JP2017081862A - Pharmaceutical composition for reducing weight loss after extraction surgery - Google Patents
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- 230000004580 weight loss Effects 0.000 title claims abstract description 32
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 44
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、水素ガスを含む医薬組成物、典型的には、器官または組織の摘出による体重減少を軽減するための気体状医薬組成物に関する。 The present invention relates to a pharmaceutical composition containing hydrogen gas, typically a gaseous pharmaceutical composition for reducing weight loss due to removal of an organ or tissue.
手術侵襲は、医原性の外傷であり、様々な生体反応を引き起こすことが知られている。かかる生体反応は、手術後の患者の回復に大きく影響していると考えられる。手術侵襲の中でも、手術後の体重減少は、患者の予後に影響を与える重要な要素の１つである。例えば、がん患者など、器官または組織の摘出が伴う手術を受けた患者は、術後の炎症および発熱、術前または術後の身体的または精神的ストレス、食欲減衰など、様々な要因により、体重が急激に減少することが知られている。このような、手術後の体重減少は、患者にとって体力的および精神的に負担がかかるため、早期に回復させる薬剤が求められている。 Surgical invasion is an iatrogenic trauma and is known to cause various biological reactions. This biological reaction is considered to have a great influence on the recovery of the patient after the operation. Among surgical invasions, post-surgical weight loss is one of the important factors affecting patient prognosis. For example, patients undergoing surgery with removal of organs or tissues, such as cancer patients, may experience a variety of factors, including postoperative inflammation and fever, pre- or post-operative physical or mental stress, and appetite loss. It is known that body weight decreases rapidly. Such weight loss after surgery is physically and mentally burdensome for the patient, so a drug that can be recovered early is required.
分子状水素は、これまでに、酸素ラジカルのスカベンジャーとして有用であること（非特許文献１）、およびそのようなフリーラジカルスカベンジャーとしての性質を利用して、虚血再灌流障害を治療することが報告されている（特許文献１、非特許文献２）。また、分子状水素には、抗炎症効果など、多面的な効果があることが報告されている。 Molecular hydrogen has hitherto been useful as a scavenger for oxygen radicals (Non-patent Document 1), and can be used to treat ischemia-reperfusion injury by utilizing such a property as a free radical scavenger. It has been reported (Patent Document 1, Non-Patent Document 2). In addition, molecular hydrogen has been reported to have multifaceted effects such as an anti-inflammatory effect.
一方、分子状水素がどのように多面的な効果を発揮するか、その作用機序は未だに明らかにされていない。 On the other hand, how the molecular hydrogen exhibits multifaceted effects has not yet been clarified.
本発明は、器官または組織の摘出による体重減少を軽減するために有用な医薬組成物を提供することを目的とする。 An object of the present invention is to provide a pharmaceutical composition useful for reducing weight loss due to removal of an organ or tissue.
本発明者らは、ラット５／６腎摘モデルの腎不全に対する分子状水素の影響を調査する過程で、意外にも、水素ガスを吸入させた場合に、腎摘後のラットの体重減少を顕著に軽減できることを見出し、本発明を完成させるに至った。 In the process of investigating the influence of molecular hydrogen on renal failure in the rat 5/6 nephrectomy model, the present inventors surprisingly reduced the weight of the rat after nephrectomy when hydrogen gas was inhaled. It has been found that it can be remarkably reduced, and the present invention has been completed.
本発明は、上記の知見に基づくものであり、以下の特徴を包含する。
［１］水素ガスを含む気体状医薬組成物であって、
器官または組織の摘出による体重減少を軽減するための、
医薬組成物。
［２］［１］に記載の医薬組成物であって、
酸素ガスをさらに含むことを特徴とする、
医薬組成物。
［３］［１］または［２］に記載の組成物であって、
不活性ガスをさらに含むことを特徴とする、
医薬組成物。
［４］［１］〜［３］のいずれかに記載の医薬組成物であって、
前記水素ガスの濃度が、１〜４％（ｖ／ｖ）である
ことを特徴とする、
医薬組成物。
［５］［２］または［３］のいずれかに記載の医薬組成物であって、
前記水素ガスの濃度が、１〜４％（ｖ／ｖ）であり、
前記酸素ガス濃度が２１〜９９％（ｖ／ｖ）である
ことを特徴とする、
医薬組成物。
［６］［１］〜［５］のいずれかに記載の医薬組成物であって、
１日あたり０．５〜２４時間投与される
ことを特徴とする、
医薬組成物。
［７］［１］〜［６］のいずれかに記載の医薬組成物であって、
手術日後少なくとも１日以上投与される
ことを特徴とする、
医薬組成物。
［８］［１］〜［７］のいずれかに記載の医薬組成物であって、
手術前、および／または、手術中において投与される
ことを特徴とする、
医薬組成物。
［９］［１］〜［８］のいずれかに記載の医薬組成物であって、
前記「器官または組織の摘出」が癌、腫瘍、胆石、挫滅した組織の摘出；肺感染症による肺切除；弁置換、弁形成、大血管置換術、慢性肺血栓塞栓症に対する血栓内膜剥皮術；脳内血腫の除去；大腿骨頭置換術；またはドナーからの臓器摘出に伴う
ことを特徴とする、
医薬組成物。
［１０］［１］〜［９］のいずれかに記載の医薬組成物であって、
前記「器官または組織」が、循環器系：消化器系；呼吸器系；神経系；生殖器系；泌尿器；内分泌系；感覚器系；運動器系；乳房；または皮膚からなる群から選ばれる器官または組織の全部または一部である
ことを特徴とする、
医薬組成物。
［１１］［１］〜［９］のいずれかに記載の医薬組成物であって、
前記「器官または組織」が、大血管、心臓、食道、胃、十二指腸、小腸、大腸、脾臓、胆嚢、膵臓、肝臓、気管、肺、脳、子宮、卵巣、腎臓、甲状腺、副甲状腺、下垂体、副腎、ランゲルハンス島、松果体、眼、耳、骨、筋肉、乳房、および皮膚からなる群から選ばれる器官または組織の全部または一部である
ことを特徴とする、
医薬組成物。
［１２］［１］〜［１１］のいずれかに記載の医薬組成物であって、
水素ガスを投与しない場合との比較において、器官または組織の摘出後の最大体重減少を、３０％以上軽減することを特徴とする、
医薬組成物。
The present invention is based on the above findings and includes the following features.
