著者

山本 緑 石井 祐次

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.140, no.11, pp.1397-1403, 2020-11-01 (Released:2020-11-01)

参考文献数

25

被引用文献数

3

---

Pharmacological cognitive enhancement (PCE) usually refers to the use of medical substances by healthy individuals to improve mental performance. Given that certain substances have been frequently used for years, the long-term effectiveness and safety are essential to know but particularly difficult and costly to determine. Although PCE is a widespread and frequent phenomenon among university students in other countries, PCE prevalence in Japan has not been elucidated. The present study aimed to investigate the prevalence of and the attitude toward PCE among Japanese undergraduates over 3 years (2017-2019). Almost no student had ever used prescription drugs for cognitive enhancement. When asked, “Would you like to use drugs to enhance your cognitive performance?” 68.6-72.0% of the students answered, “No,” 25.4-26.7% answered, “I couldn't say,” and 2.5-4.8% answered, “Yes.” These answers were associated with sex (2017-2018) and stress sensitivity (2019) but not with drinking, smoking, or stress of academic performance. Half of the students had used energy drinks for neural enhancement prior to an examination, which is similar to Western usage. The users of soft enhancers, such as energy drinks, are more likely to use other drugs. Given that caffeine can be a gateway for cognitive enhancement, future education addressing PCE among students should emphasize the side effects of prescription drugs as well as health risks of caffeine products.

著者

馬来 秀行 白石 朗 三木 晶子 佐藤 宏樹 小西 ゆかり 浅井 康平 舟橋 健一 臼井 順信 澤田 康文

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.137, no.8, pp.1041-1049, 2017-08-01 (Released:2017-08-01)

参考文献数

4

被引用文献数

2 4

---

In our previous research, there was no collaboration between care workers and pharmacists, for the most part. As a result, it was discovered that in some cases, problems concerning medication of nursing home residents had not been resolved. To solve this issue, we brought together care workers and pharmacists for a workshop we conducted. We assigned 12 care workers with at least two years of experience and 12 pharmacists to four mixed groups and guided them in the management of in-home long-term medical care and conducted small group discussions (SGD) using the KJ method. In the pre-survey before the workshop, all 12 care workers replied “yes” to having experienced “concerns over medication” and nine (75%) replied “no” to having experienced “discussions (consultations) with pharmacists regarding the medication of residents”. As a result of the SGD, “information sharing among professionals” was revealed as a problem common to all groups. Furthermore, common countermeasures for this issue included communication notes and holding collaborative meetings. In the post-survey after the workshop, 67% of the participants replied that their thoughts concerning countermeasures were “coherent”, and everyone replied that their “awareness was increased”. In a follow-up survey after the workshop, 82% of the participants replied that they were using some form of what they had learned and discovered in the workshop in their actual work.

著者

飯盛 挺造

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

no.5, pp.140-144, 1882-04

著者

飯盛 挺造

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

no.6, pp.172-178, 1882-05

著者

丹波 敬三

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

no.408, 1916-02-26

著者

飯盛 挺造

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

no.194, pp.330-339, 1898-04-26

著者

飯盛 挺造

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

no.336, pp.99-103, 1910-02-26

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水ノ表面張力ニ由テ金屬ノ球・線・板等ノ如キ比重大ナルモノ、一定量モ亦能ク之ヲ水面ニ浮メ得ルヤ否ヤ先ツ之ヲ水銀球ニ由リ然ル後鉛球ヲ以テ研究シ其一定量ハ浮泛スルコトヲ證明セリ

