WO2019049163A1 - Reproduction of fish by induced spawning with an injection containing both buserelin and domperidone - Google Patents
Reproduction of fish by induced spawning with an injection containing both buserelin and domperidone Download PDFInfo
- Publication number
- WO2019049163A1 WO2019049163A1 PCT/IN2018/000011 IN2018000011W WO2019049163A1 WO 2019049163 A1 WO2019049163 A1 WO 2019049163A1 IN 2018000011 W IN2018000011 W IN 2018000011W WO 2019049163 A1 WO2019049163 A1 WO 2019049163A1
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- fish
- gnrh
- domperidone
- spawning
- buserelin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
- A61D19/00—Instruments or methods for reproduction or fertilisation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to improving the reproduction efficiency in fish with a process by injecting a liquid peptide preparation that contains an analog of gonadotropin releasing hormone ⁇ GnRH) ⁇ Buserelin and a brain neurotransmitter (dopamine) inhibitor- Pomperidone.
- the process induces spawning in fish to increase harvest in fish culture.
- the first is to provide an environment similar to that in which spawning occurs naturally.
- Catfish for example, like to spawn in enclosed spaces such as hollow logs.
- a farmer can simulate this by putting milk cans in a pond.
- the presence of vegetation and an increase in temperature will usually work for goldfish.
- Changing the photoperiod in a hatchery can accelerate or delay maturation and ovulation in many salmon and trout species.
- the second strategy is to inject the fish with one or more naturally occurring reproductive hormones or their synthetic analogues. This is only effective in fish that are already in breeding condition and have mature eggs in which the germinal vesicle has migrated. Often the two strategies are used sequentially: the first to manipulate maturation, then the second to induce ovulation.
- LHRH GnRH Analog with Dopamine Antagonist - Luteinizing Hormone Releasing Hormone
- LHRHa synthetic analogues of LHRH, referred to as LHRHa, have been developed that are far moire effective. Because they are purer and are not rapidly metabolized by fish/they remain active for longer periods.
- HCG Human Chorionic Gonadotropin ⁇ HCG
- fish pituitary extracts are made by removing the pituitary from a fish and extracting the hormones, which may then be injected into another fish. Carp, catfish, salmon, and other fish have been used for this. HCG offers three major advantages over the pituitary extract: 1) it is much less expensive, 2) it is more stable and thus has a longer shelf life, and 3) it comes in a purified form.
- the first is manipulation of the culture environment to mimic some important quality in the fish's natural environment.
- the second is injection of hormones to stimulate spawning.
- the hormonas may be
- the present invention is a breakthrough with the use of a combination of active ingredients of Buseretin and Domperidone into a special formula to get maximum benefits for enhanced reproduction in all species offish.
- the present disclosure addresses the gaps in the existing procedures of improving the reproduction efficiency in fish and accordingly few objects of the present disclosure are listed hereunder -
- the main object of the present disclosure is to provide a reliable method of induced spawning and an aqueous solution so easy to administer with an injection comprising of active ingredients Buserelin IP and Domperidone BP to improve the reproduction efficiency in fish and to increase harvest in fish culture. It is also another object that the method stimulates the milt production for a longer period and for greater volume; moves fish forward In the spawning season; and spawns a population in a shorter period of time.
- the process comprises of potent-ovulating and sperm- forming agent optimizing reproduction in all species of fish.
- the process wherein the carrier compresses and advances the spawning season and coordinates spawning dates It is still a further object that the process wherein the carrier comprises maximizing reproductive potential in all spawners within a population.
- Maturation- is the growth and development of the gametes (eggs in female fish and sperm in male fish] to a point where fertilization can occur
- Ovulation- is the process of release of eggs from the ovary
- Spawning- is the process of deposition of eggs and sperm so that they can unite.
- the Pituitary Gland An endocrine or hormone-producing gland found on the underside of the brain just behind the eyes.
- the Pituitary extract is an aqueous, alcoholic, or acetone extract of the pituitary gland used for artificial induction of spawning.
- Mammalian gonadotropin (hormone) that has been used to induce the reproductive cascade in fish.
- GnRH Gonadotropin Releasing Hormone
- a hormone produced by the hypothalamus travels from there to Pituitary G!and that stimulates the pituitary to release gonadotropin.
