Therapeutic index

The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect.[1] The related terms therapeutic window or safety window refer to a range of doses optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

Classically, for clinical indications of an approved drug, TI refers to the ratio of the dose of the drug that causes adverse effects at an incidence/severity not compatible with the targeted indication (e.g. toxic dose in 50% of subjects, TD50) to the dose that leads to the desired pharmacological effect (e.g. efficacious dose in 50% of subjects, ED50). In contrast, in a drug development setting TI is calculated based on plasma exposure levels.[2]

In the early days of pharmaceutical toxicology, TI was frequently determined in animals as lethal dose of a drug for 50% of the population (LD50) divided by the minimum effective dose for 50% of the population (ED50). In modern settings, more sophisticated toxicity endpoints are used.

For many drugs, severe toxicities in humans occur at sublethal doses, which limit their maximum dose. A higher safety-based therapeutic index is preferable instead of a lower one; an individual would have to take a much higher dose of a drug to reach the lethal threshold than the dose taken to induce the therapeutic effect of the drug. However, a lower efficacy-based therapeutic index is preferable instead of a higher one; an individual would have to take a higher dose of a drug to reach the toxic threshold than the dose taken to induce the therapeutic effect of the drug.

Generally, a drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of its blood levels in the person taking it. This may be achieved through therapeutic drug monitoring (TDM) protocols. TDM is recommended for use in the treatment of psychiatric disorders with lithium due to its narrow therapeutic range.[3]

Term Full form Definition
ED Effective Dose the dose or concentration of a drug that produces a biological response.[4][5]
TD Toxic Dose the dose at which toxicity occurs in 50% of cases.
LD Lethal Dose the dose at which death occurs in 50% of cases.[6]: 73 [7][8]
TI Therapeutic Index a quantitative measurement of the relative safety of a drug by comparison of the amount of a therapeutic agent that causes toxicity to the amount that causes the therapeutic effect[1]

Types

Based on efficacy and safety of drugs, there are two types of therapeutic index:

Safety-based therapeutic index


It is desirous for the value of LD50 to be as large as possible, to decrease risk of lethal effects and increase the therapeutic window. In the above formula, TIsafety increases as the difference between LD50 and ED50 increases—hence, a higher safety-based therapeutic index indicates a larger therapeutic window, and vice versa.

Efficacy-based therapeutic index


Ideally the ED50 is as low as possible for faster drug response and larger therapeutic window, whereas a drugs TD50 is ideally as large as possible to decrease risk of toxic effects. In the above equation, the greater the difference between ED50 and TD50, the greater the value of TIefficacy. Hence, a lower efficacy-based therapeutic index indicates a larger therapeutic window.

Protective index

Similar to safety-based therapeutic index, the protective index uses TD50 (median toxic dose) in place of LD50.

For many substances, toxicity can occur at levels far below lethal effects (that cause death), and thus, if toxicity is properly specified, the protective index is often more informative about a substance's relative safety. Nevertheless, the safety-based therapeutic index () is still useful as it can be considered an upper bound of the protective index, and the former also has the advantages of objectivity and easier comprehension.

Since the protective index (PI) is calculated as TD50 divided by ED50, it can be mathematically expressed that:

which means that is a reciprocal of protective index.

All the above types of therapeutic index can be used in both pre-clinical trials and clinical trials.

Drug development

A low efficacy-based therapeutic index () and a high safety-based therapeutic index () are preferable for a drug to have a favorable efficacy vs safety profile. At the early discovery/development stage, the clinical TI of a drug candidate is unknown. However, understanding the preliminary TI of a drug candidate is of utmost importance as early as possible since TI is an important indicator of the probability of successful development. Recognizing drug candidates with potentially suboptimal TI at the earliest possible stage helps to initiate mitigation or potentially re-deploy resources.

