For Irritable Bowel Syndrome
Alosetron hydrochloride is a new medication to treat irritable bowel syndrome (IBS) in women whose predominant bowel symptom is diarrhoea. Like existing IBS therapies, alosetron treats the symptoms associated with the syndrome. How the drug works is not completely understood. Alosetron slows intestinal movement and may provide relief by targeting the underlying neurological activity associated with IBS.
Amprenavir is a protease inhibitor antiviral drug for HIV and AIDS. It is administered together with other protease inhibitors for the treatment of AIDS. The most common adverse effects are nausea, diarrhea, vomiting, and oral rashes. As with other protease inhibitors, elevated blood glucose levels and altered body fat distribution have been reported. Amprenavir is advocated with caution in patients with impaired liver function. Drug interactions occur with triazolam, ergotamine, cisapride, warfarin and the statins.
Capecitabine is indicated for women with locally advanced or metastatic breast cancer after an anthracycline-containing regimen and paclitaxel have failed. On absorption from the gut, it is converted to 5-fluorouracil (5FU). Metabolism of 5FU damages, in particular, rapidly proliferating cells. In a trial of 162 patients, most of whom had failed previous treatment and 82% of whom had already been exposed to 5FU, there were 3 responses and the overall response rate was 20%. The patients survived for a median of 13 months. Capecitabine is administered twice daily for two weeks, followed by a week's break. The dose is adjusted according to tolerability. Diarrhoea, nausea and vomiting are the common adverse effects. About 45% patients develop peripheral numbness, paraesthesia, erythema, swelling and blistering of the limbs. Treatment is interrupted if symptoms are severe.
Clopidogrel is a antiplatelet drug similar to ticlopidine. It inhibits the activation of platelets by adenosine diphosphate. In a comparison with aspirin involving over 19,000 patients over 2 years, the risk of death from vascular causes was 5.83% in the aspirin group versus 5.32% in the clopidogrel group. The difference was statistically significant. In patients with peripheral vascular disease, there was a big reduction in risk, but not in patients with myocardial infarction. Administered orally once daily, the drug is well absorbed and exrensively metabolised in the liver. The frequency of adverse reactions is similar to aspirin. Gastrointestinal discomfort and bleeding are commoner with aspirin, and rash and diarrhoea are commoner with clopidogrel. Clopidogrel inhibits cytochrome P450 2C9 and can interact with drugs such as tolbutamide and phenytoin.
Children with severe longstanding juvenile rheumatoid arthritis (JRA) respond, often dramatically, to the drug etanercept. Etanercept represents a dramatic advancement in treating JRA and is an improvement over current therapies in terms of both safety and effectiveness. Etanercept is a protein-based drug that inhibits the binding of tumor necrosis factor (TNF), a protein secreted by different types of cells that regulates the immune response. Normally, when a person gets a viral or bacterial infection, these proteins help fight off the infection. JRA, however, is an autoimmune disease in which these proteins create a cascade of inflammatory effects in joints that can actually destroy one’s own joint tissue. Etanercept blocks TNF and suppresses the cascade reaction. Etanercept may be employed for polyarticular course JRA and severe to moderate rheumatoid arthritis. Etanercept is safe and well tolerated even with prolonged use.
Phenytoin is not recommended for intramuscular injection because of local adverse reactions and unpredictable absorption. If given intravenously, it is not very soluble and can be precipitated by other intravenous infusions. Fosphenytoin, a prodrug of phenytoin, is less soluble than phenytoin and can be given intramuscularly, but this route may not be suitable for status epilepticus as it takes 30 minutes to achieve peak plasma concentrations. Fosphenytoin is indicated in status epilepticus and to prevent or treat seizures associated with neurosurgery or head trauma.
Gabapentin is a structural analogue of GABA. It is effective in treating partial seizures. Doses of up to 2400 mg daily, if tolerated, are administered. Adverse effects are uncommon, with drowsiness, somnolence and fatigue often being dose related. These symptoms may occur with starting the drug and often resolve with time. The safety of gabapentin in pregnancy has not been established.
Insulin - new
Inhaler : Recent clinical trials have demonstrated that insulin delivered via a Pulmonary Drug Delivery System is rapidly absorbed from the lung and reduces blood glucose faster than traditional injections. Furthermore, the studies showed that unlike injected insulin, higher concentrations of an inhaled insulin can be given without delaying the reduction in blood glucose.