[1] A gaseous pharmaceutical composition containing hydrogen gas,
To reduce weight loss due to removal of organs or tissues,
Pharmaceutical composition.
[2] The pharmaceutical composition according to [1],
Further comprising oxygen gas,
Pharmaceutical composition.
[3] The composition according to [1] or [2],
Further comprising an inert gas,
Pharmaceutical composition.
[4] The pharmaceutical composition according to any one of [1] to [3],
The concentration of the hydrogen gas is 1 to 4% (v / v),
Pharmaceutical composition.
[5] The pharmaceutical composition according to any one of [2] or [3],
The concentration of the hydrogen gas is 1-4% (v / v);
The oxygen gas concentration is 21 to 99% (v / v),
Pharmaceutical composition.
[6] The pharmaceutical composition according to any one of [1] to [5],
It is administered for 0.5 to 24 hours per day,
Pharmaceutical composition.
[7] The pharmaceutical composition according to any one of [1] to [6],
It is administered at least one day after the operation day,
Pharmaceutical composition.
[8] The pharmaceutical composition according to any one of [1] to [7],
Administered before and / or during surgery,
Pharmaceutical composition.
[9] The pharmaceutical composition according to any one of [1] to [8],
The above-mentioned "extraction of organ or tissue" is the removal of cancer, tumor, gallstone, extinct tissue; pulmonary resection due to pulmonary infection; Removal of intracerebral hematoma; femoral head replacement; or associated with organ removal from a donor,
Pharmaceutical composition.
[10] The pharmaceutical composition according to any one of [1] to [9],
An organ selected from the group consisting of the circulatory system: digestive system; respiratory system; nervous system; genital system; urinary system; endocrine system; sensory organ system; motor organ system; breast; Or all or part of an organization,
Pharmaceutical composition.
[11] The pharmaceutical composition according to any one of [1] to [9],
Said "organ or tissue" is a large blood vessel, heart, esophagus, stomach, duodenum, small intestine, large intestine, spleen, gallbladder, pancreas, liver, trachea, lung, brain, uterus, ovary, kidney, thyroid, parathyroid, pituitary gland. Characterized by being all or part of an organ or tissue selected from the group consisting of: adrenal gland, islets of Langerhans, pineal gland, eye, ear, bone, muscle, breast, and skin,
Pharmaceutical composition.
[12] The pharmaceutical composition according to any one of [1] to [11],
In comparison with the case where hydrogen gas is not administered, the maximum weight loss after removal of an organ or tissue is reduced by 30% or more,
Pharmaceutical composition.
上記に挙げた本発明の態様の一または複数を任意に組み合わせた発明も、本発明の範囲に含まれる。 Inventions obtained by arbitrarily combining one or more of the above-described aspects of the present invention are also included in the scope of the present invention.
本発明によれば、器官または組織の摘出による体重減少を軽減するために有用な医薬組成物が提供される。 According to the present invention, there is provided a pharmaceutical composition useful for reducing weight loss due to removal of an organ or tissue.
以下、本発明の実施の形態を具体的に説明する。 Hereinafter, embodiments of the present invention will be specifically described.
本発明において、「器官または組織の摘出による体重減少」とは、器官または組織の摘出手術によって惹起される手術後の体重減少を指す。したがって、器官または組織の摘出行為自体、すなわち器官または組織の摘出部位に起因する重量の減少は、本発明における「器官または組織の摘出による体重減少」には該当しない。 In the present invention, “weight loss due to removal of an organ or tissue” refers to weight loss after surgery caused by surgery to remove the organ or tissue. Therefore, the action of removing an organ or tissue itself, that is, a decrease in weight due to the removed site of the organ or tissue does not fall under “weight loss due to removal of an organ or tissue” in the present invention.