著者

吉川 雅之 P0NGPIRIYADACHA Yutana 來住 明宣 蔭浦 禎士 王 涛 森川 敏生 松田 久司

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

vol.123, no.10, pp.871-880, 2003-10-01

参考文献数

27

被引用文献数

15 63

---

デチンムル科(Hippocerateaceae)Salacia属植物は,インド,スリランカを始め,タイやインドネシアなどの東南アジア,ブラジルなどの熱帯地域に広く分布し,約120種が知られている.スリランカ,インド,タイなどに多く自生するSalacia(S.)reticulata,S.oblonga及びS.chinensis(syn.S.prinoides)は,つる性の多年性木本で,その根部や幹は,インドやスリランカの伝統医学であるアーユルヴェーダを始め,中国やタイの伝承医学などにおいて天然薬物として利用されてきた.スリランカでは,S.reticulataの根皮は,リウマチ,淋病及び皮膚病の治療に用いられるほか,特に糖尿病の初期の治療に有効であると伝承されている.インドでは,S.reticulataやS.oblongaの根部が,リウマチ,淋病,皮膚病及び糖尿病の治療に用いられている.S.chinensisは,S.prinoidesと同一植物であると言われており,インドや中国及びタイ,インドネシアなどの東南アジアに広く分布している.インドにおいては,S.prinoidesは糖尿病の治療のほかに,堕胎,通経,性病の治療に用いられている.一方,中国伝統医学では,S.prinoidesはサラツボクと称され,リウマチ性関節炎,腰筋の疲労,体力の虚脱や無力感の改善に用いられている.タイにおいてはS.chinensisの幹の煎じ液が緩下や筋肉痛の緩和によいとされているが,糖尿病や肥満の治療に用いられることはない.我々は,代表的な生活習慣病の1つで,現在日本人の約1割が発病又はその予備軍と言われている糖尿病あるいはその主たる因子の1つとされている肥満の予防に役立つ機能性素材を世界各地の薬用食物に求めて解明研究を進めている.その探索研究の一環として,スリランカ産S.reticulata及びインド産S.oblongaの幹及び根部エキスにショ糖負荷ラットにおける強い血糖値上昇抑制活性を見出し,その作用メカニズムが糖質加水分解酵素阻害作用であることを明らかにした.また,活性成分として,新奇なチオ糖スルホニウム硫酸分子内塩構造を有するsalacinol(1)及びkotalanol(2)を単離するとともに,1や2が,市販のα-glucosidase阻害薬と同等の強いα-glucosidase阻害や糖の吸収抑制作用を示すことを見出した.また,糖尿病性合併症である白内障や神経障害に関与するポリオール代謝系の律速酵素であるaldose還元酵素に対する阻害作用成分を探索したところ,Salacia属植物から活性成分としてmangiferin(3)及び数種のトリテルペン類を見出した.さらに,肥満及び肝障害など種々の生活習慣病に関連した活性評価を行い,3やポリフェノール成分などに活性を見出している.これまでに,タイ産S.chinensisの成分として,茎からdulcitol,proanhocyanidin及びleucopelargoninの2量体が単離され,葉からはproanthocyanidinが単離されている.また,インド産S.prinoidesから多数のトリテルペン成分が報告されている.最近,Salacia属植物の幹部や根部がダイエット素材としていわゆる健康食品に利用されるようになっている.しかし,これらのSalacia属植物は,現在のところいずれも栽培化に成功しておらず,もっぱら野生品が供給されているのが現状で,基源植物の同定を始め採取地や採取時期などが明確でないことも多い.また,抗糖尿病関連の活性が伝承されていないタイ産S.chinensisが,ダイエット素材として利用されている.今回,タイ産S.chinensisの80%含水メタノール抽出エキスについて,スリランカ産S.reticulataとインド産S.oblongaとの比較のもとに,抗糖尿病作用や炎症に関連した活性評価試験として,i)糖負荷ラットにおける血糖値上昇抑制作用(in vivo,ii)ラット小腸刷子縁膜由来及びパン酵母由来α-glucosidase阻害活性,iii)ラットレンズ由来aldose還元酵素阻害活性(in vivo),iv)アマドリ化合物及び終末糖化産物[advanced glycation end-products(AGEs)]生成抑制活性,v)DPPH及びO^-_2ラジカル消去活性,vi)マウス腹腔マクロファージからのリポ多糖(LPS)誘発一酸化窒素(NO)産生抑制活性について検討した.また,S.chinensisの80%含水メタノール抽出エキスからsalacinol(1)を単離,同定するとともに,タイ各地で入手したS.chinensisについてラット小腸由来α-glucosidase阻害活性を比較した結果について報告する.

