Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
  • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
  • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
  • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
  • A61K31/355—Tocopherols, e.g. vitamin E
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
  • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants

Definitions

• the present invention provides compositions comprising melatonin and/or an antioxidant metabolite, derivative or analogue thereof as the essential ingredient for preventing and treating injury to the urinary bladder due to ionizing radiation by introducing the composition into the bladder.
• compositions comprising melatonin and/or an antioxidant metabolite, derivative or analogue thereof as the essential ingredient for preventing and treating injury to the urinary bladder due to ionizing radiation by introducing the composition into the bladder.
• it is particularly relevant to the fields of urological, prostatic, gynecological and colorectal oncology and radiotherapy, as well as surgery when this is part of a combined treatment with radiotherapy.
• Radiation cystitis in its acute and chronic manifestations, has been well reviewed by Muruve (2014), to whose article the following summary is indebted. Radiation cystitis is a complication of radiation therapy to pelvic tumors.
• the urinary bladder can be irradiated intentionally for the treatment of bladder cancer or incidentally for the treatment of other pelvic malignancies.
• Manifestations of radiation cystitis can range from minor, temporary voiding symptoms and painless, microscopic hematuria to more severe complications, such as gross hematuria, contracted, nonfunctional bladder, persistent incontinence, fistula formation, bladder necrosis, and death.
• Tumors of the pelvic organs such as the prostate gland, urinary bladder, colon and rectum are common in men, constituting 42% of expected new cancer diagnoses in 2014.
• cancer of the colon and rectum, bladder, and genital tract (uterus, ovary, and vagina/vulva) are expected to make up 22% of new cancer diagnoses in 2014.
• Radiation therapy is important for the treatment of these malignancies, creating a significant potential for the development of radiation injury to the urinary bladder.
• Therapeutic radiation may be delivered via various external sources. It may be applied directly to the tumor, such as in interstitial or intracavitary therapy (brachytherapy), or it can be delivered by external beam therapy.
• Radiation therapy works through the transfer of energy from ionizing radiation to molecules within tumor cells and related tissues. Radiation interacts with intracellular water and produces free radicals to an extent that exceeds the cells' intrinsic scavenging capabilities and can thus interfere with DNA synthesis, resulting in cell death. Cells that divide rapidly are most susceptible to radiation injury. Peak sensitivity to radiation is at the M and G2 phases of the cell reproductive cycle.
• Radiation may also directly cause rapid cell death from mitotic arrest, point mutations in deoxyribonucleic acid (DNA), and cell membrane damage.
• Concomitant use of cytotoxic chemotherapeutic agents may work synergistically to increase the risk of developing bladder injury from radiation.
• cytotoxic agents that are known to cause tissue injury or exacerbate radiation injury are bleomycin, mitomycin C, bis-chloroethylnitrosourea (BCNU or carmustine), cyclophosphamide, busulfan, methotrexate, doxorubicin, gemcitabine, paclitaxel, docetaxel and carboplatin. Radiation can also cause vascular changes.
• Subendothelial proliferation, edema, and medial thickening may progressively deplete the blood supply to the irradiated tissue.
• Collagen deposition may also cause severe scarring and further blood-vessel obliteration, resulting in tissue hypoxia and necrosis.
• the fibrotic barriers left behind can also impair revascularization.
• Pathologic findings in radiated bladders can be grouped into early and late findings.
• Early findings are here defined as those occurring within 12 months after treatment, whereas late findings occur more than 12 months after treatment.
• Early findings include submucosal inflammation and fibrosis, perineural inflammation, surface ulceration, and epithelial atypia such as nuclear pleomorphism, hyperchromatism and granular cytoplasm, which may also be a late finding.
• Late findings include changes that are mainly fibrovascular and demonstrated by luminal occlusion, vascular ectasia, and necrosis of vessel walls. Cells with epithelial damage show cytoplasmic vacuolization and epithelial proliferation. Physiologically, these changes may produce clinical symptoms resulting from ischemia and fibrosis leading to loss of bladder muscle fibers and thus to dysfunctional voiding, and denervation hypersensitivity from ischemia causing abnormal neural stimulation of the bladder.