Pen : The premixed insulin pen will help patients control blood-glucose levels and manage challenges in taking their medication with regimented meal schedules. It is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia and is available in a prefilled insulin pen, a pen-like injection device shown to increase dosing accuracy and convenience.
Lamotrigine acts by blocking voltage-dependent sodium channels and inhibiting the release of excitatory amino acids. This may stabilise neurons in epileptic foci. It has a broad spectrum of action and is effective in both partial and generalised epilepsy, including many intractable cases. Lamotrigine is effective as monotherapy and may be as effective as carbamazepine and phenytoin, but is associated with fewer adverse effects. Sodium valproate inhibits the metabolism of lamotrigine, increasing the half life from 30 hours to 60 hours. Enzyme inducing drugs like carbamazepine reduce the half life to about 15 hours. Patients are given 25 mg/day if treated with an enzyme inducer, and 25 mg every second day if taken with sodium valproate. The maximum daily dose of lamotrigine is 200-400 mg for patients not on sodium valproate, and 100-200 mg if on sodium valproate. Adverse effects include a cutaneous reaction, commoner in patients also being treated with sodium valproate, and is usually a maculopapular rash, but more serious reactions including Stevens-Johnson syndrome have been reported. Other effects include headache and dizziness.
Levalbuterol is the R isomer of salbutamol (albuterol), which itself is a mixture of two isomers - R and S. The R isomer is considered to be the more active compound and the S isomer is said to contribute to some of salbutamol's side effects. Levalbuterol is a beta-2 adrenergic agonist which stimulates beta-2 receptors in the bronchial smooth muscle to produce bronchodilation. Tremor is the most commonly reported side effect. Others reported include nervousness, headache, leg cramps, anxiety, dizziness, chest pain, and heart palpitations.
Linezolid belongs to a new class of human antibiotics, oxazolidinones, which have been used in agricultural therapy. The oxazolidinones act by inhibiting the formation of the ribosomal initiation complex, a unique site not overlapping other ribosomally active antimicrobials. Extremely rare resistance has been associated with amino acid substitutions in the 23S rRNA -- highlighting the pivotal role of this nucleic acid. Linezolid has primary activity against gram-positive organisms, including vancomycin resistant enterococci, with 80% clinical and microbiologic responses in clinical trials. It is active against atypical bacteria, but has borderline Haemophilus and meningococcal activity, thus limiting its role in respiratory infections. The class lacks gram-negative activity. Linezolid's 5- to 7-hour half-life permits b.i.d. dosing (400 mg or 600 mg). It has virtually complete bioavailability, with no cytochrome p450 effects. No dosing adjustment is necessary with renal or hepatic impairment.
In asthma, the inflammatory process involves leukotrienes which are involved in bronchoconstriction. Monteleukast competes with leukotrienes for their receptors and inhibits their effects. Bronchodilation occurs within two hours of taking a dose.Monteleukast is less effective than inhaled steroids and may be useful in patients whose asthma is not controlled by existing preventive drugs.
Moxifloxacin is a fluoroquinolone antibacterial with a 12- to 15-hour half-life permitting 400 mg once-daily dosing. The pharmacokinetic parameters of this agent may be so favorable that it will be less likely to induce resistance, or do so more slowly. It lacks a secondary fluorine or chlorine atom and so photosensitivity is unlikely. Its anaerobic and respiratory pathogen activity profile is excellent. Although it is slightly less active than ciprofloxacin against Pseudomonas, it retains good gram-negative activity.
Nartriptan is a serotonin agonist for the treatment of migraine. It can be considered for patients who have a history of attacks which do nt respond to simple analgesics or ergotamine. Naratriptan should be taken early in an attack. Peak plasma concentrations are reached within 3 hours. Half the dose is excreted in the urine. The mean half life is 6 hours. Bioavailability is higher in women than in men. In a study of 586 patients, 68% achieved relief with naratriptan compared to 33% with placebo. Compared to sumatriptan, more patients will obtain relief within 4 hours by taking 100 mg of sumatriptan, but the headache is less likely to recur in the patients with 2.5 mg naratriptan. Adverse effects include those occurring with sumatriptan e.g. feelings of heaviness, heat, dizziness, drowziness, and chest pain. Naratriptan is contraindicated in patients with ischaemic heart disease, uncontrolled hypertension or periphearl vascular disease. Concomitant administration of ergotamine or a derivative is not recommended.