著者

飯塚 幸澄 櫻井 栄一 田中 頼久

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 = Journal of the Pharmaceutical Society of Japan (ISSN:00316903)

巻号頁・発行日

vol.121, no.5, pp.365-369, 2001-05-01

参考文献数

12

被引用文献数

7 10

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The antidiabetic effect of hot water extracts from Folium Mori was investigated in GK rat; one of the animal models of non-insulin dependent diabetic mellitus types. Folium Mori extracts (150 mg/kg) significantly reduced the blood glucose of GK rat from 203.8±29.8 to 138.5±21.2 mg/dl at 14 days after oral administration. However, in normal rats, blood glucose and insulin levels were not changed by treatment with Folium Mori. The Folium Mori also decreased blood glucose and improved glucose tolerance at 14 days after repeated administration in GK rats. The Folium Mori treatment significantly increased glucose metabolism in the glucose clamp test for GK rats. These results suggest that Folium Mori has quite unique properties such as raising insulin sensitivity and improving insulin resistance.

著者

玉木 啓文 佐藤 宏樹 堀 里子 澤田 康文

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.138, no.10, pp.1305-1312, 2018-10-01 (Released:2018-10-01)

参考文献数

17

被引用文献数

1 1

---

Similar-appearing press-through package (PTP) sheets (also known as blister packs) that contain different medicines may result in incorrect medication due to confusion errors. To evaluate the significance of this problem and to identify the factors that may lead to such errors, we conducted a questionnaire survey for pharmacists. Three hundred and eighty-two pairs of PTP sheets with similar appearance were included in the questionnaire. Factors related to color (sheet color at the front of the sheet 90.9%, color of tablet/capsule 57.1%, print color at the front of the sheet 45.9%) were most frequently selected as influencing the perceived similarity of the reported pairs, followed by tablet/capsule shape (46.2%), sheet size (32.4%), and mark and character positioning on sheets (6.8%). In the pairs of similar PTP sheets, pairs manufactured by the same pharmaceutical company accounted for 15%. The frequency of confusion errors or near-errors due to similar appearance of PTP sheets was highest at the time of collecting PTP sheets from the medicine shelf and returning the sheets to the medicine shelf, followed by the time of inspection of prepared medicines and medication instructions. The questionnaire results also indicate that patients themselves can confuse similar PTP sheets and take the wrong medicine. Further quantitative studies are needed to clarify the key factors that cause confusion errors due to similar appearance and to identify potential remedial measures.

著者

飯塚 幸澄 桜井 栄一 田中 頼久

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.121, no.5, pp.365-369, 2001-05-01 (Released:2002-09-27)

参考文献数

12

被引用文献数

8 10

---

The antidiabetic effect of hot water extracts from Folium Mori was investigated in GK rat; one of the animal models of non-insulin dependent diabetic mellitus types. Folium Mori extracts (150 mg/kg) significantly reduced the blood glucose of GK rat from 203.8±29.8 to 138.5±21.2 mg/dl at 14 days after oral administration. However, in normal rats, blood glucose and insulin levels were not changed by treatment with Folium Mori. The Folium Mori also decreased blood glucose and improved glucose tolerance at 14 days after repeated administration in GK rats. The Folium Mori treatment significantly increased glucose metabolism in the glucose clamp test for GK rats. These results suggest that Folium Mori has quite unique properties such as raising insulin sensitivity and improving insulin resistance.