• the rate of long-term complications depends on the volume and area of bladder affected, the trigone being more symptomatic than the bladder dome, the dose rate and daily fraction size, doses >2 Gy/fraction increasing the risk, and the total dose of irradiation received, the risk being higher with total doses >60 Gy.
• the RTOG grading scale of complications of bladder irradiation is as follows:
• Grade 1 Any slight epithelial atrophy, microscopic hematuria, mild telangiectasia;
• Grade 2 Any moderate frequency, generalized telangiectasia, intermittent macroscopic hematuria, intermittent incontinence;
• Grade 3 Any severe frequency and urgency, severe telangiectasia, persistent incontinence, reduced bladder capacity ( ⁇ 150 mL), frequent hematuria;
• Grade 4 Any necrosis, fistula, hemorrhagic cystitis, bladder capacity ( ⁇ 100 mL), refractory incontinence requiring catheter or surgical intervention;
• Grade 5 (Death. This scale has been used in epidemiological surveys and as an aid to prognosis and clinical decision-making.
• Oral phenazopyridine a urinary analgesic
• Oral pentosan polysulfate sodium may be used to try to restore the bladder glycosaminoglycan layer, and oral pentoxifylline may be given to reduce blood viscosity and hence improve bladder oxygenation and reduce pain.
• oral conjugated estrogens may be given and a variety of agents may be instilled into the bladder.
• the antifibrinolytic agent aminocaproic acid may be instilled to promote hemostasis by inhibiting clot dissolution.
• Alum may be instilled to coagulate proteins and inhibit further bleeding.
• Formalin may be instilled as a sclerosing agent or applied endoscopically to bleeding points, both these procedures requiring general anesthesia.
• ethoxysclerol may be injected endoscopically into bleeding areas.
• hyperbaric oxygen therapy is tried. This can potentially reverse some aspects of radiation damage, e.g. by stimulating angiogenesis.
• significant fibrosis and ischemia cannot be reversed.
• the invention consists of providing pharmaceutical compositions comprising melatonin and/or an antioxidant metabolite, derivative or analogue thereof (individually referred to as the protective agent) to improve the prevention and treatment of radiation cystitis by the direct administration of the compositions to the bladder epithelium in the form of a solution or emulsion introduced into the bladder.
• the advantage of the invention is that the protective agent is delivered at high dose directly to the tissue for which protection from radiation damage is desired, while in cases other than bladder cancer there is no direct delivery to the tumor that is to be treated by radiotherapy.
• a further advantage will be that the directly applied melatonin will not be subject to the low bioavailability of melatonin given orally, which is subject to individually variable first-pass metabolism in the liver.
• the compositions are intended to be administered immediately or less than an hour before each dose of radiotherapy is given and at various other times during and after a course of radiotherapy.
• compositions which comprise melatonin and/or an antioxidant metabolite, derivative or analogue thereof together with a pharmaceutically acceptable form of vitamin E and/or coenzyme Q10 and/or alpha-lipoic acid and/or vitamin C.
• compositions comprise essentially:
• the invention fulfills the medical need for a preventive, pre-emptive and continuing treatment of the root intracellular cause of radiation injury to urinary bladder, for which current treatments are symptomatic or directed at post-hoc alleviation of longer-term pathological consequences.
• the present invention provides compositions comprising melatonin or an antioxidant metabolite, derivative or analogue thereof as the principal active substance to be instilled into the urinary bladder for the prevention and treatment of radiation cystitis.
• Radiation cystitis may be exacerbated by the concurrent use of cytotoxic chemotherapy, and the compositions are also intended for use to prevent and treat damage to the urinary bladder caused or exacerbated by cytotoxic agents.
• the invention also provides for compositions for the same purpose, which additionally comprise a pharmaceutically acceptable form or derivative or analogue of one or more of the substances vitamin E, coenzyme Q10, alpha-lipoic acid and vitamin C.