- LHRHa and GnRHa Synthetic Analogues of LHRH and GnRH referred to as LHRHa and GnRHa are developed which are proved far more effective as they are purer. And also they are not rapidly metabolized by fish, and thus they remain active for longer periods.
- the hypothalamus located at the base of the brain, is sensitive to signals from sensory receptors and releases hormones in response to environmental cues. Principal among these hormones are gonadotropin releasing hormones (GnRH), which travel from the GnRH.
- hypothalamus to the pituitary gland.
- the pituitary is responsible for a wide variety of functions, including growth and reproduction. Certain cells of the pituitary receive GnRH and release gonadotropic hormones into the bloodstream. The gonadotropic hormones travel to the gonads, which synthesize steroids responsible for final maturation of the gametes.
- GnRH analogue or analog also known as a luteinizing hormone releasing hormone agonist (LHRH agonist) or LHRH analogue is a synthetic peptide modeled after the human hypothalamic gonadotropin-releasing hormone (GnRH).
- LHRH agonist luteinizing hormone releasing hormone agonist
- GnRH analogue is designed to interact with the GnRH receptor and modify the release of pituitary gonadotropins FSH and LH for therapeutic purposes.
- a gonadotropfn-releasing hormone agonist is an analogue that activates the GnRH receptor resulting in increased secretion of FSH and LH.
- GnRH agonist is an analogue that activates the GnRH receptor resulting in increased secretion of FSH and LH.
- agonists could be used as potent and prolonged stimulators of pituitary gonadotropin release, but it was soon recognized that agonists, after their initial stimulating action - termed a "flare” effect - eventually caused a paradoxical and sustained drop in gonadotropin secretion.
- This second effect was termed "downregulation" and can be observed after about 10 days. While this phase is reversible upon stopping the medication, it can be maintained when GnRH agonists use is continued for a long time.
- a gonadotropin-releasing hormone antagonist is an analogue that blocks the GnRri receptor resulting in an immediate drop in gonadotropin (FSH, LH) secretion.
- the GnRH antagonist is primarily used in 1VF treatments to block natural ovulation.
- GnRH GnRH Is synthesized in the hypothalamus and controls the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary.
- FSH. and LH stimulate the gonads (ovaries in females, testes in mates), leading to the production of androgens in males.
- GnRH is released in a pulsatile manner. This intermittent release is crucial for the proper synthesis and release of FSH and LH
- GnRH Pulsatile (physiologic) release of GnRH results in increased gonadotropin release. Continuous administration of GnRH results in suppression of gonadotropin release via down-regulation of GnRH receptors, a process called desensitization.
- GnRH agonists can be administered via pulsatile or continuous fashion, depending on the desired effect (stimulation or suppression of gonadotropins respectively).
- GnRH antagonists simply block the GnRH receptor, resulting in reduced release of FSH and LH.
- GnRH agonist administration has been the treatment of choice for central precocious puberty.
- Continuous administration of the agonist instead of permanently stimulating gonadotropin secretion, deeply suppresses LH and FSH levels and induces a marked inhibition of gonadal activity and regression of clinical symptoms.
- This inhibitory effect is due both to specific kinetic parameters relative to natural GnRH, and to marked alterations of the biosynthetic pathways of gonadotropin subunits.
- the half disappearance time of infused agonists is 3-10 fold that of natural GnRH. This means that the residence time of GnRH agonists is significantly longer than that of GnRH.
- Domperidone is a dopamine antagonist with anti-emetic properties domperidone does not readily cross the blood-brain barrier. In domperidone users, especially in adults, extrapyramidal side effects are very rare, but domperidone promotes the release of prolactin from the pituitary. Its anti-emetic effect may be due to a combination of peripheral (gastro kinetic) effects and antagonism of dopamine receptors in the chemoreceptor trigger zone, which lies outside the blood-brain barrier in the area postrema. Animal studies, together with the low concentrations found in the brain, Indicate a predominantly peripheral effect of domperidone on dopamine receptors.