著者

陳 福君 中島 登 木村 郁子 木村 正康

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.115, no.6, pp.476-482, 1995-06-25 (Released:2008-05-30)

参考文献数

12

被引用文献数

70 93

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Averaged blood glucose levels were 400 mg/dl in nonfasted mice, and 250 mg/dl in fasted mice in 4 weeks after injection with streptozotocin (STZ, 150 mg/kg, i.v.). These mice were used for experiments. Hypoglycemic effects of hot water extracts (W) from Folium Mori (Mulberry leaves, Morus alba L., China and Japan) or Cortex Mori Radicis (Morus alba L., China) were observed in fasted and nonfasted STZ-induced diabetic mice at a single dose of 200 mg/kg (i.p.). The W from Folium Mori exhibited most potent hypoglycemic effects. The most potent fractions of Folium Mori and Cortex Mori Radicis were ethanol-insoluble extracts (A2). These A2 fractions demonstrated a fall in blood glucose levels of 24.6±6.0% and 60.5±9.1% at nonfasted STZ-mice, and 81.4±7.9% and 77.3±5.8% at fasted STZ-mice, respectively. The increase in glucose uptake was a mechanism of hypoglycemic actions by W and A2 of Folium Mori.

著者

八木 秀樹 益子 高

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.133, no.9, pp.939-945, 2013-09-01 (Released:2013-09-01)

参考文献数

17

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Antibodies have greatly contributed to the development of medical science and pharmacology, because of their high specificity. The cell fusion method has developed monoclonal antibodies (mAb) technology, such that massive amounts of mAb with a uniform structure can be produced. Although mAb have been produced against many proteins so far, the production of mAb against multi-pass transmembrane proteins, such as G-protein coupled receptor (GPCR) and various transporter proteins has been extremely difficult. The complicated structures, poorly extracellular regions, and high hydrophobicity of multiple-transmembrane proteins make it difficult to produce mAb against them. Production of mAb that recognize the extracellular region of living cells is thought to be important in determining the ability of a protein. Based on these findings, we tried to produce mAb against a multi-pass transmembrane transporter using green fluorescent protein (GFP)-fused full-length target proteins as immunogens. Furthermore, the immunizing method has proved to be important in generating functional mAb. We succeeded in producing functional mAb that react against the extracellular region of a 12-pass transmembrane transporter in a living cell. Based on this success, we began to produce mAb against seven-transmembrane GPCR. In this symposium, we report on the results of producing mAb against S1P receptors, a type of GPCR.

著者

大村 智

出版者

公益社団法人 日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

vol.106, no.9, pp.729-757, 1986

被引用文献数

2

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After structure elucidation of 16-membered macrolide antibiotic leucomycin, the structures of spiramycin, tylosin, megalomicin, irumamycin and virustomycin were determined by chemical degradation and nuclear magnetic resonance (NMR) spectroscopy. The studies on the chemical modification and structure activity correlation of macrolides led to the elaboration of clinically useful new derivatives.<BR>The biosynthetic origin of the carbon skeletone of macrolide aglycone was investigated by means of <SUP>13</SUP>C NMR and the feeding experiments of <SUP>13</SUP>C labeled precursors. We found that an antifungal antibiotic cerulenin is a specific inhibitor of fatty acid and &ldquo;polyketide&rdquo; biosyntheses, and applied the antibiotic to the biosynthetic studies of macrolides after formation of the lactone ring and to the production of a new &ldquo;hybrid&rdquo; macrolide, chimeramycin. Furthermore, a strain which produces a new &ldquo;hybrid&rdquo; antibiotic mederrhodin was breaded from actinorhodin and medermycin producers by gene manipulation.<BR>Sixty five or more new antibiotics have been discovered from secondary microbial metabolites using newly devised screening systems. Azureomycins and izupeptins were found as bacterial cell wall biosynthesis inhibitors. In combination with the above screening, several new antibiotics, nanaomycins, frenolicin B, cervinomycins, asukamycin and so on were discovered as antimycoplasmal substances. Diazaquinomycins as antifolate substance, hitachimycin and avermectin as anthelmintics, herbimycin, phosalacine and oxetin as herbicids have been found by the corresponding each screening system. The structure elucidation, biosynthesis and mode of action of these antibiotics have been studied. Among of them, nanaomycin A and avermectin (or ivermectin) have been employed as antifungal and antiparasitic therapeutics, respectively, for veterinary use.