• compositions of the invention The principal active ingredient of the compositions of the invention is melatonin or an antioxidant metabolite, derivative or analogue thereof.
• Melatonin N-acetyl-5-methoxytryptamine
• Melatonin is a hormone produced by the pineal gland in human beings and other mammals by enzymatic modification of the amino acid tryptophan.
• Melatonin is involved in maintaining the circadian rhythm of various biological functions, being secreted in hours of darkness and acting on high-affinity melatonin G i -coupled transmembrane receptors MT1 and MT2, which are widely distributed in many cells and tissues of the body.
• melatonin acts at supraphysiological concentrations as a powerful antioxidant and free radical scavenger for ROS and reactive nitrogen species (Gomez-Moreno et al 2010).
• Melatonin can also activate cytoprotective antioxidative enzymes such as copper-zinc and manganese superoxide dismutases (CuZnSOD and MnSOD) and glutathione peroxidase (Rodriguez et al 2004). Melatonin also has anti-inflammatory effects to prevent the upregulation or cause the down-regulation of the expression of nuclear factor kappa B (NF- ⁇ B) and pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF- ⁇ ) and interleukin 1 beta (IL-1 ⁇ ).
• NF- ⁇ B nuclear factor kappa B
• IL-1 ⁇ interleukin 1 beta
• Melatonin as an agent to protect against radiation injury Because of melatonin's efficiency as a free radical scavenger, especially of hydroxyl radicals (Tan et al 1993) and ROS, it has been proposed as an agent to protect against radiation injury to cells and tissues.
• the protective effect of high dose systemic melatonin against the harmful effects of whole-body irradiation has been studied chiefly in rodents. Melatonin has typically been given at intravenous or intraperitoneal doses of 5 mg to 100 mg per kilogram of body weight and protective effects on DNA and nuclear morphology, as well as prolonged survival after lethal doses of irradiation have been observed.
• melatonin Many chemical derivatives of melatonin, including breakdown products and natural metabolites of melatonin, retain the antioxidant and free-radical scavenging properties of the parent molecule. This makes melatonin a more effective antioxidant than other natural antioxidants such as vitamins C and E (cited by Reiter et al 2007). However, these vitamins show synergy with melatonin with respect to antioxidant activity.
• C3-OHM metabolite cyclic 3-hydroxymelatonin
• AFMK N 1 -acetyl-N 2 -formyl-5-methoxykynuramine
• AFMK is also a reducing agent, capable of donating electrons to detoxify radical species, and has been shown to preserve the integrity DNA exposed to oxidizing agents.
• the action of aryl formamidase or catalase on AFMK produces N 1 -acetyl-5-methoxykynuramine (AMK), which is an even more effective scavenger of hydroxyl radicals and reactive nitrogen species, protecting proteins from oxidative destruction.
• AMO 3-acetamidomethyl-6-methoxycinnolinone
• AMNK 3-nitro-AMK
• the liver is the principal site of the classically reported metabolic pathway for melatonin. This consists chiefly of 6-hydroxylation by the cytochromes P450 CYP1A1, CYP1A2, and CYP1 B1, and the formation of the minor metabolite N-acetylserotonin by CYP2C19.
• the main product 6-hydroxymelatonin (6-OHM) is then conjugated at the hydroxyl group to form the 6-OHM glucuronide or 6-OHM sulfate.
• 6-OHM is an effective free radical scavenger in a variety of situations, but is also reported to show pro-oxidant effects in others. Its status as an antioxidant thus remains equivocal (Maharaj et al 2007).
• N-acetylserotonin is not only the immediate biosynthetic precursor but also a minor metabolite of melatonin. Like 6-OHM, it is conjugated to form the glucuronide or sulfate. Its protective effect against oxidative damage in certain model systems is reportedly 5 to 20 times as strong as that of melatonin (Oxenkrug 2005).
• Melatonin can also be chemically modified by introducing chemical groups at one or more of any of its constituent atoms susceptible of such modification or by introducing such groups in de novo synthesis of melatonin analogues or derivatives.