Olanzapine is indicated for the treatment of schizophrenia and other psychotic disorders. It binds to serotonergic, dopaminergic, histaminergic H1, alpha1-adrenergic, and muscarinic receptors. Oral bioavailability is good and inactivation is primarily by liver metabolism. One study showed modest efficacy for 16 ± 2 mg/day of olanzapine (48% with >40 % improvement in Brief Psychiatric Rating Scale) which was similar to that with haloperidol 16±4 mg/day (47%). Another study showed the response to olanzapine was better than to haloperidol, however, the efficacy of both drugs was less than the first. Olanzapine (mean modal dose 17 mg/day) has also been compared to risperidone (mean modal dose 7 mg/day) in an 8-week interim analysis of a 28-week double-blind trial. The response rates at 8 weeks (> 40% improvement) were similar for olanzapine, 29% and risperidone, 26%. Olanzapine is administered in single daily doses of 10 to 20 mg. Olanzapine has fewer extrapyramidal side effects in short-term trials. Long-term effectiveness and safety remain to be established.
Oxcarbazepine is indicated for the treatment of partial seizures as monotherapy in adults or adjunctive therapy (use in combination with other antiepileptic drugs) in adults and children as young as four years of age. Partial seizures, which are seizures that begin in a localized area of the brain, account for up to 70% of seizure disorders, making them the most common kind of seizure. In adult and paediatric patients, oxcarbazepine significantly reduced the frequency of seizures as compared to placebo. Oxcarbazepine has demonstrated a good safety profile and tolerability with fewer drug interactions than other first-line monotherapy AEDs.
Pioglitazone is a new drug in the thiazolidinedione class of drugs for use as monotherapy for patients with type 2 or adult-onset diabetes who are not adequately controlled by diet and exercise alone. Pioglitazone can also be used in combination with sulfonylureas, metformin, or insulin in patients who are not adequately controlled on these agents alone. Pioglitazone improves the patient's ability to utilize insulin. Pioglitazone was well-tolerated in clinical studies. Commoner adverse events include headache, upper respiratory infections and muscle pain. Another drug of the thiazolidinedione class, troglitazone, has been associated with idiosyncratic hepatotoxicity or liver failure. In clinical studies of patients treated with pioglitazone, there was no evidence of drug-induced hepatotoxicity.
Proton pump inhibitor
Rabeprazole is a new proton pump inhibitor belonging to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+,K+)-ATPase enzyme system. In duodenal ulcer, rabeprazole 20 mg daily showed similar healing rates when compared to omeprazole 20 mg daily in the treatment of patients with duodenal ulcers. Rabeprazole showed significantly greater efficacy than ranitidine 300 mg per day. Rabeprazole was also associated with a significantly greater improvement in daytime pain at four weeks and nighttime pain severity and complete pain resolution at two weeks. In gastric ulcer, rabeprazole was superior to famotidine. In gastroesophageal reflux disease (GERD), rabeprazole 20 mg was superior to ranitidine 150 mg four times a day.
Oestrogen receptor binding agent
Raloxifene provides another option for preventing osteoporosis in postmenopausal women. While tamoxifen protects against osteoporosis, it can increase the incidence of endometrial cancer. Raloxifene does not cause endometrial proliferation. In 601 postmenopausal women with low/normal bone density administered 30, 60 or 150 mg raloxifene or placebo daily for 2 years, there was a significant desrease in bone turnover in patients taking raloxifene. The greatest increase in bone density at the hip occurred with 60 mg daily, which is now the recommended daily dose. Like oestrogen, raloxifene also alters the lipoprotein profile, significantly reducing total and LDL cholesterol. However, raloxifene is not as effective as oestrogen in reducing hot flushes. Recent studies are encouraging, but more studies will be needed to study how raloxifene affects the long term risk of breast cancer. Raloxifene is not advocated in patients liver disease and those with a history of venous thrombosis.