著者

輿石 徹 奥山 清

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.136, no.12, pp.1675-1679, 2016-12-01 (Released:2016-12-01)

参考文献数

7

被引用文献数

1 1

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A 70-year-old woman, residing in a nursing home, was admitted to our hospital because of cerebral hemorrhage. She had excessive sweating, a temperature above 37°C, and intermittent muscle spasm such as myoclonus, since the time of admission. We suspected that these symptoms were related to side effects caused by the milnacipran she was taking for depression, prior to hospitalization. After we discontinued milnacipran, the patient began exhibiting withdrawal symptoms such as excitement and insomnia. When we substituted milnacipran with mianserin, the withdrawal symptoms diminished and the excessive sweating and involuntary movement disappeared. Serotonin-norepinephrine reuptake inhibitor (SNRI) and selective serotonin reuptake inhibitor (SSRI) have been widely utilized in the clinic to treat depression; serious side effects such as serotonin syndrome and withdrawal syndrome associated with their discontinuation, have been reported. However, it is unlikely that serotonin syndrome and withdrawal syndrome due to a precedent use of milnacipran would have been reported. This case was suspected to be related to serotonin syndrome and withdrawal syndrome from the course of treatment. This case provides valuable information for addressing new similar cases caused by milnacipran.

著者

宗 可奈子

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.140, no.1, pp.1-6, 2020-01-01 (Released:2020-01-01)

参考文献数

14

被引用文献数

3

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Dysesthesia is an unpleasant abnormal sensation, often accompanied by pain, paresthesia (abnormal sensation), and numbness (decrease or loss of sensation). Dysesthesia has been associated with various conditions, although its underlying mechanisms are largely unknown. This study assessed the roles of transient receptor potential ankyrin 1 (TRPA1) in dysesthesia by utilizing three animal models of dysesthesia characterized by reductions in blood flow to the skin: a transient hindlimb ischemia/reperfusion model, characterized by spontaneous licking and tactile hypoesthesia of the ischemic hindpaw; a streptozotocin-induced diabetic neuropathy model in mice, characterized by cold hypersensitivity, which is likely parallel to the reduced skin blood flow of the hindpaw; and a hindlimb ischemia model. TRPA1 inhibition or deficiency blocked spontaneous licking in the transient hindlimb ischemia/reperfusion model and cold hypersensitivity in the diabetic mouse model mice. Consistent with these results, the nocifensive behaviors induced by intraplantar injection of a TRPA1 agonist were enhanced in the diabetic neuropathy and hindlimb ischemia models. Hypoxia enhanced H2O2-induced TRPA1 responses in human TRPA1-expressing cells and cultured mouse dorsal root ganglion neurons, with this hypoxia-induced TRPA1 sensitization to H2O2 being associated with hypoxia-induced inhibition of the hydroxylation of prolyl hydroxylases. These results suggest that dysesthesia following blood flow reduction is caused by the activation of TRPA1 sensitized by hypoxia and that hypoxia-induced TRPA1 sensitization plays a pivotal role in painful dysesthesia induced by peripheral blood flow reduction.

著者

佐久嶋 明世 西部 三省 久田 末雄

出版者

公益社団法人日本薬学会

雑誌

薬学雑誌 (ISSN:00316903)

巻号頁・発行日

vol.98, no.10, pp.p1395-1397, 1978-10

被引用文献数

1

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From the methanolic extract of leaves of Apocynum venetum L. var. basikurumon HARA, eight constituents were isolated and identified with respective authentic samples as succinic acid, chlorogenic acid, isoquercitrin, hyperoside, D-(-)-bornesitol, sucrose, β-sitosterol, and β-amyrin.