本発明の一実施形態において、器官または組織の摘出は、これに限定されるものではないが、手術後から一定の期間にわたって惹起される体重減少であって、全体重の少なくとも５％の減少、好ましくは全体重の少なくとも１０％の減少、より好ましくは全体重の少なくとも１５％の減少、より好ましくは全体重の少なくとも２０％の減少を引き起こすものである。 In one embodiment of the present invention, the removal of an organ or tissue is, but is not limited to, a weight loss caused over a period of time after surgery, wherein at least a 5% decrease in total body weight; Preferably it causes at least a 10% reduction in total body weight, more preferably at least 15% reduction in total body weight, more preferably at least 20% reduction in total body weight.
本発明の一実施形態において、「器官または組織の摘出」は、これに限定されるものではないが、悪性黒色腫、腎臓癌、前立腺癌、膀胱癌、乳癌、肺癌、膵臓癌、大腸癌、小腸癌、肝細胞癌、胆道癌、胃癌、卵巣癌、食道癌、十二指腸癌、皮膚癌、喉頭癌、咽頭癌、口腔内の癌などの固形がんの摘出；子宮筋腫、卵巣嚢腫、肺腫瘍、乳房腫瘍、結腸腫瘍、脳腫瘍などの各種の腫瘍の摘出；胆石の摘出；挫滅した組織の摘出；肺感染症による肺切除；弁置換、弁形成、大血管置換術、慢性肺血栓塞栓症に対する血栓内膜剥皮術；脳内血腫の除去；大腿骨頭置換術；ドナー（臓器提供者）からの臓器摘出、などに伴うものであり得る。 In one embodiment of the present invention, “extraction of an organ or tissue” includes, but is not limited to, malignant melanoma, kidney cancer, prostate cancer, bladder cancer, breast cancer, lung cancer, pancreatic cancer, colon cancer, Removal of solid cancer such as small intestine cancer, hepatocellular carcinoma, biliary tract cancer, stomach cancer, ovarian cancer, esophageal cancer, duodenal cancer, skin cancer, laryngeal cancer, pharyngeal cancer, cancer in the oral cavity; uterine fibroid, ovarian cyst, lung tumor Removal of various tumors such as breast, colon, and brain tumors; removal of gallstones; removal of destroyed tissues; pulmonary resection due to pulmonary infection; valve replacement, valvuloplasty, large vessel replacement, for chronic pulmonary thromboembolism Thrombus intimal debarking; removal of intracerebral hematoma; femoral head replacement; organ removal from donor (organ donor), etc.
本発明の一実施形態において、「器官または組織」として、これに限定されるものではないが、大血管、心臓（例えば弁又は心筋の一部）などの循環器系：食道、胃、十二指腸、小腸、大腸等の腸、脾臓、胆嚢、膵臓、肝臓などの消化器系；気管、肺などの呼吸器系；脳などの神経系；子宮、卵巣などの生殖器系；腎臓などの泌尿器；甲状腺、副甲状腺、下垂体、副腎、ランゲルハンス島、松果体などの内分泌系；眼、耳などの感覚器系；骨、筋などの運動器系；乳房；皮膚などを挙げることができる。上記器官または組織は、その一部であってもよいし、全部であってもよい。 In one embodiment of the invention, “organs or tissues” include, but are not limited to, circulatory systems such as large blood vessels, heart (eg, a valve or part of the heart muscle): esophagus, stomach, duodenum, Intestines such as small intestine and large intestine, digestive system such as spleen, gallbladder, pancreas and liver; respiratory system such as trachea and lung; nervous system such as brain; genital system such as uterus and ovary; urinary organ such as kidney; thyroid gland; Endocrine systems such as parathyroid gland, pituitary gland, adrenal gland, islets of Langerhans, pineal gland; sensory organ systems such as eyes and ears; motor system such as bones and muscles; breast; skin and the like. The organ or tissue may be a part or all of the organ or tissue.
以下、本発明に係る器官または組織の摘出による体重減少を軽減するための医薬組成物（以下、本発明の医薬組成物とも称する）について説明する。 Hereinafter, a pharmaceutical composition for reducing weight loss due to the removal of an organ or tissue according to the present invention (hereinafter also referred to as the pharmaceutical composition of the present invention) will be described.
本発明の医薬組成物は、水素ガスを含む気体状の医薬組成物であることを特徴とする。本発明において、水素原子は、その全ての同位体、すなわちプロチウム（Ｐまたは１Ｈ）、ジュウテリウム（Ｄまたは２Ｈ）、およびトリチウム（Ｔまたは３Ｈ）、のいずれであってもよい。したがって、分子状水素として、Ｐ2、ＰＤ、ＰＴ、ＤＴ、Ｄ2およびＴ2が含まれうる。本発明の好ましい態様において、本発明の医薬組成物に含まれる水素ガスの９９％以上は天然の分子状水素であるＰ２である。 The pharmaceutical composition of the present invention is a gaseous pharmaceutical composition containing hydrogen gas. In the present invention, the hydrogen atom may be any of all of its isotopes, namely, protium (P or 1 H), deuterium (D or 2 H), and tritium (T or 3 H). Thus, molecular hydrogen can include P 2 , PD, PT, DT, D 2 and T 2 . In a preferred embodiment of the present invention, 99% or more of the hydrogen gas contained in the pharmaceutical composition of the present invention is P 2 which is natural molecular hydrogen.