Reboxetine mesylate is a selective norepinephrine reuptake inhibitor (SNRI), the first of a new class of antidepressant drugs. Reboxetine appears to produce fewer side effects such as nausea, headache, and sexual dysfunction, compared with traditional antidepressants. Reboxetine possesses a faster onset of action compared to selective serotonin reuptake inhibitors (SSRI), tricyclics and monoamine oxidase inhibitors. A lack of norepinephrine in the central nervous system (CNS) is said to be responsible for several symptoms of depression and reboxetine inhibits the reuptake of norepinephrine by the presynaptic nerve terminals, increasing its availability. In a study involving reboxetine 8-10 mg/day and oral fluoxetine 20-40 mg/day for 8 weeks, both treatments were found to be similarly effective. A sub-analysis of patients with severe depression showed reboxetine to have superior efficacy compared to fluoxetine. Both treatments resulted in improvement in Social Adaption Self-evaluation Scale total scores; however, the improvement was more evident in patients who received reboxetine and achieved remission. Clinical trials have shown a reduced risk for nausea, diarrhea, and somnolence with reboxetine compared with fluoxetine, but an increase in risk for dry mouth, constipation, hypotension, paresthesia, urinary hesitancy and flushing.
Remifenatil is an opioid agonist with a structure related to fetanyl. An infusion of remifenatil produces analgesia and can be used as an adjunct and during the maintenance of anaesthesia when endotracheal intubation and ventilation are planned. Remifenatil is rapidly metabolised, has a half-life of 3-10 minutes, and the drug effect wears off within 5-10 minutes.Like other opioids, it can cause respiratory depression, hypotension and bradycardia.
Risdronate is a bisphosphonate, a relatively new drug category, effective in the prevention and treatment of osteoporosis. These agents are structurally similar to pyrophosphate, a normal by-product of metabolism having potent inhibitory effects on bone resorption. Thus the bisphosphonates inhibit the resorption of bone by osteoclasts (which remove bone) and may also act on the osteoblasts (which contribute to bone formation). These properties make the bisphosphonates useful in the treatment of conditions associated with increased bone resorption, such as osteoporosis, hypercalcaemia of cancer, bony metastasis, multiple myeloma and Paget’s disease. Risedronate is considered to be upto 10,000 times more potent than the older bisphosphonate etidronate in some experimental systems. It is administered in a dose of 5 mg daily orally.
For Alzheimer's Disease
Rivastigmine, tacrine and donepezil are acetylcholinesterase inhibitors which enhance cholinergic neurotransmission in Alzheimer's disease. Patients given 6-12 mg/day showed improvement in cognitive function but lower doses of 1-4 mg/day were not significantly different from placebo. Adverse effects include nausea, vomiting, anorexia and giddiness.
Cyclooxygenase (COX) is an enzyme involved in many aspects of normal cellular function and also in the inflammatory response. Two forms of cyclooxygenase designated COX-1 and COX-2, have been identified. COX-2 is associated with inflammation whereas COX-1 is associated with the gastric toxicity that occurs with traditional nonsteroidal antiinflammatory drugs (NSAIDs). Selective inhibition of COX-2, therefore, can decrease inflammation without the risk gastric side effects. The earlier COX-2 inhibitor to be introduced, celecoxib, has been widely accepted as an important advance in therapy. Rofecoxib is useful in inflammatory conditions and rheumatic diseases, and has been found to be as effective and better tolerated than diclofenac in patients with osteoarthritis of the knee or hip. Patients report improvements in their quality of life during treatment. Rofecoxib reduces pain associated with primary dysmenorrhea and post-surgical dental pain. The analgesic activity of 50 mg of rofecoxib is similar to that of 400 mg of ibuprofen, but with a longer duration of action; and to 550 mg of naproxen sodium.
Rosiglitazone is a new drug in the thiazolidinedione class for patients with type II or adult-onset diabetes who are not taking insulin. Rosiglitizone improves patients' ability to utilize insulin produced in the body. Rosiglitazone was well-tolerated in clinical studies. Adverse events commonly reported included infection, pain and headache, but these occurred at rates comparable to those in the placebo-treated patients. Mild to moderate oedema, increase in blood cholesterol and anemia were also reported in patients treated with rosiglitazone, but did not usually require discontinuation of treatment. Another drug of the thiazolidinedione class, troglitazone, has been associated with idiosyncratic hepatotoxicity or liver failure. In clinical studies of patients treated with rosiglitazone, there was no evidence of drug-induced hepatotoxicity.
For Irritable Bowel Syndrome
Tegaserod belongs to a new chemical class of compounds which selectively target and act on 5-HT4 receptors present throughout the GI tract. These serotonin receptors are believed to play a key role in pain perception and GI motility. By acting on the 5-HT4 receptor pathway, tegaserod reduces abdominal pain and may normalize altered GI function in IBS patients who suffer from abdominal pain, constipation and bloating as their predominant symptoms.
Telmisartan is an angiotensin II receptor antagonist which blocks the binding of angiotensin II to type 1 angiotensin II receptors. Telmisartan is useful in the treatment of hypertension. Telmisartan is well tolerated. Cough, a side effect with ACE inhibitors, is avoided with telmisartan. Telmisartan is not advocated in pregnancy.
Tiagabine inhibits GABA reuptake, thereby increasing GABA levels. It is effective in the treatment of partial epilepsies but its efficacy in generalised epilepsies has not been established. The recommended initial dose is 7.5 mg/day given as 3 divided doses, and gradually increased, as tolerated, up to 30 mg/day. The commonest adverse effect is dose-related somnolence, particularly on initiation of therapy. The safety of tiagabine in pregnancy is not established.
Topiramate blocks voltage-dependent sodium channels, enhancing GABA activity. It also blocks excitatory transmission and has weak inhibition of carbonic anhydrase isoenzymes. Topiramate is effective in partial onset epilepsy, particularly in reducing the frequency of secondarily generalised seizures. There are reports of its value in Lennox Gastaut syndrome. The recommended daily dose is 200-400 mg in divided doses.
Trovafloxacin is a quinolone antibacterial with a broad spectrum of activity covering Gram positive and Gram negative organisms such as streptococci, staphylococci, E.coli, H.influenzae, M.catarrhalis, N.gonorrhoeae, Ps.aeruginosa and Chlamydia pneumoniae. Thus trovafloxacin can be used in a variety of conditions including pneumonia, pelvic inflammatory disease, gonorrhoea, chlamydial cervicitis and skin & skin structure infections. The drug is adminstered orally once daily and has a bioavailability of 88%, unaffected by food. Antacids and morphine can interfere with its absorption. There is minimal involvement of the cytochrome P450 system, so drug interactions are fewer. It is widely distributed, with concentrations in some tissues exceeding those in plasma. The half life is 11 hours. Common adverse effects are dizziness, headache and nausea. There is a risk of severe liver toxicity. The intravenous form contains alatrofloxacin, which is the prodrug of trovafloxacin.
For macular degeneration
Verteporfin is an alternative to laser photocoagulation for destroying new abnormal blood vessels in macular degeneration. Being poorly soluble, it is formulated in a liposomal delivery system. It is administered as an infusion over 10 minutes and is transported in the body by lipoproteins. The drug is activated by a non-thermal laser light shone into the affected eye 15 minutes after beginning the infusion. Exposure for 83 seconds generates reactive oxygen radicals which damage the vascular endothelium leading to occlusion of the abnormal vessels. In clinical studies, verteporfin was significantly better than placebo, and it was particularly beneficial in classic subfoveal choroidal neovascularisation.
Vigabatrin acts by increasing GABA (gamma aminobutyric acid) levels by inhibiting the enzyme GABA transaminase. The drug is particularly effective in partial or focal epilepsies. It is also effective in treating infantile spasms, but is less effective in generalised epilepsies and may exacerbate absence and myoclonic seizures. The dose is 1500-3000 mg/day, usually in two divided doses. Adverse effects include drowsiness, and mood changes with depression and aggression. There have been concerns about visual loss in patients treated with vigabatrin. The drug should be avoided in patients with a past history of psychiatric illness. Safety in pregnancy has not been established.