TI is the quantitative relationship between pharmacological efficacy and toxicological safety of a drug, without considering the nature of pharmacological or toxicological endpoints themselves. However, to convert a calculated TI into something useful, the nature and limitations of pharmacological and/or toxicological endpoints must be considered. Depending on the intended clinical indication, the associated unmet medical need and/or the competitive situation, more or less weight can be given to either the safety or efficacy of a drug candidate in order to create a well balanced indication-specific efficacy vs safety profile.

In general, it is the exposure of a given tissue to drug (i.e. drug concentration over time), rather than dose, that drives the pharmacological and toxicological effects. For example, at the same dose there may be marked inter-individual variability in exposure due to polymorphisms in metabolism, DDIs or differences in body weight or environmental factors. These considerations emphasize the importance of using exposure instead of dose to calculate TI. To account for delays between exposure and toxicity, the TI for toxicities that occur after multiple dose administrations should be calculated using the exposure to drug at steady state rather than after administration of a single dose.

A review published by Muller and Milton in Nature Reviews Drug Discovery critically discusses TI determination and interpretation in a translational drug development setting for both small molecules and biotherapeutics.[2]

Range of therapeutic indices

The therapeutic index varies widely among substances, even within a related group.

For instance, the opioid painkiller remifentanil is very forgiving, offering a therapeutic index of 33,000:1, while Diazepam, a benzodiazepine sedative-hypnotic and skeletal muscle relaxant, has a less forgiving therapeutic index of 100:1.[9] Morphine is even less so with a therapeutic index of 70.

Less safe are cocaine (a stimulant and local anaesthetic) and ethanol (colloquially, the "alcohol" in alcoholic beverages, a widely available sedative consumed worldwide): the therapeutic indices for these substances are 15:1 and 10:1, respectively.[10] Paracetamol, alternatively known by its trade names Tylenol or Panadol, also has a therapeutic index of 10.[11]

Even less safe are drugs such as digoxin, a cardiac glycoside; its therapeutic index is approximately 2:1.[12]

Other examples of drugs with a narrow therapeutic range, which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity, include dimercaprol, theophylline, warfarin and lithium carbonate.

Some antibiotics and antifungals require monitoring to balance efficacy with minimizing adverse effects, including: gentamicin, vancomycin, amphotericin B (nicknamed 'amphoterrible' for this very reason), and polymyxin B.

Cancer radiotherapy

Radiotherapy aims to shrink tumors and kill cancer cells using high energy. The energy arises from x-rays, gamma rays, or charged or heavy particles. The therapeutic ratio in radiotherapy for cancer treatment is determined by the maximum radiation dose for killing cancer cells and the minimum radiation dose causing acute or late morbidity in cells of normal tissues.[13] Both of these parameters have sigmoidal dose–response curves. Thus, a favorable outcome in dose–response for tumor tissue is greater than that of normal tissue for the same dose, meaning that the treatment is effective on tumors and does not cause serious morbidity to normal tissue. Conversely, overlapping response for two tissues is highly likely to cause serious morbidity to normal tissue and ineffective treatment of tumors. The mechanism of radiation therapy is categorized as direct or indirect radiation. Both direct and indirect radiation induce DNA mutation or chromosomal rearrangement during its repair process. Direct radiation creates a DNA free radical from radiation energy deposition that damages DNA. Indirect radiation occurs from radiolysis of water, creating a free hydroxyl radical, hydronium and electron. The hydroxyl radical transfers its radical to DNA. Or together with hydronium and electron, a free hydroxyl radical can damage the base region of DNA.[14]