本発明の医薬組成物は、酸素ガスをさらに含むことができる。酸素ガスは、水素ガスと予め混合されて、混合ガスの形態で存在してもよいし、対象への投与直前にまたは投与時に、水素ガスと混合されてもよい。 The pharmaceutical composition of the present invention may further contain oxygen gas. The oxygen gas may be premixed with hydrogen gas and present in the form of a mixed gas, or may be mixed with hydrogen gas immediately before or upon administration to a subject.
本発明の医薬組成物は、不活性ガスをさらに含むことができる。不活性ガスは、水素ガスまたは酸素ガスの防爆を目的として使用され、したがって、水素ガスおよび／または酸素ガスとの混合ガスの形態で存在し得る。本発明の医薬組成物に使用できる不活性ガスとしては、これに限定されるものではないが、窒素ガス、ヘリウムガス、アルゴンガスなどを使用することができる。本発明の一実施形態では、不活性ガスとして安価な窒素ガスが使用される。 The pharmaceutical composition of the present invention may further contain an inert gas. The inert gas is used for the purpose of explosion-proofing hydrogen gas or oxygen gas, and can therefore exist in the form of a mixed gas with hydrogen gas and / or oxygen gas. The inert gas that can be used in the pharmaceutical composition of the present invention is not limited to this, but nitrogen gas, helium gas, argon gas, and the like can be used. In one embodiment of the present invention, inexpensive nitrogen gas is used as the inert gas.
本発明の医薬組成物において、水素ガスの濃度範囲は、これに限定されるものではないが、例えば１〜４％（ｖ／ｖ）とすることができる。水素ガス濃度の下限値は、器官または組織の摘出による体重減少を軽減する効果を発揮できる濃度の下限値として設定されるものである。したがって、摘出される器官または組織の種類等、摘出される範囲または量、摘出の原因となった疾患または症状などに応じて、摘出による体重減少を軽減することができる最小濃度を適宜設定することができる。一方、水素ガス濃度の上限値は、空気中における酸素の爆発限界が４％であるため、安全性の観点から設定されるものである。 In the pharmaceutical composition of the present invention, the hydrogen gas concentration range is not limited to this, but may be, for example, 1 to 4% (v / v). The lower limit value of the hydrogen gas concentration is set as the lower limit value of the concentration at which the effect of reducing weight loss due to removal of an organ or tissue can be exhibited. Therefore, the minimum concentration that can reduce weight loss due to extraction should be set appropriately according to the type or range of organ or tissue to be extracted, the range or amount to be extracted, the disease or symptom that caused the extraction, etc. Can do. On the other hand, the upper limit value of the hydrogen gas concentration is set from the viewpoint of safety because the explosion limit of oxygen in the air is 4%.
本発明の医薬組成物において、酸素ガスの濃度は、水素ガス濃度が１〜４％（ｖ／ｖ）の前提のとき、２１％〜９９％（ｖ／ｖ）の範囲とすることができる。 In the pharmaceutical composition of the present invention, the concentration of oxygen gas can be in the range of 21% to 99% (v / v) when the hydrogen gas concentration is assumed to be 1 to 4% (v / v).
本発明の医薬組成物において、不活性ガスの濃度は、水素ガスおよび／または酸素ガスの濃度を適切に維持し、かつ、これらのガスの防爆効果が得られる範囲で設定される。したがって、不活性ガスの濃度は、使用される水素ガスおよび／または酸素ガスの濃度に応じて、当業者は適宜適切な濃度を設定することができる。そのような不活性ガスの濃度は、例えば不活性ガスが窒素ガスの場合、例えば、０〜７８％（ｖ／ｖ）の範囲で任意にとり得る。 In the pharmaceutical composition of the present invention, the concentration of the inert gas is set within a range in which the concentration of hydrogen gas and / or oxygen gas is appropriately maintained and the explosion-proof effect of these gases is obtained. Therefore, the concentration of the inert gas can be appropriately set by those skilled in the art according to the concentration of the hydrogen gas and / or oxygen gas used. For example, when the inert gas is nitrogen gas, the concentration of the inert gas can be arbitrarily set within a range of 0 to 78% (v / v), for example.
なお、本明細書を通じて使用されるガスの濃度は、２０℃、１０１．３ｋＰａでの含有率を示すものとする。 In addition, the density | concentration of the gas used throughout this specification shall show the content rate in 20 degreeC and 101.3 kPa.
本発明の医薬組成物において、水素ガスによる本発明の効果を損なわない限り、二酸化炭素などの他の大気中のガス、空気、または麻酔ガスなどをさらに含んでもよい。 The pharmaceutical composition of the present invention may further contain other atmospheric gases such as carbon dioxide, air, or anesthetic gas, as long as the effects of the present invention by hydrogen gas are not impaired.