Zaleplon interacts with the GABA-BZ receptor-chloride channel macromolecular complex. Unlike other hypnotic agents, it remains at the binding site only until sleep is initiated. It is then rapidly eliminated, allowing the natural sleep process to occur. The effects of zaleplon last for four hours. This enables the patient to take zaleplon in the middle of the night and not experience severe next-day effects. The effects of 5 mg, 10, mg, and 20 mg zaleplon were compared with placebo on time to sleep onset (TSO). Zaleplon 10 mg and 20 mg were consistently superior to placebo for TSO; whereas zaleplon 5 mg was less consistently effective than 10 mg and 20 mg. Sleep latency with the 10 mg and 20 mg doses was 10-20 minutes less than with placebo. Double-blind studies have demonstrated that zaleplon 10 mg and 20 mg was superior to placebo in reducing latency to persistent sleep (LPS) on the first 2 nights of treatment. A significant difference from placebo was not observed beyond 2 nights. The most common adverse events were headache, drowsiness, and dizziness. There was no evidence of memory or psychomotor impairment four or more hours after administration. Caution should be advocated when undertaking tasks that require complete alertness. Alcohol should not be consumed while taking zaleplon, as it increases the side effects of the drug. The recommended dose is 5 mg for elderly patients and 10 mg for younger adults.
Leokotrienes are involved with causing inflammation and bronchial smooth muscle contraction in asthmatics. Zafirlukast competes for leukotriene receptors and counters the effects of leukotrienes. Zafirlukast may not be more potent than inhaled steroids, but it does reduce the requirement for beta agonist inhalers. Zafirlukast is useful chiefly in the prevention of asthmatic attacks, in those whose asthma is not controlled by other agents or in patients who cannot be administered other prophylactic agents. The drug is administered twice daily orally. Food reduces its absorption upto 40%. It is extensively metabolised in the body and is not recommended in cases with hepatic impairment. Since its liver metabolism involves the cytochrome P450 system, drug interactions occur involving warfarin, terfenadine, erythromycin and aspirin. Adverse effects reported with zafirlukast include headache, gastrointestinal upsets and altered liver function.
Zileuton is a 5-lipoxygenase inhibitor. Leukotrines modulate neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability and smooth muscle cell contraction contributing to inflammation, edema, mucus secretion and bronchoconstriction in the airways of asthmatic patients. Zileuton is rapidly absorbed following oral administration with a mean time to peak plasma levels of 1.7 hours. In vitro studies show that zileuton can be metabolized by cytochrome P450 enzymes 1A2, 2C9, and 3A4. The mean terminal elimination half-life is 2.5 hours. The efficacy of Zyflo was established in two double blind placebo controlled studies using FEV1 (forced expiratory volume at 1 second) as a clinical endpoint. In both studies, the FEV1 was significantly higher in the zileuton treated group. Zileuton is administered in a dosage of 600 mg four times per day.
Zoledronate is a third generation bisphosphonate, and is more potent than the older agents. The bisphosphonates inhibit the resorption of bone by osteoclasts (which remove bone) and may also act on the osteoblasts (which contribute to bone formation). These properties make the bisphosphonates useful in the treatment of conditions associated with increased bone resorption, such as osteoporosis, hypercalcaemia of cancer, bony metastasis, multiple myeloma and Paget’s disease. Zoledronate may be administered by intravenous infusion.
Like sumatriptan, zolmitriptan also acts on 5HT receptors, and the drugs have similar efficacy. Since it does not have a sulfonamide side chain, zolmitriptan may be more suitable for patients who are allergic to sulfonamides. In 2058 patients with at least one attack of migraine, the severity of the attacks reduced 2 hours after a dose in 80% of patients, and 35% of patients with severe headache became pain free. Adverse effects include asthenia, nausea, somnolence, dizziness and parasthesia. Zolmitriptan is contraindicated in patients with ischaemic heart disease, uncontrolled hypertension or myocardial infarction. Concomitant administration of zolmitriptan with monoamine oxidase inhibitors or ergotamine is contraindicated.
Zolpidem acts on the benzodiazepine receptors and has similar, though somewhat more selective, effects to the benzodiazepines. Peak plasma levels are achieved in 3 hours and the hypnotic effect lasts for up to 6 hours. Zolpidem does not appear to be more effective than temazepam in chronic insomnia. Side effects include dizziness, drowsiness, nausea and headache. The drug interacts with CNS depressant agents such as alcohol.