- domperidone In fasting subjects, domperidone is rapidly absorbed after oral administration with peak plasma concentrations at 30 to 60 minutes. The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wail and liver. Although domperidone's bioavailability is enhanced in normal subjects when taken after a meal, patients with gastro-intestinal complaints should take domperidone 15- 30 minutes before a meal. Reduced gastric acidity impairs the absorption of domperidone. Oral bioavailability is decreased by prior concomitant administration of cimetidine and sodium bicarbonate. The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal. Distribution
- Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21 ng/ml after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/ml after the first dose. Domperidone is 91-93% bound to pjasma proteins. Distribution studies with radio labelled drug in animals have shown wide tissue distribution, but low brain concentration. Small amounts of drug cross the placenta in rats.
- Urinary and faecal excretions amount to 31 and 66% of the oral dose respectively, the proportion of the drug excreted unchanged is small (10% of faecal excretion and approximately 1% of urinary excretion).
- the plasma half-life after a single oral dose is 7-9 hours in healthy subjects but is prolonged in patients with severe renal insufficiency.
- Injectable Solution (Buserelin 20 ug/ml + Domperidone 10 mg/ml) For intraperitoneal or intramuscular Injection in fish.
- Injectable solution is a liquid peptide preparation that contains an analog of gonadotropin releasing hormone (GnRH) and a brain neurotransmitter (dopamine) inhibitor.
- GnRH gonadotropin releasing hormone
- dopamine brain neurotransmitter
- the GnRH in the injection elicits the release of stored gonadotropins from the pituitary.
- the dopamine inhibitor serves to remove other inhibition of GnRH release. Release of stored pituitary gonadotropins may aid spawning by stimulating ovulation and spermiation in sexually mature fish.
- Domperidone serves to remove other inhibition of GnRH release. Release of stored pituitary gonadotropins may aid spawning by stimulating ovulation and spermiation in sexually mature fish.
- Buserelin & Domperidone Injection (For Veterinary use only) - Pack Size 10 ML.
- composition is as follows:
- the invention consists of a sterile injection and each ml of injectable solution contains 20 micrograms of Buserelin and 10 milligrams of Domperidone.
- Buserelin is a longer acting synthetic peptide analog of the naturally occurring gonadotropin- releasing hormone (GnRH/LHRH). Substitution of glycine In position 6 by D-serine and that of glyclnamlde tn position 10 by ethyl amtde, leads to a nanopeptide with a significantly enhanced LHRH effect.
- the effects of Buserelin on follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release are approximately 20 to 170 times higher than those of natural LHRH.
- the Injection can be used in all species of fish.
- the forms of GnRH that naturally occur in the brains of fishes differ throughout the more than 25,000 fish species.
- the Buserelin form of GnRH is present in most of these fish and thus the GnRH in the injection is the peptide of choice.
- the other types of GnRH found in the other fishes there is such a conservation of form and function that the injection works successfully.
- the Injection has been used successfully in all major types of fish including:
- post-transport may reduce the incidence of transport shock.
- Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.
- GnRH Buserelin
- [D-ArgA 3 , Pro9 NEt] GnRH the most commonly available one
- analogues of mammalian GnRH such as [D-Ala6, Pro9 NEt] LHRH.
- GnRH is only the "on" part of an "on-off" control system for gonadotropin release means that the analogue one uses may be less important than whether it is accompanied by a dopamine inhibitor.
- Domperidone is a medication developed by Janssen Pharmaceutica that is a peripheral, specific blocker of dopamine receptors. It is administered orally, rectally, or. intravenously.
- Domperidone In order to relieve nausea and vomiting; to increase the transit of food through the stomach (as a prokinetic agent through increase in gastrointestinal peristalsis); and to increase lactation (breast milk production) by release of prolactin. It is also used fn the scientific study of the way dopamine (an important neurotransmitter) acts in the body.
- the physical and chemical test are made with a quarterly regularity during the first semester year and semester during the second. A sample of each batch is analyzed by triplicate for the physical-chemical test
- the stability test takes place on three pilot batches of the specialty.
- the packages are identified with an individually labelled.
- the batches subjected to stability test are kept in conditioned stability chamber to an average temp, of 25c +-2 c and one relative humidity of 60 +- 5 % in a closed chamber and safe from the light Temperature and Humidity is register in the data sheet attached to the stability chamber- Assay Method
- the injectable solution is a liquid peptide preparation that contains an analog of gonadotropin releasing hormone (GnRH) and a brain neurotransmitter (dopamine) inhibitor.
