Thursday, June 27, 2013

Uses, Administration, Adverse Effects and Treatment ACE Inhibitors



Uses and Administration
ACE inhibitors are antihypertensive drugs that act as vasodilators and reduce peripheral resistance. They inhibit angiotensin-converting enzyme (ACE), which is involved in the conversion of angiotensin I to angiotensin II. Angiotensin II stimulates the synthesis and secretion of aldosterone and raises blood pressure via a potent direct vasoconstrictor effect. ACE is identical to bradykininase (kininase II) and ACE inhibitors also reduce the degradation of bradykinin, which is a direct vasodilator and is also involved in the generation of prostaglandins. The pharmacological actions of ACE inhibitors are thought to be primarily due to the inhibition of the renin-angiotensin-aldosterone system, but since they also effectively reduce blood pressure in patients with low renin concentrations other mechanisms are probably also involved. ACE inhibitors produce a reduction in both preload and afterload in patients with heart failure. They also reduce left ventricular remodelling, a process that sometimes follows myocardial infarction. Normally, renal blood flow is increased without a change in glomerular filtration rate. ACE inhibitors also reduce proteinuria associated with glomerular kidney disease. ACE inhibitors are used in the treatment of hypertension and heart failure and are given to improve survival after myocardial infarction and for the prophylaxis of cardiovascular events in patients with certain risk factors. They are also used in the treatment of diabetic nephropathy. They are generally given orally. In some hypertensive patients there may be a precipitous fall in blood pressure when starting therapy with an ACE inhibitor and the first dose should preferably be given at bedtime; if possible, any diuretic therapy should be stopped a few days beforehand and resumed later if necessary. In patients with heart failure taking loop diuretics, severe first-dose hypotension is common on introduction of an ACE inhibitor, but temporary withdrawal of the diuretic may cause rebound pulmonary oedema. Thus treatment should start with a low dose under close medical supervision (Sweetman).

Adverse Effects and Treatment
Many of the adverse effects of ACE inhibitors relate to their pharmacological action and all therefore have a similar spectrum of adverse effects. Some effects, such as taste disturbances and skin reactions, were at one time attributed to the presence of a sulfhydryl group (as in captopril) but have now also been reported with other ACE inhibitors; however, they may be more common with captopril. The most common adverse effects are due to the vascular effects of ACE inhibitors and include hypotension, dizziness, fatigue, headache, and nausea and other gastrointestinal disturbances. Pronounced hypotension may occur at the start of therapy with ACE inhibitors, particularly in patients with heart failure and in sodium- or volume-depleted patients (for example, those given previous diuretic therapy). Myocardial infarction and stroke have been reported and may relate to severe falls in blood pressure in patients with ischaemic heart disease or cerebrovascular disease. Other cardiovascular effects that have occurred include tachycardia, palpitations, and chest pain. Deterioration in renal function, including increasing blood concentrations of urea and creatinine, may occur, and reversible acute renal failure has been reported. Renal effects are most common in patients with existing renal or renovascular dysfunction or heart failure, in whom vasodilatation reduces renal perfusion pressure; it may be aggravated by hypovolaemia. Proteinuria has also occurred and in some patients has progressed to nephrotic syndrome. Hyperkalaemia and hyponatraemia may develop due to decreased aldosterone secretion. Other adverse effects include persistent dry cough and other upper respiratory tract symptoms, and angioedema; these may be related to effects on bradykinin or prostaglandin metabolism. Skin rashes (including erythema multiforme and toxic epidermal necrolysis) may occur; photosensitivity, alopecia, and other hypersensitivity reactions have also been reported. Blood disorders have been reported with ACE inhibitors and include neutropenia and agranulocytosis (especially in patients with renal failure and in those with collagen vascular disorders such as systemic lupus erythematosus and scleroderma), thrombocytopenia, and anaemias. Other less common adverse effects reported with ACEinhibitors include stomatitis, abdominal pain, pancreatitis, hepatocellular injury or cholestatic jaundice, muscle cramps, paraesthesias, mood and sleep disturbances, and impotence. ACE inhibitors have been associated with fetal toxicity. Most of the adverse effects of ACE inhibitors are reversible on withdrawing therapy. Symptomatic hypotension, including that after overdosage, generally responds to volume expansion with an intravenous infusion of sodium chloride 0.9%  (Sweetman).

Wednesday, June 26, 2013

Produksi Xilanase dari Mikroorganisme

Jenis mikroorganisme yang sudah umum menghasilkan xilanase ialah jamur dan bakteri. Contoh beberapa mikroorganisme penghasil endoxilanase disajikan pada Tabel 1. Beberapa jenis bakteri dan jamur diketahui mampu menghasilkan xilanase secara ekstraseluler. Xilanase dari Clostridium acetobuty-licum telah diteliti oleh Lee et al. (1985), yaitu dari 20 strain Clostridium sp. ternyata C. acetobutylicum NRRL B527 dan ATCC 824 menghasilkan xilanase terbanyak. Strain NRRL B527 menghasilkan xilanase pada pH 5,2, sedangkan strain ATCC 824 menghasilkan xilanase, xilopiranosidase, dan arabinofuranosidase pada kultur anaerob. Bacillus sp. penghasil xilanase bersifat alkalofilik yang telah diteliti adalah Bacillus sp. YC 335 (Park et al., 1992), Bacillus sp. 41M-1 (Nakamura et al., 1993), dan Bacillus sp. TAR-1 yang juga bersifat termofilik (Nakamura et al., 1994). Genus Bacillus diketahui sebagai penghasil xilanase yang aktif pada suhu 50 °C – 60°C, dengan pH 7 - 9, sehingga enzim dari bakteri ini diharapkan dapat diproduksi dan digunakan pada proses awal pemutihan pulp di industri pulp dan kertas.Kubata et al. (1992) telah mengisolasi Aeromonas caviae ME-1 penghasil xilanase I dari usus herbivorous insect, sedangkan Dung et al. (1993) melakukan penelitian β-1,4-xilanase 2 dan 3 dari A. caviae W-61. Irawadi (1992) berhasil memproduksi selulase dan xilanase dari Neurospora sitophila pada substrat padat limbah kelapa sawit. Richana et al. (2000) telah melakukan isolasi bakteri penghasil xilanase alkalofilik yang berasal dari tanah berkapur pH 7,9. Seleksi dilakukan berdasarkan ukuran koloni dan zona bening di sekeliling koloni yang tumbuh pada media pertumbuhan.

Winterhalter dan Liebl (1995) telah melakukan produksi xilanase thermostabil dari bakteri Thermotoga maritima MSB8, sedangkan Ruiz-Arribas et al. (1995) telah mendapatkan Streptomyces halstedii JM8 penghasil xilanase (xys I) yang diisolasi dari jerami. Lin et al., (1999), melakukan pemurnian dan karakterisasi biokimia xilanase dari fungi termofilik Thermomyces lanuginosus- SSBP.
Komposisi medium fermentasi dapat sederhana atau kompleks tergantung jenis mikroba dan kondisi fermentasinya. Baik medium sederhana maupun kompleks dapat merupakan medium sintetik atau medium kasar (crude). Medium sintetik cocok untuk skala laboratorium dan industri kecil karena mempunyai beberapa keuntungan antara lain setiap komponen dapat dengan mudah dikurangi, dihilangkan atau ditambahkan. Di samping itu, pada medium sintetik biasanya tidak membentuk buih selama proses berlangsung, dan kesalahan atau kelainan yang mungkin terjadi selama fermentasi akibat komposisi yang kurang tepat dapat dicegah. Pada industri skala besar medium sintetik tidak sesuai digunakan (Richana, 2002).
Kriteria sumber nutrisi untuk skala besar menurut Rachman (1989) adalah
1. Dapat memproduksi biomassa dengan hasil maksimal untuk tiap gram substrat yang digunakan.
2. Memungkinkan pembentukan produk fermentasi dengan laju maksimal.
3. Dapat menekan pembentukan produk yang tidak diinginkan sampai serendah mungkin.
4. Mutu konstan, murah, dan tersedia sepanjang tahun.
5. Tidak menimbulkan masalah terhadap aerasi, agitasi, ekstraksi, dan pemurnian hasil serta perlakuan limbah.
Substrat yang digunakan dalam proses fermentasi berpengaruh terhadap aktivitas dan produktivitas enzim. Adanya substrat tertentu di dalam medium produksi dapat memacu mikroorganisme untuk mensekresi metabolit selnya. Zat makanan utama bagi pertumbuhan mikroorganisme adalah sumber karbon, nitrogen, dan komponen mineral terutama fosfat. Formulasi media dalam pertumbuhan dan produksi hasil fermentasi merupakan suatu tahap penting dalam mendesain percobaan dalam skala kerja (Stanbury dan Whitaker, 1984).
Beberapa sumber karbon yangsering digunakan adalah molases, serealia, pati, glukosa, sukrosa, dan laktosa. Produksi enzim xilanase sebagai sumber karbon adalah xilan. Xilan dengan aktivitas xilanase yang dihasilkan oleh mikroorganisme akan terhidrolisis menjadi xilosa.