本発明の医薬組成物は、例えば吸引手段を用いた吸引により、対象に投与することができる。そのような吸引手段としては、これに限定されるものではないが、例えば吸引マスクを挙げることができる。吸引マスクは、対象への適切な濃度での投与が実現されるように、対象の口および鼻を同時に覆うものであることが好ましい。 The pharmaceutical composition of the present invention can be administered to a subject, for example, by suction using a suction means. Such suction means is not limited to this, and examples thereof include a suction mask. The suction mask preferably covers the subject's mouth and nose at the same time so that administration at an appropriate concentration to the subject is realized.
本発明の一実施形態において、本発明の医薬組成物は、対象にそのまま投与し得る形態で提供される。例えば、この実施形態では、本発明の医薬組成物は、水素ガスおよび不活性ガスのほか、呼吸のための酸素ガス、およびその他任意のガスを、適切な濃度で予め混合することによって調製された、混合ガスの形態で提供される。 In one embodiment of the present invention, the pharmaceutical composition of the present invention is provided in a form that can be directly administered to a subject. For example, in this embodiment, the pharmaceutical composition of the present invention was prepared by premixing hydrogen gas and inert gas, oxygen gas for breathing, and any other gas in appropriate concentrations. , Provided in the form of a mixed gas.
本発明の別の態様において、本発明の医薬組成物は、対象への投与直前または投与時に調製される形態で提供される。例えば、この実施形態では、本発明の医薬組成物は、水素ガスと不活性ガスとの混合ガスを収容した容器と、酸素ガスを収容した容器とが、配管を介して吸引マスクに接続され、対象への投与に適切な濃度となるような流量で吸引マウスに送り込まれることによって、提供される。本発明の一態様では、前記容器は、ガスボンベである。 In another aspect of the invention, the pharmaceutical composition of the invention is provided in a form that is prepared immediately before or upon administration to a subject. For example, in this embodiment, in the pharmaceutical composition of the present invention, a container containing a mixed gas of hydrogen gas and an inert gas and a container containing oxygen gas are connected to a suction mask via a pipe, Provided by being delivered to aspirated mice at a flow rate that results in an appropriate concentration for administration to a subject. In one embodiment of the present invention, the container is a gas cylinder.
本発明の別の態様において、本発明の医薬組成物は、ガスの濃度が一定に維持されるように、密閉小室に水素ガスを供給することによって提供される。例えば、この実施形態では、本発明の医薬組成物は、対象が存在する密閉小室に、前記密閉小室中の水素濃度が適切な濃度に維持されるような流量で、水素ガスと不活性ガスとからなる混合ガスを供給することによって提供される。 In another aspect of the present invention, the pharmaceutical composition of the present invention is provided by supplying hydrogen gas to a sealed compartment so that the gas concentration is maintained constant. For example, in this embodiment, the pharmaceutical composition of the present invention contains hydrogen gas and inert gas at a flow rate such that the hydrogen concentration in the sealed chamber is maintained at an appropriate concentration in the sealed chamber where the subject exists. Provided by supplying a mixed gas consisting of
本発明の医薬組成物は、ガスを収容する１個または複数個の容器の形態、またはガスを収容する複数の容器と、ガスを吸入するための吸入手段と、前記複数の容器とガス吸入手段とを接続する配管とを含む、ガス吸入用デバイスの形態で提供され得る。本発明の一実施形態において、ガス吸入用デバイスは、ガスを収容する各容器からのガス吸入手段へのガスの流量を制御する制御機構を備えることが好ましい。 The pharmaceutical composition of the present invention is in the form of one or a plurality of containers for storing gas, or a plurality of containers for storing gas, inhaling means for inhaling gas, the plurality of containers and gas inhaling means And in the form of a gas suction device. In one embodiment of the present invention, the gas suction device preferably includes a control mechanism that controls the flow rate of the gas from each container containing the gas to the gas suction means.
本発明の医薬組成物の対象への投与は、手術前、手術中または手術後のいずれの時点で開始することができ、また、手術前、手術中、または手術後のいずれか、または全ての時点で投与することができる。 Administration of a pharmaceutical composition of the present invention to a subject can begin at any time before, during or after surgery, and before, during, or after surgery, or all Can be administered at a time.
本発明の医薬組成物の投与間隔および投与回数は、対象の症状、体重減少の早さ、その他対象の年齢および性別などに応じて、当業者が、適宜適切な投与間隔および投与回数を設定することができる。本発明の一実施形態では、本発明の医薬組成物は、手術後一定の期間にわたって、複数回投与される。例えば、本発明の医薬組成物は、手術後少なくとも１日以上、好ましくは少なくとも５日以上、より好ましくは少なくとも１０日以上、より好ましくは少なくとも１５日以上、より好ましくは少なくとも２０日以上、より好ましくは少なくとも２５日以上、より好ましくは少なくとも３０日以上、連日投与される。手術後、体重の減少が増加に転じるまで吸入させることが好ましい。 The administration interval and number of administrations of the pharmaceutical composition of the present invention are appropriately set by the person skilled in the art according to the symptoms of the subject, the rate of weight loss, other age and sex of the subject, and the like. be able to. In one embodiment of the invention, the pharmaceutical composition of the invention is administered multiple times over a period of time after surgery. For example, the pharmaceutical composition of the present invention is at least 1 day after surgery, preferably at least 5 days, more preferably at least 10 days, more preferably at least 15 days, more preferably at least 20 days, more preferably Is administered daily for at least 25 days or more, more preferably at least 30 days or more. After surgery, it is preferable to inhale until weight loss begins to increase.