- GnRH gonadotropin releasing hormone
- dopamine brain neurotransmitter
- the GnRH in the injection elicits the release of stored gonadotropins from the pituitary.
- the dopamine inhibitor serves to remove other inhibition of GnRH release. Release of stored pituitary gonadotropins may aid spawning by stimulating ovulation and spermiation in sexually mature fish.
- ii Use in a well-ventilated area. Wear gloves, goggles and suitable protective clothing. iii. Not for use in humans.
- LHRH luteinizing hormone releasing hormone
- GnRH Gonadotropin releasing hormone
- LHRH is the key mediator in the liberation of the pituitary gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH).
- LHRH may modify reproductive ability by influencing plasma gonadotropin levels and concomitantly gonadal steroid levels.
- Syringes/needles should be sterile prior to use.
- a general dose of injection is 0.5 ml per kilogram of bodyweight. This dose may vary among finfish species and physiological state of individual animals. Environment and temperature also play a significant role in the reproductive process and may affect dose and timing. For most species, only a single dose of the injection is required; but treatment offish with a single dose of the injection is only effective in fish that are within or near their natural spawning season. For other species, a split dose may be needed. For split dosing, a loading dose of 10% of the total dose should be injected, followed by injection of the remaining 90% of the total dose at least 6 hours later. In warm water species, ovulation may occur in as little as 4 hours post treatment, so fish should be monitored accordingly.
- Signs of ovulation/spermiation may include a noticeable swelling and "softening 0 of the abdomen; presence of eggs in the water; the ability to easily express eggs from the female and milt from males; and when sexes are held together in the same tank, onset of spawning behaviour (e.g., males "chasing” females).
- onset of spawning behaviour e.g., males "chasing” females.
- the dose is calculated based on the weight of the fish.
- Intramuscular injection may result in bleeding at the injection site. Swelling, ulceration, whiteness, redness, or hypo pigmentation - may also be observed at the injection site.
- Salmon GnRHa and Domperidone combination is widely used in Europe and Northern America mainfy for Salmon and Trout culture. Over, ten years of research of developing the sGnRHa and Domperidone formulation, it is concluded that Buserelin and Domperidone combination works much better than sGnRHa and Domperidone. Salmon and trout are not the kind of species which can live well in ASIAN waters and that is the reason Asian countries do not even culture these species. Carp, Cat Fish, Tilapia and other kind of fish species which are cultured in Asian countries are giving excellent results with the injection of Buserelin and domperidone formulation, when compared to sGnRHa and domperidone formulation.
- GnRH gonadotropin-releasing hormone
- dopamine an agent that inhibits the release of GtH
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IN201741031502 | 2017-09-06 | ||
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114467808A (en) * | 2021-12-31 | 2022-05-13 | 湖南岳麓山水产育种科技有限公司 | Large-scale preparation method of bighead carp grown from distant hybridization natural gynogenesis |
CN117143186A (en) * | 2023-08-04 | 2023-12-01 | 华中农业大学 | Polypeptide for promoting ovulation of female pelteobagrus fulvidraco and application |
-
2018
- 2018-02-06 WO PCT/IN2018/000011 patent/WO2019049163A1/en active Application Filing
Non-Patent Citations (1)
Title |
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BASAVARAJA, N. ET AL.: "Successful induced spawning of Indian Major Carps following injection of Buserelin and Domperidone", ASIAN FISHERIES SCIENCE, vol. 20, 2007, pages 287 - 297, XP055581224 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114467808A (en) * | 2021-12-31 | 2022-05-13 | 湖南岳麓山水产育种科技有限公司 | Large-scale preparation method of bighead carp grown from distant hybridization natural gynogenesis |
CN117143186A (en) * | 2023-08-04 | 2023-12-01 | 华中农业大学 | Polypeptide for promoting ovulation of female pelteobagrus fulvidraco and application |
CN117143186B (en) * | 2023-08-04 | 2024-05-28 | 华中农业大学 | Polypeptide for promoting ovulation of female pelteobagrus fulvidraco and application |
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