Cancer cells cause an imbalance of signals in the cell cycle. G1 and G2/M arrest were found to be major checkpoints by irradiating human cells. G1 arrest delays the repair mechanism before synthesis of DNA in S phase and mitosis in M phase, suggesting it is a key checkpoint for survival of cells. G2/M arrest occurs when cells need to repair after S phase but before mitotic entry. It is known that S phase is the most resistant to radiation and M phase is the most sensitive to radiation. p53, a tumor suppressor protein that plays a role in G1 and G2/M arrest, enabled the understanding of the cell cycle through radiation. For example, irradiation of myeloid leukemia cells leads to an increase in p53 and a decrease in the level of DNA synthesis. Patients with Ataxia telangiectasia delays have hypersensitivity to radiation due to the delay of accumulation of p53.[15] In this case, cells are able to replicate without repair of their DNA, becoming prone to incidence of cancer. Most cells are in G1 and S phase. Irradiation at G2 phase showed increased radiosensitivity and thus G1 arrest has been a focus for therapeutic treatment. Irradiation of a tissue induces a response in both irradiated and non-irridiated cells. It was found that even cells up to 50–75 cell diameters distant from irradiated cells exhibit a phenotype of enhanced genetic instability such as micronucleation.[16] This suggests an effect on cell-to-cell communication such as paracrine and juxtacrine signaling. Normal cells do not lose their DNA repair mechanism whereas cancer cells often lose it during radiotherapy. However, the high energy radiation can override the ability of damaged normal cells to repair, leading to additional risk of carcinogenesis. This suggests a significant risk associated with radiation therapy. Thus, it is desirable to improve the therapeutic ratio during radiotherapy. Employing IG-IMRT, protons and heavy ions are likely to minimize the dose to normal tissues by altered fractionation. Molecular targeting of the DNA repair pathway can lead to radiosensitization or radioprotection. Examples are direct and indirect inhibitors on DNA double-strand breaks. Direct inhibitors target proteins (PARP family) and kinases (ATM, DNA-PKCs) that are involved in DNA repair. Indirect inhibitors target protein tumor cell signaling proteins such as EGFR and insulin growth factor.[13]

The effective therapeutic index can be affected by targeting, in which the therapeutic agent is concentrated in its desirable area of effect. For example, in radiation therapy for cancerous tumors, shaping the radiation beam precisely to the profile of a tumor in the "beam's eye view" can increase the delivered dose without increasing toxic effects, though such shaping might not change the therapeutic index. Similarly, chemotherapy or radiotherapy with infused or injected agents can be made more efficacious by attaching the agent to an oncophilic substance, as in peptide receptor radionuclide therapy for neuroendocrine tumors and in chemoembolization or radioactive microspheres therapy for liver tumors and metastases. This concentrates the agent in the targeted tissues and lowers its concentration in others, increasing efficacy and lowering toxicity.

Safety ratio

Sometimes the term safety ratio is used, particularly when referring to psychoactive drugs used for non-therapeutic purposes, e.g. recreational use.[10] In such cases, the effective dose is the amount and frequency that produces the desired effect, which can vary, and can be greater or less than the therapeutically effective dose.

The Certain Safety Factor, also referred to as the Margin of Safety (MOS), is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population (LD1/ED99).[17] This is a better safety index than the LD50 for materials that have both desirable and undesirable effects, because it factors in the ends of the spectrum where doses may be necessary to produce a response in one person but can, at the same dose, be lethal in another.

Synergistic effect

A therapeutic index does not consider drug interactions or synergistic effects. For example, the risk associated with benzodiazepines increases significantly when taken with alcohol, opiates, or stimulants when compared with being taken alone.[medical citation needed] Therapeutic index also does not take into account the ease or difficulty of reaching a toxic or lethal dose. This is more of a consideration for recreational drug users, as the purity can be highly variable.

Therapeutic window

The therapeutic window (or pharmaceutical window) of a drug is the range of drug dosages which can treat disease effectively without having toxic effects.[18] Medication with a small therapeutic window must be administered with care and control, frequently measuring blood concentration of the drug, to avoid harm. Medications with narrow therapeutic windows include theophylline, digoxin, lithium, and warfarin.

Optimal biological dose

Optimal biological dose (OBD) is the quantity of a drug that will most effectively produce the desired effect while remaining in the range of acceptable toxicity.