本発明の医薬組成物の一回あたりの投与時間は、対象の症状、体重減少の早さ、その他対象の年齢および性別などに応じて、当業者が、適宜適切な投与間隔および投与回数を設定することができる。例えば、本発明の医薬組成物の一回あたりの投与時間は、１日あたり、０．１時間〜２４時間、好ましくは０．５時間〜１２時間、より好ましくは０．５時間〜１２時間、より好ましくは０．５時間〜６時間、より好ましくは０．５時間〜３時間、例えば１時間とすることができる。 The administration time per administration of the pharmaceutical composition of the present invention is appropriately determined by a person skilled in the art according to the symptoms of the subject, the speed of weight loss, and other age and sex of the subject. can do. For example, the administration time per time of the pharmaceutical composition of the present invention is 0.1 to 24 hours, preferably 0.5 to 12 hours, more preferably 0.5 to 12 hours per day. More preferably, it can be 0.5 to 6 hours, more preferably 0.5 to 3 hours, for example 1 hour.
本発明の医薬組成物の投与対象は、特に限定されないが、典型的にはヒトである。 The administration target of the pharmaceutical composition of the present invention is not particularly limited, but is typically a human.
本発明の医薬組成物によれば、水素ガスを投与しない場合との比較において、器官または組織の摘出後の最大体重減少を、１０％以上、好ましくは２０％以上、より好ましくは３０％以上、より好ましくは４０％以上、より好ましくは５０％以上、より好ましくは６０％以上、より好ましくは７０％以上、より好ましくは８０％以上、そして最も好ましくは９０％以上軽減することができる。 According to the pharmaceutical composition of the present invention, the maximum weight loss after removal of an organ or tissue is 10% or more, preferably 20% or more, more preferably 30% or more, as compared with the case where hydrogen gas is not administered. More preferably, it can be reduced by 40% or more, more preferably 50% or more, more preferably 60% or more, more preferably 70% or more, more preferably 80% or more, and most preferably 90% or more.
あるいは、本発明の医薬組成物によれば、水素ガスを投与しない場合との比較において、器官または組織の摘出後の体重減少を、少なくとも２０％以下、好ましくは１５％以下、より好ましくは１０％以下、より好ましくは９％以下、より好ましくは８％以下、より好ましくは７％以下、より好ましくは６％以下、そして最も好ましくは５％以下に抑制することができる。 Alternatively, according to the pharmaceutical composition of the present invention, the weight loss after removal of the organ or tissue is at least 20% or less, preferably 15% or less, more preferably 10%, as compared with the case where hydrogen gas is not administered. Below, more preferably 9% or less, more preferably 8% or less, more preferably 7% or less, more preferably 6% or less, and most preferably 5% or less.
本明細書において用いられる用語は、特定の実施態様を説明するために用いられるのであり、発明を限定する意図ではない。 The terminology used herein is for the purpose of describing particular embodiments and is not intended to be limiting of the invention.
また、本明細書において用いられる「含む」との用語は、文脈上明らかに異なる理解をすべき場合を除き、記載された事項（部材、ステップ、要素または数字等）が存在することを意図するものであり、それ以外の事項（部材、ステップ、要素または数字等）が存在することを排除しない。 In addition, the term “comprising” as used in this specification intends that there is a matter (a member, a step, an element, a number, or the like) described unless the context clearly requires different understanding. It does not exclude the presence of other items (members, steps, elements, numbers, etc.).
本明細書中に引用される文献は、それらのすべての開示が、本明細書中に援用されているとみなされるべきであって、当業者は、本明細書の文脈に従って、本発明の精神および範囲を逸脱することなく、それらの先行技術文献における関連する開示内容を、本明細書の一部として援用することができる。 References cited in this specification are to be regarded as the entire disclosure of which is hereby incorporated by reference, and those skilled in the art will recognize the spirit of the invention in accordance with the context of this specification. And the relevant disclosures in those prior art documents can be incorporated as part of this specification without departing from the scope and scope.
以下、実施例を示して本発明をより具体的に説明するが、本発明は以下に示す実施例によって何ら限定されるものではない。 EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated more concretely, this invention is not limited at all by the Example shown below.
ラット５／６腎摘モデルを作製し、水素混合ガス環境下での術後の経過を観察し、体重減少への影響を評価した。 A rat 5/6 nephrectomy model was prepared, the postoperative course in a hydrogen mixed gas environment was observed, and the effect on weight loss was evaluated.
