Ichthyosis linearis circumflexa
الثلاثاء، ديسمبر 31
الأحد، ديسمبر 1
الأحد، نوفمبر 24
قصة الأمس واليوم
قصة الأمس واليوم لمن يريد أن يفهم أو يتدبر تتلخص في الرعب اليهودي من الإسلام والخشية الأبدية من النبوءة الإسلامية بفناء إسرائيل. فالصهيونية اليهودية هي المحرك والفاعل والطرف الثالث الدموي واللاعب الخفي لكل الشخوص والأفاعي والدمى على مسرح الحياة منذ آلاف السنين... والهدف الأوحد هو... الخلاص من الإسلام... العدو الأبدي...الصهيونية اليهودية التي يحرسها المارد الأمريكي بعد أن أقنعته أن عدو الحضارة الرئيس هو الإسلام وحده، فاخترعوا مصطلح الأصولية الإسلامية وألبسوها ثوب الإرهاب، وهو يكذبون ليلا ونهارا عندما يقولون أن عداءهم ليس مع الإسلام بل مع الإرهاب الذي هو من صناعتهم هم وحدهم وثمرة زرعهم بأيديهم...ولأن اليهود أصلا نابغون في التجارة وجمع المال وأساتذة فن الاستغلال وهم من درسوا جيدا النفس البشرية ووعوا الضعف البشري الغريزي تجاه المال، فقد بدأت القصة منذ القدم. حيث استطاع الصهاينة خلال سنوات طوال من العمل الدؤوب والبطئ صناعة دولة إسرائيل ثم تسللوا للسلطة والحكم في أمريكا وبلاد العرب، لا كرؤساء أو ملوك أو سلاطين، بل كمستشارين يصنعون القرارات من خلف الستائر والحجب، حتى أصبحت السلطة الفعلية في يدهم ولكن في الخفاء، فلا تظنن "جلالة" الملك أبو عقال أو سمو الأمير بطيخة الذي يرتفع كرشه فوق صدره يجيد الإدارة أو التخطيط، فعقول هؤلاء أتخن من كروشهم وبطونهم! ثم نجح صهاينة اليهود بعد في امتلاك نواصي المال في العالم، فامتلكوا البورصات والبنوك وأقاموا المؤسسات المالية الدولية التي تهدف لجعل الغني أكثر غنا والفقير أكثر فقرا!! ولأنهم درسوا النفس البشرية كان من أهم أسلحتهم النجاح في امتلاك كل أدوات غسيل المخ من صحافة وإذاعة وقنوات تليفزيونية وسينما ومسرح، فاستطاعوا خلال سنوات طوال تشكيل رأي عام يتفق وأهدافهم. بل والأدهى من ذلك وأمر أنهم أنشئوا كل التنظيمات الإجرامية السرية من مافيا وعصابات للمخدرات وتجار الأسلحة وبيوت الدعارة والقوادين وتجار اللحم الأبيض والأسود، واستطاعوا أن يجعلوا من المال عل مدار السنين صنمهم المعبود، وقدس أقداسهم، فأسسوا للرأسمالية والامبريالية والماسونية، ثم خرج من عباءتهم من أسس للشيوعية ثم أتى من بعده من هدم الشيوعية على رأس اصحابها. وهم من يشعل فتيل الحروب ويدقون نواقيس الصراعات في الأرض لسبب بسيط أن الحروب والصراعات هي وقود بورصاتهم فيصبح اليوم لليورو وغدا للدولار، ويجني حيتان المضاربين منهم وممن صار في ركبهم المليارات في ثوان بلا جهد ولا عناء ولا تعب فضلا على كون الحروب والصراعات سوقا لتصريف مخازنهم مما صنعوا من أسلحة لا يقتتلون بها بل ليقتلوا بها غيرهم فإن لم يفعلوا باعوها لأعدائهم وهيئوا لهم الأسباب ليقتل بعضهم بعضا فكان كمن ضرب عصفورين بحجر، استنزف ثروات المتغطرسين المعتوهين ثم تركهم نارا يأكل بعضها بعضا. فليس المطلوب لنهب ثروات العالم غير قليل من الذكاء الخبيث وإشعال في فتيل الحروب، ونفخ في رماد الصراعات وصناعة الثورات والانقلابات العسكرية في شتى أنحاء الأرض وخصوصا أرض المسلمين والعرب. ولو قرأنا ودرسنا حروب التاريخ فلن نتعب كثيرا حتى نكتشف وندرك المحرك الرئيس والفاعل الحقيقي لكل هاتيك الحروب وكان دينهم وديدنهم الأساس في كل الصراعات كلمتين فقط... (فرق... تسد)! فنجح الصهاينة وأعوانهم الأمريكان في تقليب المسيحيين على المسلمين وسنة المسامين على شيعتهم والعرب على الأكراد والإيرانيين، وحتى تقليب العرب لبعضهم البعض في حروب عديدة كغزو العراق للكويت، فالهدف دائما واحد...تأليف الطوائف والأعراق بغرض تفرقتهم وعدم توحدهم أبدا لأن في توحدهم نهاية الصهيونية اليهودية وإسرائيل. والأمثلة كثيرة في فلسطين بين فتح وحماس ، ولبنان بين المسيحي والمسلم والسني والشيعي والدرزي وفي أفغانستان والعراق والصومال والبوسنة وصربيا وكشمير وبورما والفلبين والهند والشيشان وفي مصر بين المسلمين والمسيحيين بل وبين المسلمين أنفسهم....أمثلة لا حصر لها...ثم استطاعت الصهيونية العالمية بمساعدة أمريكا أن تؤسس النظام العالمي الجديد الذي يزرع الفتن والموت والدماء في كل بقاع الأرض وخاصة ديار الإسلام والمسلمين، فأصبحوا مثل الأخطبوط تحيط أذرعه بكل النخب الحاكمة، وخدعونا وخدعوا العالم ب(عملية السلام) التي هي بالأساس وهم كبير من اختراعهم وأغنية لطيفة من تأليفهم لكي يلهوا العالم بها. واستطاعوا تجنيد بعض أشباه الفقهاء المتأسلمين من بني جلدتنا فرسموا لهم المخططات وأمدوهم بالأموال لصناعة الإرهاب وتنفيذ الاغتيالات وبذر الدماء باسم الإسلام حتى يلصقوا بالإسلام تهمة الإرهاب، والأمثلة كثيرة من بن لادن لحكمتيار لمحمد سياد بري للملا عمر للزرقاوي. وعبر أفلامهم وأبواقهم أقنعوا العالم بأن أمريكا والغرب هما قبلة الحضارة والعلم والرقي وأن الإسلام هو الرجعية والظلامية والتكفيرية والتخلف وسبب بلاء أتباعه!!!! ونجحوا كذلك عبر شراء حكام العرب بالمال والفاتنات من النساء وأضواء السلطة المبهرة وزينتها الباهية في إقناع الكثيرين بأن أمريكا وحليفتها إسرائيل هي صاحبة اليد العليا والعصا الغليظة، رغم أننا بما وهبنا الله من كنوز للطاقة وبأسواق بشرية هائلة لتجارة غيرنا وموقع جغرافي فريد وتحكمنا في معابر التجارة عبر العالم كان من المفترض أن نكون نحن أصحاب اليد الأعلى والعصا الأغلظ، ولكن حكامنا أضاعوا الثروات على موائد القمار ونهود النساء وإشباع الشهوات بالملذات حرامها قبل حلالها، وأعانهم على ذلك هوان شعوبهم ورضاهم بالعيش الذليل واستكانتهم ورضاهم بحياة العبودية للسفهاء من قومهم. ولما علم أعداؤنا أننا فقط أصحاب حناجر عنترية وأن كل أسلحتنا ألسنة وكلمات وربابة تطاولوا علينا وتهاووا على قصعتنا فسبوا رسولنا وأهانوا ديننا وقرأننا، بل واخترقونا فنجحوا في استمالة الحثالة من نخبتنا التي صنعوها هم لنا. وما السيسي أو غيره من أشباه الأصنام من حكامنا، أو غيره من الإعلاميين الذين يصرخون في آذاننا ليل نهار، أو بعض المفكرين والخبراء والمثقفين أو (فجار الدين) من بعض أصحاب العمائم عندنا سوى أذناب لأسيادهم في الموساد والمخابرات الأمريكية يهتدون بهديهم ويدينون بدينهم وليس لهم هم ولا هدف سوى صرف الناس عن إسلامهم (الذي هو نظام حياة) بالنساء ولقمة العيش وبالغناء والعبث وحصر الإسلام في حركات بهلوانية في صلوات يخرج المرء منها ولا يتذكر حرفا مما قاله أو في فقه يختص بالحيض والنفاس وجلباب ولحية أو في أيام معدودات يصومها المسلم على مضض كل عام. أما العدل والتقوى والبر والعدالة الاجتماعية وحسن الخلق والفضيلة وتجهيز ما استطعنا من قوة نرهب بها عدونا فهي محرمات علينا في نظرهم وهي عين الإرهاب عندهم. والسحرة كثيرون والرايات البراقة كثيرة والشعارات الرنانة جاهزة كالحرية والتنوير والحضارة والعلمانية والمواطنة والمدنية وغيرها!!!!