Maximum tolerated dose

The maximum tolerated dose (MTD) refers to the highest dose of a radiological or pharmacological treatment that will produce the desired effect without unacceptable toxicity.[19][20] The purpose of administering MTD is to determine whether long-term exposure to a chemical might lead to unacceptable adverse health effects in a population, when the level of exposure is not sufficient to cause premature mortality due to short-term toxic effects. The maximum dose is used, rather than a lower dose, to reduce the number of test subjects (and, among other things, the cost of testing), to detect an effect that might occur only rarely. This type of analysis is also used in establishing chemical residue tolerances in foods. Maximum tolerated dose studies are also done in clinical trials.

MTD is an essential aspect of a drug's profile. All modern healthcare systems dictate a maximum safe dose for each drug, and generally have numerous safeguards (e.g. insurance quantity limits and government-enforced maximum quantity/time-frame limits) to prevent the prescription and dispensing of quantities exceeding the highest dosage which has been demonstrated to be safe for members of the general patient population.

Patients are often unable to tolerate the theoretical MTD of a drug due to the occurrence of side-effects which are not innately a manifestation of toxicity (not considered to severely threaten a patient's health) but cause the patient sufficient distress and/or discomfort to result in non-compliance with treatment. Such examples include emotional "blunting" with antidepressants, pruritus with opiates, and blurred vision with anticholinergics.

See also

References

  1. ^ a b Trevor A, Katzung B, Masters S, Knuidering-Hall M (2013). "Chapter 2: Pharmacodynamics". Pharmacology Examination & Board Review (10th ed.). New York: McGraw-Hill Medical. p. 17. ISBN 978-0-07-178924-0. The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, determined from quantal dose–response curves.
  2. ^ a b Muller PY, Milton MN (October 2012). "The determination and interpretation of the therapeutic index in drug development". Nature Reviews. Drug Discovery. 11 (10): 751–61. doi:10.1038/nrd3801. PMID 22935759. S2CID 29777090.
  3. ^ Ratanajamit C, Soorapan S, Doang-ngern T, Waenwaisart W, Suwanchavalit L, Suwansiri S, Jantasaro S, Yanate I (November 2006). "Appropriateness of therapeutic drug monitoring for lithium". Journal of the Medical Association of Thailand = Chotmaihet Thangphaet. 89 (11): 1954–60. PMID 17205880.
  4. ^ Filloon, T. G. (May 1995). "Estimating the minimum therapeutically effective dose of a compound via regression modelling and percentile estimation". Statistics in Medicine. 14 (9–10): 925–932, discussion 933. doi:10.1002/sim.4780140911. ISSN 0277-6715. PMID 7569511.
  5. ^ Street, Farnam (2014-02-13). "The Minimum Effective Dose: Why Less is More". Farnam Street. Retrieved 2023-05-23.
  6. ^ Goodman, Louis S. (2011). Brunton, Laurence L.; Chabner, Bruce; Knollmann, Björn C. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12 ed.). New York: McGraw-Hill. ISBN 9780071624428.
  7. ^ "IUPAC - median lethal dose (M03810)". goldbook.iupac.org. The International Union of Pure and Applied Chemistry (IUPAC). doi:10.1351/goldbook.M03810. Retrieved 2024-07-25.
  8. ^ "CCOHS: What is a LD₅₀ and LC₅₀?". www.ccohs.ca. Canadian Centre for Occupational Health and Safety. 2024-05-10. Retrieved 2024-07-25.
  9. ^ Stanley TH (January 2000). "Anesthesia for the 21st century". Proceedings. 13 (1): 7–10. doi:10.1080/08998280.2000.11927635. PMC 1312206. PMID 16389318.
  10. ^ a b Gable RS (June 2004). "Comparison of acute lethal toxicity of commonly abused psychoactive substances" (PDF). Addiction. 99 (6): 686–96. doi:10.1111/j.1360-0443.2004.00744.x. PMID 15139867.
  11. ^ Bertolini A, Ferrari A, et al. (2006). "Paracetamol New Vistas of an Old Drug". CNS Drug Reviews. 12 (3–4): 250–275. doi:10.1111/j.1527-3458.2006.00250.x. PMC 6506194. PMID 17227290. Vol. 12, No. 3–4, pp. 250–275
  12. ^ Becker DE (Spring 2007). "Drug therapy in dental practice: general principles. Part 2 – pharmacodynamic considerations". Anesthesia Progress. 54 (1): 19–23, quiz 24–25. doi:10.2344/0003-3006(2007)54[19:DTIDPG]2.0.CO;2. PMC 1821133. PMID 17352523.
  13. ^ a b Thoms J, Bristow RG (October 2010). "DNA repair targeting and radiotherapy: a focus on the therapeutic ratio". Seminars in Radiation Oncology. 20 (4): 217–22. doi:10.1016/j.semradonc.2010.06.003. PMID 20832013.
  14. ^ Yokoya A, Shikazono N, Fujii K, Urushibara A, Akamatsu K, Watanabe R (2008-10-01). "DNA damage induced by the direct effect of radiation". Radiation Physics and Chemistry. The International Symposium on Charged Particle and Photon Interaction with Matter – ASR 2007. 77 (10–12): 1280–85. Bibcode:2008RaPC...77.1280Y. doi:10.1016/j.radphyschem.2008.05.021.
  15. ^ "Ataxia Telangiectasia". National Cancer Institute. Retrieved 2016-04-11.
  16. ^ Soriani RR, Satomi LC, Pinto Td (2005-07-01). "Effects of ionizing radiation in ginkgo and guarana". Radiation Physics and Chemistry. 73 (4): 239–42. doi:10.1016/j.radphyschem.2005.01.003.
  17. ^ "FAQs: Dr. Damaj". Retrieved 4 October 2015.
  18. ^ Rang H, et al. (2015). "Pharmacokinetics". Rang & Dale's Pharmacology (8th ed.). Churchill Livingstone. p. 125. ISBN 978-0-7020-5362-7.
  19. ^ "maximum tolerated dose". Dictionary of Cancer Terms. National Cancer Institute. Retrieved 26 July 2010.
  20. ^ Public Domain This article incorporates public domain material from Jasper Womach. Report for Congress: Agriculture: A Glossary of Terms, Programs, and Laws, 2005 Edition (PDF). Congressional Research Service.

Read other articles:

У статті наведено список втрат українських військовослужбовців у російсько-українській війні за лютий 2015 року. Докладніше: Втрати силових структур внаслідок російського вторгнення в Україну Зміст 1 Список загиблих за лютий 2015 року 1.1 Лютий 2 Невстановлена дата смерті 3

 

本條目存在以下問題,請協助改善本條目或在討論頁針對議題發表看法。 此條目或其章節极大或完全地依赖于某个单一的来源。 (2022年12月25日)请协助補充多方面可靠来源以改善这篇条目。致使用者:请搜索一下条目的标题(来源搜索:长光卫星技术股份有限公司 — 网页、新闻、书籍、学术、图像),以检查网络上是否存在该主题的更多可靠来源(判定指引) 此條目過於

 

Road in Taiwan Provincial Highway 10台10線Route informationMaintained by Directorate General of HighwaysLength21.13 km (13.13 mi)Major junctionsWest end Prov 17 in Qingshui, TaichungMajor intersections Prov 61 in Qingshui Nat 3 in Shalu Nat 1 in Shengang East end Prov 13 in Fengyuan, Taichung LocationCountryTaiwan Highway system Highway system in Taiwan ← Prov 9→ Prov 11 Provincial Highway 10 (PH 10, Chinese: 台10線)is a short east–west highway that...

У Вікіпедії є статті про інші географічні об’єкти з назвою Солтілло. Місто Солтіллоангл. Saltillo Координати 34°22′23″ пн. ш. 88°41′21″ зх. д. / 34.37310000002777599° пн. ш. 88.68940000002778845° зх. д. / 34.37310000002777599; -88.68940000002778845Координати: 34°22′23″ пн. ш. 88°41′21″ ...

