Drugs
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Lopinavir is a novel protease inhibitor (PI) developed from ritonavir. Coadministration with low-dose ritonavir significantly improves the pharmacokinetic properties and hence the activity of lopinavir against HIV-1 protease. Coformulated lopinavir/ritonavir was developed for ease of administration and to ensure both drugs are taken together, as part of combination therapy with other antiretroviral agents. Coformulated lopinavir/ritonavir-based regimens provide adequate and durable suppression of viral load and sustained improvements in CD4+ cell counts, as demonstrated in randomised trials in antiretroviral therapy-naive and -experienced adults and children. To date, development of primary resistance to lopinavir/ritonavir has not been observed in 470 antiretroviral therapy-naive patients treated for >48 weeks. The lopinavir/ritonavir-based regimen was more effective than nelfinavir in antiretroviral therapy-naive HIV-1-infected patients in a phase III trial. The coformulation is also effective as 'salvage' therapy, as shown by low cross-resistance rates in patients who failed to respond to treatment with other PIs in phase II trials. Coformulated lopinavir/ritonavir was well tolerated in both antiretroviral therapy-naive and -experienced HIV-1-infected adults and children with low rates of study drug-related treatment discontinuations. The most common adverse event in adults associated with lopinavir/ritonavir was diarrhoea, followed by other gastrointestinal disturbances, asthenia, headache and skin rash. The incidence of moderate-to-severe adverse events in children was low, skin rash being the most common. Changes in body fat composition occurred with equal frequency in lopinavir/ritonavir- and nelfinavir-treated naive patients, through week 60 in a phase III study. Although laboratory abnormalities occurred with similar frequency in both treatment groups, triglycerides grade 3/4 elevations were significantly more frequent with lopinavir/ritonavir. Total cholesterol and triglycerides grade 3/4 elevations appear to occur more frequently in PI-experienced than in PI-naive lopinavir/ritonavir-treated patients. A number of clinically important drug interactions have been reported with lopinavir/ritonavir necessitating dosage adjustments of lopinavir/ritonavir and/or the interacting drugs, and several other drugs are contraindicated in patients receiving the coformulation. ⋯ Coformulated lopinavir/ritonavir has the potential to interact with wide variety of drugs via several mechanisms, mostly involving the CYP enzymes. Coadministration of lopinavir/ritonavir is contraindicated with certain drugs (i.e. flecainide, propafenone, astemizole, terfenadine, ergot derivatives, cisapride, pimozide, midazolam and triazolam) that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Coadministration with lopinavir/ritonavir is also not recommended for drugs or herbal products (i.e. rifampicin [rifampin] and St. John's wort [Hypericum perforatum]) that may substantially reduce lopinavir plasma concentrations, or drugs whose plasma concentrations elevated by the coformulation may lead to serious adverse reactions (i.e. simvastatin and lovastatin). However, a recent study in healthy volunteers suggests that adequate lopinavir concentrations may be achieved during rifampicin coadministration by increasing the twice-daily dosage of lopinavir/ritonavir in conjunction with therapeutic drug monitoring. The liquid (but not the capsule) formulation of lopinavir/ritonavir contains 42.4% ethanol (v/v) and should not be coadministered with drugs capable of producing disulfiram-like reactions (e.g. disulfiram, metronidazole). Coadministration with saquinavir or indinavir requires no dosage adjustment, whereas coadministration with amprenavir, nevirapine or efavirenz requires a dosage increase of the coformulation typically by 33%. As the oral bioavailability of both didanosine and lopinavir/ritonavir is significantly affected by concurrent food ingestion, didanosine should be administered 1 hour before or 2 hours after lopinavir/ritonavir has been taken with food. Interactions between lopinavir/ritonavir and other nucleoside reverse transcriptase inhibitors (NRTIs) are not expected. The coformulation is also likely to increase plasma concentrations of non-antiretroviral drugs metabolised through the CYP3A pathway. To reduce the risk of their toxicity when coadministered with lopinavir/ritonavir, the recommended actions include: (i) monitoring of the drug plasma concentration (antiarrhythmics and immunosuppressants) or the international normalised ratio (warfarin); (ii) the use of alternative treatment (atorvastatin) or birth control methods (ethinylestradiol); and (iii) dosage adjustment (clarithromycin [only in patients with renal failure], rifabutin, dihydropyridine calcium-channel blockers, atorvastatin, ketoconazole and itraconazole). (ABSTRACT TRUNCATED)
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Stress of critical illness is often accompanied by hyperglycaemia, whether or not the patient has a history of diabetes mellitus. This has been considered to be part of the adaptive metabolic response to stress. The level of hyperglycaemia in patients with acute myocardial infarction (MI) or stroke upon admission to the hospital has been related to the risk of adverse outcome. ⋯ Intensive insulin therapy reduced intensive care mortality by more than 40% and also decreased a number of morbidity factors including acute renal failure, polyneuropathy, ventilator-dependency and septicaemia. Future studies will be needed to further unravel the mechanisms that explain the beneficial effects of this simple and cost-saving intervention. Although available evidence supports implementation of intensive insulin therapy in surgical intensive care, the benefit for other patient populations, such as patients on medical intensive care units or hospitalised patients who do not require intensive care but who do present with stress-induced hyperglycaemia, remains to be investigated.
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Buprenorphine is a low molecular weight, lipophilic, opioid analgesic. Recently, a transdermal matrix patch formulation of buprenorphine has become available in three dosage strengths designed to release buprenorphine at 35, 52.5 and 70 micro g/h over a 72-hour period. At least satisfactory analgesia with minimal requirement for rescue medication (
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Review
Postoperative analgesia and sedation in the adult intensive care unit: a guide to drug selection.
An essential goal of all critical care physicians should be to maintain an optimal level of pain control and sedation for their patients. This has become increasingly important because of evidence showing that the combined use of sedatives and analgesics may ameliorate the detrimental stress response in critically ill patients. Unfortunately, both pain and anxiety are subjective and difficult to measure, thereby limiting our ability to analyse these states and making management more challenging. ⋯ These include daily cessation of drugs to evaluate the patient and frequent reassessment of the level of sedation required by each specific patient. Much is still unknown about the long-term effects of sedative and analgesic drugs used as infusions that may last from days to weeks to months. Hopefully, as more studies are performed, we will have more defined clinical end-points, newer drugs with rapid onset and offset and no active metabolites, and decreased morbidity and mortality for our patients.
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The orally administered fixed combination tablet of tramadol (centrally-acting opiate) plus paracetamol (acetaminophen; nonopiate, nonsalicylate analgesic) [37.5/325 mg] provides effective analgesia in patients with moderate to severe acute pain and those with chronic painful conditions characterised by intermittent exacerbations of pain. Two tramadol/paracetamol 37.5/325 mg tablets provided greater relief of dental pain over an 8-hour period than either agent alone, with a faster onset of action than tramadol alone and a longer duration of action than either agent as monotherapy. ⋯ The addition of one or two tramadol/paracetamol 37.5/32 5mg tablets (up to four times daily) for 5 days to existing NSAID or cyclo-oxygenase-2 inhibitor analgesic therapy provided effective pain relief in patients with osteoarthritis flare pain. Tramadol/paracetamol 37.5/325 mg provided similar efficacy to that of codeine/paracetamol 30/300 mg in patients with chronic back pain in a 4-week, randomised, double-blind trial (a maximum of 10 tablets or capsules per day of the active drug).