وملخص الحال الآن معسكران... معسكر الصهيونية اليهودية والمسيحية العلمانية ومن شايعهم وسار في ركبهم من الملحدين والعلمانيين المسلمين بالوراثة وبقايا الشيوعيين، ومعسكر الإسلام والمسلمين وفيه قلة أصبحت اليوم مستضعفة مستهدفة مثلهم كزبد البحر. المعسكر الأول بقادته ورموزه وسطوته وقوته وصوته العالى الذي يملأ الأرض حاليا لا مانع أبدا لديه أن يترك الآخرة بنعيمها وجنانها وأنهارها لأصحاب الهلاوس الدينية من أهل المعسكر الآخر في مقابل أن ينفردوا هم بالسلطة والثروة الدنيوية وكنوز الأرض وخيراتها ونعيمها. وهم لا يريدون أي تقدم علمي أو أخلاقي للمعسكر الآخر حتى يظلوا في حاجتهم وحمايتهم. كذلك هم لا يريدون نجاح أي مشروع إسلامي أو أي نظام حكم إسلامي أو أي نموذج اسلامي لان في ذلك كل الخطر على مصالحهم، فيضعون على كراسي الحكم في بلاد الثروة والبلاد المؤثرة بالتزوير تارة والانقلابات العسكرية والتمويل والدعم تارة أخرى من يخدم مصالحهم فقط..ونحن نعيش مثالا صارخا لا يقبل الشك...فلو كان مثلا بشار الأسد جزار سوريا ممانعا أو مقاوما حقاً لما ظل على الحياة أصلا بين عشية وضحاها...وبالمقابل فلأن محمد مرسى لم يكن ليخدم أهدافهم فقد اجتمعوا عليه جميعا منذ اليوم الأول لانتخابه فوضعوا له الفخاخ والعراقيل وأوغروا عليه الصدور حتى اغتصبوا منه شرعيته في عام واحد فقط!!! ويصدق في الوضع الحالي قول الله تعالى (قل كل متربص فتربصوا فستعلمون من أصحاب الصراط السوي ومن اهتدى).
أما أصحاب معسكر الإسلام والمسلمين المقابل، فليس عند المؤمنين الحقيقيين منهم أدنى شك في نصر الله لدينه، وهو تحقيق لوعد الله الحق (هو الذي أرسل رسوله بالهدي ودين الحق ليظهره على الدين كله). أما كيف سيتحقق هذا أو متى فهو غيب ليس يعلمه سوى الله سبحانه هو وحده الذي يجري المقادير وهو خير الماكرين. كل ما نؤمن به - نحن أمة محمد - بأن الله لن يغير حالنا حتى نغير نحن أنفسنا. فاللهم إنا نسألك أن تصلح حالنا و أن تشد من أزرنا حتى نصبح كما تحب وترضى فيتحقق فينا وعدك الحق، ومن أصدق من الله وعدا؟
وملخص الحال الآن معسكران... معسكر الصهيونية اليهودية والمسيحية العلمانية ومن شايعهم وسار في ركبهم من الملحدين والعلمانيين المسلمين بالوراثة وبقايا الشيوعيين، ومعسكر الإسلام والمسلمين وفيه قلة أصبحت اليوم مستضعفة مستهدفة مثلهم كزبد البحر. المعسكر الأول بقادته ورموزه وسطوته وقوته وصوته العالى الذي يملأ الأرض حاليا لا مانع أبدا لديه أن يترك الآخرة بنعيمها وجنانها وأنهارها لأصحاب الهلاوس الدينية من أهل المعسكر الآخر في مقابل أن ينفردوا هم بالسلطة والثروة الدنيوية وكنوز الأرض وخيراتها ونعيمها. وهم لا يريدون أي تقدم علمي أو أخلاقي للمعسكر الآخر حتى يظلوا في حاجتهم وحمايتهم. كذلك هم لا يريدون نجاح أي مشروع إسلامي أو أي نظام حكم إسلامي أو أي نموذج اسلامي لان في ذلك كل الخطر على مصالحهم، فيضعون على كراسي الحكم في بلاد الثروة والبلاد المؤثرة بالتزوير تارة والانقلابات العسكرية والتمويل والدعم تارة أخرى من يخدم مصالحهم فقط..ونحن نعيش مثالا صارخا لا يقبل الشك...فلو كان مثلا بشار الأسد جزار سوريا ممانعا أو مقاوما حقاً لما ظل على الحياة أصلا بين عشية وضحاها...وبالمقابل فلأن محمد مرسى لم يكن ليخدم أهدافهم فقد اجتمعوا عليه جميعا منذ اليوم الأول لانتخابه فوضعوا له الفخاخ والعراقيل وأوغروا عليه الصدور حتى اغتصبوا منه شرعيته في عام واحد فقط!!! ويصدق في الوضع الحالي قول الله تعالى (قل كل متربص فتربصوا فستعلمون من أصحاب الصراط السوي ومن اهتدى).
أما أصحاب معسكر الإسلام والمسلمين المقابل، فليس عند المؤمنين الحقيقيين منهم أدنى شك في نصر الله لدينه، وهو تحقيق لوعد الله الحق (هو الذي أرسل رسوله بالهدي ودين الحق ليظهره على الدين كله). أما كيف سيتحقق هذا أو متى فهو غيب ليس يعلمه سوى الله سبحانه هو وحده الذي يجري المقادير وهو خير الماكرين. كل ما نؤمن به - نحن أمة محمد - بأن الله لن يغير حالنا حتى نغير نحن أنفسنا. فاللهم إنا نسألك أن تصلح حالنا و أن تشد من أزرنا حتى نصبح كما تحب وترضى فيتحقق فينا وعدك الحق، ومن أصدق من الله وعدا؟
الأربعاء، نوفمبر 20
من أجمل ما قرأت هذا الأسبوع للأستاذ عبد الوهاب مطاوع رحمه الله...
"بعض ما ميز به الله سبحانه
وتعالي الإنسان عن وحوش الغابة التي لا يردعها عن تحقيق
أهدافها البدائية رادع من دين أو أخلاق، هو القدرة علي التمييز بين الحق
والباطل أو ما اصطلح على تسميته بالضمير، وهو شئ فطري في الإنسان لكنه يتأثر بالوسط الذي ينشأ فيه، ويشبهه بعض العلماء
بإحدى عضلات الجسم التي إن لم تستخدم ضعفت، ومشكلة بعض
البشر هي أنهم لا يستخدمون عضلة الضمير هذه كثيرا في حياتهم الشخصية،
مما يؤدي إلى ضعفها ووهنها ويزيد من تعقيد الحياة وعنائها ومشاكلها على الغير. ومن المؤسف أنهم بذلك إنما
يتنازلون طوعا عما كرمهم به ربهم وميزهم عن وحوش الغابة،
فيتصرفون في حياتهم كالوثنيين الذين لا يرجون بأعمالهم الله واليوم
الآخر، ولا يخشون عقابا سماويا عاجلا أو مؤجلا على شئ مما يصنعون، وكأنما لا حساب ولا عقاب في الدنيا أو الآخرة علي
إيذاء الغير أو الافتراء عليهم بالباطل أو خيانة الشرف
والأمانة أو اغتصاب حقوق الآخرين والطمع فيما لا يحق لهم، أو إعانة الظالم على
ظلمه رجاء منفعة أو طلبا لعرض من أعراض الدنيا أو إيثارا
للسلامة.
وعلي الناحية الأخرى يؤمن أصحاب النفوس الشريفة أن الضمير المستريح هو أفضل منوم في العالم كما يقول أحد الحكماء، وأن اجتناب الإثم والفواحش وإيذاء الغير والافتراء عليهم بالباطل هو خير ضمان لراحة القلب والضمير.. وأفضل دعاء إلى السماء أن تحميهم من غوائل الأيام ولا عجب في ذلك لأن النفس الشريفة كما يقول لنا الإمام شمس الدين محمد بن قيم الجوزيه: لا ترضى من الأشياء إلا بأعلاها وأفضلها وأحمدها عاقبة، والنفس الدنيئة تحوم حول الدناءات وتقع عليها كما يقع الذباب علي الأقذار، وهذا هو معنى قوله سبحانه وتعالي : "قل كل يعمل على شاكلته" الإسراء84."
وعلي الناحية الأخرى يؤمن أصحاب النفوس الشريفة أن الضمير المستريح هو أفضل منوم في العالم كما يقول أحد الحكماء، وأن اجتناب الإثم والفواحش وإيذاء الغير والافتراء عليهم بالباطل هو خير ضمان لراحة القلب والضمير.. وأفضل دعاء إلى السماء أن تحميهم من غوائل الأيام ولا عجب في ذلك لأن النفس الشريفة كما يقول لنا الإمام شمس الدين محمد بن قيم الجوزيه: لا ترضى من الأشياء إلا بأعلاها وأفضلها وأحمدها عاقبة، والنفس الدنيئة تحوم حول الدناءات وتقع عليها كما يقع الذباب علي الأقذار، وهذا هو معنى قوله سبحانه وتعالي : "قل كل يعمل على شاكلته" الإسراء84."
*******
"لا يستطيع الإنسان مهما
فعل أن يمنع الآخرين من الإساءة إليه إذا تحركت نوازع الغدر والشر فى أعماقهم ..
ولا غرابة فى ذلك، فأفعال الآخرين لا تقع فى نطاق سيطرتنا ولا نملك أن نخضعها
لإرادتنا مهما أجهدنا أنفسنا فى محاولة ذلك ، ومهما كان حجم العطاء الذي نقدمه لهم
، إذ أننا حتى لو كنا نستطيع أن نأسرهم بمعاملتنا الطيبة وعطائنا الصادق لهم فى
كثير من الأحيان ، فإن نزعات النفس البشرية الغامضة كثيرة أيضا، وغرائزنا وأهواؤنا
الجامحة وحوش ضارية تتلوى داخلنا تريد أن تحطم القيود الأخلاقية والدينية التي
نكبلها بها لتنطلق فى الحياة كما تنطلق الوحوش فى الغابة ، فإذا وهنت هذه القيود
لدى البعض أو ضعفت درجة سيطرتهم على وحوش الغرائز والأهواء فى أعماقهم ، انطلقت من
مكامنها تسعى إلى كل ما يحقق لها رغباتها دون توقف كثير أو قليل أمام القيم الأخلاقية
أو أمام حقوق الآخرين علينا وواجباتنا تجاههم ، والإنسان يسأل فى النهاية عما يفعل
هو وليس عما ارتكبه الآخرون ضده من خيانة أو غدر أو تصرفات خسيسة .. وليس مما يسىء
إلينا فى نظر أنفسنا وأنظار المنصفين أيضا أن نتعرض أحيانا لشىء من ذلك فالجريمة
عار مرتكبها لا عار ضحيتها .. والسارق أحق بأن يشعر بالمهانة من المسروق ، لأنه هو
الذى ارتكب عملا شائنا يفقده اعتباره لدى الآخرين وليس الضحية. أما غدر الغادرين
.. فعارهم وحدهم ولو آذى مشاعرنا وألحق بنا أقصى الألم. وكل ما يملكه المرء فى
مواجهة إساءة الآخرين له هو أن يدفع الإساءة الجارحة عن نفسه وأن يرفض السكوت
عليها أو التسامح معها ، وأن يتخذ ممن أساء إليه موقفا عادلا ترضى به نفسه وكرامته."
*******
"لو سطر كل إنسان تجربته في الحياة علي
الورق سعيدة كانت أم شقية لأضافت بكل تأكيد إلي معرفة الآخرين بالنفس البشرية الكثير.. وفي الحق انه ليست هناك دائما تجارب شقية أو تجارب سعيدة من البداية إلي النهاية, لأن الحياة مزيج عجيب من الاثنين ولا بأس بذلك لأنه سنة الحياة , ولأن المهم هو أن يسقط المطر وينبت الخير في النهاية لمن بذر الحب والوفاء والعطاء
للآخرين!"الاثنين، نوفمبر 18
Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-Lidose) and the innovator isotretinoin formulation: A randomized, 4-treatment, crossover study
Journal of the American Academy of Dermatology, November, 2013
Guy F. Webster, MD, PhD
Background
A high-fat meal is needed for optimal absorption of isotretinoin. A new formulation of isotretinoin, which enhances absorption of isotretinoin in the absence of dietary fat, has recently been approved by the Food and Drug Administration (FDA).Objective
We sought to compare the pharmacokinetic profiles of a new formulation of isotretinoin (isotretinoin-Lidose) with the innovator isotretinoin formulation.Methods
This study was an open-label, single-dose, randomized, 4-treatment, crossover comparative trial between a new and innovator formulation of isotretinoin in the fasting and fed states.Results
Both formulations were bioequivalent under fed conditions. As expected in a fasting state, absorption of both formulations was reduced. A considerable difference between the 2 drugs occurred under fasted conditions–there was a marked improvement in overall bioavailability of the isotretinoin-Lidose formulation. Mean plasma levels of the isotretinoin-Lidose formulation during fasting reached 66.8% of that observed with a fatty meal, and those of the isotretinoin formulation only reached 39.6% of that observed with a fatty meal.Limitations
Only the FDA-stipulated standard high-fat, high-calorie meal of 50-g fat was studied in the fed state.Conclusion
Isotretinoin-Lidose formulation is bioequivalent to the innovator formulation under fed conditions with regard to its pharmacokinetic profile but delivers twice as much isotretinoin and 4-oxo-isotretinoin when administered after an overnight fast.
Key words: acne, area under the curve, bioavailability, fasting, fed, isotretinoin, maximum measured plasma concentration over sampling time period, systemic exposure, time of maximum measured plasma concentration
Abbreviations used: AUCt, area
under plasma concentration versus time curve from time zero (0 hour) to
time of last measurable plasma concentration, calculated by linear
trapezoidal method, AUCi, area
under plasma concentration verus time curve from time zero (0 hour) to
infinity (AUCi calculated as sum of AUCt + measured plasma concentration
at time of last measurable plasma concentration/apparent first order
elimination rate constant), BA, bioavailability, BE, bioequivalent, Cmax, maximum measured plasma concentration over sampling time period, FDA, Food and Drug Administration, Tmax, time of maximum measured plasma concentration
Capsule Summary
Absorption of an orally administered drug is influenced by its solubility and intestinal permeability.∗
Food is a well-known agent that can have an impact in drug absorption.
For some drugs, food will have no effect and for other drugs, it can
either increase or decrease the amount of absorption. Isotretinoin is a
molecule with good permeability and poor solubility in the aqueous
environment of the intestine, and its absorption is greatly enhanced by
fatty foods. When taken without food, absorption (permeability) is low.
Fasted plasma levels of current isotretinoin formulations are nearly 60%
lower than levels in the fed state.1
To ensure optimal and consistent absorption and maintenance of
therapeutic blood concentrations, isotretinoin must be taken with food,1 preferably with a high-fat meal (50% caloric intake from fat) as defined by the Food and Drug Administration (FDA).2A technology (Lidose) now exists that enhances the intestinal absorption of poorly soluble agents, such as isotretinoin. Lidose is a novel formulation that uses lipid agents to encase lipophilic drugs and create an optimal environment for absorption.3 The FDA has recently approved isotretinoin-Lidose, a new formulation of isotretinoin, which can be taken without regard to meals.
In this study, we describe the pharmacokinetic profiles of this new agent and compare it with the innovator formulation of isotretinoin.
Methods
This trial was an open-label, single-dose, randomized, 4-treatment, crossover comparative bioavailability (BA) study. The ethics review board at Optimum Clinical Research Inc approved the study protocol, its amendments, and informed consent form. Full trial protocol was submitted to the FDA during the approval process for isotretinoin-Lidose.Subjects
All 60 individuals who were selected for the study met the inclusion and exclusion criteria, and were judged by the investigator to be healthy.Inclusion criteria included:
•Healthy, nonsmoking, men and nonpregnant, nonlactating women, 18 to 55 years of age, inclusive.
•Body weight within ±15% of the appropriate weight for the individual's height and frame.
•Women
were either unable to have children, willing to remain abstinent, used
an effective method of double-barrier birth control, or used a hormonal
contraceptive agent.
Exclusion criteria included:
•Known history or presence of any clinically significant disease.
•Known or suspected carcinoma.
Study drugs and administration
Study drugs were administered in a clinical facility over 4 periods/intervals with a 21-day washout period between successive administrations:Isotretinoin-Lidose (Absorica) capsules manufactured for Cipher Pharmaceuticals Inc, Barbados, by Galephar PR Inc, lot 28A02.
Isotretinoin (Accutane) capsules manufactured by Roche Laboratories Inc, Nutley, NJ, lot U0622.
A predetermined computer-generated randomization scheme for the 4 treatment periods (assigned to participants in 1 of 12 different sequences):
Treatment A: Isotretinoin-Lidose (2 × 20 mg) administered after an overnight fast of at least 10 hours.
Treatment B: Isotretinoin-Lidose (2 × 20 mg) 30 minutes after consumption of a modified∗ high-fat, high-calorie breakfast with a reduced vitamin-A content.
Treatment C: Isotretinoin (1 × 40 mg) administered after an overnight fast of at least 10 hours.
Treatment D: Isotretinoin (1 × 40 mg) administered 30 minutes after consumption of a modified∗ high-fat, high-calorie breakfast with a reduced vitamin-A content.
Blood sample collection and handling
Blood samples were collected within 1 minute of their scheduled time at regular intervals from 10 hours before to 72 hours after each drug administration.Analyses for isotretinoin, 4-oxo-isotretinoin, tretinoin, and 4-oxo-tretinoin in human plasma were performed using a validated analytical method with a calibration range of 1.00 to 750 ng/mL (isotretinoin and 4-oxo-isotretinoin) and 1.00 to 250 ng/mL (tretinoin and 4-oxo-tretinoin). All laboratory personnel were blinded regarding the randomization scheme and treatment plan.
Clinical evaluations
Laboratory tests included those for hematology, serum chemistry, urinalysis, HIV, hepatitis B antigen, and hepatitis C for all individuals, and human chorionic gonadotropin pregnancy tests on women who were not postmenopausal and who did not have a hysterectomy. Blood pressure, pulse rate, temperature, and respiration were also measured.A physical examination was performed on all individuals upon study completion or upon removal from the study.
Data analysis
Pharmacokinetic analysis was conducted using a noncompartmental approach.4 The following parameters were estimated: area under plasma concentration versus time curve from time zero (0 hour) to time of last measurable plasma concentration, calculated by linear trapezoidal method (AUCt); area under plasma concentration versus time curve from time zero (0 hour) to infinity (AUCi) (AUCi calculated as sum of AUCt + measured plasma concentration at time of last measurable plasma concentration/apparent first order elimination rate constant); maximum measured plasma concentration over sampling time period (Cmax); and time of maximum measured plasma concentration (Tmax).Statistical analysis was performed to compare the BE of the isotretinoin-Lidose formulation and the isotretinoin formulation under fasting and fed conditions. The pharmacokinetic parameters were statistically analyzed according to current FDA guidance.5
Arithmetic means, SD, and coefficients of variation were calculated. Analyses of variance were performed on the log-transformed AUCt, AUCi, and Cmax and on the untransformed Tmax. A 5% level of significance was used for within-subject comparisons (ie, period, treatment). Each analysis of variance included a calculation of least-squares means, adjusted differences between treatment means, and the SE associated with these differences.
The 90% confidence intervals for the ratio of drug treatment least-squares means were calculated for the AUCt, AUCi, and Cmax parameters using log-transformed data. The confidence intervals are expressed as a percentage relative to the least-squares mean of the isotretinoin formulation.
Results
Patient demographics
A total of 60 healthy individuals (40 male and 20 female) were dosed in period 1. Three individuals did not complete period 2 of the study: 1 withdrew after period 2 check-in for personal reasons, and 2 were dismissed because of nonadherence. The remaining individuals, 57, were dosed in periods 3 and 4 and completed the study. They had a mean ± SD (range) age of 36 ± 9 (21-55) years, height of 169.7 ± 8.7 (150.0-188.0) cm, and weight of 71.5 ± 9.1 (49.8-86.4) kg.Pharmacokinetic analyses
The average of the measured predose concentration levels of isotretinoin, 4-oxo-istoretinoin, tretinoin, and 4-oxo-tretinoin at −10, −2, and 0 hours was used as baseline for each individual, within each period. The subject- and period-specific baseline values were subtracted from the subsequent postdose measured levels. The 0-hour levels of isotretinoin and its metabolites and the negative levels for the baseline-adjusted concentrations were set to 0. The pharmacokinetic analysis was performed on the baseline-adjusted analyte levels.Arithmetic means and geometric means for AUCt, AUCi, Cmax, and Tmax in the 4 dosing periods were calculated for isotretinoin, 4-oxo-isotretinoin, tretinoin, and 4-oxo-isotretinoin, respectively.
Effect of food
The high-fat, high-caloric meal produced the highest observed plasma concentrations of isotretinoin and metabolites for both formulations when compared with the fasting state. Food increased the systemic exposure to isotretinoin to 6695.87 ng•h/mL with the isotretinoin-Lidose formulation and to 6315.15 ng•h/mL with the innovative isotretinoin formulation. The peak exposure to isotretinoin (Cmax) was 434.33 ng/mL for the isotretinoin-Lidose formulation and 431.88 ng/mL for the isotretinoin formulation. Food triggered a similar delay between the 2 formulations in the time to reach Cmax. Time of maximum plasma concentrations reached with food was 6.85 hours for the isotretinoin-Lidose formulation and 6.75 hours for the isotretinoin formulation.Table I. Menu for modified, high-fat, high-calorie breakfast
| Calories | Carbohydrates | Protein | Fat | |
|---|---|---|---|---|
| 1 Regular bagel | 300 | 67 g | 12 g | 3 g |
| 2 T peanut butter | 250 | 9 g | 12 g | 22 g |
| 5 Slices bacon | 125 | 0.2 g | 10 g | 10 g |
| 6 Fluid oz apple juice | 80 | 22 g | 0.1 g | 0.1 g |
| 1 Dutchie donut (square donut containing raisins and coated with sugary glaze from Canadian Tim Hortons chain) | 250 | 33 g | 3 g | 15 g |
| Total | 1005 | 131.2 g | 37.1 g | 50.1 g |
Pharmacokinetic data from the 2 formulations were BE under fed conditions. The 90% confidence interval of the ratios of geometric means of the 2 formulations conducted under fed conditions for AUCt, AUCi, and Cmax were within the 80% to 125% range for isotretinoin, 4-oxoisotretinoin, tretinoin, and 4-oxo-tretinoin. Given these results, isotretinoin-Lidose exhibited equivalent rate and extent of exposure to isotretinoin under high-fat fed conditions in human beings after a single dose.
Effect of fasting
AUCt, AUCi, and Cmax for both formulations were reduced in the absence of food. Significant differences were observed between the 2 formulations in the fasting state. After an overnight fast, the isotretinoin-Lidose formulation delivered approximately twice as much isotretinoin (4470.45 vs 2500.01 ng•h/mL) and 4-oxo-isotretinoin (11,865.08 vs 6049.60 ng•h/mL) as did the isotretinoin formulation. Similar findings were observed for tretinoin and 4-oxo-tretinoin (data not shown), respectively. Mean AUCi plasma levels of isotretinoin from the isotretinoin-Lidose formulation during fasting reached 66.8% of that observed with food, and those of the isotretinoin formulation only reached 39.6% of that observed with food.Cmax for isotretinoin was also twice as high with the isotretinoin-Lidose formulation when compared with the isotretinoin formulation: 323.18 versus 161.43 ng•h, respectively. Similar to that observed with AUCi, Cmax for isotretinoin with the isotretinoin-Lidose formulation during fasting represented 74% of the Cmax achieved after a meal and with the isotretinoin formulation, it only represented 37% of the Cmax achieved after a meal. For 4-oxo-isotretinoin, Cmax was 163.73 ng•h after fasting for the isotretinoin-Lidose formulation (46.5% of the Cmax after a meal) and 70.55 ng•h for the isotretinoin formulation (22.7% of the Cmax after a meal).
Mean plasma concentrations of isotretinoin over time
Although both formulations share a similar Tmax for isotretinoin in the fasting state (about half of the Tmax under fed conditions), mean peak plasma concentration of isotretinoin is clearly higher with the isotretinoin-Lidose formulation, reaching 289.49 ng/mL at 3 hours after ingestion versus the isotretinoin formulation, which reached 133.75 ng/mL at 3.5 hours (Fig 1). After reaching peak concentrations, plasma concentrations of isotretinoin declined at approximately the same rate for both formulations; however, overall, isotretinoin levels from the Lidose formulation always remained higher during the clearance phase.
Fig 1.
Mean baseline-adjusted plasma isotretinoin concentration (conc) versus time curves (N = 57).
Mean measured plasma concentrations of 4-oxo-isotretinoin, tretinoin, and 4-oxo-tretinoin over time followed similar kinetics as mean plasma concentrations of isotretinoin (data not shown).
Adverse events
There were 55 adverse events involving 25 individuals during the course of the 4 periods of the study. Headache was the most commonly reported adverse event for all 4 periods. There were no serious adverse events recorded, and none of the adverse events had a significant impact on the safety of the participants or on the integrity of the study results.Discussion
Results from this crossover comparative study demonstrate a BE of the isotretinoin-Lidose formulation and the isotretinoin formulation under fed conditions: AUCt, AUCi, Cmax, and Tmax for the 4 analytes were comparable. As anticipated, a high-fat, high-calorie meal increased the relative BA of both formulations compared with the fasting state and is in agreement with results reported by Colburn et al.1In contrast, striking differences in the BA of isotretinoin were observed between the 2 formulations in the fasting state. Systemic exposure of isotretinoin was 1.8-fold higher with isotretinoin-Lidose than with the isotretinoin formulation. In addition, mean Cmax of isotretinoin in the fasting state was 66.8% of the mean Cmax observed in the fed state with the isotretinoin-Lidose formulation versus 39.6% with the isotretinoin formulation.
More than 75% of individuals in this study absorbed less than 50% isotretinoin when it was taken in a fasting state compared with a high-fat meal (Fig 2). In the case of isotretinoin-Lidose, 75% of individuals absorbed 60% or more isotretinoin in the fasting state compared with taking it with a fatty meal. The box plot analysis (Fig 2) shows the variability of absorption of these formulations. Only 1 individual had a higher ratio of fasting to fed area under the curve (AUC) for isotretinoin and only in a handful of individuals was the isotretinoin-Lidose not more effective than isotretinoin alone.
Fig 2.
Effect of food on absorption. Top and bottom of the box are the 75th and 25th percentiles, respectively, dash line is the median, solid line is the mean, bars are the highest and lowest values of not more than 1.5 times the length of the box, circles are outliers, and x is an extreme outlier (greater than 3 times the intrabox distance). More than 75% of individuals in the fasting state achieved plasma levels less than 50% of that when isotretinoin was taken with food (mean difference 39.6%). In the same individuals, plasma levels with the new formulation reached 66.8% of that found with food. AUC, Area under the curve.
In summary, isotretinoin-Lidose is a novel formulation of isotretinoin that is BE to innovator isotretinoin under fed conditions with regard to its pharmacokinetic profile but delivers twice as much isotretinoin and 4-oxo-isotretinoin when administered after an overnight fast. The clinical consequences of the decreased variability in absorption between the fed and fasted states with isotretinoin-Lidose will need to be established in future studies.
الأحد، نوفمبر 3
Ghamriny's clinical collection; Image of the month, November 2013, مجموعة حالات د. الغمريني
AGEP (Acute generalized exanthematous pustulosis).
الأربعاء، أكتوبر 9
Ghamriny's clinical collection; Image of the month, October 2013, مجموعة حالات د. الغمريني
Acrokeratosis verruciformis of hopf
الثلاثاء، سبتمبر 10
Ghamriny's synopsis of dermatology, andrology & STDs.
كتاب الأمراض الجلدية والذكورة والأمراض التناسلية لطلبة بكالوريوس الطب
الطبعة الأولى بالمكتبات الآن بكليات الطب
The easiest and yet strongest introduction to dermatology & andrology
الجمعة، سبتمبر 6
مواعيد عمل عيادة اكتوبر اعتبارا من 7 سبتمبر 2013
مواعيد عمل عيادة أكتوبر من الساعة السابعة مساءا وحتى التاسعة والنصف مساءا..
الثلاثاء، سبتمبر 3
Ghamriny's clinical collection; Image of the month, September 2013, مجموعة حالات د. الغمريني
Lichen planus; nail dystrophy.
« PreviousNext »Journal of the American Academy of Dermatology
Volume 69, Issue 3 , Pages 450-462, September 2013
Volume 69, Issue 3 , Pages 450-462, September 2013
The skin and hypercoagulable states
Article Outline
- Abstract
- Hemostasis
- Hypercoagulable states
- Skin manifestations and syndromes
- The use of antiplatelet and anticoagulant therapy in dermatology
- Conclusion
- References
- Copyright
Hypercoagulable states (HS) are inherited or acquired conditions that predispose an individual to venous and/or arterial thrombosis. The dermatologist can play a vital role in diagnosing a patient's HS by recognizing the associated cutaneous manifestations, such as purpura, purpura fulminans, livedo reticularis, livedo vasculopathy (atrophie blanche), anetoderma, chronic venous ulcers, and superficial venous thrombosis. The cutaneous manifestations of HS are generally nonspecific, but identification of an abnormal finding can warrant a further workup for an underlying thrombophilic disorder. This review will focus on the basic science of hemostasis, the evaluation of HS, the skin manifestations associated with hypercoagulability, and the use of antiplatelet and anticoagulant therapy in dermatology.
Key words: anetoderma, antiphospholipid antibody syndrome, chronic venous ulcer, hemostasis, hypercoagulable states, livedo reticularis,livedo vasculopathy, purpura, superficial venous thrombosis, thrombosis
Abbreviations used: APC, activated protein C, APLA, antiphospholipid antibody, APLS, antiphospholipid antibody syndrome, CVU, chronic venous ulceration, DIC, disseminated intravascular coagulation, DVT, deep venous thrombosis, HIT, heparin-induced thrombocytopenia, HS,hypercoagulable states, LMWH, low-molecular-weight heparin, LR, livedo reticularis, LV, livedo vasculopathy, PE, pulmonary embolism, PF,purpura fulminans, SVT, superficial venous thrombosis, TF, tissue factor, TTP, thrombotic thrombocytopenic purpura, VTE, venous thromboembolism
Capsule Summary
Hemostasis
Hemostasis is the physiologic response that minimizes blood loss while maintaining blood flow after an injury to a vessel. Endothelial injury triggers immediate vasoconstriction and exposes tissue factor (TF) and collagen in the subendothelial matrix, providing a surface for platelet adherence and plug formation. Traditionally, coagulation has been described as a cascade of enzyme reactions, consisting of the extrinsic and intrinsic pathways converging on the common pathway to produce an insoluble fibrin clot.1, 2, 3 Although the extrinsic and intrinsic pathways correlate with the laboratory values of prothrombin time and partial thromboplastin time, respectively, this model has shortcomings and fails to describe the importance of cells during the coagulation process.3 Thus, a “cell-based” model of coagulation has been proposed, which consists of 3 phases: initiation, amplification, and propagation (Fig 1), and results in platelet activation and fibrin clot production.3 TF, a cell membrane glycoprotein, is responsible for the initiation of coagulation, which occurs on the surface of a TF-bearing cell and results in the production of small amounts of thrombin (activated [a] factor [F] II).3 During amplification, thrombin generated in the initiation phase activates factors V, VIII, and XI on the negatively charged phospholipid surface of a platelet leading to platelet activation.3 Finally, in the propagation phase, significant amounts of thrombin are generated on the surface of an activated platelet, resulting in the conversion of fibrinogen into insoluble fibrin.3, 4, 5
Fig 1.
Simplified cell-based model of coagulation. A, Initiation and amplification. On surface of tissue factor (TF)-bearing cell, such as fibroblast, TF complexes with activated factor VII (FVIIa) to activate FIX and FX, ultimately resulting in thrombin (FIIa) generation via FVa and FXa prothrombinase complex.3, 4 Amplification occurs on platelet, and thrombin formed during initiation phase activates FV, FVIII, and FXI, leading to activated platelet. B,Propagation. During propagation, significant amounts of thrombin are formed on surface of activated platelet via prothrombinase complex and tenase complex (FIXa and FVIIIa).5Thrombin cleaves soluble fibrinogen to insoluble fibrin, which polymerizes and is cross-linked by FXIIIa. Plasmin, activated by tissue plasminogen activator from plasminogen, is responsible for fibrinolysis.
Hypercoagulable states
Venous and arterial thromboses are major causes of morbidity and mortality. Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE). Hypercoagulability, in addition to stasis (slow flow) and endothelial injury, compose the Virchow triad of risk factors for venous thrombosis.6 Several components can contribute to a thrombophilic state, including genetic and acquired risk factors (Table I), triggering factors, and/or a lack of appropriate pharmacologic or nonpharmacologic prophylaxis. Arterial thrombosis results in an ischemic event, such as acute coronary syndrome, stroke, or limb ischemia. These events are often the consequence of a ruptured atherosclerotic plaque that provides a surface for platelet aggregation that can lead to vessel occlusion.7 In these high-flow vessels, platelets are the primary mediators of thrombosis.
Table I. Primary and secondary hypercoagulable states
Hypercoagulable states (HS) can be divided into primary (inherited) or secondary (acquired) conditions (Table I) and are associated with increased risk of venous thrombosis or both venous and arterial thrombosis (Table II). The cutaneous manifestations of HS are generally not specific for a certain condition, but recognition of an abnormal finding can warrant a further workup for an underlying thrombophilic condition or VTE.
Table II. Risks factors for venous and arterial thrombosis
The evaluation of HS begins with a thorough history and physical examination. The dermatologist can recognize cutaneous findings that are associated with underlying HS and perform a skin biopsy and laboratory tests to further evaluate. The preliminary laboratory tests used to evaluate for HS are listed in Table III, and include gene mutations, antiphospholipid antibodies (APLAs), and anticoagulant activity levels. In addition to blood work, compression ultrasonography can be used to evaluate the deep venous system if a patient has a suspected DVT or superficial venous thrombosis (SVT). If there are symptoms to suggest PE, imaging studies such as a high-resolution computed tomography scan of the chest with contrast or ventilation perfusion scan may be obtained. For arterial thrombosis, Doppler studies, angiography, or magnetic resonance angiography can be performed. Appropriate referral to specialists should be considered, including the hematologist, internist, or intensivist, depending on the clinical scenario.
Table III. Laboratory tests for evaluation of hypercoagulable states
APLA, Antiphospholipid antibody; dRVVT, dilute Russell viper venom test; HS, hypercoagulable states; MTHFR, methyltetrahydrofolate reductase; PL, phospholipid; PTT, partial thromboplastin time.
Primary HS
Factor V Leiden
Factor V Leiden is the most common primary HS, occurring in 5% to 15% of the population and inherited in an autosomal dominant pattern.6 Approximately 20% of patients presenting with their initial episode of VTE have a FV Leiden mutation.8 A point mutation in the FV gene switches guanine (G) to adenine (A) at nucleotide 1691 and codes for glutamine instead of arginine. FV is usually inactivated by activated protein C (APC) by cleavage at 3 sites, however, the FV Leiden mutant is resistant to degradation by APC.9, 10 The FV Leiden mutation accounts for over 90% of APC resistance.11
Prothrombin G20210A
Prothrombin G20210A mutation is the second most common primary HS, present in approximately 5% of the population, and also inherited in an autosomal dominant pattern.11 This mutation is present in approximately 10% of patients presenting with their initial episode of VTE.8 A mutation at nucleotide 20210 in the 3'-untranslated region of the prothrombin gene causes a guanine (G) to adenine (A) substitution.12 This mutation is associated with elevated plasma levels of prothrombin and increased thrombin formation.13
Methyltetrahydrofolate reductase and hyperhomocysteinemia
Homocysteine is an amino acid, with elevated serum levels leading to increased risk of both venous and arterial thrombosis through an unknown mechanism. Inherited causes are secondary to mutation of the enzyme methyltetrahydrofolate reductase, or less commonly cystathione-β-synthase; the enzyme deficiency in congenital homocystinuria.11 Patients with a homozygous methyltetrahydrofolate reductase mutation are at increased risk of VTE.14 Acquired hyperhomocysteinemia can be secondary to renal or thyroid disease, smoking, aging, or a vitamin deficiency (B12, B6, or folate).
Antithrombin III
Antithrombin III deficiency was the first primary thrombophilic state identified, inherited in an autosomal dominant pattern and occurring in less than 0.02% of the population.11, 15 Antithrombin III degrades thrombin (IIa) and multiple other activated coagulation factors (IXa, FXa, XIa, and XIIa), thus a deficiency leads to a thrombophilic state because of increased levels of these activated factors. The heterozygous deficiency can be quantitative (type I) or qualitative (type II). The homozygous condition is usually fatal in the neonatal period. Antithrombin III deficiency, and protein C and S deficiency, can be acquired secondary to consumption (infection, sepsis, disseminated intravascular coagulation [DIC]), decreased production (hepatic failure), or excess loss (nephrotic syndrome).
Protein C or protein S deficiency
Heterozygous protein C deficiency is an autosomal dominant condition present in 0.2% of the population and heterozygous protein S deficiency is an autosomal dominant condition present in less than 0.1% of the population.11 Homozygous protein C or protein S deficiency often results in neonatal purpura fulminans (PF) and is usually fatal.16 There have been numerous mutations of the protein C gene identified. The deficiency can either be quantitative (type I) or qualitative (type II). APC, in conjunction with its cofactor, protein S, inactivates FVa and FVIIIa, thus protein C or protein S deficiency leads to unbalanced activation of these factors and increased production of thrombin.9 Protein C or protein S deficiency can also be acquired secondary to consumption, decreased production, or excess loss, by similar mechanisms as acquired antithrombin III deficiency.
Secondary HS
Hospitalization, trauma, and surgery
Hospitalization is a risk factor for VTE, likely as a result of immobilization, with the severity of the illness also contributing to the risk.17 Patients admitted with major trauma are at an exceptionally high risk of DVT. A prospective study of 349 patients with major trauma identified at least 1 DVT present in 58% of the patients.18 Patients undergoing surgical procedures are also at increased risk of VTE, with numerous associated risk factors, including patient age, a history of VTE, the type and duration of the surgery, and comorbid conditions.
Obesity
The cause of venous and arterial hypercoagulability in obese patients is multifactorial.19, 20 Increased levels of fibrinogen, FVII, FVIII, von Willebrand factor, and plasminogen activator inhibitor have been described, however the exact mechanisms predisposing to thrombosis are unclear.19 The body mass index (kg/m2) correlates with risk of VTE, and increased fat deposition around the abdomen and upper body is associated with arterial thrombosis.21 In addition, elevated levels of leptin, a hormone produced by adipocytes, has been shown to increase the risk of arterial thrombosis.22
Cancer
Patients with cancer are at a higher risk of VTE and arterial thrombosis, with venous thrombosis as the second leading cause of mortality.23 Venous or arterial thrombosis occurs in 15% to 20% of patients with cancer.24 The risk of thrombosis is related to the actual disease and to the associated treatments and procedures. Elevated levels of fibrinogen, FV, FVIII, FIX, FX, fibrin degradation products, and platelets have been reported with malignancy.25 In addition, TF is expressed at higher levels on the surfaces of tumor cells.26 Surgery, chemotherapy, indwelling catheters, immobilization, and infections are other common risk factors leading to an increased risk of thrombosis in patients with cancer.27, 28 The most common malignancies associated with thrombosis include pancreas, stomach, uterus, kidney, lung, and primary brain tumors.29Stomach and pancreas cancer are at very high risk for chemotherapy-associated VTE.29
Medications
Medications can be associated with HS. Hormonal medications, including oral contraceptive pills, estrogen replacement therapy, and selective estrogen receptor modulations are associated with increased risk of thrombosis. Chemotherapeutic agents, including bevacizumab, thalidomide, lenalidomide, cyclophosphamide, chlorambucil, and nitrogen mustard contribute to hypercoagulability in patients with cancer. Commonly used anticoagulants, including heparin and warfarin, can paradoxically be associated with thrombosis, as discussed later.
Pregnancy
Women are at an increased risk of VTE during pregnancy and the postpartum period, with VTE occurring in 0.5 to 2.2 of 1000 pregnancies.30, 31 Women are at the highest risk of DVT during the third trimester, whereas the risk of PE is highest during the postpartum period.31 There are several mechanisms contributing to hypercoagulability in pregnancy, including venous stasis, alterations in coagulation factors, and damage to the venous system.32 During pregnancy, there is increased production of thrombin33 and increased levels of factors VII, VIII, and X; fibrinogen; and von Willebrand factor.32 In addition, there are decreased levels of protein S and resistance to APC.31 Pregnant women should be assessed for thrombophilic risk factors, especially a history of VTE, with low-molecular-weight heparin (LMWH) as the treatment of choice if prophylaxis or treatment of VTE if indicated.32
Skin manifestations and syndromes
Purpura and associated conditions
Purpura
Purpura consists of 5- to 20-mm nonblanching erythematous to violaceous macules, often located on the lower extremities. Many HS produce noninflammatory purpura with microvascular occlusion (Fig 2, A) and the associated conditions include: PF, thrombotic thrombocytopenic purpura (TTP), warfarin (Coumadin) necrosis, heparin-induced thrombotic thrombocytopenia, calciphylaxis, and catastrophic APLA syndrome (APLS).
Fig 2.
Purpura fulminans (PF). A, Noninflammatory microvascular occlusion. B, PF manifesting as purpura and hemorrhagic bullae from Escherichia coli sepsis. (A, Hematoxylin-eosin stain; original magnification: ×10.)
PF (Fig 2) is a dermatologic emergency and presents as multiple violaceous, nonblanching retiform macules and skin necrosis. Cutaneous findings can also include hemorrhagic bullae. Noninfectious neonatal PF occurs secondary to a congenital homozygous deficiency of protein C or S.16 The most common infectious cause of PF is meningococcemia and 15% to 25% of patients with this infection develop PF.34 Neonatal PF has also been reported with group B streptococcus infection.34 Acquired PF is secondary to DIC, sepsis, trauma, malignancy, obstetric complications, hepatic failure, or toxic or immunologic reactions.35 In DIC, the consumption of clotting factors and platelets leads to both thrombosis and hemorrhage. The laboratory abnormalities of DIC include prolonged prothrombin time and partial thromboplastin time, thrombocytopenia, decreased fibrinogen, and increased fibrin split products, including D-dimer. The treatment of DIC involves treating the underlying cause, and cautious use of anticoagulants and blood products.
Thrombotic thrombocytopenic purpura
TTP can be congenital, acquired, or idiopathic, and is classically described by the pentad of fever, hemolytic anemia, thrombocytopenia, renal failure, and neurologic symptoms. The pathogenesis for the majority of patients with acquired TTP involves deficiency of ADAMTS13, a metalloprotease responsible for cleaving polymers of von Willebrand factor during thrombus formation.36, 37 Decreased levels of this enzyme lead to platelet accumulation and microthrombi. The congenital form is a result of a deficiency of ADAMTS13 whereas the acquired form is a result of an IgG antibody to ADAMTS13. Idiopathic TTP cannot be explained by ADAMS13 deficiency and the cause remains unknown. The diagnosis of TTP is based on the characteristic clinical findings. Cases of suspected acquired TTP may be confirmed by the presence of anti-ADAMTS13 antibodies. The most common treatments for TTP include plasmapheresis and rituximab.37
Warfarin necrosis
Warfarin (Coumadin) necrosis can occur in patients with heterozygous protein C or S deficiency after starting the anticoagulant warfarin.11 Warfarin, a vitamin-K antagonist, is used for anticoagulation via inhibition of the vitamin K–dependent coagulation factors, which include FII, FVII, FIX, and FX, as well as proteins C and S. Within 3 to 5 days of initiating warfarin, patients with protein C or S deficiency are at risk for developing warfarin necrosis because of a temporary HS caused by the inhibition of protein C and S. Treatment starts with discontinuing warfarin and reversing its effects with vitamin K and/or fresh frozen plasma.38 Heparin is often used for anticoagulation after the warfarin is stopped, and this condition can be prevented by starting heparin before starting warfarin treatment.38 Local wound care, debridement of ulcers, mastectomy, and amputation may be necessary depending on the severity of the skin necrosis.38
Heparin-induced thrombotic thrombocytopenia
Heparin induced thrombocytopenia (HIT) is caused by the formation of antibodies to the complex of platelet factor 4 and heparin.39 HIT usually occurs 5 to 14 days after initiating heparin and is characterized by a decrease in platelets to less than 150,000, a 30% to 50% decrease in platelets from baseline, or any evidence of thrombosis.40 Symptomatic HIT occurs in 1% to 5% of patients receiving unfractionated heparin, LMWH, or fondaparinux.41, 42 Of patients with HIT, 30% develop thrombosis, also known as heparin-induced thrombotic thrombocytopenia, which has a mortality of 30% and is complicated by loss of limb in 20% of patients.40 These patients are 4 times more likely to form venous thrombosis than arterial thrombosis.40 The treatment involves discontinuing all heparin products and using an alternative anticoagulation therapy, such as a direct thrombin inhibitor, followed by a transition to long-term anticoagulation with a vitamin-K antagonist (warfarin).40
Calciphylaxis
Calciphylaxis, also known as calcific uremic arteriolopathy, is characterized by purpura, skin necrosis, nonhealing ulcers, and calcification of blood vessels. Calciphylaxis primarily affects patients with end-stage renal disease on dialysis but can also occur in nonuremic patients. This condition is associated with mortality as high as 80% when lesions are ulcerated.43The pathogenesis of this disorder is poorly understood, although it has been associated with HS, including protein C or S deficiency44, 45, 46, 47, 48 and APLS.49 In a review of reports of protein C and protein S levels and calciphylaxis, protein C was decreased in 38% of patients and protein S was decreased in 43% of patients.44 A review of 36 patients with nonuremic calciphylaxis revealed protein C or S deficiency in 11% of the patients.50 These deficiencies occurred in the setting of hepatorenal syndrome,51 alcoholic cirrhosis,52 chemotherapy,53 and rheumatoid arthritis.54 Additional evidence for the association with HS has been shown by the use of LMWH46, 55 and tissue plasminogen activator56 for the treatment of calciphylaxis, although the treatment remains controversial.
APLS and associated cutaneous findings
Antiphospholipid antibody syndrome
An APLA is an acquired antibody against cell membrane phospholipids. The most common APLAs include the lupus anticoagulant, anticardiolipin antibody, and anti-β2-glycoprotein I antibody. There are several proposed mechanisms of thrombogenesis associated with APLAs, including the inhibition of the activation of protein C and fibrinolysis, induction of TF, and activation of platelets.57 The APLA must be detected on 2 occasions (at least 12 weeks apart) to diagnose the presence of an APLA.58
APLS is diagnosed by the presence of an APLA, and a thrombotic event, such as VTE or miscarriage.58 Primary APLS occurs without an underlying medical condition whereas secondary APLS is associated with underlying autoimmune conditions, infection, malignancy, or medications. The syndrome can be associated with heart valve vegetations, thrombocytopenia, nephropathy, and neurologic complications, including transient ischemic attack and stroke. The reported skin findings associated with this condition include anetoderma (Fig 3, A), livedo reticularis (LR) (Fig 3, B), chronic venous ulcers, pseudovasculitis (Fig 3, C), superficial thrombophlebitis, superficial skin bullae (Fig 3, D), infarcts and distal gangrene, acrocyanosis, and relapsing polychondritis.
Fig 3.
Antiphospholipid antibody syndrome. A, Anetoderma. B, Livedo reticularis. C, Chronic leg ulcer and pseudovasculitic lesions. D, Superficial skin bullae.
Catastrophic APLS (Fig 4) is an accelerated form of the disease that affects the small vessels of multiple organs via acute thrombotic microangiopathy. Less than 1% of patients with APLS develop catastrophic APLS.59 Diagnosis is made by the presence of an APLA, evidence of 3 or more affected organs or systems within 1 week of onset of the disease, and demonstration of histologic vessel occlusion of at least 1 organ.59 The differential diagnosis includes DIC, however, in catastrophic APLS, the D-dimer is negative and there is a positive APLA. The treatment options include unfractionated heparin, high-dose steroids, intravenous immunoglobulin, or plasmapheresis.
Fig 4.
Catastrophic antiphospholipid antibody (APLA) syndrome. A, Auricular and facial purpura in critically ill patient with negative disseminated intravascular coagulation workup and positive APLAs. B, Right shoulder purpura in same patient.
Anetoderma, also called macular atrophy, is an elastolytic disorder of unknown origin characterized by localized areas of flaccid skin, which can appear atrophic (Fig 3, A) or protuberant. Histopathology shows a loss of dermal elastic fibers with an elastin stain, such as the Verhoeff-van Gieson stain. Primary anetoderma occurs in areas of skin with no prior skin pathology, whereas secondary anetoderma occurs in areas of skin with prior pathology, most commonly acne or varicella.60Primary anetoderma has been reported in association with HIV, penicillamine use, and autoimmune diseases including lupus and thyroiditis.61, 62, 63 Primary anetoderma has been reported as a specific skin manifestation for the underlying presence of an APLA.60, 62, 63, 64, 65, 66, 67, 68, 69 A study of 9 patients with primary anetoderma revealed APLAs in all 9 patients, with 4 patients also having APLS.70 A case report of anetoderma and chronic lower leg ulceration has been reported in association with decreased antithrombin III levels.71
Livedo reticularis
LR (Fig 3, B) is a blanching erythematous to violaceous netlike vascular pattern on the skin. Livedo racemosa is atypical LR that has prominent asymmetry and breaks in the netlike pattern. LR can be a normal physiologic finding that resolves with warming, or it can be indicative of an underlying HS. The 3 subtypes of LR not associated with systemic disease include: physiologic (cutis marmorata), primary, and idiopathic.72 A review72 of secondary LR describes the numerous associated conditions, including the following HS: APLAs,73, 74, 75 APLS,76 protein C and S deficiency, antithrombin III deficiency, DVT, DIC, and TTP. Other systemic associations include systemic vasculitis, connective tissue disease, emboli, vessel wall deposition, medications, infections, malignancy, neurologic disease, and endocrine and nutritional diseases.72
Livedo vasculopathy
Livedo vasculopathy (LV), also known as livedoid vasculopathy, atrophie blanche, segmental hyalinizing vasculitis, PURPLE (painful purpuric ulcers with reticular pattern of the lower extremities), and LR with winter or summer ulceration, is a chronic, painful, recurrent, and progressive skin disease often occurring on the lower extremities (Fig 5).77 The lesions are varied, and may consist of focal purpura with shallow ulcerations that heal leaving atrophic, stellate, scarlike white plaques stippled with telangiectasis and peripheral hyperpigmentation.78 There are many proposed mechanisms of pathogenesis of LV, including venous flow abnormalities, vascular endothelial dysfunction, immune complex deposition, and microthrombi of the dermal vessels secondary to HS.79 The reported associated HS include FV Leiden mutation,80, 81, 82 prothrombin gene mutation,83, 84 antithrombin III deficiency,85 protein C deficiency,86, 87 double heterozygous FV Leiden and prothrombin mutations,88 APLAs,89, 90 APLS,91 and hyperhomocysteinemia.92, 93, 94
Fig 5.
Atrophie blanche from livedo vasculopathy.
Chronic venous ulceration (CVU) often occurs in the setting of chronic venous insufficiency, varicose veins, or both. A prior DVT is a major risk factor for chronic venous insufficiency. Studies have shown that patients with CVU and varicose veins have increased rates of primary HS or the presence of an APLA.95 In a study of 110 patients with CVU, approximately one third of patients had an underlying primary HS, compared with 1.8% of the control patients.95 Another study of 97 patients with CVU showed 41% of patients with a thrombophilic state.96
Superficial venous thrombosis
SVT, or superficial thrombophlebitis, presents as a swollen, red, tender, cordlike area of inflammation along a superficial vein, most commonly in the lower extremities. This was once considered a benign condition however it has recently been proven to be associated with VTE in 20% to 30% of patients.97, 98 An anatomic communication between the superficial and deep venous systems exists, which presents the potential for the development of DVT by direct extension of the clot into the deeper vasculature. In the POST study, 25% of 844 patients with SVT also had DVT, PE, or both.98 In the OPTIMEV study, 29% of 788 patients had DVT.99 Varicose veins are present in 60% to 90% of patients before developing SVT.100, 101 The most commonly affected vein is the great saphenous vein, which accounts for 60% to 80% of SVT.101 This condition is more common in women with an average age of onset at 60 years.101 When SVT is associated with varicose veins, it is less likely to be complicated by extension into the deep venous system.102 Superficial thrombophlebitis has been found in association with anticardiolipin antibodies, protein C or S deficiency, FV Leiden mutation, prothrombin mutation, and antithrombin III deficiency.103, 104, 105, 106, 107 One study showed FV Leiden mutation was present in 14.3% of patients presenting with superficial thrombophebitis.106
The use of antiplatelet and anticoagulant therapy in dermatology
The pharmacologic treatments available for VTE include antiplatelet and anticoagulant medications (Table IV) and thrombolytic agents. Embolectomy may be performed to remove large thromboses and inferior vena cava filters can be placed to help prevent additional pulmonary emboli.
Table IV. Antiplatelet and anticoagulant therapies
Aspirin
LMWH, Low-molecular-weight heparin.
In dermatology, the most frequently reported use of antiplatelet and anticoagulant medication is for the treatment of LV. There have been reports of the use of unfractionated heparin or LMWH, such as enoxaparin92, 108, 109 or dalteparin.109 Other reported treatments of LV include warfarin, aspirin, dipyridamole, clopidogrel, ticlopidine, recombinant tissue plasminogen activator, and rivaroxaban.79, 110 In a case report of LV associated with a positive lupus anticoagulant and methyltetrahydrofolate reductase mutation, the patient achieved complete remission after treatment with tinzaparin (LMWH) for 6 months.111 The use of warfarin has been reported in patients with LV and FV Leiden mutation,109, 112, 113 prothrombin mutation,84 and hyperhomocysteinemia.77 Recently, the oral factor Xa inhibitor rivaroxaban was shown to decrease pain and ulceration in 3 patients with LV.110
In patients with CVU, there have been case reports of the successful use of warfarin, LMWH (enoxaparin or dalteparin), clopidogrel, and aspirin. One case of anetoderma and chronic ulceration of the lower leg associated with antithrombin III deficiency demonstrated resolution of ulceration with enoxaparin followed by fondaparinux.71
The treatment of APLS with anticoagulation has been shown to decrease recurrent thrombosis, however when the anticoagulation is stopped, the patient is at an increased risk of thrombosis during the first 6 months after discontinuation of therapy.114 If APLS is suspected, referral to a hematologist for anticoagulation recommendations is preferred for long-term management.
In patients with an SVT of at least 5 cm in length, recommended treatment includes a prophylactic dose of fondaparinux (2.5 mg subcutaneously daily).115 In the CALISTO study of 3002 patients with SVT, fondaparinux was superior to placebo in the prevention of VTE.115 Various doses and durations of LMWH have been reported with SVT. A recent randomized, double-blind study of parnaparin determined that an intermediate dose of parnaparin for 30 days was effective treatment for at least 4-cm-long SVT.116 Nonsteroidal anti-inflammatory medications have been the mainstay of treatment, and although these medications reduce the pain and recurrence of SVT, they do not decrease the incidence of VTE.117 In a patient with a first episode of DVT of the leg, the recommended treatment is warfarin for 3 months.118
Conclusion
Primary and secondary HS are associated with cutaneous manifestations, including purpura, PF, LR, LV (atrophie blanche), anetoderma, SVT, and chronic venous ulcers. The dermatologist can identify these abnormal findings and pursue a workup for an underlying HS. The successful use of numerous antiplatelet and anticoagulant medications have been reported in patients with HS and skin manifestations, however, prospective studies are still needed to determine the optimal treatment for many of these conditions.
الاشتراك في:
الرسائل (Atom)