 

يفتقر محتوى هذه المقالة إلى الاستشهاد بمصادر. فضلاً، ساهم في تطوير هذه المقالة من خلال إضافة مصادر موثوق بها. أي معلومات غير موثقة يمكن التشكيك بها وإزالتها. (ديسمبر 2018) السعودية في الألعاب الأولمبية علم السعودية رمز ل.أ.د.  KSA ل.أ.و. اللجنة الأولمبية العربية السعودي

 

إسبانيا للطيرانSpanair   إياتاJK إيكاوJKK رمز النداءSPANAIR تاريخ الإنشاء 1986 الجنسية إسبانيا  التوقف عن النشاط 27 يناير 2012 المطارات الرئيسية مطار مدريد باراخاس الدوليمطار برشلونة الدولي برنامج المسافر الدائم إسبانيا للطيران بلاس التحالفات تحالف ستار حجم الأسطول 45 الوجهات 25 ال

ثورة عيد الفصح جزء من حرب الاستقلال الأيرلندية  إعلان الجمهورية الإيرلندية، في أسبوع عيد فصح عام 1916 معلومات عامة التاريخ 24–29 أبريل 1916 البلد المملكة المتحدة لبريطانيا العظمى وأيرلندا  الموقع دبلن، إيرلندا النتيجة استسلام غير مشروط لقوات المتمردين، وتنفيذ حكم الإ...

 

Artikel ini sebatang kara, artinya tidak ada artikel lain yang memiliki pranala balik ke halaman ini.Bantulah menambah pranala ke artikel ini dari artikel yang berhubungan atau coba peralatan pencari pranala.Tag ini diberikan pada Oktober 2022. Artikel atau sebagian dari artikel ini mungkin diterjemahkan dari Collapse of the Atlantic northwest cod fishery di en.wikipedia.org. Isinya masih belum akurat, karena bagian yang diterjemahkan masih perlu diperhalus dan disempurnakan. Jika Anda mengua...

 

この記事は検証可能な参考文献や出典が全く示されていないか、不十分です。出典を追加して記事の信頼性向上にご協力ください。(このテンプレートの使い方)出典検索?: ヴォルフスブルク – ニュース · 書籍 · スカラー · CiNii · J-STAGE · NDL · dlib.jp · ジャパンサーチ · TWL(2014年8月) この記事の項目名には以下のような表...

2014 single by Alexander RybakInto a FantasySingle by Alexander Rybakfrom the album How to Train Your Dragon 2 soundtrack Released12 June 2014Recorded2013GenrePopLength3:34LabelAlexander Rybak ASSongwriter(s)Alexander RybakProducer(s)Knut Bjørnar Asphol, Alexander RybakAlexander Rybak singles chronology Leave Me Alone (2012) Into a Fantasy (2014) Typisk norsk (2015) Into a Fantasy is a song by Norwegian singer-songwriter Alexander Rybak. It was released on 12 June 2014 as a digital download ...

 

قائمة البلديات في بيسكاي  - بلدية -  تقسيم إداري البلد إسبانيا  المقاطعة بيسكاي تعديل مصدري - تعديل   يفتقر محتوى هذه المقالة إلى الاستشهاد بمصادر. فضلاً، ساهم في تطوير هذه المقالة من خلال إضافة مصادر موثوق بها. أي معلومات غير موثقة يمكن التشكيك بها وإزالتها. (...

 

This article is about the southern part of the Australian continent plus Tasmania. For the Australian state, see South Australia. This article possibly contains original research. Please improve it by verifying the claims made and adding inline citations. Statements consisting only of original research should be removed. (July 2018) (Learn how and when to remove this template message) This article needs additional citations for verification. Please help improve this article by adding citation...

