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While drinking has been shown to decline with age, this may not be a reliable predictor of future trends since recent research has shown that changes in drinking patterns appear to be more closely associated with period rather than age effects. These considerations may render assessment of risk for problem drinking (with its attendant drug interactions) more difficult in the elderly.
Given the prevalence of Candida esophagitis in AIDS, empiric antifungal therapy is widely prescribed for symptomatic patients. A prospective randomized trial comparing endoscopy with empiric fluconazole in HIV-infected patients with esophageal symptoms demonstrated a high response rate and substantial cost savings with flucona-zole, and no patient failing empiric therapy developed complications before definitive endoscopic examination (Wilcox et al, 1996). Although not critically studied, an empirical approach is commonly employed in other immunocompromised patients. If patients do not improve rapidly following empiric therapy, I do not recommend additional empiric trials, such as with antiviral therapy. Similarly, immunosuppressed transplant patients who develop esophageal symptoms while already receiving prophylactic antimicrobial therapy, warrant endoscopic examination rather than additional empiric trials or radiological studies. This is particularly true if the patient is...
Chemotherapy without antiretrovirals has been studied due to concerns of drug interactions with chemotherapy and noncompliance with HAART resulting in increased resistance.81 Further, protease inhibitors (in HAART regimens) have been associated with neutropenia with concomitant chemotherapy.98
Tuberculosis in HIV infection is treated in the standard way with isoniazid and rifampicin plus either pyrazinamide or ethambutol. Rifampicin is a potent enzyme inducer and increases the metabolism of drugs such as oral contraceptives, dapsone, fluconazole, ketoconazole and anticonvulsants. Clinicians should also be aware of drug interactions between rifamycins (rifampicin and rifabutin) and antiretroviral drugs, particularly the protease inhibitors (Pls) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs). Certain combinations of each are contraindicated or require dose adjustment to
Most research in the UK has focused on touch and mind-body therapies. Cancer organisations and charities have information on these therapies. There is little information available, however, on medicinal and nutritional approaches such as vitamin use and dietary supplements. Patients do use these products, often without the knowledge of their health professionals. Their use may be intended as complementary but the effects may not be. Further attention needs to be given to this issue with consideration of possible drug interactions and interference with orthodox treatment and educating patients to make informed decisions about their use.
The additional risks of general anaesthesia for Caesarean section are compounded in the pre-eclamptic woman by the potential for a significantly compromised airway and the hypertensive response to intubation and extubation. There may also be potential drug interactions, especially between magnesium sulphate and neuromuscular blocking agents.
Systemic treatments for oral candidosis include fluconazole, itraconazole, and ketoconazole. Systemic treatments tend to be effective and are particularly useful in widespread disease. The drawbacks of these drugs are their contraindications, drug interactions, and the emergence of antifungal drug resistance. Resistance to the azole group of drugs seems to be a growing problem in palliative care, though for most patients in this setting they are generally still effective.
A recent US patent describes derivatives of amiodarone (27) for the treatment of ventricular fibrillation in patients with heart failure 46 . In the past, amiodarone has been reported to reduce arrhythmias in patients with congestive heart failure undergoing antihypertensive therapy. However, amiodarone has long-term toxicity related to its long half-life, drug-drug interactions and cardiac side effects. