness, pain), impairment of central neural function (including nausea, vomiting, ototoxicity, cranial nerve and ocular toxicities. For the purposes of this invention, cis-diammine dichloro platinum is also referred to as "cisplatin" and "CDDP" interchangeably and without restriction. The instant invention which encompasses novel compositions and methods of use of 2,2'-dithio-bis-ethane sulfonate has tremendous utility in preventing, retarding the development of and reducing the risk of these cisplatin induced toxicities in human patients with cancer. This invention also teaches methods of manufacture of said compositions in the instant invention containing the water soluble disulfide 2,2'-dithio-bis-ethane sulfonate (or pharmaceutically acceptable salts thereof) alone or in combination with other medicaments, when desired and add additional utility to this invention.
B. Cis-Diammine Dichloro Platinum
(1) Background of Cis-Diammine Dichloro Platinum
Cis-diammine dichloro platinum (referred herein to as "cisplatin" or "CDDP") is a widely used anticancer drug which is used in combination with other anticancer drugs in the treatment of cancers of the lung, breast, head and neck, ovary, esophagus, bladder, and testis. Along with its potent anticancer properties, cisplatin also has demonstrated clinically significant toxicities which limit its clinical utility and pose certain serious risks to patients undergoing treatment for cancer. The therapeutic benefits of cisplatin must always be carefully weighed against the possibility of these significant drug related toxicities associated with its use. It is well known that one of the most important and common dose limiting toxicities of cis-diammine dichloro platinum is renal damage in patients receiving this drug for treatment of their cancer. Neurotoxicity and myelosuppression are also important toxicities relating to cisplatin therapy in human patients (Perry, M. C., (1992) The Chemotherapy Source Book, Williams and Wilkins, 1172 pp.).
A stable and sterile aqueous solution of cisplatin in a sealed ampoule or vial containing a unit dosage form suitable for intravenous administration to a human patient with cancer was described in U.S. Pat. No. 4,310,515, entitled "Pharmaceutical Compositions of Cisplatin" (Issued Jan. 12, 1982). The patent claims cisplatin provided in a concentration between about 0.1 and about 1.0 mg/ml and a pH in a range of 2.0 to 3.0. The sterile aqueous cisplatin solutions may also contain sodium chloride and mannitol. The present invention claims aqueous compositions containing 2,2'-dithio-bis-ethane sulfonate alone or with any of the following components, in any combination without restriction: (a) sterile water for injection, (2) saline solutions with NaCl concentrations of about 0.1 to about 2.5%, (c) cisplatin in a concentration of about 0.1 to 1.0 mg/ml, (d) sufficient quantities of formulation hydrochloric acid or phosphoric acid to maintain the pH of said formulation in a pH range of about 2.0 to about 6.0, (e) pharmaceutical buffers such as sodium acetate or phosphate, and (f) mannitol in a concentration of about 1.0 to about 2.5%. The present invention also claims lyophilized formulations containing 2,2'-dithio-bis-ethane sulfonate and pharmaceutically acceptable salts thereof alone or in combination with any of the following without restriction: (a) cisplatin, (b) NaCl, (c) mannitol, (d) phosphoric acid, and (e) pharmaceutical buffers such as sodium acetate or phosphate. The present invention claims compositions and methods of use of said compositions which contain 2,2'-dithio-bis-ethane sulfonate in lyophilized or aqueous compositions that can be prepared and administered before, during or after the administration of cisplatin to human subjects with cancer.
(2) Mechanisms of Action of Cis-Diammine Dichloro Platinum
Cisplatin exchanges chloride ions for nucleophilic groups such as RS.sup.-, R--S--CH.sub.3, imidazole nitrogens and R--NH.sub.2 to form linkages which can be very stable. In an aqueous solution, one or both chloride ions may be replaced by water to produce a hydrated intermediate known as an "aquo cisplatin" species (See Reactions 1 and 2 below). The water molecule(s) attached to the cisplatin can be subsequently eliminated by an incoming nucleophile. In some cases there can be direct displacement of the chloride ion by an incoming nucleophile without the participation of the solvent. Thus, several species of cisplatin ("Pt") exist in solution as defined according to the following equilibria: EQU Pt(NH.sub.3).sub.2 Cl.sub.2 +H.sub.2 O.fwdarw.Pt(NH.sub.3).sub.2 Cl(H.sub.2 O)!.sup.+ Reaction 1 EQU Pt(NH.sub.3).sub.2 Cl(H.sub.2 O)!.sup.+ +H.sub.2 O.fwdarw.Pt(NH.sub.3).sub.2 (H.sub.2 O).sub.2 !.sup.++ Reaction 2
The addition of chloride ions to the medium shifts the equilibrium to the left and the reactivity of the cisplatin species depends on the chloride concentration of the medium. Isotonic and hypertonic saline solutions have high chloride ion concentrations and cisplatin will predominate as the Pt(NH.sub.3).sub.2 Cl.sub.2 species. The displacement of chloride ions from Pt(NH.sub.3).sub.2 Cl.sub.2 in an environment with a high chloride concentration occurs very slowly over time with exposure to the strongest nucleophiles, such as the sulfur anion. For example, formulation of cisplatin with sodium thiosulfate or 2-mercapto ethane sulfonate (mesna) is impractical because of the chemical quenching of cisplatin with the sulfur anion or the sulfhydryl moiety of thiosulfate and mesna, respectively. Cisplatin is also directly incompatible with diethyldithiocarbamate due to the presence of the sulfur anion, and thus cannot be formulated in the same solution for parenteral administration.
Cisplatin is believed to act on tumor cell DNA by forming intrastrand crosslinks of the drug attaching to the N7 atom of the imidazole between adjacent purine bases comprising predominantly sequences of 5'-GG-3', 5'-AG-3', 5'-GA-3' or 5'-GXG-3' where X is a naturally occurring purine or a pyrimidine (e.g., adenine, thymine, cytosine or guanine)(Eastman, A., Biochemistry, 25, 3912-3915, 1986; Pinto, A. L. and Lippard, S., Biochem. Biophy. Acta, 780, 167-180, 1986). Cisplatin is believed to exert its antitumor effects by the formation of intrastrand crosslinks which may result in alterations in DNA structure or function. In order for cisplatin to react with certain nucleic acid sequences in cellular DNA, it must first undergo chemical conversion to an active species by the displacement of chloride ligands with water to form the mono-aquo or di-aquo species. The aquo species of cisplatin is reactive with nucleophilic species, including the imidazole nitrogens on DNA or sulfhydryl groups which are also present in cells forming the renal tubular epithelium in humans.
Cisplatin readily reacts with compounds containing sulfhydryl moieties. Sulfhydryl groups are found in cysteine, glutathione, and homocysteine. Metallothionein is a 7 kDa protein which has a high (approximately 30%) cysteine content (Kelly, S. L. et al., Science, 241, 1813-1815, 1988). Increased cellular concentrations of metallothionein and glutathione have been correlated with drug resistance to cisplatin therapy. Thus, if the local renal tubular concentration of sulfhydryl groups from 2-mercapto ethane sulfonate is increased, then cisplatin toxicity may be reduced by the chemical quenching of the cisplatin aquo species in the renal tubules. The present invention accomplishes this objective.
The claimed invention teaches a new discovery in direct contrast to previously reported views of the pharmacology and metabolism of 2-mercapto ethane sulfonate (mesna). For the purposes of this invention, the administration of 2,2'-dithio-bis-ethane sulfonate preceding, following or simultaneously with cisplatin administration provides a physiologically safe source of additional sulfhydryl groups in the proximal and distal convoluted tubules to prevent renal toxicity. Unlike mesna, 2,2'-dithio-bis-ethane sulfonate is chemically inert with respect to cis-diammine dichloro platinum, and thus is compatible in the claimed formulation.
In the present invention, the chemical and pharmacologic behavior of parenterally or orally administered 2,2'- dithio-bis-ethane sulfonate is substantially different from the parenteral or oral administration of mesna as follows:
1. The 2,2'-dithio-bis-ethane sulfonate contained in the composition remains largely intact in the plasma; PA1 2. 2,2'-dithio-bis-ethane sulfonate is a dianionic species and enters cells to a much lesser degree than mesna-cysteine, mesna-glutathione, and mesna-homocysteine disulfide conjugates. Therefore, more disulfide is filtered and excreted via the renal route, making more thiols available for detoxification in the kidney relative to parenterally or orally administered mesna; and PA1 3. In the kidney, 2,2'-dithio-bis-ethane sulfonate undergoes reduction by renal glutathione reductase and thiol transferase enzymes to form free 2-mercapto ethane sulfonate, which in turn reacts with aquo species of cisplatin resulting in renal excretion of non-toxic cisplatin -2-mercapto ethane sulfonate conjugates. PA1 a. Parenteral administration of hypertonic (3%) NaCl; (Ozols et al., 1984, High-dose cisplatin in hypertonic saline, Ann. Intern. Med., 100, 19); PA1 b. Parenteral administration of normal (0.9%) NaCl; PA1 c. Mannitol diuresis (Hayes et al., 1977, High dose cisplatin diammine dichloride, amelioration of renal toxicity by mannitol diuresis, Cancer, 39, 1372); PA1 d. Pre- and/or post treatment hydration (oral or parenteral); PA1 e. Forced diuresis by the administration of loop diuretics such as furosemide (Ostrow et al., 1981, High-dose cisplatin therapy using mannitol versus furosemide diuresis: comparative pharmacokinetics and toxicity, Cancer Treat. Rep., 65, 73); and PA1 f. Oral or parenteral administration of reduced thiols such as diethyldithiocarbamate (rodents), thiosulfate (humans), or 3-aminopropyl amino ethylphosphorothioic acid (WR-2721).
For the purposes of this invention, the simultaneous or separate administration of cisplatin with 2,2'-dithio-bis-ethane sulfonate will provide a physiologically safe source of additional sulfhydryl groups in the proximal and distal convoluted tubules to prevent renal toxicity. Unlike mesna, 2,2'-dithio-bis-ethane sulfonate is chemically inert under proper conditions with respect to cis-diammine dichloro platinum, and thus is compatible in claimed formulations, and additionally when convenient, 2,2'-dithio-bis-ethane sulfonate can be administered separately preceding or following the administration of cisplatin as claimed in this invention.
It has been previously reported that oral or parenteral administration of 2-mercapto ethane sulfonate (mesna) to mice, rats or humans results in spontaneous autoxidation of mesna to form 2,2'-dithio-bis-ethane sulfonate (dimesna) in the plasma. James and Rogers reported an HPLC assay for plasma thiols using an electrochemical detector (James, C. A. and Rogers, Journal of Chromatography, 382, 394-398, 1986). The inventors submit that by using the method of James and Rogers, the detection and chemical characterization of dimesna (the putative human plasma metabolite of mesna) is indirect because this method can not chemically distinguish between dimesna, mesna-cysteine, and mesna-homocysteine conjugates. The HPLC method of James and Rogers involved the reduction of the samples by sodium borohydride and the samples were subsequently assayed for thiols. The difference in concentration from the unreacted initial sample and the sample that had been reacted with sodium borohydride was used to determine the amount of what was thought to be dimesna in the plasma. The inventors contend that sodium borohydride would react with mesna-mesna, mesna-cysteine, mesna-glutathione, mesna-homocysteine conjugates and thus, they submit that the method of James and Rogers fails to distinguish and quantitate the relative amounts of these entities which would form as a consequence of mesna metabolism. Other investigators rely on a similar or identical method as used by James and Rogers. All of these reports fail to mention or take into account the possibility of mesna forming a significant proportion of thiol conjugates with entities other than mesna, e.g., mesna-cysteine, mesna-glutathione, mesna-homocysteine. The inventors submit that the method of James and Rogers is ambiguous, imprecise and not capable of specifically identifying the disulfide conjugate formed.
The inventors also note that increased cysteine elimination in the urine has been reported in association with the administration of mesna to human subjects (Sidau, B. and Shaw, I. C., J. Chromatography, 311, 234-238, 1984). This observation indirectly supports the inventors' current hypothesis of disulfide conjugation of mesna with other thiols in the plasma (FIG. 1, "New Hypothesis", Middle Column). The enhanced cysteine elimination in urine, as reported by Sidau et al., can be explained by the current invention. The inventors contend that a disulfide linkage forms between mesna and cysteine in the plasma and reduction by glutathione reductase and thiol transferase of the mesna-cysteine conjugates occurs in the renal tubular system to generate free thiols. The free thiols are predicted to react with toxic aquo metabolites of cisplatin.
In view of the above discussion, the inventors submit that the concurrent, pre- or post -administration of 2,2'-dithio-bis-ethane sulfonate with cisplatin is chemically and pharmacologically superior to using mesna because: (1) a greater amount of disulfides will be delivered to the renal tubular system whereupon these disulfides are available for reduction by glutathione reductase and thiol transferases to form the free thiol, 2-mercapto ethane sulfonate, and (2) a lower amount of energy is needed to reduce the 2,2'-dithio-bis-ethane sulfonate disulfide linkage which in turn will generate a greater amount of free thiols in the renal tubules whereupon these free thiols can react with the toxic aquo species of cisplatin .
An object of this invention is the simultaneous or separate, parenteral administration of 2,2'-dithio-bis-ethane sulfonate and cisplatin to human subjects with cancer. Another object of the present invention is the separate administration of 2,2'-dithio-bis-ethane sulfonate preceding or following the administration of cisplatin. Another object of this invention is oral or parenteral administration of 2,2'-dithio-bis-ethane sulfonate to human patients with cancer. Yet another object of this invention is the administration of 2,2'-dithio-bis-ethane sulfonate for the purpose of preventing, reducing or retarding the development of cisplatin related neurotoxicity, myelosuppression and the use of 2,2'-dithio-bis-ethane sulfonate for the purposes of potentiating (increasing) the antitumor activity of cisplatin in human subjects with cancer. The following characteristics of 2,2'-dithio-bis-ethane sulfonate support its use in the present invention:
1. 2,2'-dithio-bis-ethane sulfonate will predominate in the plasma compartment.
2. 2,2'-dithio-bis-ethane sulfonate is an anionic species because it has two negatively charged oxygens. Because of this anionic characteristic, the molecule penetrates cell membranes, especially those of cancer cells, very poorly.
3. The highly anionic nature and small molecular size of 2,2'-dithio-bis-ethane sulfonate are key properties which account for its rapid and nearly exclusive excretion in high concentrations through the kidney.
4. In the absence of any other treatment, 2,2'-dithio-bis-ethane sulfonate has reportedly been tested only once in normal human volunteers (Shaw, I. C. and Weeks, M. S., Eur J Cancer Clin Oncology 23:933-935; 1987; Brock N., et al., J. Cancer Res. Clin. Oncol., 108, 87-97, 1984; Brock N., et al., Eur. J. Cancer Clin. Oncol. 18, 1377-1387, 1982; Brock, N. et al., Eur. J. Cancer Clin. Oncol. 17, 1155-1163, 1981). However, the investigators in that instance failed to confirm the chemical identity of the metabolites in the plasma and urine of the human subjects. 2,2'-dithio-bis-ethane sulfonate has not been administered to human subjects being treated with platinum based therapies.
Cisplatin induced nephrotoxicity may be reduced because of the high local concentration of 2-mercapto ethane sulfonate that may be generated from 2,2'-dithio-bis-ethane sulfonate by renal tubular enzymes such as gamma glutamyl transpeptidase and thiol transferases in the same region of the renal tubules where the formation or delivery of a high concentration of aquo species of cisplatin is achieved. If cisplatin is conjugated with glutathione or other free thiols, these cisplatin conjugates are likely to be nephrotoxic if further metabolized to mercapturic acids (Hanigan M. H. et al. Cancer Research 54:5925; 1995). 2,2'-dithio-bis-ethane sulfonate, or its metabolite 2-mercapto ethane sulfonate, may prevent conjugation of cisplatin with glutathione or other endogenous thiols and/or further metabolism of cisplatin conjugates to mercapturic acids which are believed to be nephrotoxic.
This invention is also useful because the simultaneous or separate oral or parenteral administration of 2,2'-dithio-bis-ethane sulfonate and cisplatin: (1) insures treatment compliance, (2) will reduce pharmacy preparation costs, (3) will reduce errors in prescribing both drugs, (4) will reduce the amount of additional prophylactic maneuvers needed in order to reduce toxicity and avoid iatrogenic related complications (i.e. furosemide, or hypertonic saline administration as described above), and (5) for greater utility when a longer shelf life is desired, this invention also teaches methods to make and use lyophilized formulations containing 2,2'-dithio-bis-ethane sulfonate alone or in combination with cisplatin, mannitol, buffers and sodium chloride. 2,2'-dithio-bis-ethane sulfonate can be contained in a lyophilized formulations with other useful medicaments such as cisplatin, sodium chloride, mannitol, and buffers in any combination and without restriction.
Formulations of cisplatin and 2,2'-dithio-bis-ethane sulfonate must be maintained at a pH less than 7.0 and greater than 1.0 because of the need to prevent the formation of aquo species of cisplatin and also to prevent the formation of mesna which could subsequently react with cisplatin species. Another important component of this invention is the use of sufficiently high concentrations of NaCl (e.g., 0.9% or greater) and HCl because the stability of cisplatin is proportionally related to the chloride ion concentration of the solution.
C. Nephrotoxicity Associated with Cis-Diammine Dichloro Platinum Administration
One of the most important limitations in the human clinical use of cisplatin is the nephrotoxicity which develops as a consequence of cumulative and dose dependent exposure to the drug, or which may occur in setting the administration of cisplatin to patients with renal insufficiency or co-administration of other nephrotoxic agents (e.g., aminoglycosides) (Rozencweig et al., 1977, Cis-diamminedichloroplatinum (II), Ann. Intern. Med., 86, 803; Gonzalez-Vitale et al., 1977, The renal pathology in clinical trials of cisplatin (II) diamminedichloride, Cancer, 39, 1362; Campbell et al., 1983, Plasma platinum levels: Relationship to cisplatin dose and nephrotoxicity, Cancer Treat. Rep., 67, 169; Offerman et al., 1984, Acute effects of cis-diammine-dichloroplatinum (CDDP) on renal function, Cancer Chemother. Pharnacol., 12, 36).
The major clinical features of cisplatin induced nephrotoxicity include decreases in creatinine clearance, elevated creatinine, elevated BUN, elevated uric acid and hypomagnesemia. The dose limiting toxicity of cisplatin when administered as a single dose per cycle is nephrotoxicity. Nephrotoxicity associated with cisplatin administration may also be related to the peak plasma concentration of the drug. Hyperuricemia and hypoalbuminemia are predisposing factors to cisplatin nephrotoxicity along with renal insufficiency, concomitant administration of other drugs, including aminoglycoside antibiotics and possibly by amphotericin B.
Typical pathological changes in the kidneys after cisplatin application have been observed in laboratory animals and humans. (Kociba and Sleight, 1971, Acute toxicologic and pathologic effects of cis-diammine dichloro platinum in the male rat, Cancer Chemother. Rep., 55, 1; Choie et al., 1981, Acute and chronic cisplatin nephropathy in rats, Lab. Invest., 44, 397; Goldstein and Gilbert, 1983, The nephrotoxicity of cisplatin, Life Sci., 32, 685). Certain strains of rats have been noted for their excellent correlation with human nephrotoxicity, including Fischer, Wistar, and Harlan-Sprague Dawley rats. These cisplatin induced renal lesions are dose and time dependent, and are mainly localized in the outer stripe of the medulla of the kidney, which corresponds to the microscopic anatomic location of the glomerulus and convoluted tubules.
Thus, cisplatin induced nephrotoxicity usually occurs as a result of the cumulative and dose dependent exposure to the drug, or when administered to patients with renal insufficiency or when coadministered with another nephrotoxic agent (e.g., aminoglycosides). The dose limiting toxicity of cisplatin, when the drug is administered as a single dose per cycle, is nephrotoxicity which may be related to the peak plasma concentration of the drug itself.
Cisplatin induced nephrotoxicity is a clinically important problem associated with the use of the drug, and certain clinical maneuvers are generally employed in an attempt to reduce the risk of this complication. These prophylactic maneuvers include:
However, these maneuvers have certain drawbacks which limit the practical use of cisplatin and introduce additional definite risks for treatment related complications in patients undergoing treatment. For example, the administration of hypertonic saline (NaCl 3.0%) poses the risk of iatrogenic hypernatremia. Hypernatremia is a life threatening medical emergency which can be fatal, and the administration of hypertonic saline is contraindicated in patients with elevated serum sodium or patients with congestive heart failure. The administration of normal saline (NaCl 0.9%) in patients increases the risk of fluid overload in patients. The use of powerful loop diuretics to increase urine production by the kidney such as furosemide increase the iatrogenic risk of hypokalemia, hyponatremia, hypocalcemia, hypovolemia, metabolic alkalosis and hypochloremia. All of these conditions can be life threatening and in some cases are fatal.
It is important to note that these maneuvers aimed at prophylaxis of cisplatin nephrotoxicity require additional clinical services, additional patient monitoring (e.g., physicians, nurses, and pharmacists), and additional hospitalization expense. Additionally, since these prophylactic maneuvers (aimed at reducing the risk of nephrotoxicity) are separate from the administration of the drug (cis-diammine dichloro platinum), the patient runs the risk of experiencing additional toxicity due to the maneuver itself (e.g., fluid overload, congestive heart failure, hyperosmotic state, hypernatremia or by physician, nurse, pharmacist or support staff human error).
This invention reduces cisplatin induced nephrotoxicity, neurotoxicity and myelosuppression and potentiates the antitumor activity of cisplatin by the oral or parenteral administration of 2,2'-dithio-bis-ethane sulfonate to human subjects being treated with cisplatin for cancer therapy. The 2,2'-dithio-bis-ethane sulfonate and cis-diammine dichloro platinum are in compositions suitable for administration to human subjects with cancer, or alternatively 2,2'-dithio-bis-ethane sulfonate is administered separately from cisplatin. As discussed above, parenteral formulations of mesna (mercapto ethane sulfonate sodium) or sodium thiosulfate with cisplatin are not practical because the sulfhydryl groups on mesna or the sulfate anion of sodium thiosulfate will react with cisplatin yielding inactive species of cisplatin.
D. Water Soluble Thiols as Detoxifying Agents in the Kidney
1. 2-Mercaptoethane Sulfonate Sodium or "Mesna"
Mesna is a pharmacologically safe thiol that has been used clinically in human subjects for approximately two decades. Mesna has been reported to be rapidly eliminated through the kidneys, accumulates in the urine and, unlike cysteine or N-acetyl cysteine, only slightly penetrates cellular membranes. In the rat, over 80% of the administered dose of mesna is reportedly recovered in the urine within three hours after intravenous administration (Pohl et al., Meth. Find. Clin. Pharnacol. 3(Suppl 1), 95-101, 1981).
For the purposes of the present invention, the inventors wish to point out that the analytical methods previously used to detect the presence of mesna metabolite in the plasma or in the urine in the studies are incapable of determining the chemical identity of the thiol (see discussion above). Mesna is widely used to reduce or prevent the risk of hemorrhagic cystitis to the uroepithilium which is associated with the use of chloroethylnitrosoureas (including BCNU, CCNU and MeCCNU) and certain oxazaphosphorine type anticancer drugs which include cyclophosphamide, ifosfamide and trophosphamide. Mesna administered orally or parenterally to human subjects significantly reduces the incidence of uroepithelial toxicity in patients receiving therapy with these drugs. Oxazaphosphorine induced hemorrhagic cystitis can be a life threatening condition due to profuse bleeding from the uroepithelial surfaces involving the ureters, bladder and urethra.
It is especially important to note for the present invention that oxazaphosphorine or chloroethylating agent induced uroepithelial toxicity is chemically, biochemically, anatomically and pathologically distinct from the renal toxicity which is observed with administration of cisplatin. Cisplatin is an inorganic molecule whereas oxazaphosphorines and chloroethylating type anticancer drugs are organic molecules. The toxic species of cisplatin is the inorganic mono- and di-aquo species whereas the toxic species of oxazaphosphorines is the organic molecule, acrolein and for chloroethylating drugs are the chloroethyl intermediates. The toxic species of oxazaphosphorines and chloroethylating anticancer drugs are chemically distinct and result from entirely different precursors and produce damage in tissues which is clearly different from that of cisplatin and its metabolites. Cisplatin damages renal tubular cells whereas oxazaphosphorines and chloroethylating type anticancer drugs damage the uroepithelium (renal pelvis, ureters, bladder and urethra). It is also important to note that the organic chemical interactions of mesna with acrolein, the toxic species produced by the metabolism of anticancer oxazaphosphorines which directly damages the uroepithelium, is entirely different than the proposed inorganic chemical interactions which lead to detoxification of cisplatin by mesna.
Dimesna, the only reported metabolite of mesna, is reportedly formed spontaneously by autoxidation of mesna in the plasma. Mesna dimers (two mesna molecules covalently attached via a disulfide linkage) are reported to predominate in the blood following mesna administration. This mesna dimer metabolite is reportedly eliminated through the kidneys by glomerular filtration, being partly reduced to mesna during excretion (Brock, et al., Arzneim Forsch, 32, 486-487, 1982). Reportedly, an average of approximately 45% of the administered mesna dose is found in the urine in the form of mesna, the reactive thiol. The remainder found is reportedly a mesna metabolite, dimesna.
2. Bioavailability of Orally Administered Mesna
In 1984, Burkert et al. described the bioavailability of orally administered mesna (sodium 2-mercaptoethane sulfonate, Uromitexan; Burkert et al., Arzneim.-Forsch./Drug Res. 34, 1597, 1984). Previous experimental studies in rats had demonstrated that mesna was absorbed from the intestine following oral administration and that it passed unchanged through the hepatic vascular system (Brock et al., J. Cancer Res. Clin. Oncol. 108, 87 1984; Ormstad et al., Cancer Research, 43, 333, 1983). It was proposed that in the plasma mesna was rapidly oxidized to disulfide dimesna and that the reaction occurs when mesna was injected intravenously. It was further proposed that after glomerular filtration, about 50% of dimesna was reduced to mesna in the renal tubular epithelium.
The inventors propose that it is unlikely that oral or parenterally administered mesna would necessarily be oxidized in the plasma to form significant quantities of dimesna (e.g., quantities greater than 40% of an administered dose). The inventors propose that the significant majority of mesna reacts with other plasma thiols to form conjugates with cysteine, glutathione and other thiol containing amino acids which are small enough to still undergo glomerular filtration and possibly tubular secretion and would be cleaved to form mesna (plus the free amino acid) in the tubular lumen. The inventors also specifically propose for the first time that mesna reacts predominantly with other thiols in the plasma such as cysteine, homocysteine, or the cysteine contained in glutathione (See above discussion). Since mesna forms a disulfide linkage with thiol containing amino acids or peptides it could still be filtered by the glomerulus or secreted in the proximal tubule. The therapeutic disadvantage of these mesna-cysteine and other similar disulfide conjugates is that their disulfide linkages are chemically more stable than the 2,2'-dithio-bis-ethane sulfonate conjugate proposed in the present invention, which results in a less facile chemical production of free thiols in the kidney.
In their study, Burkert et al. (Burkert et al., Bioavailability of orally administered mesna, Arzneim.-Forsch./Drug Res. 34, 1597, 1984) confirmed the established bioavailability of orally administered mesna with studies in healthy volunteers and patients with tumors. Burkert et. al. tested the oral administration of mesna (Uromitexan drink ampoules) in 18 healthy probands and in 5 tumor patients. Following a single oral administration of either 20 or 40 mg/kg mesna, approximately 52% of the dose was excreted in the urine as reactive thiol groups and the only metabolite of mesna, mesna disulfide or dimesna, comprised the remaining 48%. The experimental methods used to characterize mesna or dimesna in these studies are not conclusive in establishing with certainty the precise chemical identity of mesna or dimesna as urinary metabolites. It is far more likely that mesna was conjugated with certain thiols such as cysteine, homocysteine or glutathione. The key description used to characterize the identity of the putative dimesna metabolite by previous research groups is "thiol groups" which could represent other amino acids.
This study also concluded that after intravenous injection of 20 mg/kg mesna, about 48% of the dose administered appeared as thiol groups in the urine. It took approximately 13 hours (20 mg/kg p.o.) or 18 hours (40 mg/kg p.o.) for the concentration to drop below the minimum concentration presumed to still be protective (100 ug/ml). However, the elimination pattern and the time required to reach the threshold concentration of mesna varies dramatically from patient to patient.
3. Concomitant Use of Oral Mesna in Rats or Thiosulfate in Humans to Reduce the Urotoxic Effects of the Cisplatin
Kempf et al. studied the effects of per os administration of sodium 2-mercaptoethane-sulfonate (mesna) in rats in preventing the nephrotoxic effects of cisplatin administered intraperitoneally (Kempf et al., Effective prevention of the nephrotoxicity of cisplatin (CDDP) by administration of sodium 2-mercaptoethane-sulfonate (mesna) in rats, Br. J. Cancer, 52, 937-939, 1985). As described above, mesna is extensively used in patients who receive oxazaphosphorine antitumor drugs such as cyclophosphamide and ifosfamide to protect the urinary tract, especially the ureters and bladder, against the toxic organic metabolite, acrolein (Brock, et al., 1982). In the case of oxazaphosphorines, acrolein is produced as a result of their metabolism and mesna undergoes addition to the double bond of acrolein, resulting in a stable thioether adduct which has no damaging effects on the uroepithelium and is excreted in the urine.
For the purpose of this invention, it is important to distinguish that the acrolein metabolite, an organic molecule, of the oxazaphosphorines is associated with uroepithelial toxicity, and in absolute contrast, cisplatin and its aquo species, which are inorganic molecules, are associated with direct toxicity to the kidney (nephrotoxicity or renal toxicity). Therefore, the uses of 2-mercapto ethane sulfonate as a protective agent against oxazaphosphorine and chloroethylating agent associated toxicities are entirely different from the protective uses of 2,2'-dithio-bis-ethane sulfonate in the present invention.
Howell and colleagues (Howell et al., Intraperitoneal cisplatin with systemic thiosulfate protection, Ann. Int. Med., 97, 845-851, 1982) administered thiosulfates by intravenous infusion to cancer patients receiving intraperitoneal cisplatin. They observed that much higher (more than two fold) doses of cisplatin per meter square could be administered intraperitoneally and that renal toxicity could be prevented when thiosulfates are administered by the intravenous route. The inventors note that the use of sodium thiosulfate in an aqueous formulation of cis-diammine dichloro platinum is not practical because thiosulfate will inactivate cisplatin and is incompatible in the same solution.
Protection against the nephrotoxicity of intraperitoneally administered cisplatin in rats through oral mesna administration has not been established until the work of Kempf et al. As stated above, mesna disulfide is the only reported metabolite of mesna and mesna disulfide does not readily react with electrophilic alkylating agents such as nitrogen mustard or oxazaphosphorines (Brock et al., The development of mesna for the inhibition of urotoxic side effects of cyclophosphamide, ifosfamide, and other oxazaphosphorine anticancer drugs, Rec. Res. Cancer Res., 74, 270, 1980). After oral administration of mesna, the formation of dimesna reportedly occurs almost solely in the blood. After i.v. administration of mesna, the disulfide is reportedly spontaneously formed by autoxidation and found predominantly in the blood stream (Brock et al., Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention. Eur. J. Cancer. Clin. Oncol. 18, 1377, 1982). Brock and co-workers reported that dimesna is eliminated through the kidneys by glomerular filtration, and, to a great extent, reduced to mesna during excretion.
Using per os administration of mesna, Kempf et al. demonstrated complete prevention of renal damage in rats after a single i.p. dose of 3 mg cisplatin/kg body weight. Their data demonstrated a clear dose/effect relationship, in that low doses of mesna only partially protected the kidneys of rats from renal damage. The inventors wish to point out that 2-mercapto ethane sulfonate differs vastly from 2,2'-dithio-bis-ethane sulfonate on a physicochemical, biochemical, toxicological and pharmacologic basis in terms of formulation compositions and methods of use claimed in the instant invention.
The study of Kempf et al. notably involved the intraperitoneal administration of cisplatin with prior and subsequent oral administration of mesna in rats. The pharmacokinetics of intraperitoneally administered cisplatin differ substantially from the parenteral (e.g., intravenous) administration of cisplatin. In the case of intraperitoneal administration of cisplatin, it is possible to achieve much higher local (intraperitoneal) concentrations of cisplatin, and there is less risk of nephrotoxicity because intraperitoneal cisplatin and its various species do not achieve similar peak plasma concentrations to those achieved with intravenous administration of cisplatin. The oral administration of 2,2'-dithio-bis-ethane sulfonate is predicted by the inventors to be substantially different as follows: (a) intravenous or intraarterial administration of 2,2'-dithio-bis-ethane sulfonate is predicted to reach higher plasma concentrations and greater area under the curve values at given dosages relative to orally administered 2,2'-dithio-bis-ethane sulfonate, and (b) the plasma half life of 2-mercapto ethane sulfonate versus 2,2'-dithio-bis-ethane sulfonate will be different in humans. It is also important to note that at maximally tolerated dosages, the peak plasma concentration and the amount of cisplatin excreted by the kidney is less during intraperitoneal administration than the peak plasma concentration and amount of cisplatin excreted by the kidney when cisplatin is administered intravenously.
The experiments reported by Kempf et al. in rats completely fails to test or describe the ability of parenterally or orally administered 2,2'-dithio-bis-ethane sulfonate in humans to protect against any toxicities related to intravenously administered cisplatin. The inventors point out that there is no art which teaches the administration of 2,2'-dithio-bis-ethane sulfonate to humans with any type of platinum anticancer drug. Because of the above discussion and the literature, one could surmise that the simultaneous administration of mesna would result in the inactivation of cisplatin. Mesna is directly incompatible with cisplatin and is reported in the Physician's Desk Reference (p. 661 1994 Edition, Medical Economics Data Production Company). The inventors have determined that the parenteral administration of 2,2'-dithio-bis-ethane sulfonate and cisplatin can result in an increase in cisplatin nephrotoxicity at lower doses of 2,2'-dithio-bis-ethane sulfonate; this increase in toxicity can be overcome by administration of higher doses of 2,2'-dithio-bis-ethane sulfonate. This observation has not been reported before. Prior to this invention, one cannot predict that the simultaneous administration of 2,2'-dithio-bis-ethane sulfonate would or would not result in cisplatin inactivation or an increase in cisplatin toxicity. The inventors further believe that the administration of mesna does not result in the formation of substantial amounts of dimesna in the plasma; rather mesna predominantly forms conjugates with other plasma thiols, especially the amino acid cysteine which is abundant in the plasma (see above discussion). Additionally, the inventors have determined that the administration of 2,2'-dithio-bis-ethane sulfonate with cisplatin abrogates other cisplatin related toxicities, including myelosuppression and neurotoxicity. The inventors have also made the unexpected discovery that the administration of 2,2'-dithio-bis-ethane sulfonate can potentiate the antitumor activity of cisplatin. The 2,2'-dithio-bis-ethane sulfonate mediated abrogation of cisplatin induced myleosuppression and neurotoxicity, and the potentiation of cisplatin antitumor activity are new discoveries and have not been previously reported by others.
Thus, this invention is novel because: (1) novel methods of use involving the parenteral administration of cisplatin and oral or parenteral administration of 2,2'-dithio-bis-ethane sulfonate are claimed, (2) methods of making and using compositions of 2,2'-dithio-bis-ethane sulfonate alone or with cisplatin in sterile aqueous or lyophilized compositions wherein said compositions are suitable for use in human patients with cancer are claimed, (3) the present invention describes the use of 2,2'-dithio-bis-ethane sulfonate as a key ingredient for the purpose of retarding or abrogating the development of cisplatin induced nephrotoxicity, myelosuppression and neurotoxicity, and (4) the present invention teaches that 2,2'-dithio-bis-ethane sulfonate as a key ingredient can be used to potentiate the antitumor activity of cisplatin.
As stated above, this invention challenges the previous reports that mesna, to a large extent, forms dimesna in the plasma of humans. The inventors submit that oral or parenteral administration of mesna to human subjects results in the formation of more mesna-cysteine conjugates which are excreted by the kidney as compared to mesna-mesna conjugates. Cysteine, homocysteine and glutathione are endogenous thiols in human plasma and therefore could undergo reaction with mesna.
The inventors have also determined that the administration of 2,2'-dithio-bis-ethane sulfonate with cisplatin can result in protection against cisplatin induced myelosuppression and neurotoxicity, and have observed potentiation of the antitumor activity of cisplatin in tumor bearing animals. The inventors do not wish to be bound by any hypothetical explanation of the possible mechanisms of these beneficial effects of the administration of 2,2'-dithio-bis-ethane sulfonate in humans treated with cisplatin. The inventors postulate that the beneficial increase in antitumor activity in tumor bearing animals may be the result of altered pharmacokinetic behavior of cisplatin in the presence of 2,2'-dithio-bis-ethane sulfonate as a consequence of an increased peak plasma concentration or area under the curve of cisplatin, or a combination of the two pharmacokinetic parameters. Another hypothesis relating to the potentiation of the antitumor activity of cisplatin is that 2,2'-dithio-bis-ethane sulfonate is forming a complex with cisplatin that results in altered pharmacokinetic behavior of cisplatin in the form of any of the following parameters: increased effective tumor uptake of cisplatin, increased peak plasma concentrations of cisplatin or increased area under the curve of cisplatin.

Formulations and methods of use 2,2'-dithio-bis-esthane sulfonate


An apparatus (100) for measuring quality of a urea solution is operated with at least a portion of the apparatus inserted into the urea solution. The apparatus (100) includes a configuration of sensors (180, 190, 200) for measuring mechanical and electrical properties within a volume of the urea solution, the measurements of mechanical and electrical properties being mutually differently influenced by components present in the urea solution. A data processing arrangement (230) of the apparatus (100) is operable to process the measurements of mechanical and electrical properties for generating output data (120) indicative of a quality of the urea solution. The apparatus (100) is also capable of being adapted to measure qualities of other types of solution.

Contemporary combustion engines beneficially operate with combustion in their one or more combustion chambers occurring at a high combustion temperature for achieving more efficient engine operation. However, engine operation at high combustion temperatures has associated therewith generation of soot and nitrogen oxide exhaust products, for example nitrous oxides (NOx). Soot and nitrogen oxide exhaust products are hazardous materials when ejected into the environment. For reducing concentrations of exhaust pollutants to within limits defined by legislation, for example contemporary European legislation pertaining to exhaust emissions, vehicle manufacturers conventionally employ Selective Catalytic Reduction (SCR) and/or Exhaust Gas Recirculation (EGR) in their vehicles. SCR is effective for absorbing nitrous oxides whereas EGR ensures more complete oxidation of nitrogen oxides present in exhaust gases.
SCR operation is improved by using chemical agents which are transported and/or stored on vehicles, marine facilities and industrial facilities. For example, "AdBlue" and "DEF" are trade names for a chemical agent corresponding substantially to aqueous urea solution 32.5%. This solution is injected into exhaust gases of modern diesel engines during a post-combustion process for treating engine exhaust gases for reducing a proportion of harmful nitrous oxide (NOx) present in these gases. AdBlue, DEF, "Adblu" is only ever used in conjunction with an SCR. Moreover, vehicles which are equipped with an SCR will carry an AdBlue, DEF or "Adblu" storage tank in addition to a fuel tank. In operation, AdBlue, DEF, or "Adblu" is transferred from the storage tank and injected under pressure into exhaust gases where a series of chemical reactions occur as outlined in Table 1 below.
In FIG. 1, an exhaust system for a combustion engine 15 is indicated generally by 10. The system 10 includes in sequence an inlet 20 for receiving combustion gases from the engine 15, an oxidation catalyst 30, an AdBlue injection region 40, an hydrolysis catalyst 50, an SCR catalyst 60, an oxidation catalyst 70 and finally an outlet 80.
TABLE 1RegionReactionOxidation catalyst 302NO + O2 = 2NO22CO + O2 = 2CO24HC + 3O2 = 2CO2 + 2H2OHydrolysis catalyst 50CO(NH2)2 + H2O = 2NH3 + CO2SCR catalyst 608NH3 + 6NO2 + 7N2 + 12H2O4NH3 + 4NO = O2 + 4N2 + 6H2O2NH3 + NO + NO2 = 2N2 + 3H2OOxidation catalyst 704NH3 + 3O2 = 2N2 + 6 H2O
Essentially, the process occurring in the exhaust system 10 involves an AdBlue mixture being passed onto a super-heated porous ceramic head of the SCR catalyst 60 whereat the de-ionised water evaporates and remaining urea of the injected AdBlue is passed on as a reagent which is operable to break nitrous oxide components (NOx) into mostly Nitrogen and water. Any contaminants present in the AdBlue will collect on the SCR catalyst 60, eventually causing it to clog and fail. It is therefore imperative that the AdBlue remains free from impurities through all stages of production, storage and dispensing.
Detection of ingredients in AdBlue, DEF or "Adblu" is highly desirable; detection of such ingredients is to be understood to be a quality measurement, not merely a measurement of urea concentration which is something different. Agricultural grades of urea are designated for use in agriculture, for example to improve soil quality, whereas industrial grades of urea, for example Adblue, DEF, are adapted for use in road vehicles, for example trucks and buses. When agricultural urea is cheaper on account of more contaminants therein in comparison to industrial AdBlue, there is a temptation for users to employ agricultural AdBlue in trucks and buses for exhaust gas treatment during road use in breach of legal regulations; impurities in agricultural grades of urea can potentially poison catalysts in exhaust systems as well as risk creating airborne pollution including, for example, heavy metals. Moreover, there is also a potential risk that agricultural urea or industrial AdBlue, DEF is contaminated by extraneous material on account of conditions of its storage, for example in unclean tanks which have previously employed to store other materials, for example insecticides.
Another risk is an unintentional confusion by personnel of different tanks available on a vehicle, wherein Diesel fuel, wind screen washer liquid and similar is filled into the Adblue, DEF tank by accident. Another risk is that personnel try to substitute Adblue, DEF with other materials, for example a saline solution, in Adblue, DEF tanks of vehicles to save money. Many farmers face extreme economic pressures which can result in them being attempted to save wherever feasible
Unwanted contamination in Adblue, DEF can have other consequences, for example resulting in a catastrophic event such as a complete SCR failure. Attempting to operate vehicles with defective SCR can represent a criminal offence. AdBlue, DEF is very susceptible to contamination from both foreign matter and incorrect material selection. A main influence concerns the de-ionised water element of the solution which draws ions from materials which it comes into contact with; this changes the chemical composition of the AdBlue, DEF and causes salts to form which in turn clog the ceramic head on the SCR catalyst 60. Most common causes of premature failure of the SCR catalyst 60 are typically either a result of the ingress of damaged pump parts being accidentally transferred into the AdBlue tank or as a result of incorrect material selection. Inert materials should thus always be used to handle AdBlue.
Thus, poor quality of AdBlue can cause increased vehicle pollution and also damage to engine exhaust gas systems. It is not always possible for vehicle drivers to be certain about the origin of AdBlue, DEF that is utilized in their vehicles, and can in consequence unintentionally cause, for example, dangerous pollution from contaminants present in the AdBlue, DEF. However, devices for metering concentrations of urea solution are known, for example a device as described in published United States patent application US 2005/0011183A1 (Ripper et al.). The device includes a sensor unit for monitoring one or more physical state variables of an enzyme-free urea solution. The sensor unit is designed for detecting pH, a dielectric constant of the urea solution and/or conduction of the enzyme-free urea solution. Electrodes of the sensor unit are, for example, implemented as an intermeshed comb-like structure. Moreover, the sensor unit includes a vibration generator for testing mechanical properties of the urea solution, wherein the vibration generator includes a quartz oscillator and/or a piezoelectric crystal. It is to be appreciated that the device described in published United States patent application US 2005/0011183A1 (Ripper et al.) is essentially a urea solution concentration measureing device, which is very different to a urea solution quality measuring apparatus.
However, such known devices for metering urea solution concentration are not sensitive enough and/or accurate enough for distinguishing between various qualities of urea solution for vehicle use, for example distinguishing agricultural-grade urea from transport-grade urea due to presence of trace metal salts that hardly cause any perceptible change in urea solution concentration. Urea solution quality spatially varies within a vehicle urea tank and known sensors measure in a given spatial locality which is potentially not representative of the generally quality of the urea solution in the tank; thus, the aforementioned device described in published United States patent application US 2005/0011183A1 (Ripper et al.) would be unsuitable for constructing a urea quality monitoring apparatus.


A tire includes: a tire frame member formed in a ring shape from a frame resin material, and including a pair of bead sections, a pair of side sections, and a crown section; a ring shaped bead core that is embedded in and joined to each of the bead sections, and that is formed by a single strand, or plurality of strands, of bead cord extending in the tire circumferential direction, and covered with, and joined to, a covering resin material; and an extension portion that extends from each of the bead cores in a direction that intersects with the tire circumferential direction when viewed from a tire side face, and that is joined to the tire frame member.

Known pneumatic tires employed in vehicles such as cars are configured for example from rubber members, members made from organic fiber materials, and steel members. However, used rubber has limited applications in recycling, with rubber being disposed of, for example, with thermal recycling by incineration, or by shredding for use as a road surfacing material.
Recently, the use of thermoplastic materials such as thermoplastic resins and thermoplastic elastomers as tire materials is being demanded from the perspectives of weight reduction and ease of recycling. For example, Japanese Patent Application Laid-Open (JP-A) No. 2010-188634 (Patent Document 1) discloses a tire manufacturing method in which a tire frame member that configures a frame section of a tire is formed from a thermoplastic material. In the tire manufacturing method disclosed in JP-A No. 2010-188634, a bead core is laid out in a cavity of a mold for forming the tire frame member, and then molten thermoplastic material is poured into the cavity to form the tire frame member.    Patent Document 1: JP-A No. 2010-188634


The character or nature of cooling water is correctly estimated. A cooling system for an internal combustion engine includes a radiator, a bypass passage which bypasses the radiator, a thermostat, and a control unit which changes a valve opening temperature of the thermostat. The cooling system for the internal combustion engine further includes an estimating unit which forbids valve opening of the thermostat and which estimates the character of the cooling water on the basis of temperature transition of the cooling water provided in this state.

Cooling water, in which the specific heat is changed at a predetermined temperature, is known (see, for example, Patent Document 1). The cooling water is constructed such that capsules, in which a substance to cause the phase transition is enclosed, are dispersed in the liquid. On the other hand, a technique is known, in which the cooling water temperature is raised by forbidding the valve opening of a thermostat (see, for example, Patent Document 2).
In this context, the control of an electronic thermostat, which is performed in the same manner as in the conventional technique when the cooling water, in which the specific heat is changed at a predetermined temperature, is used in a system for controlling the electronic thermostat so that a preset cooling water temperature is provided, does not affirm that the characteristic, in which the specific heat of the cooling water is changeable, is utilized sufficiently.
On the other hand, the cooling water is exchanged by a user in some cases. Therefore, the cooling water is sometimes exchanged from cooling water in which the specific heat is changeable (i.e., cooling water that contains a substance to cause the phase transition) to cooling water in which the specific heat is not changed (i.e., cooling water that does not contain a substance to cause the phase transition). Further, the cooling water is sometimes exchanged to cooling water in which the specific heat is changed at any different temperature. The proper valve opening timing of the thermostat differs among these types of cooling water respectively. Therefore, unless the thermostat is controlled depending on the character or nature of the cooling water, it is feared that the overheat of the internal combustion engine may be caused, or a long period of time may be required until the warming-up of the internal combustion engine is completed.

Cooling system for internal combustion engine


A buffer tube for an optical fiber cable provided by the present disclosure includes an optical fiber ribbon stack, a first layer, a second layer, an optical fiber cable, a central strength member, a plurality of buffer tubes, a water blocking layer, and a sheath and plurality of rip cords. The first layer is an inner layer of the buffer tube. The first layer is made of a soft material. The soft material of the first layer is one of low smoke zero halogen, thermoplastic elastomers and thermoplastic polyurethane. The second layer is an outer layer of the buffer tube. The second layer surrounds the first layer. The second layer is made of a hard material. The hard material of the second layer is one of polypropylene, polybutylene terephthalate, and nylon.

In the present scenario, optical fiber cables have secured an important position in building network of modern communication systems across the world. The optical fiber cables are sensitive to conditions like crushes, kinks, bends and presence of water and/or moisture. Specifically, the ingression of water and other waste in due course of time degrade or destroy the optical fiber cables. Traditionally, optical fiber cables include a buffer tube that encloses a plurality of optical fibers ribbons in the buffer tube. The buffer tube protects the plurality of optical fiber ribbons from physical damage. Conventionally, the buffer tube is made of Polybutylene Terephthalate (PBT) or Polypropylene (PP) or High-density polyethylene (HDPE) material with sufficient spaces between the plurality of optical fiber ribbons and inner diameter of the buffer tube. This leads to increase in the overall diameter of the buffer tube. In addition, the buffer tube with large diameter makes the optical fiber cable bulky. However, if distance between the buffer tube and the plurality of optical fiber ribbons decreases, the overall diameter of the buffer tube decreases but attenuation increases. Further, this leads to increase in data transmission losses especially in high fiber count cables.
In light of the foregoing discussion, there is a need for a buffer tube that overcomes the above cited drawbacks of conventionally known buffer tubes.


A method for optimizing a twelve-cornered strengthening member comprises: modeling a vehicle assembly including a strengthening member having a twelve-cornered cross section; parameterizing a geometry of the strengthening member with a plurality of control parameters; defining a design of experiment using the plurality of control parameters; modeling a vehicle using the vehicle assembly; simulating a frontal impact event with the vehicle; generating a response surface based on the frontal impact event; and determining a set of optimized control parameters for the strengthening member based on the response surface.

It is desirable, for vehicle strengthening members, to maximize impact energy absorption and bending resistance while minimizing mass per unit length of the strengthening member.
When a compressive force is exerted longitudinally on a strengthening member, for example a force due to a front impact load on a vehicle's front rail or other strengthening member in the engine compartment, the strengthening member can crush in a longitudinal direction to absorb the energy of the collision. In addition, when a bending force is exerted on a strengthening member, for example a force due to a side impact load on a vehicle's front side sill, B-pillar or other strengthening member, the strengthening member can bend to absorb the energy of the collision.
U.S. Pat. No. 6,752,451 discloses a strengthening member having concave portions at the four corners of a basic rectangular cross section, resulting in four U-shaped portions forming an angle of 90 degrees with each other. To avoid cracks at the concave portions at the four corners and to increase strength, the concave portions have increased thickness and hardness. Increased thickness and hardness of the corner portions is disclosed to be achievable only by drawing or hydroforming, and therefore decreases manufacturing feasibility while increasing the mass per unit length of the strengthening member.
U.S. Pat. No. 6,752,451 makes reference to Japanese Unexamined Patent Publication No. H8-337183, which also discloses a strengthening member having concave portions at the four corners of a basic rectangular cross section, resulting in four U-shaped portions forming an angle of 90 degrees with each other. U.S. Pat. No. 6,752,451 states that its thickened concave portions provide improved crush resistance and flexural strength over H8-337183.
It may be desirable to provide a strengthening member configured to achieve the same or similar strength increase as provided by the thickened corners, while minimizing mass per unit length of the member and maintaining a high manufacturing feasibility.
It may further be desirable to provide a strengthening member that can achieve increased energy absorption and a more stable axial collapse when forces such as front and side impact forces are exerted on the strengthening member. Additionally, it may be desirable to provide a strengthening member that possesses improved noise-vibration-harshness performance due to work hardening on its corners.
In various applications, a strengthening member can be used as a crush can attached directly to a bumper beam in alignment with a vehicle's front rails. Crush cans may, for example, manage impact energy and intrusion during a frontal collision. To protect a vehicle's occupants in high speed crash events, a crush can (as part of a vehicle's front end) acts as an energy absorber to absorb a maximum amount of impact energy within a limited crush distance (i.e., a crush can must absorb a high amount of impact energy over a short crush distance). To minimize vehicle repair costs in low speed crash events, however, a crush can must both absorb energy with a limited stroke and be sequentially collapsible within a low speed protection zone to avoid damage to costly vehicle components.
It may be desirable, therefore, to provide a method of optimizing a strengthening member to provide crush cans that are progressive, stable, and energy efficient in both high and low speed frontal impact events.


A storage cabinet includes a frame assembly having a forward facing surface and defining an interior configured to store items; a door assembly having a lateral surface; and a hinge assembly pivotally coupling the frame assembly to the door assembly such that the door assembly is moveable from a closed position to a plurality of open positions. The hinge assembly includes a frame component mounted to the forward facing surface of the frame assembly; and a door component mounted to the lateral surface of the door component and configured to rotate relative to the frame component upon rotation of the door assembly relative to the frame assembly. The hinge assembly is configured to enable a user to remove the door assembly from the frame assembly by lifting the door in a vertical direction only when the door assembly is moved from the closed position at least a predetermined amount.

The present disclosure relates generally to the field of cabinet assemblies, and more particularly, to cabinet assemblies usable, for example, as computer server storage cabinets, and having one or more security hinges.
There are many challenges associated with providing hinge assemblies having a robust design and various security features to ensure the security of the contents within, for example, a cabinet or similar enclosure. As such, various embodiments disclosed herein provide for an improved cabinet and/or hinge assembly.


The invention provides a hand held razor-containing cutting device formed from two separable halves that are connected together during use along a centrally located longitudinally extending parting line. The two halves of the tool are held in contact with one another by means of frictional connecting elements that allow the halves of the tool to snap together for use. A pair of adjacent disassembly tabs are provided. One such tab is located on each half of the tool to facilitate separating the halves of the tool by prying the halves apart, usually with a screwdriver or similar tool that is placed between the tabs and then twisted to pry the tabs away from one another for separating the two portions of the cutting device so that the razor blade can be removed and replaced when required. The frictional connecting elements comprise C-shaped cooperating retaining studs that extend from one half of the tool and during assembly snap into openings provided in the other half.

Several hand-held tools have been provided for holding a razor blade that is used in cutting articles such as packaging, twine and other products. Some of them, such as that described in U.S. Pat. No. 2,254,199, are made of two halves which separate along a center line extending longitudinally to facilitate removing and replacing the razor blade. The present invention employs resilient retaining studs for holding the two halves of the tool together. In the development of the present invention, it was found quite difficult to separate the two halves of the tool. It is thus an object to find a way of enabling the user to quickly and easily separate the two halves of the tool whenever the blade requires changing.
Another problem concerned replacement blades held inside the tool. There was no way to tell if replacement blades were present. Accordingly, another object of the invention is to provide a feature that allows the user to know whether or not additional blades are available.
A further problem concerned the resiliency of the elastic retaining studs used for holding the two halves together. There is a tendency for the studs to be too rigid. Accordingly, another object is to find a way of making the studs used for releasably locking the two halves of the tool together more resilient and less likely to be damaged during use.
A further object of the invention is to find a way of making the tool economical to produce with a minimum of material but yet to strengthen, rigidify and reinforce the slot and guide the article that is being cut to the razor edge so that it will give good life and not be damaged during use.
These and other more detailed and specific objects of the present invention will be apparent in view of the following description setting forth by way of example but a few of the various forms of the invention that will be apparent to those skilled in the art once the principles described herein are understood.

Hand held razor-containing cutting device


The head-protecting airbag apparatus of the present invention includes an airbag and a guide bracket. The guide bracket includes two guide walls and a joint wall, thereby has a generally U-shaped cross section, and accommodates the folded airbag between the two guide walls. The guide bracket is located above a pillar portion while being covered by an airbag cover, and serves to guide the inflating airbag toward vehicle's inner side and prevent the airbag from entering vehicle's outer side of the pillar garnish. The dimension of a clearance between the two guide walls is set such that: a gap arises between the housed airbag and at least one of the guide walls, thereby the airbag is allowed to inflate in the gap in the initial stage of airbag inflation; and that the deployment direction of the airbag is controlled by the guide walls, toward vehicle's inner side. In the head-protecting airbag apparatus of the present invention, the airbag housed in the upper periphery of windows smoothly protrudes inward of vehicle without providing any gas-leakage preventing means such as a reinforcing patch.

1. Field of the Invention
The present invention relates to a head-protecting airbag apparatus provided with an airbag, which, when fed with inflation gas, is deployable downward from upper edge of side windows of a vehicle to protect occupants' head.
2. Description of Related Art
Conventionally, a head-protecting airbag apparatus is provided with an airbag folded and housed in the upper periphery of windows inclusive of upper part of pillar portions. The housed airbag is covered by an airbag cover, and when fed with inflation gas, inflates to push and open the airbag cover, and deploys downward from the upper periphery of windows. The inflated airbag covers the vehicle's interior side of pillars and windows.
In the prior art, Japanese Patent Laid-Open No. 11-091490 is illustrative of a head-protecting airbag apparatus provided with a jump stand that prevents a deploying airbag from entering the vehicle's outer side of pillar garnish covering the inner side of a pillar portion, such that the airbag smoothly deploys toward inward of vehicle. This jump stand is disposed above, and in vehicle's outer side of, a pillar garnish, and includes a slanted guide face, in the top surface thereof. The jump stand serves to guide an inflating airbag inward of vehicle over the upper end of the pillar garnish, by having the airbag slide on its guide face.
Japanese Patent Laid-Open No. 2002-067860 is illustrative of a head-protecting airbag apparatus provided with a guide bracket. The guide bracket has a U-shaped cross section. The guide bracket includes two guide walls confronting each other, and a joint wall joining the two guide walls at the outer ends of the guide walls, and serves to guide the inflating airbag to predetermined direction inside the vehicle.
This guide bracket accommodates the folded airbag between the two guide walls, and upon airbag deployment, allows the airbag to protrude from an opening provided between the leading ends of the guide walls while controlling the deployment direction of the airbag by the two guide walls. In other words, since the bracket guides the airbag with two guide walls extending from the joint wall, the guide bracket secures more stable airbag protrusion in a predetermined direction in comparison with the jump stand. As a result, upon airbag deployment, the guide bracket prevents the airbag from bumping against or hitching on the pillar garnish, and prevents the airbag from bumping against an airbag cover located above the pillar garnish as well.
However, in the conventional guide bracket, the dimension of a clearance between the two guide walls was so set as to accommodate the folded airbag with no gaps. With this construction, if an output of the inflator for supplying inflation gas to the airbag is great, the airbag inflates rapidly in between the confronting guide walls, which can cause gas leakage. That is, the airbag must be provided with certain gas-leakage preventing means such as reinforcing patch, in a region of the guide bracket and therearound. This has increased manufacturing processes and volume of the airbag.


A program that is to be preferentially loaded into a memory is stored in a specific memory and the program stored in the specific memory is changeable to another program. Thus, the program that is to be preferentially loaded into the memory is thereby made changeable.

1. Field of the Invention
The present invention relates to an apparatus which can execute a plurality of functions and a control method thereof.
2. Description of the Related Art
Programs of an apparatus, typified by an apparatus such as a digital multifunction peripheral, are stored on a hard disk apparatus in binary format, loaded into RAM when being executed, and executed under the control of the CPU. In particular, these programs comprise a plurality of functions, and the capacity of total program data tends to increase as the digital multifunction peripheral increases in performance and function. In a case that the size of program data increases in this manner, the time required to read out the program from the hard disk apparatus and store it in RAM becomes longer, leading to a longer wait until it is possible for the user to begin use. Even if a user wishes to use only a part of the digital multifunction peripheral, the user must wait until programs for all functions are loaded into RAM. In order to solve this type of problem, it is possible, for example, to prepare a program of small size for any particular function, as disclosed in Japanese Patent Laid-Open Publication No. 2004-213469. This document discloses a method in which a program is loaded exclusively for each function of the digital multifunction peripheral to be executed. By loading a program restricted to a specific function, the time required to start up the digital multifunction peripheral can be shortened.
However, since it is conventional for a digital multifunction peripheral to make it possible for all functions to be used, the art of exclusively loading a program each time a function is used is not a solution to the above problem. This is because programs that have been set not to be started up will not be started up even if the user requests the function executed by the program. In other words, if the user uses the above conventional art to make it possible to use only a particular function (for example, the copy function), functions other than copying cannot be used under that condition.
A means to solve the above problem involves the "division of program" and the "program storage medium" configurations. These configurations allow preferred functions to be made quickly usable by storing the corresponding programs in a flash memory, while the remaining programs are stored on the hard disk. When the digital multifunction peripheral is started up, programs corresponding to the preferred function is rapidly loaded into a memory from flash memory and made executable, and subsequently programs for executing the remaining functions are successively loaded into the memory from the hard disk, making each function effective. However, if the programs to be stored in a flash memory are fixed, the functions to be made preferentially usable after starting up the digital multifunction peripheral will always be the same, and there may be cases in which functions that differ from the functions that the user desires are preferentially started up.

Multifunction processing apparatus and control method thereof


An LCD test device and a test process thereof are disclosed, in which a defect of an LCD panel is exactly identified through exact electrical connection between an LCD panel and a probe unit. The LCD test device includes a work table on which an LCD panel is mounted, a clamping unit on the work table, clamping a top surface of an edge of the LCD panel mounted on the work table, a probe unit electrically connected with a pad of the LCD panel fixed to the work table by the clamping unit, and a back light unit supplying light to the LCD panel fixed to the work table. Accordingly, since the defect of the LCD panel can be tested exactly, reliability of the test is improved, and it is possible to prevent yield and the cost from being reduced in advance.

1. Field of the Invention
The present invention relates to a test device for a panel of a liquid crystal display (LCD) device, and more particularly, to an LCD test device and a test process thereof, in which an improved structure is provided for exact electrical connection between an LCD panel and a probe unit.
2. Discussion of the Related Art
Generally, an LCD test device is designed for easy testing with the naked eye whether an LCD panel has a defect.
FIG. 1 is a front view illustrating a related art LCD test device, and FIG. 2 is a side view illustrating a related art LCD test device.
As shown in FIGS. 1 and 2, the related art LCD test device includes a test unit 2 arranged at one side of a main body 1 to test an LCD panel 10, and a loading/unloading unit 7 arranged at one side of the test unit 2 to load and unload the LCD panel 10.
The related art LCD test device further includes a carrier 9 movably arranged in both directions to carry the LCD panel 10 from the loading/unloading unit 7 to the test unit 2 or from the test unit 2 to the loading/unloading unit 7.
The test unit 2 includes a probe unit 3 and a work table 4 connecting the LCD panel to the probe unit 3 and supplying a light source. The work table 4 includes a polarizer 4a and a back light unit 4b. A moving stage 5 is at the rear of the work table 4 to align the work table 4 with the probe unit 3 and connect the work table 4 with the probe unit 3.
The loading/unloading unit 7 had a sub table 8 that tilts the LCD panel 10 carried from a loader (not shown) at a predetermined angle (for example, 60°).
Also, a microscope 6 is provided, which is movable in all directions at the front of the test unit 2, to allow a worker to more precisely identify an error found during test of the LCD panel 10 with the naked eye.
The process of testing the LCD panel using the related art LCD test device will be described in brief.
First, the LCD panel 10 is transferred from the loader of the loading/unloading unit 7 to the sub table 8, and the sub table 8 is tilted at a predetermined angle to transfer the LCD panel 10 to the carrier 9.
Subsequently, the carrier 9 carries the LCD panel 10 to the test unit 2. If the LCD panel 10 to be tested is arranged in the test unit 2, the work table 4 is moved by driving of the moving stage 5 to fix the LCD panel 10 of the carrier 9 using a vacuum suction, and the work table 4 connects a pad (not shown) of the fixed LCD panel 10 to a lead pin (not shown) of the probe unit 3.
If the LCD panel 10 is electrically connected with the probe unit 3, a predetermined image signal is applied through the probe unit 3 and at the same time illumination of the back light unit 4b is changed to various patterns by a pattern generator (PG) which is an external image signal input unit, so that the worker identifies any defects of the patterns.
However, the related art LCD test device has the following problems.
FIG. 3 is a sectional view illustrating where the LCD panel is mounted on the work table.
As shown in FIG. 3, because the work table 4 has an inner open area, the LCD panel 10 is connected to the probe unit 3 where it contacts the work table 4.
A middle portion of the LCD panel 10 that is not in contact with the work table 4 may sag due to self-loading. For this reason, the pad of the LCD panel 10 may not fully and properly connect with the lead pin of the probe unit 3.
In other words, an edge of the LCD panel 10 adheres to the work table 4 due to the vacuum suction, but the middle portion of the LCD panel 10 sags due to self-loading, so that the LCD panel 10 mounted on the work table 4 is misaligned a little, whereby the lead pin of the probe unit 3 is not fully and properly connected with the pad of the LCD panel 10.
If the pad of the LCD panel 10 is not fully connected with the lead pin of the probe unit 3, it is difficult to exactly identify a defect of the LCD panel 10. For this reason, the LCD panel 10 may be regarded as defective even when there is no defect. As a result, problems occur in that yield is reduced and the cost is increased.
In particular, the above problems occur more often as LCD panels 10 become larger.

LCD test device and test process thereof


Scheduling techniques are disclosed that employ one or more predictive scheduling classification algorithms configured to exploit historical data of previously scheduled and completed medical procedures. Thus, a new patient that is similarly-situated to previously treated patients can have a medical procedure automatically predicted and scheduled based on historical procedure data associated with those previously treated patients.

Traditional scheduling systems rely on table driven rules or a rules processor to determine the optimal scheduling slot for a healthcare procedure, by matching a patient to resources and a time allotted to perform that procedure. There a number of issues associated with scheduling techniques that rely substantially on rules processors and table driven rules.
For instance, inflexible rules require constant tweaking to maximize resource and people utilization. As such, resources (including people's time) are wasted, thereby resulting in expensive healthcare services. In addition, conventional scheduling techniques require a manual process, where statistical reports are reviewed against usage of resources and people. Such statistical review is after the patient procedure is completed, with manual tweaking of the rules processor to correct for inefficient usage of resources and staff.
Also, typical scheduling systems utilize hard-coded time increments for procedures that can result in the over-booking of resources, which is frustrating for both staff and patients. On the other hand, hard-coded time increments for procedures can also under-book resources, which under-utilize staff and equipment, thereby causing poor return on investment (ROI) for the healthcare provider and unnecessary waiting for emergency or walk-in procedures.
Furthermore, a rules processor typically tracks a limited set of attributes to determine the best usage of resources to patient condition/procedure. The problem here is that rules processors are only as accurate as the rules and information to which they are programmed to respond. Also, a rules processor language may need to be re-compiled and the underlying table driven rules software must be changed, to accommodate changing parameters that drive scheduling engine.
What is needed, therefore, are scheduling techniques that are relatively more flexible and require less user intervention than conventional techniques.

Predictive scheduling for procedure medicine


In a printing press of a lenticular lens sheet, a cocking adjustment unit adjusts the relative angle between a plate on which a pattern formed from a plurality of pattern portions is formed such that boundary lines between the adjacent pattern portions become parallel and a transparent lenticular lens sheet on which a plurality of lenses are formed such that groove lines between the adjacent lenses become parallel. An adjustment amount calculation unit calculates an adjustment amount for the cocking adjustment unit based on the relationship between the boundary lines and the groove lines in a state in which the lenticular lens sheet is overlaid on the plate. A printing method of a lenticular lens sheet is also disclosed.

The present invention relates to a printing press for performing printing on a lenticular lens sheet and a printing method.
As shown in FIG. 45A, a lenticular lens sheet 1 is formed by arranging a plurality of long lenses each having a semicircular section in stripes at a pitch of 0.1 mm to 0.7 mm. As shown in FIG. 45B, pairs of pattern portions A1/B1, A2/B2, . . . , for right and left eyes are printed on the reverse surface of the lenticular lens sheet 1 at an interval of ½ the lens width. An observer views different images with depth on one lenticular lens sheet 1 in accordance with his/her observation direction. This realizes stereopsis by so-called optical illusion.
There are not only the above-described lenticules having a pattern printed on the lenticular lens sheet 1 to provide a view of a stereoscopic image but also lenticules that combine a plurality of totally different patterns to change the image depending on the viewing angle and lenticules that combine a plurality of gradually changing patterns to produce a moving image.
Such an effect of lenticules can be obtained by accurately positioning the lenticular lens sheet 1 formed by arranging a number of long lenses at a specific pitch and a pattern formed by arranging a number of long patterns at a specific pitch. Even in a very small amount, a positional shift between them makes it impossible to obtain the effect. For this reason, alignment between the lenticular lens sheet 1 and the pattern to be printed is very important.
Japanese Patent Laid-Open No. 2007-152818 (literature 1) proposes, as a register adjustment device of a printing press for performing printing on the lenticular lens sheet 1, a device that adjusts the position of a plate with respect to the lenticular lens sheet 1 using a register adjustment mechanism. In the technique of literature 1, when the operator inputs a misregistration amount to the control console, the register adjustment mechanisms of all printing units operate based on the misregistration amount and perform register adjustment of the plate cylinders.
In the technique of literature 1, however, the operator needs to visually confirm the misregistration amount of the printed lenticular lens sheet 1, determine the actual register adjustment amount based on the misregistration amount, and perform printing again after that. For this reason, a lot of rejected sheets are produced. As a result, the advantages of directly printing the pattern on the lenticular lens sheet 1, lead time shortening and large cost reduction, are lost.

Printing press and printing method of lenticular lens sheet