ラット５／６腎摘モデルの作製には、１０週齢のＬｅｗｉｓラット（雄）を用いた。ラット５／６腎摘モデルは、ラットを、イソフルランを用いた笑気吸入麻酔下におき、以下の外科的処置を施すことによって作製した。すなわち、腹部を正中切開し、右腎を露出し、右腎を周囲脂肪織より剥離した後、腎門部で腎動静脈・尿管を結紮切離、右腎を摘出した。次いで、左腎を露出し、腎臓を周囲脂肪織より剥離した後、上下腎動脈分枝を結紮した。なお、コントロール群は、開腹後、両腎の脂肪織からの剥離のみを行い、体重変化のみを調査した。 For preparation of the rat 5/6 nephrectomy model, 10-week-old Lewis rats (male) were used. The rat 5/6 nephrectomy model was prepared by placing rats under laughing inhalation anesthesia with isoflurane and performing the following surgical procedures. That is, a midline incision was made in the abdomen, the right kidney was exposed, the right kidney was peeled from the surrounding fat tissue, the renal arteriovenous and ureters were ligated and separated at the hilar region, and the right kidney was removed. Next, the left kidney was exposed and the kidney was detached from the surrounding fat tissue, and then the upper and lower renal artery branches were ligated. In the control group, after the laparotomy, only the exfoliation of both kidneys from the fat tissue was performed, and only the change in body weight was investigated.
上記処置を行った各ラットは、術後当日、麻酔から完全に覚醒した段階で、ラット用ケース内に維持し、ガス吸入試験に供した。ラットを水素群（窒素＋１．３％水素＋２６％酸素、Ｎ＝３）、窒素群（窒素＋２６％酸素、Ｎ＝３）の２群に分け、ラット用ケース内で１時間ずつ各ガスを吸入させた。吸入は、前記組成の水素混合ガスまたは窒素ガスを、ラット用ケース内に一定の流量で供給することにより行った。なお、ラット用ケース内の水素濃度が均一に維持されていることは、吸引式ガス濃度計でモニタリングすることにより確認した。 Each of the rats subjected to the above treatment was maintained in a rat case at the stage of complete awakening from anesthesia on the day after the operation, and subjected to a gas inhalation test. Rats are divided into two groups: a hydrogen group (nitrogen + 1.3% hydrogen + 26% oxygen, N = 3) and a nitrogen group (nitrogen + 26% oxygen, N = 3), and each gas is inhaled for one hour in the rat case. I let you. Inhalation was performed by supplying a hydrogen mixed gas or nitrogen gas having the above composition into the rat case at a constant flow rate. In addition, it was confirmed by monitoring with a suction-type gas concentration meter that the hydrogen concentration in the rat case was maintained uniformly.
水素吸入は、１時間／日のスケジュールで、術後２８日目まで連日行い、その間、術後２８日までの体重を測定した（図１）。 Hydrogen inhalation was performed every day until the 28th day after the operation on a schedule of 1 hour / day, during which the body weight was measured until the 28th day after the operation (FIG. 1).
水素群および窒素群ともに手術直後に急激な体重減少を示したが、水素群では術後２日に減少のピークを迎え、術後３日目には体重増加に転じたのに対し、窒素群では術後７日まで体重減少が続き、体重増加に転じたのは術後９日目であった。また、窒素群では、最大体重減少が、ラット全体重のおよそ１８％に達したのに対し、水素群では、ラット全体重のおよそ７．５％に留まった。２−３日の間に２０％以上の体重減少、もしくは、７日間で２５％以上の体重減少が認められる動物は、安楽死の対象にするべきとの倫理基準もあることから、水素群の動物は、安楽死を十分に免れるレベルにまで体重減少を抑制できたという点で、極めて驚くべき結果であった。またこの結果は、水素ガスの吸入によって、吸入を行わなかった群に比較して、ラットの体重減少がおよそ６０％近くも軽減されたことを示している。 Both the hydrogen and nitrogen groups showed rapid weight loss immediately after surgery, but the hydrogen group peaked on the second day after surgery and started to gain weight on the third day after surgery, whereas the nitrogen group Then, weight loss continued until 7 days after the operation, and it was 9 days after the operation that the weight started to increase. In the nitrogen group, the maximum weight loss reached approximately 18% of the total weight of the rat, whereas in the hydrogen group, it remained at approximately 7.5% of the total weight of the rat. There is also an ethical standard that animals with a weight loss of 20% or more in 2-3 days or 25% or more in 7 days should be euthanized. The animals were extremely surprising in that they were able to suppress weight loss to a level that was sufficiently immune to euthanasia. This result also shows that the weight loss of rats was reduced by about 60% by inhalation of hydrogen gas compared to the group that did not inhale.
本発明の医薬組成物によれば、器官または組織の摘出による体重減少を軽減することができる。
According to the pharmaceutical composition of the present invention, weight loss due to removal of an organ or tissue can be reduced.
Claims (12)
器官または組織の摘出による体重減少を軽減するための、
医薬組成物。 A gaseous pharmaceutical composition comprising hydrogen gas,
To reduce weight loss due to removal of organs or tissues,
Pharmaceutical composition.
酸素ガスをさらに含むことを特徴とする、
医薬組成物。 A pharmaceutical composition according to claim 1,
Further comprising oxygen gas,
Pharmaceutical composition.
