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Israel and the Palestinian Territories tours & travel
The enduring religious centre of the Western world, Israel and the Palestinian Territories are alive with history.
A pilgrimage to Israel and the Palestinian Territories opens up a world of ancient tales, faith-driven worshippers, intricate cuisines and contemporary attitudes. From the glistening northern coastlines to the depths of the Dead Sea, simple mountain village communities to cosmopolitan cities full of bars and boutiques; a vacation here is a varied and complex adventure. It will challenge your perceptions on faith and spirituality, bring you face to face with the significance of centuries-old traditions, serve up some mouth-watering food, and, most importantly, will surprise you at every turn.
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Holy Land Highlights
Tel Aviv to Jerusalem
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Israel and the Palestinian Territories travel highlights
This is the focal point of Western religions, as congregations gather in the Old City's Christian, Jewish, Muslim and Armenian quarters. Outside the walls, a diverse city is alive with streets and marketplaces, so take it all in from the Mount of Olives.
Holy Land Highlights, 8 days
Five Days in Israel & the Palestinian Territories, 5 days
Ride the cable car up to explore the ancient palace and fort of hilltop Masada, then head down into Ein Gedi for a super salty float and mud bath in the Dead Sea – the lowest point on Earth.
Discover Israel & the Palestinian Territories, 8 days
A blend of traditional architecture and modern living creates an infectious atmosphere in the beachside and party-centric Tel Aviv – the contemporary centre of the country.
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Get a bird's eye view of this port city and the Mediterranean coast with a visit to the manicured and cascading Baha'i Gardens, located right in its heart.
Israel & the Palestinian Territories Real Food Adventure, 9 days
Buq'ata
Indulge in a home-cooked meal with a local family while visiting a Druze village in the north-eastern outcrops of the country – you'll get to know all the secrets of baking bread and preparing a largely vegetarian feast.
Head deep into the first International Dark Sky Park in the Middle East, the Ramon Crater, on a jeep safari and set up camp for a night of unforgettable stargazing, unimpeded by light pollution.
Transport in Israel and the Palestinian Territories
Intrepid believes half the fun of experiencing a new country is getting there, and getting around once there! Where possible, Intrepid uses local transport options and traditional modes of transport – which usually have less of an environmental impact, support small local operators and are heaps more fun.
Depending what trip you're on while in Israel and the Palestinian Territories, you may find yourself travelling by:
There's no easier way to cross the dunes and head deep into the desert than in the back of a jeep. This is safari travel, Middle East style.
Israel and the Palestinian Territories holiday information
Capital city: Jerusalem (population approximately 875,000)
Population: Approximately 8.7 million
Languages: Hebrew, Arabic
Currency: ILS
Time zone: (GMT+02:00) Jerusalem
Electricity: Type C (European 2-pin) Type H (Israeli 3-pin)
Calling code: +972
Israel and the Palestinian Territories are a crossroads of cultures and ethnicities, so there are many annual events marking important dates in religious and cultural calendars. Jerusalem, also known as the Holy Land, is touted as the historical and religious centre of the Western world, with followers of Christianity, Judaism and Islam all holding the city sacred.
As you would expect from such a destination, there are daily displays of devotion and pilgrimage that happen on the streets and in public arenas, as well as a wide range of things to see. Take note though – it's important to know of any traditions or events that occur which might affect your travel plans.
Shabbat, or the Sabbath, is a weekly day of rest recognised by the religious and non-religious Jewish populations, as well as some others across the region. The resting period lasts from 20-30 minutes before sundown on Friday to an hour after sundown on Saturday night, and depending on which part of the country you are in, you will notice different levels of impact on public transport and businesses.
In Tel Aviv, for example, Friday night is one of the city's busiest nights, so you shouldn't be too affected. In Jerusalem, however, many restaurants close until Saturday night, and your hotel front desk may close for Friday evening and the next day as workers may be observing Shabbat. If you find yourself in Jerusalem and parts of Galilee during Shabbat, ensure that you have researched places to eat and things to see that will be open and available over this time. In other parts of the country, like the North Coast, Negev Desert, Dead Sea and Tel Aviv, your stay should be mainly unaffected; however, it's best to have a back-up plan just in case your preferences aren't open.
It is important to understand how Shabbat could affect your visit, as you may find yourself without many restaurant or cafe options, or having to walk or take an expensive taxi (if you can find one) to get around.
During the ninth and holiest month in the Islamic calendar (the Gregorian, or 'Western', calendar equivalent dates of which change each year) Ramadan is observed by Muslims across the world as a time of spiritual rejuvenation. For this month, Muslims fast from sunrise to sunset – refraining from eating and drinking during daylight hours. The period of Eid marks the end of fasting with three days of feasting and celebration. For the duration of Ramadan, expect almost all restaurants and some other establishments in Muslim areas to be closed during daylight hours, with the exception of hotels.
History and government
The roots of Israel extend back thousands of years, and many stories of origin stem from the Hebrew Bible and trace back to Abraham, who is considered both the father of Judaism (through his son Isaac) and Islam (through his son Ishmael). Descendants of Abraham are said to have been held captive in Egypt for centuries before settling in Canaan, located where some of Israel and the Palestinian Territories' contested regions are today. These sites, and especially Jerusalem, have been besieged and ruled by many empires over the centuries of their history – Babylonian, Persian, Greek Hellenistic, Roman, Byzantine and Ottoman, among others.
Fast-forward to the 20th century, when Great Britain supported an establishment of a permanent Jewish state in the region then recognised as Palestine. British Foreign Secretary Arthur Balfour stated intentions to set up a 'national home' in Palestine for Jewish populations under the Balfour Declaration. In late 1947, the United Nations approved a plan for the partition of Palestine. On 14 May 1948, Israel proclaimed its independence under the rule of the head of the Jewish Agency, David Ben-Gurion. For Palestinian Arabs, this meant a mass exodus from what was to become Israel.
Since then, as over many points during the region's history, there has been a series of conflicts regarding control in the territories. Currently, parts of Israel and the Palestinian Territories are still contested, and complex political relationships exist in the country to navigate administration over certain regions, whether the responsibility of Israel, Palestine, or a combination of both. Israel has peace agreements with Jordan and Egypt, but not some other Middle Eastern neighbours, so border crossing can be complicated.
These regions are full of delightful things to taste. Whether you're fine-dining in Tel Aviv or having a street-side snack at Machane Yehuda market in Jerusalem, there's no shortage of Middle Eastern cuisine to keep your mouth watering.
Found in food stands on street corners and in markets all around the country, falafel is touted as Israel's national dish and, despite competing stories of where they were invented, these snacks are now a staple in Israeli cuisine. Made from fava beans, chickpeas or a combination of both, enjoy them as either part of a Middle Eastern mezze, or stuffed into a pita with hummus, tahini, pickles and salad.
Shakshuka accurately translates as 'a mixture', describing a dish of eggs baked in a spiced tomato, chilli, pepper and garlic sauce and served in a traditional pan. Every street food vendor or shakshuka master believes they've got the best recipe, so it's a good idea to taste a broad sample in order to decide for yourself!
Can anything be more perfect? This silky chickpea dip is a pita's best friend, and can be lathered on nearly anything and everything, for breakfast, lunch and dinner. To take things up a notch, order a hummus masabacha (topped with chickpeas, paprika, lemon and tahini) or hummus kawarma (topped with lamb mince, onions and parsley).
The Greeks have got souvlaki, the Turkish have got doner, but in these parts, it's called shawarma. This type of local kebab is all about the traditional spices used and the ingredients that get stuffed inside – think hummus, salad, pickled turnips and tahini. An easy on-the-go lunch.
Sabich
Obviously, many Middle Eastern classic dishes are hard to trace back their origin; however, sabich is one that definitely finds its roots as Jewish Israeli. Brought here in the 1950s by Jewish immigrants from Iraq, this pita stuffed with fried eggplant, hard boiled eggs, salad, hummus and tahini is now one of the country's most popular street food dishes. Sabich is often topped off with a drizzle of amba – a spicy sweet mango chutney.
Lechem bread
If you haven't realised already, Israeli cuisine is big on bread. In particular, lechem bread plays not only an important role in the country's diet, but is also of religious significance in Jewish cultures – often breaking two loaves of this bread signifies the start of a meal during Shabbat.
A sweet dessert found all around the Middle East, knafeh is a cheese pastry soaked in sugar syrup, often flavoured with rosewater or orange blossom. Perfect for an after-dinner snack, or an afternoon pick-me-up.
This part of the world is also known for growing wine grapes. The biggest wine-growing region, the Sharon Plain near the Mount Carmel range, boasts perfect conditions – a temperate climate and sediment-rich soils on slopes that face the Mediterranean Sea. Visit Zichron Yaakov, a town in this region, on an Intrepid Real Food Adventure for a day of wine tasting.
Geography and environment
With beaches and chalk cliffs on the Mediterranean coastline, parched desert in the north, mountains (and more desert!) in the south and fertile valleys in the centre, Israel and the Palestinian Territories boast an astounding amount of diverse landscapes to travel through in a small area, meaning you can bounce from one geographic wonder to another with minimal travel time.
Sharing borders and cultures with Egypt, Jordan, Lebanon, Syria, the West Bank and Gaza Strip, the people here live in vastly different ways – from the modern, upwardly-mobile population of faced-paced Tel Aviv to the relative simplicity of village life in the mountains.
From the ultra-modern shopping malls of Tel Aviv to the laneway markets of Jerusalem's Old City, there's no shortage of shopping spots in Israel and the Palestinian Territories. In Tel Aviv and some parts of Jerusalem, expect to see some big global brands, as well as local favourites, such as Hamashbir and Castro.
During your time here, you'll have opportunities to walk around and shop at local markets. For purchases under roughly USD 8 (ISL 30), it's best to carry small denominations of currency, as stallholders or retailers likely won't accept credit cards as payment.
Outside of markets and Jerusalem's Old City, bartering is usually not accepted, and most stores have fixed prices for their products. If you do have any questions about shopping at markets or stores during your time in Israel and the Palestinian Territories, ask your group leader who'll be able to let you in on the dos and don'ts.
Many Jewish, Muslim and some Christian faith-based public holidays are celebrated with events and festivities throughout the year. See the 'What public holidays are celebrated in Israel and the Palestinian Territories?' in the FAQs below for a list of the major celebrations.
Observed in late April or early May, with the date changing to avoid clashing with observation of Shabbat, this celebration is both to commemorate Yom Hazikaron – the Israeli Fallen Soldiers and Victims of Terrorism Remembrance Day – and the day the State of Israel was established in 1948. During this time, celebrations include fireworks, concerts, family meetings and picnics, and displays of national symbols, including the Israeli flag.
Purim is a joyous holiday in the Jewish calendar and remembers the story of Esther who helped save Jews living in Persia from extermination. Costumes and masks are worn, baskets of goods are gifted to friends and family, and a festive meal is had with loved ones.
Tel Aviv Pride Week
Tel Aviv Pride is touted as one of the most lively and interesting Pride celebrations in the world – with colourful costumes, posters, slogans and food all week, culminating in the Pride Week Parade that attracts upwards of 200,000 attendees. Revellers come from around the world to celebrate the week-long festival in Tel Aviv.
Also known as the Feast of the Tabernacles, this Jewish festival spans over a week, usually held in September, and comes five days after Yom Kippur. It is one of many festivals throughout the year where Jewish people are commanded to visit pilgrimage sites.