• modifications which do not alter the fundamental indole structure of melatonin, are herein called derivatives.
• the fundamental indole structure of melatonin can also be modified by substituting other bicyclic aromatic structures.
• Such modifications are herein called analogues, which may also have different chemical side groups removed, introduced or modified. Many such analogues and derivatives have been prepared, but most of them have not been tested for their antioxidant or free-radical scavenging properties.
• a large number of natural antioxidant agents that have been used pharmaceutically may potentially act synergically with melatonin. These may have additive antioxidant effects, but only a few have been demonstrated to act synergically.
• Vitamins C and E have been cited in this context.
• a related but not identical property, which is less well assessed, is their efficiency as free radical scavengers and in conferring protection against the harmful effects of radiation and cytotoxic medication.
• Further natural antioxidants that come under consideration as conferring addition protective effect are alpha-lipoic acid and coenzyme Q10 (also known as ubidecarenone). Both are effective as free radical scavengers and their capacity to ameliorate radiation damage has been demonstrated in vitro and in animal models in which the substances have usually been given intraperitoneally or by dietary supplementation.
• N 1 -acetyl-N 2 -formyl-5-methoxykynuramine AMFK
• 6-hydroxymelatonin 6-OHM
• NAS N-acetylserotonin
• Antioxidant melatonin derivatives The chemical structure of melatonin can be represented as in Figure (I), in which sites suitable for chemical modification by the substitution of different chemical groups have been indicated by R 1 , R 2 , R 3 , R 4 , R 5 and R 6 . These numbers do not correspond to the conventional numbering of positions in the indole ring of melatonin.
• R 1 and R 6 represent CH 3
• R 2 , R 3 , R 4 , R 5 and R 7 represent H.
• Antioxidant melatonin derivatives may comprise, as non-exclusive examples, those in which
• the present invention also provides compositions comprising melatonin or an antioxidant analogue or metabolite thereof together with a synergically acting antioxidant such as vitamin E, coenzyme Q10, alpha-lipoic acid or vitamin C as active substances.
• a synergically acting antioxidant such as vitamin E, coenzyme Q10, alpha-lipoic acid or vitamin C as active substances.
• Said substances are herein referred to collectively as the active substances or ingredients.
• vitamin E is an oil
• coenzyme Q10 is an almost water-insoluble solid of low melting point
• alpha-lipoic acid is a water-insoluble solid organic acid
• vitamin C is a solid organic acid.
• a water-soluble form of vitamin E is D-alpha-tocopheryl succinate.
• Coenzyme Q10 or a suitable antioxidant analogue or derivative thereof, non-limiting examples of which are coenzyme Q9, decylubiquinone and idebenone may be rendered water-soluble by adsorption to a biologically acceptable carrier such as beta-cyclodextrin during the formulation process.
• Alpha lipoic acid R-(+)-alpha-lipoic acid, also called (R)-thioctic acid can be used as its sodium salt, sodium thioctate, which is soluble in water to yield solutions of near-physiological pH.
• an appropriate form of vitamin C is sodium ascorbate.
• DMSO dimethyl sulfoxide
• the pharmaceutical composition of the present invention may be in the form of a solution, emulsion or suspension, which may be introduced into the urinary bladder e.g. by instillation via a transurethral urinary catheter.
• the formulation typically contains from 1 mg to 100 mg of melatonin or antioxidant metabolite, derivative or analogue thereof per milliliter of the composition. If other active ingredients are added, such as a pharmaceutically acceptable form of vitamin E and/or coenzyme Q10 and/or alpha-lipoic acid and/or vitamin C, they are added in an amount ranging from 25% to 200% by weight of the amount of melatonin or a metabolite, derivative or analogue thereof.
• the formulation is a solution of the active ingredients in DMSO.
• the formulation is an aqueous solution or emulsion or suspension suitable for instillation into the bladder.
• a non-limiting example of such a formulation is a solution of a spray-dried powder prepared by mixing equal volumes of a solution of active ingredient in ethanol or DMSO and an aqueous solution of the sugar excipient, which may be lactose, mannitol or xylitol, and then spray-drying the ingredients to produce particles of median diameter less than 50 ⁇ m with over 90% by weight of particles being less than 100 ⁇ m in diameter. Small amounts, not exceeding 0.4% by weight, of biocompatible detergents such as sodium deoxycholate or lecithin may be added to the solution before spray-drying. Reconstitution of the spray-dried powder with water makes it possible to achieve aqueous solutions with concentrations of active ingredient of 2 mg/mL or more.
• the active ingredients are dissolved in another water-miscible, biologically compatible solvent, such as propylene glycol or one or more of several biocompatible solubilizing agents known to the skilled person.
• another water-miscible, biologically compatible solvent such as propylene glycol or one or more of several biocompatible solubilizing agents known to the skilled person.
• Solutes to be added to the water in the dissolved pharmaceutical composition may include hydrochloric acid, sodium hydroxide and biocompatible buffering agents, non-limiting examples being sodium dihydrogen phosphate and disodium hydrogen phosphate, sodium carbonate and bicarbonate.
• Tonicity-adjusting agents such as for example sodium chloride or calcium chloride, may also be added, as well as a suitable preservative such as methyl and/or propyl parahydroxybenzoate.
• Formulations according to the present invention may comprise pharmaceutically acceptable carriers and excipients including microspheres, liposomes, micelles, microcapsules, nanoparticles or the like.
• the liposomes are unilamellar and their production is well known to the skilled person.
• the stated formulation methods can also be applied to the melatonin metabolites, derivatives and analogues of the invention and to D-alpha-tocopheryl succinate, coenzyme Q10 or its analogues and derivatives.
• the substance is added to the mixture for spray drying in a water-soluble form complexed with a low-molecular weight dextrin, such as beta-cyclodextrin.
• Sodium ascorbate is water-soluble and presents no unusual formulation requirement.
• Administration of an effective amount of the pharmaceutical composition is by topical application to the bladder epithelium by direct introduction into the bladder. In a preferred embodiment, this is performed by instillation via a transurethral urinary catheter.
• Suitable catheters are hydrophilic, surface-coated catheters and the technique of clean, intermittent catheterization or clean, intermittent self-catheterization (CISC) is employed.
• CISC clean, intermittent catheterization or clean, intermittent self-catheterization
• the solution containing the active ingredients in DMSO is supplied in dark containers containing an effective single dose in a volume ranging from 10 mL to 50 mL, preferably 25 mL.
• the solution in DMSO is diluted with a volume of a physiologically compatible aqueous medium, which may be physiological saline (0.9% NaCl).
• the volume of aqueous medium used to dilute the DMSO solution may be an equal volume or a volume in the range of 30% to 300% of the volume of the DMSO solution.
• Aqueous solutions containing the active ingredients without DMSO are supplied in containers of an effective single dose in a volume of 20 mL to 100 mL, preferably 50 mL, for instillation without prior dilution.
• the solution is instilled slowly to avoid spasm, and analgesic suppositories may be inserted prior to catheterization and instillation in particularly sensitive patients. After the instillation, the catheter is removed. The bladder is voided after the radiotherapy has been given.
• the solution is left in the bladder for up to 4 hours or until the patient has to void the bladder.
• Pelvic external beam radiotherapy for any condition requiring it, including conditions such as prostatic carcinoma, carcinoma of the rectum or anus, carcinoma of the bladder, cervical carcinoma and endometrial carcinoma.
• Pelvic brachyradiotherapy for any condition requiring it, including conditions such as prostatic carcinoma, carcinoma of the rectum or anus, carcinoma of the bladder, cervical carcinoma and endometrial carcinoma.
• an effective amount of the pharmaceutical compositions of the present invention is meant a dose, which, when administered to a subject in need thereof, achieves a concentration which has a beneficial biological effect, i.e. by preventing or reducing radiation injury to the urinary bladder. Such an effective amount may be determined by physicians of ordinary skill in the art attending patients undergoing pelvic radiotherapy and/or brachyradiotherapy on appropriate clinical trial.