不活性ガスをさらに含むことを特徴とする、
医薬組成物。 A composition according to claim 1 or 2,
Further comprising an inert gas,
Pharmaceutical composition.
前記水素ガスの濃度が、１〜４％（ｖ／ｖ）である
ことを特徴とする、
医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3,
The concentration of the hydrogen gas is 1 to 4% (v / v),
Pharmaceutical composition.
前記水素ガスの濃度が、１〜４％（ｖ／ｖ）であり、
前記酸素ガス濃度が２１〜９９％（ｖ／ｖ）である
ことを特徴とする、
医薬組成物。 A pharmaceutical composition according to any one of claims 2 or 3,
The concentration of the hydrogen gas is 1-4% (v / v);
The oxygen gas concentration is 21 to 99% (v / v),
Pharmaceutical composition.
１日あたり０．５〜２４時間投与される
ことを特徴とする、
医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5,
It is administered for 0.5 to 24 hours per day,
Pharmaceutical composition.
手術日後少なくとも１日以上投与される
ことを特徴とする、
医薬組成物。 A pharmaceutical composition according to any one of claims 1-6,
It is administered at least one day after the operation day,
Pharmaceutical composition.
手術前、および／または、手術中において投与される
ことを特徴とする、
医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 7,
Administered before and / or during surgery,
Pharmaceutical composition.
前記「器官または組織の摘出」が癌、腫瘍、胆石、挫滅した組織の摘出；肺感染症による肺切除；弁置換、弁形成、大血管置換術、慢性肺血栓塞栓症に対する血栓内膜剥皮術；脳内血腫の除去；大腿骨頭置換術；またはドナーからの臓器摘出に伴う
ことを特徴とする、
医薬組成物。 A pharmaceutical composition according to any one of claims 1 to 8,
The above-mentioned "extraction of organ or tissue" is the removal of cancer, tumor, gallstone, extinct tissue; pulmonary resection due to pulmonary infection; valve replacement, valvuloplasty, macrovascular replacement, and thrombus intimal debarking for chronic pulmonary thromboembolism Removal of intracerebral hematoma; femoral head replacement; or associated with organ removal from a donor,
Pharmaceutical composition.
前記「器官または組織」が、循環器系：消化器系；呼吸器系；神経系；生殖器系；泌尿器；内分泌系；感覚器系；運動器系；乳房；または皮膚からなる群から選ばれる器官または組織の全部または一部である
ことを特徴とする、
医薬組成物。 A pharmaceutical composition according to any one of claims 1-9,
An organ selected from the group consisting of the circulatory system: digestive system; respiratory system; nervous system; genital system; urinary system; endocrine system; sensory organ system; motor organ system; breast; Or all or part of an organization,
Pharmaceutical composition.
前記「器官または組織」が、大血管、心臓、食道、胃、十二指腸、小腸、大腸、脾臓、胆嚢、膵臓、肝臓、気管、肺、脳、子宮、卵巣、腎臓、甲状腺、副甲状腺、下垂体、副腎、ランゲルハンス島、松果体、眼、耳、骨、筋肉、乳房、および皮膚からなる群から選ばれる器官または組織の全部または一部である
ことを特徴とする、
医薬組成物。 A pharmaceutical composition according to any one of claims 1-9,
The “organ or tissue” is a large blood vessel, heart, esophagus, stomach, duodenum, small intestine, large intestine, spleen, gallbladder, pancreas, liver, trachea, lung, brain, uterus, ovary, kidney, thyroid, parathyroid, pituitary gland. Characterized by being all or part of an organ or tissue selected from the group consisting of: adrenal gland, islets of Langerhans, pineal gland, eye, ear, bone, muscle, breast, and skin,
Pharmaceutical composition.
水素ガスを投与しない場合との比較において、器官または組織の摘出後の最大体重減少を、３０％以上軽減することを特徴とする、
医薬組成物。
The pharmaceutical composition according to any one of claims 1 to 11,
In comparison with the case where hydrogen gas is not administered, the maximum weight loss after removal of an organ or tissue is reduced by 30% or more,
Pharmaceutical composition.
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| JP2021109860A (en) * | 2020-01-15 | 2021-08-02 | ＭｉＺ株式会社 | Molecular hydrogen-containing composition for promotion of postoperative recovery |
| JP2022021279A (en) * | 2020-07-21 | 2022-02-02 | ＭｉＺ株式会社 | Compositions for preventing and/or ameliorating side effects of drug, symptoms associated with side effects of drug, and/or side effects associated with treatment |
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| JP2021109860A (en) * | 2020-01-15 | 2021-08-02 | ＭｉＺ株式会社 | Molecular hydrogen-containing composition for promotion of postoperative recovery |
| JP2022021279A (en) * | 2020-07-21 | 2022-02-02 | ＭｉＺ株式会社 | Compositions for preventing and/or ameliorating side effects of drug, symptoms associated with side effects of drug, and/or side effects associated with treatment |
| JP7019910B2 (en) | 2020-07-21 | 2022-02-16 | ＭｉＺ株式会社 | Compositions for preventing and / or ameliorating side effects of a drug, symptoms associated with the side effects of a drug, and / or side effects associated with treatment. |
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