Passover is a Jewish celebration over seven days to commemorate the flight of the Israelites from slavery in Egypt. The Hebrew term 'Pesach', meaning to pass over, is a biblical reference to Moses instructing Israelites to mark their doors with lamb's blood so that the spirit of the Lord would 'pass over' their houses and spare their first-born sons from the last of ten plagues visited upon the ancient Egyptians. Jewish families remember this period by gathering, eating unleavened bread, and performing ritual celebrations on the first (Passover Seder) and last (Mimouna) days.
On entering Israel and the Palestinian Territories, you may experience a more in-depth arrivals process than you are used to. Officials can be thorough and may seem unwelcoming, but the best approach is to stay calm and polite in response.
Expect to encounter heightened security and military presence at certain spots, especially international airports, border crossings and tourist sites. Checkpoints are set up around the country to inspect vehicles, and in a number of situations – such as entering bus or rail terminals, shopping centres or other public venues – your bags may be searched or x-rayed. Your group leader will be on hand to help your tour group through all stages of the process and act as translator if need be.
Intrepid takes the health and safety of its travellers seriously, and takes every measure to ensure that trips are safe, fun and enjoyable for everyone. We recommend that all travellers check with their government or national travel advisory organisation for the latest information before departure:
From Australia?
Go to smarttraveller.gov.au
From Canada?
Go to travel.gc.ca
From the UK?
Go to fco.gov.uk
From New Zealand?
Go to safetravel.govt.nz
From the USA?
Go to travel.state.gov
From South Africa?
Go to gov.za
From China?
Go to 12301.cn
The World Health Organization also provides useful health information. Go to who.int for more details.
For inspiring stories – and recipes – to prepare you for your Israel and the Palestinian Territories adventure, check out these books:
The Rock: A Tale of Seventh-Century Jerusalem – Kanan Makiya
A Wall of Light – Edeet Ravel
The Attack – Yasmina Khadra
The Hope – Herman Wouk
The Book of Saladin – Tariq Ali
A Tale of Love and Darkness – Amos Oz
I Saw Ramallah – Mourid Barghouti
Jerusalem – Yotam Ottolenghi
Israel and the Palestinian Territories travel FAQs
When is the best time to travel to Israel and the Palestinian Territories?
Israel and the Palestinian territories offer diverse experiences throughout the year, so there's really no one 'best' time to visit. The shoulder seasons of April–May and September–October are ideal in terms of weather – pleasantly mild temperatures and little to no rainfall. However, many people choose to travel to the area over Christmas to experience winter festivities in Bethlehem, or in summer when coastal hubs like Tel Aviv and Haifa come alive at beach resorts and with outdoor nightlife. There's a range of things to do in any weather, from skiing in the highlands to enjoying the sun near the Red Sea, so no matter what time you choose to go, it's a great place to take a vacation year-round.
Above all, it's important to note that travel will be affected during religious holidays, with the majority of shops, businesses and public transport shutting down for major public holidays and events. Be sure to consider how Jewish or other religious holidays, like Ramadan, may affect your stay.
Do I need a visa to travel to Israel and the Palestinian Territories?
Israel and the Palestinian Territories grant on-arrival visas to tourists of most nationalities. If you have evidence in your passport of visits to certain Islamic countries, Israeli border officials will scrutinise you regarding the purpose of your visit to Israel. The delay can be difficult and lengthy; however, patience and a friendly demeanour are advised when dealing with officials. Instead of an entry stamp, you will receive a loose entry card on arrival. Keep this in your passport until you leave, as this is evidence of your legal entry into Israel and the Palestinian Territories.
It is important to be aware that many Arab and Islamic countries deny entry to any person that has evidence of a visit to Israel. Syria, Iran, Libya and several other countries are included in this list. If you wish to travel to other countries in the region after Israel, please note that you may be refused entry if your passport, luggage or possessions indicate you have been to Israel.
Visas are the responsibility of the individual traveller. Entry requirements can change at any time, so it's important that you check for the latest information. Please visit the relevant consular website of the country or countries you're visiting for detailed and up-to-date visa information specific to your nationality. Check the Essential Trip Information section of your tour itinerary for more information.
Is tipping customary in Israel and the Palestinian Territories?
Tipping 10-15% for good service is standard practice in restaurants, bars and cafes, as well as on tours. Taxi drivers and other service workers like hotel staff generally don't expect tips. Tipping is not compulsory in Israel and the Palestinian Territories, but if you are satisfied with the services provided, a tip is appropriate.
What is the internet access like in Israel and the Palestinian Territories?
Internet access is widespread in Israel and the Palestinian Territories, so accessing the internet via wi-fi hot spots is easy in Israel's cities. Rural areas will have less internet connectivity, so beware of this when travelling through remote regions of the country.
Most accommodation and some eateries offer wi-fi networks, which are usually free to use with an access code. If you wish to stay connected for the majority of your trip, it may be wise to purchase a prepaid SIM card with a data package or a wi-fi hotspot.
Can I use my mobile/cellphone while in Israel and the Palestinian Territories?
Mobile phone coverage is excellent in Israel and the Palestinian Territories' major cities and built-up areas. Expect limited to no phone coverage in more isolated areas like the Negev Desert.
Global roaming can also be activated when travelling through Israel and the Palestinian Territories; however, be sure to check with your service provider to find out about any fees you may incur when using this option, as sometimes this can be expensive.
What are the toilets like in Israel and the Palestinian Territories?
Most toilets in Israel and the Palestinian Territories are of the modern, flushable variety, but if you're travelling in remote areas, you may still find squat toilets in use.
What will it cost for a…?
Israel and the Palestinian Territories' unit of currency is the shekel. Prices here are approximate and shown in US dollars for ease of comparison.
Can of soft drink = USD 1.70–2.30
One hour in an internet cafe = USD 4.50
Takeaway snack or light lunch = USD 7–8.50
Simple dinner at a cafe or restaurant = USD 17–29
Can I drink the water in Israel and the Palestinian Territories?
Tap water is considered safe to drink in Israel and the Palestinian Territories, unless marked otherwise. For environmental reasons, try to avoid buying bottled water. Fill a reusable water bottle or canteen with filtered water instead.
Are credit cards accepted widely in Israel and the Palestinian Territories?
The vast majority of large hotels, restaurants and shops will accept credit cards. For smaller purchases, such as bus and taxi fares, markets and paying for something less than roughly USD 8 (ISL 30), it is advised to have cash on you to cover these costs.
What is ATM access like in Israel and the Palestinian Territories?
ATMs are easily found in Israel and the Palestinian Territories' cities and major towns. They're less common in rural areas, so prepare accordingly before travelling out of urban centres. In general, ATMs in Israel offer a more competitive exchange rate for local currency than buying Israeli shekels outside of the country.
What is the weather like in Israel and the Palestinian Territories?
Israel and the Palestinian Territories generally share a Mediterranean climate, with the summer months providing loads of sunshine and scorching temperatures that can reach upwards of 40°C. June to August usually sees the highest temperatures, with milder weather prevailing during autumn (September–October) and spring (April–May). Winter (around November–March) means cooler temperatures and light rain. Snowfall can sometimes occur in the highlands and even in Jerusalem
Do I need to purchase travel insurance before travelling in Israel and the Palestinian Territories?
Absolutely. All passengers travelling with Intrepid are required to purchase travel insurance before the start of their tour. Your travel insurance details will be recorded by your leader on the first day of the trip. Due to the varying nature, availability and cost of health care around the world, travel insurance is very much an essential and necessary part of every journey.
For more information on insurance, please go to Travel Insurance.
What public holidays are celebrated in Israel and the Palestinian Territories?
Passover (8 days, usually in April)
Easter (March or April)
Israel Independence Day/Yom Haatzmaut (April)
Palestine Independence Day (15 November)
Ramadan (ninth month of the Islamic calendar, usually May)
Eid Al Fitr (end of Ramadan, May or June)
Shavuot (Pentecost, sixth day of Shivan – May or June)
Rosh Hashanah (Jewish New Year – usually September)
Islamic New Year (usually August, September or October)
Yom Kippur (Day of Atonement – September or October)
Sukkot (Tabernacles – usually October)
Simchat Torah (September to October)
Hanukkah (December)
Christmas Day (25 September)
For a current list of public holidays in Israel and the Palestinian Territories, including the movable dates noted above, go to worldtravelguide.net Israel and Palestine.
Are Israel and the Palestinian Territories safe for LGBTQIA+ travellers?
Compared to many of its Middle East neighbours, Israel is quite progressive when it comes to a stance on LGBTQIA+ rights. Homosexuality is legal and some protections are in place regarding gender identity discrimination. Although same-sex marriages are not performed here, they recognise same-sex marriages performed elsewhere. Since 2015, the Israeli Health Ministry has allowed transgender people to change their registered gender legally without sex reassignment surgery.
Tel Aviv has a thriving gay scene, with many of the bars and nightlife geared towards this. Tel Aviv also hosts a Gay Pride Parade each year in the second week of June, which attracts over 250,000 attendees from across the world.
In the Occupied Palestinian Territories the law does not provide any explicit protections for LGBTQIA+ persons, but there are no formal laws against same-sex sexual activities. Officially, same-sex relations are not illegal but social and cultural attitudes towards homosexuality can be conservative and laws against 'indecency' are sometimes used, on an irregular and unpredictable basis, to criminalise same-sex acts.
There are still many conservative regions around Israel and the Palestinian Territories, so be aware of the situation you find yourself in when you are travelling. In these areas, public displays of affection are not encouraged.
For more detailed and up-to-date advice, we recommend visiting Equaldex – Israel and Palestine – or ILGA before you travel.
If you are travelling solo on an Intrepid group tour, you will share accommodation with a passenger of the same gender as per your passport information. If you don't identify with the gender assigned on your passport, please let us know at time of booking and we'll arrange the rooming configuration accordingly. A single supplement is available on some tours for travellers who do not wish to share a room.
Are Israel and the Palestinian Territories accessible for travellers with disabilities?
Intrepid is committed to making travel widely accessible, regardless of ability or disability. That's why we do our best to help as many people see the world as possible, regardless of any physical or mental limitations they might have. We're always happy to talk to travellers with disabilities and see if we can help guide them towards the most suitable itinerary for their needs and, where possible, make reasonable adjustments to our itineraries.
Visitors to Israel and the Palestinian Territories with mobility issues will find most areas accessible and easy to get around, with modern infrastructure, despite the old architecture and ancient sites.
Many of Tel Aviv's beaches can be accessed by ramps, and some hotel beaches have beach wheelchairs available for use. In Jerusalem, the Old City has an accessible trail for those requiring a wheelchair, and many of the sites are wheelchair-friendly.
If you do live with a visual, hearing or other impairment, let your booking agent or group leader know early on so they're aware and suitable arrangements can be made. As a general rule, knowing some common words in the local language, carrying a written itinerary with you and taking to the streets in a group, rather than solo, can help make your travel experience the best it can be.
Learn more about Accessible Travel with Intrepid
Intrepid is committed to travelling in a way that is respectful of local people, their culture, local economies and the environment. It's important to remember that what may be acceptable behaviour, dress and language in your own country may not be appropriate in another. Please keep this in mind while travelling.
In Israel and the Palestinian Territories, we stay in locally run accommodation including guesthouses, smaller-scale hotels and homestays in an effort to support the local economies. We also visit locally run restaurants and markets where travellers will have opportunities to support community businesses and purchase handicrafts created by local artisans. Our Responsible Travel Policy outlines our commitment to being the best travel company for the world.


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Het voormalig Entrepotgebouw 'De Vijf Werelddelen' is gelegen aan het Handelsplein in Rotterdam.

Het complex was oorspronkelijk bestemd voor de belastingvrije opslag van transitogoederen. Het werd tussen 1875-1879 gebouwd in utilitaire eclectische bouwstijl op initiatief van Lodewijk Pincoffs en H.A. Then-Bergh, de directeuren van de in 1872 opgerichte Rotterdamsche Handelsvereeniging (R.H.V.).

In 1997 heeft er een grote verbouwing plaatsgevonden en wordt het complex gebruikt voor appartementen, winkels en restaurants.

Rijksmonument in Rotterdam

redpajama_set_name: RedPajamaWikipedia


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Read 020405s004lbl.pdf text version
NDA 20405/S-004 Page 3
PRESCRIBING INFORMATION Lanoxin (digoxin) Tablets, USP 125 mcg (0.125 mg) Scored I.D. Imprint Y3B (yellow) 250 mcg (0.25 mg) Scored I.D. Imprint X3A (white)
DESCRIPTION Lanoxin (digoxin) is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves of Digitalis lanata. The term "digitalis" is used to designate the whole group of glycosides. The glycosides are composed of 2 portions: a sugar and a cardenolide (hence "glycosides"). Digoxin is described chemically as (3,5,12)-3-[(O-2,6-dideoxy--D-ribo-hexopyranosyl (14)-O-2,6-dideoxy--D-ribo-hexopyranosyl-(14)-2,6-dideoxy--D-ribo hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. Its molecular formula is C41H64O14, its molecular weight is 780.95, and its structural formula is:
Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine. Lanoxin is supplied as 125-mcg (0.125-mg) or 250-mcg (0.25-mg) tablets for oral administration. Each tablet contains the labeled amount of digoxin USP and the following inactive ingredients: corn and potato starches, lactose, and magnesium stearate. In addition, the dyes used in the 125-mcg (0.125-mg) tablets are D&C Yellow No. 10 and FD&C Yellow No. 6.
CLINICAL PHARMACOLOGY Mechanism of Action: Digoxin inhibits sodium-potassium ATPase, an enzyme that regulates the quantity of sodium and potassium inside cells. Inhibition of the enzyme leads to an increase
in the intracellular concentration of sodium and thus (by stimulation of sodium-calcium exchange) an increase in the intracellular concentration of calcium. The beneficial effects of digoxin result from direct actions on cardiac muscle, as well as indirect actions on the cardiovascular system mediated by effects on the autonomic nervous system. The autonomic effects include: (1) a vagomimetic action, which is responsible for the effects of digoxin on the sinoatrial and atrioventricular (AV) nodes; and (2) baroreceptor sensitization, which results in increased afferent inhibitory activity and reduced activity of the sympathetic nervous system and renin-angiotensin system for any given increment in mean arterial pressure. The pharmacologic consequences of these direct and indirect effects are: (1) an increase in the force and velocity of myocardial systolic contraction (positive inotropic action); (2) a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect); and (3) slowing of the heart rate and decreased conduction velocity through the AV node (vagomimetic effect). The effects of digoxin in heart failure are mediated by its positive inotropic and neurohormonal deactivating effects, whereas the effects of the drug in atrial arrhythmias are related to its vagomimetic actions. In high doses, digoxin increases sympathetic outflow from the central nervous system (CNS). This increase in sympathetic activity may be an important factor in digitalis toxicity. Pharmacokinetics: Absorption: Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hours. Absorption of digoxin from Lanoxin Tablets has been demonstrated to be 60% to 80% complete compared to an identical intravenous dose of digoxin (absolute bioavailability). When Lanoxin Tablets are taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Comparisons of the systemic availability and equivalent doses for oral preparations of Lanoxin are shown in Table 1. Table 1. Comparisons of the Systemic Availability and Equivalent Doses for Oral Preparations of Lanoxin Absolute Equivalent Doses (mcg)a Product Bioavailability Among Dosage Forms Lanoxin Tablets 60 - 80% 62.5 125 250 500 Lanoxin Injection/IV 100% 50 100 200 400 a For example, 125-mcg Lanoxin Tablets equivalent to 100-mcg Lanoxin Injection/IV. In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggest that 1 in 10 patients treated with digoxin tablets will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of digoxin in such patients. Although inactivation of these bacteria by antibiotics is rapid, the serum digoxin concentration will rise at a rate consistent with the elimination half-life of digoxin. The magnitude of rise in serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as 2-fold in some cases. Distribution: Following drug administration, a 6- to 8-hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak height and slope of the early
portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects (see DOSAGE AND ADMINISTRATION: Serum Digoxin Concentrations). Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight. Metabolism: Only a small percentage (16%) of a dose of digoxin is metabolized. The end metabolites, which include 3 ß-digoxigenin, 3-keto-digoxigenin, and their glucuronide and sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system. Excretion: Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to glomerular filtration rate and is largely independent of urine flow. In healthy volunteers with normal renal function, digoxin has a halflife of 1.5 to 2.0 days. The half-life in anuric patients is prolonged to 3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to tissue and does not circulate in the blood. Special Populations: Race differences in digoxin pharmacokinetics have not been formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected. The clearance of digoxin can be primarily correlated with renal function as indicated by creatinine clearance. The Cockcroft and Gault formula for estimation of creatinine clearance includes age, body weight, and gender. Table 5 that provides the usual daily maintenance dose requirements of Lanoxin Tablets based on creatinine clearance (per 70 kg) is presented in the DOSAGE AND ADMINISTRATION section. Plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects.
Pharmacodynamic and Clinical Effects: The times to onset of pharmacologic effect and to peak effect of preparations of Lanoxin are shown in Table 2. Table 2. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of Lanoxin Product Time to Onset of Effecta Time to Peak Effecta Lanoxin Tablets 0.5 - 2 hours 2 - 6 hours b Lanoxin Injection/IV 1 - 4 hours 5 - 30 minutes a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion. Hemodynamic Effects: Digoxin produces hemodynamic improvement in patients with heart failure. Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions. Chronic Heart Failure: Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) patients with NYHA class II or III heart failure previously treated with digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with Lanoxin. Both trials demonstrated better preservation of exercise capacity in patients randomized to Lanoxin. Continued treatment with Lanoxin reduced the risk of developing worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy. The larger study also showed treatment-related benefits in NYHA class and patients' global assessment. In the smaller trial, these trended in favor of a treatment benefit. The Digitalis Investigation Group (DIG) main trial was a multicenter, randomized, double-blind, placebo-controlled mortality study of 6,801 patients with heart failure and left ventricular ejection fraction 0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving concomitant ACE inhibitor (94%) and diuretic (82%). Patients were randomized to placebo or Lanoxin, the dose of which was adjusted for the patient's age, sex, lean body weight, and serum creatinine (see DOSAGE AND ADMINISTRATION), and followed for up to 58 months (median 37 months). The median daily dose prescribed was 0.25 mg. Overall all-cause mortality was 35% with no difference between groups (95% confidence limits for relative risk of 0.91 to 1.07). Lanoxin was associated with a 25% reduction in the number of hospitalizations for heart failure, a 28% reduction in the risk of a patient having at least 1 hospitalization for heart failure, and a 6.5% reduction in total hospitalizations (for any cause). Use of Lanoxin was associated with a trend to increase time to all-cause death or hospitalization. The trend was evident in subgroups of patients with mild heart failure as well as more severe disease, as shown in Table 3. Although the effect on all-cause death or hospitalization was not statistically significant, much of the apparent benefit derived from effects on mortality and hospitalization attributed to heart failure.
Table 3. Subgroup Analyses of Mortality and Hospitalization During the First 2 Years Following Randomization Risk of All-Cause Mortality or Risk of HF-Related Mortality or a a All-Cause Hospitalization HF-Related Hospitalization n Placebo Lanoxin Relative riskb Placebo Lanoxin Relative riskb All patients 0.94 0.69 6,801 604 593 (0.88-1.00) 294 217 (0.63-0.76) (EF 0.45) 0.96 0.70 NYHA I/II 4,571 549 541 (0.89-1.04) 242 178 (0.62-0.80) 0.99 0.74 EF 0.25-0.45 4,543 568 571 (0.91-1.07) 244 190 (0.66-0.84) 0.98 0.71 4,455 561 563 (0.91-1.06) 239 180 (0.63-0.81) CTR 0.55 0.88 0.65 NYHA III / IV 2,224 719 696 (0.80-0.97) 402 295 (0.57-0.75) 0.84 0.61 EF <0.25 2,258 677 637 (0.76-0.93) 394 270 (0.53-0.71) 0.85 0.65 CTR >0.55 2,346 687 650 (0.77-0.94) 398 287 (0.57-0.75) 1.04 0.72 c 987 571 585 (0.88-1.23) 179 136 (0.53-0.99) EF >0.45 a Number of patients with an event during the first 2 years per 1,000 randomized patients. b Relative risk (95% confidence interval). c DIG Ancillary Study. In situations where there is no statistically significant benefit of treatment evident from a trial's primary endpoint, results pertaining to a secondary endpoint should be interpreted cautiously. Chronic Atrial Fibrillation: In patients with chronic atrial fibrillation, digoxin slows rapid ventricular response rate in a linear dose-response fashion from 0.25 to 0.75 mg/day. Digoxin should not be used for the treatment of multifocal atrial tachycardia.
INDICATIONS AND USAGE Heart Failure: Lanoxin is indicated for the treatment of mild to moderate heart failure. Lanoxin increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by exercise capacity and heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, Lanoxin should be used with a diuretic and an angiotensin converting enzyme inhibitor, but an optimal order for starting these 3 drugs cannot be specified. Atrial Fibrillation: Lanoxin is indicated for the control of ventricular response rate in patients with chronic atrial fibrillation.
CONTRAINDICATIONS Digitalis glycosides are contraindicated in patients with ventricular fibrillation or in patients with a known hypersensitivity to digoxin. A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin.
WARNINGS Sinus Node Disease and AV Block: Because digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. The drug may cause severe sinus bradycardia or sinoatrial block in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. In such patients consideration should be given to the insertion of a pacemaker before treatment with digoxin. Accessory AV Pathway (Wolff-Parkinson-White Syndrome): After intravenous digoxin therapy, some patients with paroxysmal atrial fibrillation or flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, leading to a very rapid ventricular response or ventricular fibrillation. Unless conduction down the accessory pathway has been blocked (either pharmacologically or by surgery), digoxin should not be used in such patients. The treatment of paroxysmal supraventricular tachycardia in such patients is usually direct-current cardioversion. Use in Patients With Preserved Left Ventricular Systolic Function: Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may be particularly susceptible to toxicity of the drug. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin. Digoxin should generally be avoided in these patients, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation.
PRECAUTIONS Use in Patients With Impaired Renal Function: Digoxin is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of digoxin (see DOSAGE AND ADMINISTRATION). Because of the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function. Use in Patients With Electrolyte Disorders: In patients with hypokalemia or hypomagnesemia, toxicity may occur despite serum digoxin concentrations below 2.0 ng/mL, because potassium or magnesium depletion sensitizes the myocardium to digoxin. Therefore, it is desirable to maintain normal serum potassium and magnesium concentrations in patients being treated with digoxin. Deficiencies of these electrolytes may result from malnutrition, diarrhea, or prolonged
vomiting, as well as the use of the following drugs or procedures: diuretics, amphotericin B, corticosteroids, antacids, dialysis, and mechanical suction of gastrointestinal secretions. Hypercalcemia from any cause predisposes the patient to digitalis toxicity. Calcium, particularly when administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. On the other hand, hypocalcemia can nullify the effects of digoxin in humans; thus, digoxin may be ineffective until serum calcium is restored to normal. These interactions are related to the fact that digoxin affects contractility and excitability of the heart in a manner similar to that of calcium. Use in Thyroid Disorders and Hypermetabolic States: Hypothyroidism may reduce the requirements for digoxin. Heart failure and/or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states are particularly resistant to digoxin treatment. Care must be taken to avoid toxicity if digoxin is used. Use in Patients With Acute Myocardial Infarction: Digoxin should be used with caution in patients with acute myocardial infarction. The use of inotropic drugs in some patients in this setting may result in undesirable increases in myocardial oxygen demand and ischemia. Use During Electrical Cardioversion: It may be desirable to reduce the dose of digoxin for 1 to 2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequences of increasing the ventricular response if digoxin is withdrawn. If digitalis toxicity is suspected, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular arrhythmias. Use in Patients With Myocarditis: Digoxin can rarely precipitate vasoconstriction and therefore should be avoided in patients with myocarditis. Use in Patients With Beri Beri Heart Disease: Patients with beri beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly. Laboratory Test Monitoring: Patients receiving digoxin should have their serum electrolytes and renal function (serum creatinine concentrations) assessed periodically; the frequency of assessments will depend on the clinical setting. For discussion of serum digoxin concentrations, see DOSAGE AND ADMINISTRATION section. Drug Interactions: Potassium-depleting diuretics are a major contributing factor to digitalis toxicity. Calcium, particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. Quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, and spironolactone raise the serum digoxin concentration due to a reduction in clearance and/or in volume of distribution of the drug, with the implication that digitalis intoxication may result. Erythromycin and clarithromycin (and possibly other macrolide antibiotics) and tetracycline may increase digoxin absorption in patients who inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis
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intoxication may result (see CLINICAL PHARMACOLOGY: Absorption). Propantheline and diphenoxylate, by decreasing gut motility, may increase digoxin absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer drugs, and metoclopramide may interfere with intestinal digoxin absorption, resulting in unexpectedly low serum concentrations. Rifampin may decrease serum digoxin concentration, especially in patients with renal dysfunction, by increasing the non-renal clearance of digoxin. There have been inconsistent reports regarding the effects of other drugs [e.g., quinine, penicillamine] on serum digoxin concentration. Thyroid administration to a digitalized, hypothyroid patient may increase the dose requirement of digoxin. Concomitant use of digoxin and sympathomimetics increases the risk of cardiac arrhythmias. Succinylcholine may cause a sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmias in digitalized patients. Although calcium channel blockers and digoxin may be useful in combination to control atrial fibrillation, their additive effects on AV node conduction can result in advanced or complete heart block. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing carvedilol. Due to the considerable variability of these interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently. Furthermore, caution should be exercised when combining digoxin with any drug that may cause a significant deterioration in renal function, since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. Drug/Laboratory Test Interactions: The use of therapeutic doses of digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity. Carcinogenesis, Mutagenesis, Impairment of Fertility: There have been no long-term studies performed in animals to evaluate carcinogenic potential, nor have studies been conducted to assess the mutagenic potential of digoxin or its potential to affect fertility. Pregnancy: Teratogenic Effects: Pregnancy Category C. Animal reproduction studies have not been conducted with digoxin. It is also not known whether digoxin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Digoxin should be given to a pregnant woman only if clearly needed. Nursing Mothers: Studies have shown that digoxin concentrations in the mother's serum and milk are similar. However, the estimated exposure of a nursing infant to digoxin via breastfeeding will be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when digoxin is administered to a nursing woman.
Pediatric Use: Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity. Digitalis glycosides can cause poisoning in children due to accidental ingestion. Geriatric Use: The majority of clinical experience gained with digoxin has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when digoxin is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions. Because some patients may be particularly susceptible to side effects with digoxin, the dosage of the drug should always be selected carefully and adjusted as the clinical condition of the patient warrants. In the past, when high doses of digoxin were used and little attention was paid to clinical status or concurrent medications, adverse reactions to digoxin were more frequent and severe. Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. However, available evidence suggests that the incidence and severity of digoxin toxicity has decreased substantially in recent years. In recent controlled clinical trials, in patients with predominantly mild to moderate heart failure, the incidence of adverse experiences was comparable in patients taking digoxin and in those taking placebo. In a large mortality trial, the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking Lanoxin compared to 0.9% in patients taking placebo. In this trial, the most common manifestations of digoxin toxicity included gastrointestinal and cardiac disturbances; CNS manifestations were less common. Adults: Cardiac: Therapeutic doses of digoxin may cause heart block in patients with pre-existing sinoatrial or AV conduction disorders; heart block can be avoided by adjusting the dose of digoxin. Prophylactic use of a cardiac pacemaker may be considered if the risk of heart block is considered unacceptable. High doses of digoxin may produce a variety of rhythm disturbances, such as first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation. Digoxin produces PR prolongation and ST segment depression which should not by themselves be considered digoxin toxicity. Cardiac toxicity can also occur at therapeutic doses in patients who have conditions which may alter their sensitivity to digoxin (see WARNINGS and PRECAUTIONS).
Gastrointestinal: Digoxin may cause anorexia, nausea, vomiting, and diarrhea. Rarely, the use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines. CNS: Digoxin can produce visual disturbances (blurred or yellow vision), headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination). Other: Gynecomastia has been occasionally observed following the prolonged use of digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed. Table 4 summarizes the incidence of those adverse experiences listed above for patients treated with Lanoxin Tablets or placebo from 2 randomized, double-blind, placebo-controlled withdrawal trials. Patients in these trials were also receiving diuretics with or without angiotensin converting enzyme inhibitors. These patients had been stable on digoxin, and were randomized to digoxin or placebo. The results shown in Table 4 reflect the experience in patients following dosage titration with the use of serum digoxin concentrations and careful follow-up. These adverse experiences are consistent with results from a large, placebo-controlled mortality trial (DIG trial) wherein over half the patients were not receiving digoxin prior to enrollment. Table 4. Adverse Experiences In 2 Parallel, Double-Blind, Placebo-Controlled Withdrawal Trials (Number of Patients Reporting) Digoxin Patients Placebo Patients Adverse Experience (n = 123) (n = 125) Cardiac Palpitation 1 4 Ventricular extrasystole 1 1 Tachycardia 2 1 Heart arrest 1 1 Gastrointestinal Anorexia 1 4 Nausea 4 2 Vomiting 2 1 Diarrhea 4 1 Abdominal pain 0 6 CNS Headache 4 4 Dizziness 6 5 Mental disturbances 5 1 Other Rash 2 1 Death 4 3 Infants and Children: The side effects of digoxin in infants and children differ from those seen in adults in several respects. Although digoxin may produce anorexia, nausea, vomiting,
diarrhea, and CNS disturbances in young patients, these are rarely the initial symptoms of overdosage. Rather, the earliest and most frequent manifestation of excessive dosing with digoxin in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmia or alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise.
OVERDOSAGE Signs and Symptoms: The signs and symptoms of toxicity are generally similar to those described in the ADVERSE REACTIONS section but may be more frequent and can be more severe. Signs and symptoms of digoxin toxicity become more frequent with levels above 2 ng/mL. However, in deciding whether a patient's symptoms are due to digoxin, the clinical state together with serum electrolyte levels and thyroid function are important factors (see DOSAGE AND ADMINISTRATION). Adults: In adults without heart disease, clinical observation suggests that an overdose of digoxin of 10 to 15 mg was the dose resulting in death of half of the patients. If more than 25 mg of digoxin was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin-binding Fab antibody fragments resulted. Cardiac manifestations are the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects generally occur 3 to 6 hours following overdosage and may persist for the ensuing 24 hours or longer. Digoxin toxicity may result in almost any type of arrhythmia (see ADVERSE REACTIONS). Multiple rhythm disturbances in the same patient are common. Cardiac arrest from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal. Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g. nausea, vomiting, anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in approximately half of the patients in most literature reports. Neurologic manifestations (e.g. dizziness, various CNS disturbances), fatigue, and malaise are very common. Visual manifestations may also occur with aberration in color vision (predominance of yellow green) the most frequent. Neurological and visual symptoms may persist after other signs of toxicity have resolved. In chronic toxicity, non-specific extra-cardiac symptoms, such as malaise and weakness, may predominate. Children: In children aged 1 to 3 years without heart disease, clinical observation suggests that an overdose of digoxin of 6 to 10 mg was the dose resulting in death in half of the patients. If more than 10 mg of digoxin was ingested by a child aged 1 to 3 years without heart disease, the outcome was uniformly fatal when Fab fragment treatment was not given. Most manifestations of toxicity in children occur during or shortly after the loading phase with digoxin. The same arrhythmias or combination of arrhythmias that occur in adults can occur in pediatrics. Sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in the pediatric population. Pediatric patients are more likely to present with an AV conduction
disturbance or a sinus bradycardia. Any arrhythmia or alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise. The frequent extracardiac manifestations similar to those seen in adults are gastrointestinal, CNS, and visual. However, nausea and vomiting are not frequent in infants and small children. In addition to the undesirable effects seen with recommended doses, weight loss in older age groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischemia, drowsiness, and behavioral disturbances including psychotic manifestations have been reported in overdose. Treatment: In addition to cardiac monitoring, digoxin should be temporarily discontinued until the adverse reaction resolves and may be all that is required to treat the adverse reaction such as in asymptomatic bradycardia or digoxin-related heart block. Every effort should also be made to correct factors that may contribute to the adverse reaction (such as electrolyte disturbances, thyroid function, or concurrent medications) (see WARNINGS and PRECAUTIONS: Drug Interactions). Once the adverse reaction has resolved, therapy with digoxin may be reinstituted, following a careful reassessment of dose. When the primary manifestation of digoxin overdosage is a cardiac arrhythmia, additional therapy may be needed. If the rhythm disturbance is a symptomatic bradyarrhythmia or heart block, consideration should be given to the reversal of toxicity with Digoxin Immune Fab (Ovine) [Digibind or Digifab] (see Massive Digitalis Overdosage subsection), the use of atropine, or the insertion of a temporary cardiac pacemaker. Digoxin Immune Fab (Ovine) is a specific antidote for digoxin and may be used to reverse potentially life-threatening ventricular arrhythmias due to digoxin overdosage. If the rhythm disturbance is a ventricular arrhythmia, consideration should be given to the correction of electrolyte disorders, particularly if hypokalemia (see Administration of Potassium subsection) or hypomagnesemia is present. Ventricular arrhythmias may respond to lidocaine or phenytoin. Administration of Potassium: Before administering potassium in digoxin overdose for hypokalemia, the serum potassium must be known and every effort should be made to maintain the serum potassium concentration between 4 and 5.5 mmol/L. Potassium salts should be avoided as they may be dangerous in patients who manifest bradycardia or heart block due to digoxin (unless primarily related to supraventricular tachycardia) and in the setting of massive digitalis overdosage. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and the serum potassium concentration is low, potassium may be administered cautiously by the intravenous route. The electrocardiogram should be monitored for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. Massive Digitalis Overdosage: Manifestations of life-threatening toxicity include ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias, or heart block.
Digoxin Immune Fab (Ovine) should be used to reverse the toxic effects of ingestion of a massive overdose. The decision to administer Digoxin Immune Fab (Ovine) to a patient who has ingested a massive dose of digoxin but who has not yet manifested life-threatening toxicity should depend on the likelihood that life-threatening toxicity will occur (see above). Digoxin is not effectively removed from the body by dialysis due to its large extravascular volume of distribution. Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric recirculation. Emesis may be indicated especially if ingestion has occurred within 30 minutes of the patient's presentation at the hospital. Emesis should not be induced in patients who are obtunded. If a patient presents more than 2 hours after ingestion or already has toxic manifestations, it may be unsafe to induce vomiting because such maneuvers may induce an acute vagal episode that can worsen digitalis-related arrhythmias. In cases where a large amount of digoxin has been ingested, hyperkalemia may be present due to release of potassium from skeletal muscle. Hyperkalemia caused by massive digitalis toxicity is best treated with Digoxin Immune Fab (Ovine); initial treatment with glucose and insulin may also be required if hyperkalemia itself is acutely life-threatening.
DOSAGE AND ADMINISTRATION General: Recommended dosages of digoxin may require considerable modification because of individual sensitivity of the patient to the drug, the presence of associated conditions, or the use of concurrent medications. In selecting a dose of digoxin, the following factors must be considered: 1. The body weight of the patient. Doses should be calculated based upon lean (i.e., ideal) body weight. 2. The patient's renal function, preferably evaluated on the basis of estimated creatinine clearance. 3. The patient's age. Infants and children require different doses of digoxin than adults. Also, advanced age may be indicative of diminished renal function even in patients with normal serum creatinine concentration (i.e., below 1.5 mg/dL). 4. Concomitant disease states, concurrent medications, or other factors likely to alter the pharmacokinetic or pharmacodynamic profile of digoxin (see PRECAUTIONS). Serum Digoxin Concentrations: In general, the dose of digoxin used should be determined on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in assigning certain probabilities to the likelihood of digoxin intoxication. About two-thirds of adults considered adequately digitalized (without evidence of toxicity) have serum digoxin concentrations ranging from 0.8 to 2.0 ng/mL (lower serum trough concentrations of 0.5 to 1 ng/mL may be appropriate in some adult patients, see Maintenance Dosing). However, digoxin may produce clinical benefits even at serum concentrations below this range. About two-thirds of adult patients with clinical toxicity have serum digoxin concentrations greater than 2.0 ng/mL. However, since one-third of
patients with clinical toxicity have concentrations less than 2.0 ng/mL, values below 2.0 ng/mL do not rule out the possibility that a certain sign or symptom is related to digoxin therapy. Rarely, there are patients who are unable to tolerate digoxin at serum concentrations below 0.8 ng/mL. Consequently, the serum concentration of digoxin should always be interpreted in the overall clinical context, and an isolated measurement should not be used alone as the basis for increasing or decreasing the dose of the drug. To allow adequate time for equilibration of digoxin between serum and tissue, sampling of serum concentrations should be done just before the next scheduled dose of the drug. If this is not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the route of administration or the formulation used. On a once-daily dosing schedule, the concentration of digoxin will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient's renal function. On a twice-daily dosing schedule, there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose. If a discrepancy exists between the reported serum concentration and the observed clinical response, the clinician should consider the following possibilities: 1. Analytical problems in the assay procedure. 2. Inappropriate serum sampling time. 3. Administration of a digitalis glycoside other than digoxin. 4. Conditions (described in WARNINGS and PRECAUTIONS) causing an alteration in the sensitivity of the patient to digoxin. 5. Serum digoxin concentration may decrease acutely during periods of exercise without any associated change in clinical efficacy due to increased binding of digoxin to skeletal muscle. Heart Failure: Adults: Digitalization may be accomplished by either of 2 general approaches that vary in dosage and frequency of administration, but reach the same endpoint in terms of total amount of digoxin accumulated in the body. 1. If rapid digitalization is considered medically appropriate, it may be achieved by
administering a loading dose based upon projected peak digoxin body stores.
Maintenance dose can be calculated as a percentage of the loading dose.
2. More gradual digitalization may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to accumulate slowly. Steady-state serum digoxin concentrations will be achieved in approximately 5 half-lives of the drug for the individual patient. Depending upon the patient's renal function, this will take between 1 and 3 weeks. Rapid Digitalization With a Loading Dose: Peak digoxin body stores of 8 to 12 mcg/kg should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Because of altered digoxin distribution and elimination, projected peak body stores for patients with renal insufficiency should be conservative (i.e., 6 to 10 mcg/kg) (see PRECAUTIONS).
The loading dose should be administered in several portions, with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 6- to 8-hour intervals, with careful assessment of clinical response before each additional dose. If the patient's clinical response necessitates a change from the calculated loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given. A single initial dose of 500 to 750 mcg (0.5 to 0.75 mg) of Lanoxin Tablets usually produces a detectable effect in 0.5 to 2 hours that becomes maximal in 2 to 6 hours. Additional doses of 125 to 375 mcg (0.125 to 0.375 mg) may be given cautiously at 6- to 8-hour intervals until clinical evidence of an adequate effect is noted. The usual amount of Lanoxin Tablets that a 70-kg patient requires to achieve 8 to 12 mcg/kg peak body stores is 750 to 1,250 mcg (0.75 to 1.25 mg). Lanoxin Injection is frequently used to achieve rapid digitalization, with conversion to Lanoxin Tablets for maintenance therapy. If patients are switched from intravenous to oral digoxin formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages (see Table 1, CLINICAL PHARMACOLOGY). Maintenance Dosing: The doses of digoxin used in controlled trials in patients with heart failure have ranged from 125 to 500 mcg (0.125 to 0.5 mg) once daily. In these studies, the digoxin dose has been generally titrated according to the patient's age, lean body weight, and renal function. Therapy is generally initiated at a dose of 250 mcg (0.25 mg) once daily in patients under age 70 with good renal function, at a dose of 125 mcg (0.125 mg) once daily in patients over age 70 or with impaired renal function, and at a dose of 62.5 mcg (0.0625 mg) in patients with marked renal impairment. Doses may be increased every 2 weeks according to clinical response. In a subset of approximately 1,800 patients enrolled in the DIG trial (wherein dosing was based on an algorithm similar to that in Table 5) the mean (± SD) serum digoxin concentrations at 1 month and 12 months were 1.01 ± 0.47 ng/mL and 0.97 ± 0.43 ng/mL, respectively. There are no rigid guidelines as to the range of serum concentrations that are most efficacious. Several post hoc analyses of heart failure patients in the DIG trial suggest that the optimal trough digoxin serum level may be 0.5 ng/mL to 1 ng/mL. The maintenance dose should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use: Maintenance Dose = Peak Body Stores (i.e., Loading Dose) x % Daily Loss/100
Where: % Daily Loss = 14 + Ccr/5
(Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body surface area.)
Table 5 provides average daily maintenance dose requirements of Lanoxin Tablets for patients with heart failure based upon lean body weight and renal function: Table 5. Usual Daily Maintenance Dose Requirements (mcg) of Lanoxin for Estimated Peak Body Stores of 10 mcg/kg Corrected Ccr Lean Body Weight Number of Days (mL/min per kg Before Steady 50 60 70 80 90 100 b 70 kg)a lb 110 132 154 176 198 220 State Achieved c 0 125 125 125 187.5 187.5 22 62.5 10 125 125 125 187.5 187.5 187.5 19 20 125 125 187.5 187.5 187.5 250 16 30 125 187.5 187.5 187.5 250 250 14 40 125 187.5 187.5 250 250 250 13 50 187.5 187.5 250 250 250 250 12 60 187.5 187.5 250 250 250 375 11 70 187.5 250 250 250 250 375 10 80 187.5 250 250 250 375 375 9 90 187.5 250 250 250 375 500 8 100 250 250 250 375 375 500 7 a 2 Ccr is creatinine clearance, corrected to 70-kg body weight or 1.73 m body surface area. For adults, if only serum creatinine concentrations (Scr) are available, a Ccr (corrected to 70 kg body weight) may be estimated in men as (140 - Age)/Scr. For women, this result should be multiplied by 0.85. Note: This equation cannot be used for estimating creatinine clearance in infants or children. b If no loading dose administered. c 62.5 mcg = 0.0625 mg. Example: Based on Table 5, a patient in heart failure with an estimated lean body weight of 70 kg and a Ccr of 60 mL/min should be given a dose of 250 mcg (0.25 mg) daily of Lanoxin Tablets, usually taken after the morning meal. If no loading dose is administered, steady-state serum concentrations in this patient should be anticipated at approximately 11 days. Infants and Children: In general, divided daily dosing is recommended for infants and young children (under age 10). In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area. Children over 10 years of age require adult dosages in proportion to their body weight. Some researchers have suggested that infants and young children tolerate slightly higher serum concentrations than do adults. Daily maintenance doses for each age group are given in Table 6 and should provide therapeutic effects with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. These recommendations assume the presence of normal renal function:
Table 6. Daily Maintenance Doses in Children With Normal Renal Function Age Daily Maintenance Dose (mcg/kg) 2 to 5 Years 10 to 15 5 to 10 Years 7 to 10 Over 10 Years 3 to 5 In children with renal disease, digoxin must be carefully titrated based upon clinical response. It cannot be overemphasized that both the adult and pediatric dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, ultimate dosage selection must be based upon clinical assessment of the patient. Atrial Fibrillation: Peak digoxin body stores larger than the 8 to 12 mcg/kg required for most patients with heart failure and normal sinus rhythm have been used for control of ventricular rate in patients with atrial fibrillation. Doses of digoxin used for the treatment of chronic atrial fibrillation should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects. Data are not available to establish the appropriate resting or exercise target rates that should be achieved. Dosage Adjustment When Changing Preparations: The difference in bioavailability between Lanoxin Injection or Lanoxin Tablets must be considered when changing patients from one dosage form to the other.
HOW SUPPLIED Lanoxin (digoxin) Tablets, Scored 125 mcg (0.125 mg): Bottles of 100 with child-resistant cap (NDC 0173-0242-55) and 1,000 (NDC 0173-0242-75); unit dose pack of 100 (NDC 0173-0242 56). Imprinted with Lanoxin and Y3B (yellow). Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature] in a dry place and protect from light. Lanoxin (digoxin) Tablets, Scored 250 mcg (0.25 mg): Bottles of 100 with child-resistant cap (NDC 0173-0249-55), 1,000 (NDC 0173-0249-75), and 5,000 (NDC 0173-0249-80); unit dose pack of 100 (NDC 0173-0249-56). Imprinted with Lanoxin and X3A (white). Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature] in a dry place. Lanoxin and Digibind are registered trademarks of GlaxoSmithKline Digifab is a registered trademark of Prostherics Inc.
GlaxoSmithKline Research Triangle Park, NC 27709 by DSM Pharmaceuticals, Inc. Greenville, NC 27834 or GlaxoSmithKline Research Triangle Park, NC 27709 ©2009, GlaxoSmithKline. All rights reserved. August 2009 LNT:1PI
Essential drugs - edition 2010
Microsoft Word - book.doc

redpajama_set_name: RedPajamaCommonCrawl


Imagine being a small business owner, getting a government grant, and then getting another grant because you qualified for the government grant. It sounds almost too good to be true. But true it is. The State University of New York at Buffalo (UB) just awarded grants to 5 scientific companies to help them expand their research capabilities.
The grants are called the UB Small Business Innovation Awards (SBIA). They are awarded to small companies who have qualified for a federal Small Business Innovation Research (SBIR) grant or Small Business Technology Transfer (STTR) grant. Those who receive the awards must be willing to use at least 30 percent of their federal grant to fund research using the UB research team. Qualifying companies may then receive up to a 20 percent SBIA match to fund additional work by the UB research team.
One recipient, Abcombi Biosciences, received a $300,000 STTR grant from the National Institutes of Health. They were awarded $35,039 from UB to fund their research in developing products such as therapies for drug-resistant flu strains. Another company, Angiograft, received a $223,501 grant from the National Heart, Lung and Blood Institute and were awarded a $14,750 grant from UB to continue their research on off-the-shelf vascular grafts for use in surgery.
The UB grants provides an opportunity for companies to grow their businesses, and also provides more research opportunities for faculty and staff, and increased learning opportunities for students.


Ovah Coffee: Hats, Hats Away!
Caps, hats, bonnets, beanies, berets... whatever they're called, I have a massive collection of them. I have 'em in different styles, shapes and colors and I think another one's on its way to my mailbox. Gotta check on that later.
Anyway, since winter's long from over yet, check these lovely winter hats [http://www.winterhatsboutique.com/] and beanies. I super like 'em!
The classic Newsboy winter hat. It is made of wool and the inside's of warm Microtherm to keep my head from freezing. In fashion, one can never go wrong with a classic!
The Tweed Cloche Hat - Its length is enough to keep both the head and the ears from freezing. I like the strap and the button accents.
I do not have this one in my collection and am actually considering to order one.
The Cotton Crochet Beanie With Side Tab is adorable, isn't it? Gotta love the light brown accent on the edge. The side tab and button also add beauty to this piece. Pretty!
My favorite of all the winter "hat, cap, whatever"... the Women's Cable Knit Brimmed Beanie. It looks a bit like the Newsboy but thie one's knitted making it perfect for a girly-girl like me!
As always, happy shopping my dear readers! Hugs from me to you!
nice kau imo mga kalo Ann and bagay sa imoha, ako kay d ko ganahan og kalo hehe pero mapugos ko og suot during winter season kay mgsakit mn ako ulo if wala koy kalo hehe..lamat sa visit..
Good to know! You look so pretty in that hat on your pic!


text:
Shell's Carbon Capture Plant Creates More Emissions Than It Captures
Surprise, surprise.
Derya Ozdemir
| Jan 31, 2022 09:59 AM EST
Created: Jan 31, 2022 09:59 AM EST
Updated: Jan 31, 2022 05:44 PM EST
Coatesy/iStock
Oil giant Shell's Quest plant has been designed to capture carbon emissions from oil sands operations and store them underground to reduce carbon emissions.
However, according to a recent study by the human rights organization Global Witness, the facility actually emits more greenhouse gas emissions than it captures.
Since 2015, it has prevented the release of five million tonnes of carbon dioxide into the atmosphere, but it has also released a further 7.5 million tonnes. To put that into perspective, Global Witness stated Shell's plant appears to have the same carbon footprint as 1.2 million gasoline-powered cars each year.
A first-of-its-kind Shell facility. But can it be green?
The plant in question is part of Shell's Scotford refinery in Alberta, Canada, where hydrogen is produced for use in processing oil sands bitumen, which is a type of petroleum deposit. Quest was billed as the world's first commercial-scale carbon capture and storage (CCS) system at an oil sands operation when it was first developed, but it does not cover the whole site's emissions.
According to the new report, between 2015 and 2019, Quest collected 5 million tonnes of carbon dioxide from the hydrogen produced at the Scotford facility. During the same period, however, the hydrogen plant emitted 7.5 million tonnes of greenhouse gases. These gases included methane, which, in the first 20 years after it reaches the atmosphere, has more than 80 times the warming power of carbon dioxide and accounts for roughly a fifth of human-caused warming.
This indicates that only 48 percent of the carbon emissions from the plant were captured. The report states that this falls significantly short of the industry's claim of 90 percent carbon capture rate for these types of projects in general, and when other greenhouse gas emissions from Shell's project are factored in, the rate drops to only 39 percent.
A Shell representative told CNBC in an email that Global Witness' study was "simply wrong" and that the Quest facility was designed to capture roughly a third of CO2 emissions.
The findings still do raise questions about whether CCS technologies are as "green" as Big Oil claims and are indeed a critical component of achieving net-zero, or whether this is another case of "greenwashing", in which green PR and green marketing are deceptively used to persuade the public that an organization's products, aims, and policies are environmentally friendly.
Global Witness stated that the findings are expected to deliver a "serious blow" to fossil hydrogen proponents which are pushing for more public funds to support its use. In this case, $654 million of the $1 billion cost of Shell's Quest facility reportedly came from Canadian government subsidies.
Meanwhile, Shell has refuted that it overstated Quest's potential, claiming that Global Witness is "comparing apples with pears."
"Our Quest facility was designed some years ago as a demonstration project to prove the underlying CCS concept, while capturing around a third of CO2 emissions. It is not a hydrogen production facility," the Shell spokesperson told CNBC. "The hydrogen projects we're planning – like Polaris – will use a new technology that captures more than 90 percent of emissions."
Where does carbon capture fit into the energy transition strategy?
Carbon capture and storage is a relatively novel initiative that the Big Oil and Big Tech believe will help them survive in the new net-zero economy, and it could indeed be a promising technology alongside other drastic systemic changes. Some experts, however, have already labeled CCS, notably in the oil and gas industry, as a poor public investment, citing its failures to significantly reduce emissions.
Hundreds of academics and scientists recently wrote a letter to Finance Minister and Deputy Prime Minister Chrystia Freeland and other ministers, urging Justin Trudeau's government not to reward companies that use carbon capture technology.
"We are deeply concerned with the government's proposal to introduce a new investment tax credit for carbon capture, utilization, and storage," they wrote, citing the technology's "limited potential" to reduce emissions significantly. "At best, it prevents some carbon dioxide from polluting facilities from reaching the atmosphere, but it is not a negative emissions technology."
The experts argued that funding such efforts "diverts resources from proven, more cost-effective solutions", and that governments should instead focus efforts on renewable energy infrastructure and electrification.
Stranger Earth: Six weird ways climate change is affecting our planet
Earth change goes beyond melting icecaps and rising sea levels. Earth is made up of smaller interconnected systems with relatively unusual changes too.
Sade Agard | 8/14/2022
innovation FIFA World Cup in Qatar: AC stadiums show how technology is shaping sports
Baba Tamim| 10/21/2022
innovation How you could develop US military tech — The Blueprint
Alice Cooke| 9/25/2022
Hindenburg report crushes Adani empire: $52 billion evaporate in a week
Online AI chatbot ChatGTP wrote a bill to regulate AI
Kavita Verma| 1/27/2023
Science journals ban ChatGPT from co-authoring papers
Ameya Paleja| 1/27/2023


text:
package com.netflix.client.ssl;

import java.security.KeyManagementException;
import java.security.KeyStore;
import java.security.KeyStoreException;
import java.security.NoSuchAlgorithmException;
import java.security.UnrecoverableKeyException;

import javax.net.ssl.KeyManager;
import javax.net.ssl.KeyManagerFactory;
import javax.net.ssl.SSLContext;
import javax.net.ssl.TrustManager;
import javax.net.ssl.TrustManagerFactory;

import org.slf4j.Logger;
import org.slf4j.LoggerFactory;

/**
 *
 * Abstract class to represent what we logically associate with the ssl context on the client side,
 * namely, the keystore and truststore.
 *
 * @author jzarfoss
 *
 */
public abstract class AbstractSslContextFactory {

    private final static Logger LOGGER = LoggerFactory.getLogger(AbstractSslContextFactory.class);

    /** The secure socket algorithm that is to be used. */
    public static final String SOCKET_ALGORITHM = "SSL";

    /** The keystore resulting from loading keystore URL     */
    private KeyStore keyStore;

    /** The truststore resulting from loading the truststore URL     */
    private KeyStore trustStore;

    /** The password for the keystore     */
    private String keyStorePassword;

    private final int trustStorePasswordLength;

    private final int keyStorePasswordLength;

    protected AbstractSslContextFactory(final KeyStore trustStore, final String trustStorePassword, final KeyStore keyStore, final String keyStorePassword){

    	this.trustStore = trustStore;
    	this.keyStorePassword = keyStorePassword;
    	this.keyStore = keyStore;

    	this.keyStorePasswordLength = keyStorePassword != null ? keyStorePassword.length() : -1;
    	this.trustStorePasswordLength = trustStorePassword != null ? trustStorePassword.length() : -1;
    }

    public KeyStore getKeyStore(){
    	return this.keyStore;
    }

    public KeyStore getTrustStore(){
    	return this.trustStore;
    }

    public int getKeyStorePasswordLength(){
    	return this.keyStorePasswordLength;
    }

    public int getTrustStorePasswordLength(){
    	return this.trustStorePasswordLength;
    }

    /**
     * Creates the SSL context needed to create the socket factory used by this factory. The key and
     * trust store parameters are optional. If they are null then the JRE defaults will be used.
     *
     * @return the newly created SSL context
     * @throws ClientSslSocketFactoryException if an error is detected loading the specified key or
     *         trust stores
     */
    private SSLContext createSSLContext() throws ClientSslSocketFactoryException {
        final KeyManager[] keyManagers = this.keyStore != null ? createKeyManagers() : null;
        final TrustManager[] trustManagers = this.trustStore != null ? createTrustManagers() : null;

        try {
            final SSLContext sslcontext = SSLContext.getInstance(SOCKET_ALGORITHM);

            sslcontext.init(keyManagers, trustManagers, null);

            return sslcontext;
        } catch (NoSuchAlgorithmException e) {
            throw new ClientSslSocketFactoryException(String.format("Failed to create an SSL context that supports algorithm %s: %s", SOCKET_ALGORITHM, e.getMessage()), e);
        } catch (KeyManagementException e) {
            throw new ClientSslSocketFactoryException(String.format("Failed to initialize an SSL context: %s", e.getMessage()), e);
        }
    }

    /**
     * Creates the key managers to be used by the factory from the associated key store and password.
     *
     * @return the newly created array of key managers
     * @throws ClientSslSocketFactoryException if an exception is detected in loading the key store
     */
    private KeyManager[] createKeyManagers() throws ClientSslSocketFactoryException {

        final KeyManagerFactory factory;

        try {
            factory = KeyManagerFactory.getInstance(KeyManagerFactory.getDefaultAlgorithm());
            factory.init(this.keyStore, this.keyStorePassword.toCharArray());
        } catch (NoSuchAlgorithmException e) {
            throw new ClientSslSocketFactoryException(
                    String.format("Failed to create the key store because the algorithm %s is not supported. ",
                            KeyManagerFactory.getDefaultAlgorithm()), e);
        } catch (UnrecoverableKeyException e) {
        	throw new ClientSslSocketFactoryException("Unrecoverable Key Exception initializing key manager factory; this is probably fatal", e);
		} catch (KeyStoreException e) {
			throw new ClientSslSocketFactoryException("KeyStore exception initializing key manager factory; this is probably fatal", e);
		}

        KeyManager[] managers = factory.getKeyManagers();

        LOGGER.debug("Key managers are initialized. Total {} managers. ", managers.length);

        return managers;
    }

    /**
     * Creates the trust managers to be used by the factory from the specified trust store file and
     * password.
     *
     * @return the newly created array of trust managers
     * @throws ClientSslSocketFactoryException if an error is detected in loading the trust store
     */
    private TrustManager[] createTrustManagers() throws ClientSslSocketFactoryException {

    	final TrustManagerFactory factory;

    	try {
    		factory = TrustManagerFactory.getInstance(TrustManagerFactory.getDefaultAlgorithm());
    		factory.init(this.trustStore);
    	} catch (NoSuchAlgorithmException e) {
    		throw new ClientSslSocketFactoryException(String.format("Failed to create the trust store because the algorithm %s is not supported. ",
    				KeyManagerFactory.getDefaultAlgorithm()), e);
    	} catch (KeyStoreException e) {
    		throw new ClientSslSocketFactoryException("KeyStore exception initializing trust manager factory; this is probably fatal", e);
    	}

    	final TrustManager[] managers = factory.getTrustManagers();

    	LOGGER.debug("TrustManagers are initialized. Total {} managers: ", managers.length);

    	return managers;

    }

    public SSLContext getSSLContext() throws ClientSslSocketFactoryException{
    	return createSSLContext();
    }

}

redpajama_set_name: RedPajamaGithub


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In this time when many people are out of work and with lost jobs, we as a society need to step up as much as we can, an help to provide whatever assisantance we can. Our neighborhood has started by cleaning out our homes and donating whatever we have. We give much clothing, toys, books, household items to our Church, Salvation Army, and Recycle stores. We make sure everything is useable and in good condition. Where ever it is donated, it is resold at a much lesser price than when new. Once aweek we go door to door an collect whatever our neighbors are able to part with. Our church sells everything in clothing for 50 cents, which they only have room for. They are always in need of clothing and many things have brand names. Salvation Army in our area has been struggling also, and the donations are down, so they have had to close a store. Recycle stores usually sell large furniture, as well as other household items. We just got a Goodwill store, but i find that their prices are alot higher, than the churches or Salvation Army.
Americans are known as collectors of everything and now is the time to share with others who have less. People can't be proud when it comes to helping their families. Why not trade those clothes that your child or you have out grown, or clean out that basement. I know we all have these things hanging around for Americans buy, use, and waste alot of things. Not only will you feel better, you can also get a tax deduction.


46308 49 App.:1472(c). Aug. 23, 1958, Pub. L. 85–726, §902(c), 72 Stat. 784.
In this section, before clause (1), the words "fined under title 18" are substituted for "a fine of not exceeding $5,000" for consistency with title 18. The words "such fine and imprisonment" are omitted as surplus. In clause (1), the words "used at" are substituted for "in connection with" for clarity. The words "airport or other" are omitted as being included in the definition of "air navigation facility" in section 40102(a) of the revised title. In clause (2), the word "due" is omitted as surplus. The word "Administrator" in section 902(c) of the Federal Aviation Act of 1958 (Public Law 85–726, 72 Stat. 784) is retained on authority of 49:106(g). In clause (3), the words "removes, extinguishes, or" are omitted as surplus.