C5H8O4 + H2O             C5H10O5
Xilan                                Xilosa

 

Prospek Xilanase dalam Biokonversi Limbah Pertanian



Perkembangan dan kemajuan bidang pertanian dan industra pertanian di Indonesia telah
menimbulkan peningkatan limbah pertanian yang sebagian besar merupakan limbah berlignoselulosa. Limbah berlignoselulosa yang tinggi potensinya di Indonesia antara lain jerami,
onggok (ampas tapioka, garut), bonggol dan kulit jagung, sabut serta tandan kosong kelapa sawit, bagase tebu, dan lain sebagainya. Seringkali limbah yang tidak tertangani, akan menimbulkan pencemaran lingkungan. Pada dasarnya limbah tidak memiliki nilai ekonomi, bahkan mungkin bernilai negatif karena memerlukan biaya penanganan. Namun demikian, bila ditelaah lebih dalam limbah lignoselulosa sebagai bahan organik memiliki potensi besar sebagai bahan baku berbagai industri, terutama untuk pembuatan kertas. Di samping itu, fraksinasi limbah ini menjadi komponen penyusunnya akan meningkatkan pendayagunaan dalam berbagai industri. Melihat potensi bahan limbah berlignoselulosa yang melimpah maka perlu penggalian yang lebih intensif tentang pemanfaatan potensi tersebut. Bahan berlignoselulosa terdiri atas hemiselulosa, selulosa, dan lignin. Hemiselulosa dapat dimanfaatkan menjadi produk xylitol, xylosa, dan fulfural. Selulosa dapat dimanfaatkan menjadi protein sel tunggal, glukosa, fruktosa, dan sorbitol. Sedangkan lignin untuk bahan bakar, pelarut, resin, produk karbon, dan matriks adsorpsi (Paturau, 1969).
Salah satu sasaran dalam pengembangan bioteknologi adalah merintis pemanfaatan mikroorganisme dalam biokonversi limbah. Pemanfaatan limbah berlignoselulosa dengan menggunakan jasa mikroorganisme dapat menghasilkan enzim ekstraseluler yang mampu mendegradasi bahan berlignoselulosa menjadi fraksi penyusunnya. Misalkan enzim selulase yang dapat merombak bahan berlignoselulosa berupa jerami atau sampah organic menjadi kompos, atau menghidrolisis selulosa menjadi glukosa. Sedangkan xilanase dapat menghidrolisis hemiselulosa menjadi xilosa, proses ini dapat diaplikasikan ke beberapa proses dan pemanfaatannya (Richana, 2002).

Pemanfaatan Xilanase untuk Proses Pembuatan Kertas
Pada pembuatan kertas, xilanase digunakan untuk menghilangkan hemiselulosa dalam proses bleaching. Enzim ini sebagai pengganti cara kimia sehingga pencemaran racun limbah kimia akan dihindari dan lebih murah (Ruiz-Arribas et al., 1995). Bahan baku kayu pembuat kertas setelah melalui proses digester dan pencucian, sebenarnya masih dalam keadaan kotor (derajat putihnya rendah). Untuk menghasilkan kertas yang bermutu tinggi perlu dilakukan proses pemutihan. Proses pemutihan bertujuan untuk menghilangkan lignin, hemiselulosa penyebab warna coklat dan zat ekstraktif yang dikandung dari hasil pencucian dan penyaringan.
Proses pemutihan biasanya dilakukan bertahap, karena mempunyai kelebihan di antaranya adalah nilai derajat putihnya tinggi. Proses bertahap ini terdiri atas tahap khlorinasi, ekstraksi, dan penambahan khlorin dioksida. Khlorin adalah bahan beracun, sehingga khlorin sisa proses yang dibuang ke perairan sungai akan membuat polusi yang tinggi. Ternyata polusi terbesar di Negara kita adalah polusi dari pabrik kertas. Penggantian penggunaan khlorin untuk pemutihan kertas telah memberikan peluang untuk aplikasi bioteknologi. Xilanase merupakan enzim yang pertama kali dilaporkan untuk pemutihan kertas dan sekarang telah digunakan pada beberapa pabrik kertas (Richana, 2002).
Jumlah pabrik kertas yang sudah beroperasi di Indonesia saat ini lebih dari 14 perusahaan dan belum satu pun menggunakan proses enzimatis dalam proses pemutihan. Dengan demikian, untuk mendukung pelestarian lingkungan maka perlu segeradiaplikasikan proses ramah lingkungan (clean processing) di Indonesia. Untuk proses pembuatan kertas diharapkan xilanase yang digunakan adalah yang termostabil dan tahan pada pH alkali (Nakamura et al., 1993) dan jenis enzimnya adalah endoxilanase.

Tuesday, June 25, 2013

Osteoarthritis (OA)

Osteoarthritis (OA), also erroneously called degenerative joint disease, represents failure of the diarthrodial (movable, synovial-lined) joint. In idiopathic (primary) OA, the most common form of the disease, no predisposing factor is apparent. Secondary OA is pathologically indistinguishable from idiopathic OA but is attributable to an underlying cause.
 
Treatment of OA is aimed at reducing pain, maintaining mobility, and minimizing disability. The vigor of the therapeutic intervention should be dictated by the severity of the condition in the individual patient. For those with only mild disease, reassurance, instruction in joint protection, and an occasional analgesic may be all that is required; for those with more severe OA, especially of the knee or hip, a comprehensive program comprising a spectrum of nonpharmacologic measures supplemented by an analgesic and/or NSAID is appropriate.


Nonpharmacologic Measures

Reduction of Joint Loading  OA may be caused or aggravated by poor body mechanics. Correction of poor posture and a support for excessive lumbar lordosis can be helpful. Excessive loading of the involved joint should be avoided. Patients with OA of the knee or hip should avoid prolonged standing, kneeling, and squatting. Obese patients should be counseled to lose weight. In patients with medial-compartment knee OA, a wedged insole may decrease joint pain.

Rest periods during the day may be of benefit, but complete immobilization of the painful joint is rarely indicated. In patients with unilateral OA of the hip or knee, a cane, held in the contralateral hand, may reduce joint pain by reducing the joint contact force. Bilateral disease may necessitate use of crutches or a walker.

Physical Therapy  Application of heat to the OA joint may reduce pain and stiffness. A variety of modalities are available; often, the least expensive and most convenient is a hot shower or bath. Occasionally, better analgesia may be obtained with ice than with heat.

It is important to note that patients with OA of weight-bearing joints are less active and tend to be less fit with regard to musculoskeletal and cardiovascular status than normal controls. An exercise program should be designed to maintain range of motion, strengthen periarticular muscles, and improve physical fitness. The benefits of aerobic exercise include increases in aerobic capacity, muscle strength, and endurance; less exertion with a given workload; and weight loss. Those who exercise regularly live longer and are healthier than those who are sedentary. Patients with hip or knee OA can participate safely in conditioning exercises to improve fitness and health without increasing their joint pain or need for analgesics or NSAIDs.

Disuse of the OA joint because of pain will lead to muscle atrophy. Because periarticular muscles play a major role in protecting the articular cartilage from stress, strengthening exercises are important. In individuals with knee OA, strengthening of the periarticular muscles may result, within weeks, in a decrease in joint pain as great as that seen with NSAIDs.

Drug Therapy of OA  Therapy for OA today is palliative; no pharmacologic agent has been shown to prevent, delay the progression of, or reverse the pathologic changes of OA in humans. Although claims have been made that some NSAIDs have a "chondroprotective effect," adequately controlled clinical trials in humans with OA to support this view are lacking. In management of OA pain, pharmacologic agents should be used as adjuncts to nonpharmacologic measures, such as those described above, which are the keystone of OA treatment.

Although NSAIDs often decrease joint pain and improve mobility in OA, the magnitude of this improvement is generally modest¾on average, about 30% reduction in pain and 15% improvement in function. In a double-blinded, controlled trial in patients with symptomatic knee OA, an anti-inflammatory dose of ibuprofen (2400 mg/d) was no more effective than a low (i.e., essentially analgesic) dose of ibuprofen (1200 mg/d) or than acetaminophen (4000 mg/d), a drug with essentially no anti-inflammatory effect. Other studies confirm that an analgesic dose of ibuprofen may be as effective as anti-inflammatory doses of other NSAIDs, including the potent agent, phenylbutazone (400 mg/d), in symptomatic treatment of OA. Even in the presence of clinical signs of inflammation (e.g., synovial effusion, tenderness), relief of joint pain by acetaminophen may be as effective as that achieved with an NSAID. Nonetheless, if simple analgesics are inadequate, it is reasonable to cautiously prescribe an NSAID for a patient with OA.

It should be recognized that concern over the use of NSAIDs in OA has grown in recent years because of side effects of these agents, especially those related to the gastrointestinal (GI) tract. Those at greatest risk for OA, i.e., the elderly, appear also to be at greater risk than younger individuals for GI symptoms, ulceration, hemorrhage, and death as a result of NSAID use. The annual rate of hospitalization for peptic ulcer disease among elderly current NSAID users was 16 per 1000¾four times greater than that for persons not taking an NSAID. Among those age 65 and older, as many as 30% of all hospitalizations and deaths related to peptic ulcer disease have been attributed to NSAID use. In addition to age, risk factors for hemorrhage and other ulcer complications associated with NSAID use include a history of peptic ulcer disease or of upper GI bleeding, concomitant use of glucocorticoids or anticoagulants, and, possibly, smoking and alcohol consumption (Table 321-4).

In patients who carry risk factors for an NSAID-associated GI catastrophe, a cyclooxygenase (Cox)-2-specific NSAID may be preferable to even a low dose of a nonselective Cox inhibitor. In contrast to the NSAIDs available to date¾all of which inhibit Cox-1 as well as Cox-2¾two Cox-2-specific inhibitors (CSIs), celecoxib and rofecoxib, are now available. Both appear to be comparable in efficacy to the nonselective NSAIDs. Endoscopic studies have shown that both agents are associated with an incidence of gastroduodenal ulcer lower than that of comparator NSAIDs and comparable to that of placebo. Of additional advantage with respect to the issue of upper GI bleeding, CSIs do not have a clinically significant effect on platelet aggregation or bleeding time, suggesting that CSIs may be especially advantageous in patients at high risk for incurring an NSAID-associated GI catastrophe. Long-term studies are now in progress that are designed to ascertain whether clinically important differences exist between CSIs and nonselective NSAIDs with respect to major GI clinical outcomes.

Systemic glucocorticoids have no place in the treatment of OA. However, intra- or periarticular injection of a depot glucocorticoid preparation may provide marked symptomatic relief for weeks to months. Because studies in animal models have suggested that glucocorticoids may produce cartilage damage, and frequent injections of large amounts of steroids have been associated with joint breakdown in humans, the injection should generally not be repeated in a given joint more often than every 4 to 6 months.

Intraarticular injection of hyaluronic acid has been approved recently for treatment of patients with knee OA who have failed a program of nonpharmacologic therapy and simple analgesics. Because the duration of benefit following treatment may exceed by months the synovial half-life of exogenous hyaluronic acid, the mechanism of action is unclear. The placebo response to intraarticular injection of hyaluronic acid is often large and sustained. Although relief of knee pain is achieved more slowly after hyaluronic acid injection than after intraarticular glucocorticoid injection, the effect may last much longer after hyaluronic acid injection than after glucocorticoid injection.

Capsaicin cream, which depletes local sensory nerve endings of substance P, a neuropeptide mediator of pain, may reduce joint pain and tenderness when applied topically by patients with hand or knee OA, even when used as monotherapy, i.e., without NSAIDs or systemic analgesics.