• the effective amounts and dosages of the ingredients of the composition are not determined in relation to body weight or body surface area, because the treatment is local to the urinary bladder.
• the effective amount of melatonin or an analogue, derivative or metabolite thereof for a single dose of intravesical administration may be from 1 mg to 500 mg, such as in the range of 10 mg to 300 mg, and especially in the range of 25 mg to 250 mg.
• the effective amount of a pharmaceutically acceptable form of vitamin E and/or coenzyme Q10 and/or alpha-lipoic acid and/or vitamin C, in admixture with melatonin or a metabolite, derivative or analogue thereof, may be the same by weight as the amount of melatonin or a metabolite, derivative or analogue thereof, or in the range of 25% to 200% by weight of said amount.
• the effective dose is preferably administered 15 minutes to 30 minutes before each dose of radiation and/or chemotherapy is given. Because melatonin may also have longer term anti-inflammatory effects that are not directly dependent on free radical scavenging, the effective dose may also be given up to twice daily between and after doses of radiation, and during and after chemotherapy, for a period of up to 12 months after the initiation of radiotherapy and/or chemotherapy.
• the daily dose may be given once a day or in divided or full effective doses twice daily, or even more, depending on practicability and tolerance, such as three times a day or four times a day.
• the total daily dose may thus be from one to four times the amount of a single effective dose.
• a dosage regimen will typically comprise administering a dose prior to each session of radiotherapy and/or chemotherapy, with further doses being given thereafter on the same day and/or on intervening days, and dosing being continued after the cessation of radiotherapy and/or chemotherapy at the discretion of the attending physician.
• a dose regimen may alternate between periods of administration of the pharmaceutical composition according to the present invention and periods without administration (a pause in treatment).
• a period with a pause of treatment in such a dose regime may last for 1 week to 2 weeks, or 2 weeks to 3 weeks, or 3 weeks to 1 month, or 1 month to two months, all at the discretion of the attending physician.
• a composition according to the present invention is tested for its efficacy in preventing radiation cystitis by means of a randomized, placebo-controlled, double-blind clinical trial on up to 50 adult patients that are to be treated with external radiotherapy to the pelvic region for cancer of a pelvic organ.
• the patients After giving written, informed consent, the patients are taught to self-catheterize the urinary bladder with a hydrophilic surface-coated catheter through which the composition is self-administered, e.g. in a volume of 50 mL for a single standard dose.
• the patients are randomized to receive a standard dose of a composition of the present invention or a placebo composition without active ingredients 15-30 minutes before each fraction of radiotherapy is given.
• the clinician in charge of the trial may also determine that the standard dose should be repeated before retiring each night for the duration of the radiotherapy.
• the primary outcome is the effect on the RTOG score described above, supplemented with the EPIC (Expanded Prostate Index Composite) score for the urinary domain (Chang et al 2011).
• the RTOG and EPIC scores are determined for each patient immediately before starting radiotherapy and again after conclusion of the radiotherapy.
• a composition according to the present invention is tested for its efficacy in alleviating established radiation cystitis by means of a randomized, placebo-controlled double-blind clinical trial on up to 50 adult patients that have been clinically and cystoscopically assessed to have established radiation cystitis.
• the patients are taught to self-catheterize the urinary bladder with a hydrophilic surface-coated catheter through which the composition is self-administered, e.g. in a volume of 50 mL for a single standard dose.
• the patients in the treatment arm self-administer a standard dose of a composition of the present invention before retiring each night for 28 consecutive nights.
• the patients in the control arm do the same with a placebo composition without active ingredients. All patients continue with their conventional symptomatic treatment.
• the primary outcome is the effect on the RTOG score described above, supplemented with the EPIC (Expanded Prostate Index Composite) score for the urinary domain (Chang et al 2011).
• the RTOG and EPIC scores are determined for each patient immediately before starting treatment and again after conclusion of the treatment period.
• the secondary outcome will consist of a blinded assessment of the findings on any cystoscopy performed after the end of treatment.

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