В статье не хватает ссылок на источники (см. рекомендации по поиску). Информация должна быть проверяема, иначе она может быть удалена. Вы можете отредактировать статью, добавив ссылки на авторитетные источники в виде сносок. (13 июня 2022) Кнопка Ctrl Клавиатура с возможностью ...

 

Liverpool MercuryFounder(s)Egerton SmithFounded5 July 1811; 212 years ago (1811-07-05)Ceased publication1904CountryUnited KingdomMedia of the United KingdomList of newspapers The Liverpool Mercury was an English newspaper that originated in Liverpool, England. As well as focusing on local news, the paper also reported on both national and international news allowing it to circulate in Lancashire, Wales, Isle of Man and London. History Founded by Egerton Smith in 1811 the new...

 

Serbian footballer (born 1988) Slobodan Lučić Personal informationDate of birth (1988-02-23) 23 February 1988 (age 35)Place of birth Belgrade, SFR YugoslaviaHeight 1.85 m (6 ft 1 in)Position(s) DefenderTeam informationCurrent team Budućnost DobanovciNumber 7Youth career Budućnost DobanovciSenior career*Years Team Apps (Gls)2004– Budućnost Dobanovci 400+ (20+) *Club domestic league appearances and goals Slobodan Lučić (Serbian Cyrillic: Слободан Лучић;...

Ambassador of the United States to BotswanaSeal of the United States Department of StateIncumbentHoward Van Vrankensince May 24, 2023NominatorThe President of the United StatesAppointerThe Presidentwith Senate advice and consentInaugural holderCharles H. Pletcheras Chargé d'AffairesFormationSeptember 1966WebsiteU.S. Embassy - Gaborone From 1885 until 1966 the area of Southern Africa that is now Botswana was part of the Bechuanaland Protectorate of Great Britain. In June 1964, Britain ac...

 

Nyai Ahmad DahlanPortrait of Nyai Ahmad DahlanBornSiti Walidah1872Kauman, Yogyakarta, Dutch East IndiesDied31 May 1946 (aged 73–74)Kauman, Yogyakarta, IndonesiaResting placeGreat Mosque of Kauman, YogyakartaNationalityIndonesianOccupationSocial workerYears active1914–1946AwardsNational Hero of Indonesia Siti Walidah (1872 – 31 May 1946), better known as Nyai Ahmad Dahlan, was a female emancipation figure, wife of Muhammadiyah founder Ahmad Dahlan, and National Hero of Indo...

 

American baseball player Baseball player Steve BlassBlass in 2009PitcherBorn: (1942-04-18) April 18, 1942 (age 81)Canaan, Connecticut, U.S.Batted: RightThrew: RightMLB debutMay 10, 1964, for the Pittsburgh PiratesLast MLB appearanceApril 17, 1974, for the Pittsburgh PiratesMLB statisticsWin–loss record103–76Earned run average3.63Strikeouts896 Teams Pittsburgh Pirates (1964, 1966–1974) Career highlights and awards All-Star (1972) World Series champion (...

Campaign meant to raise awareness of the risk of heart disease in women Former First Ladies Nancy Reagan (left) and Laura Bush (right) dedicate The Heart Truth First Ladies Red Dress Collection at the Ronald Reagan Presidential Library in Simi Valley, California on February 28, 2007 The Heart Truth is a campaign meant to raise awareness of the risk of heart disease in women.[1] The campaign is sponsored in the United States by the National Heart, Lung, and Blood Institute, an organiza...

 

Quân đội Hoa Kỳ sử dụng nâng một khúc gỗ như một bài tập xây dựng đội ngũ. Xây dựng đội ngũ là một thuật ngữ tập thể cho các loại hoạt động khác nhau được sử dụng để tăng cường quan hệ xã hội và xác định vai trò trong các nhóm, thường liên quan đến các nhiệm vụ hợp tác. Nó khác với đào tạo nhóm, được thiết kế bởi sự kết hợp giữa các nhà quản lý doanh nghiệp, h...

 

Strategi Solo vs Squad di Free Fire: Cara Menang Mudah!