著者

桜井 光一 三浦 俊明 小木曾 健人

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

vol.106, no.11, pp.1034-1039, 1986

被引用文献数

4

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Protective effects of several hydroxyl radical (HO&middot;) scavengers and superoxide dismutase on alloxan-induced diabetes were studied in vivo. Thiourea, methylthiourea, dimethylthiourea and ethanol, HO&middot; scavengers (type 1), which easily cross cellular membranes, protected initial- and permanent-hyperglycemia. In contrast, mannitol and sorbitol (type 2), which can not cross cellular membranes, protected initial-hyperglycemia, but did not protect permanent-hyperglycemia. Furthermore, superoxide dismutase which is not expected to be incorporated into pancreatic &beta;-cell, strongly protected initial-hyperglycemia but partially protected permanent-hyperglycemia. These results suggest that HO&middot;primarily damages the &beta;-cell membranes by acting at or neat a site involved in insulin release, and subsequently damages the intracellular components. From these results, the possible protective mechanism of these scavengers was discussed.

著者

佐藤 洋美

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.140, no.8, pp.963-968, 2020-08-01 (Released:2020-08-01)

参考文献数

30

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Metabolome analysis is an approach to investigate cell characteristics from the metabolites that are constantly produced and changed by those cells. We conducted a metabolome analysis of the response of 786-O renal cell carcinoma (RCC) cells to histone deacetylase (HDAC) inhibitors, which are expected to increase anticancer drug sensitivity, and compared the response with that of drug-resistant cells. Trichostatin A (TSA), an HDAC inhibitor, increased the sensitivity of 786-O cells to sunitinib. Moreover, TCA cycle and nucleotide metabolism of the cells were promoted. The findings that acetylated p53 (active form) and early apoptotic cells were increased suggests that the mechanism involved enhancement of mitochondrial metabolism and function. In addition, established sunitinib-resistant RCC cells were exposed to a combination of sunitinib and TSA, resulting in significant growth inhibition. Principal component analysis revealed that the parent and resistant cells were obviously different, but approximately half their fluctuations were illustrated by the same pathways. In summary, it was suggested that TSA reduced sunitinib resistance by triggering intracellular metabolome shifts in energy metabolism. This was the first recognized mechanism of action of TSA as an HDAC inhibitor.

著者

守屋 利佳

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.137, no.4, pp.413-419, 2017-04-01 (Released:2017-04-01)

参考文献数

41

被引用文献数

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We have experienced a series of big revolutions in medical education in Japan. In undergraduate courses, common guidelines had been established for medical education (the model core-curriculum of medical education). Then, from 2005, a standard achievement testing system [objective structured clinical examination (OSCE) and computer based testing (CBT)] was begun, and clinical clerkships were accordingly promoted. In post-graduate courses, a new clinical resident training system was initiated in 2004, and there are currently approximately 40000 clinical instructors nationwide. Accreditation of Japanese medical schools based on global standards for quality improvement has just begun. Almost the same process has taken effect in the field of pharmaceutical education (PE), such as the preparation of guidelines for PE and clinical training, a shift to a six-year course, and the establishment of an accreditation organization. The educational guidelines were revised in 2013 to provide better clinical training. Both of these educational revolutions aim at providing the proper education to train healthcare professionals committed to practicing “patient-centered medicine” and to becoming lifelong learners. To educate such professionals naturally includes improving their communicative competency, and cultivating their professionalism along with their acquisition of scientific and medical knowledge, based on both quantitative and qualitative study. The Society for Medical Education has begun a new “Medical education specialist (MES) training system” responding to the need of MES in every medical school and training hospital. A new PE specialist educational system can be expected soon, as well.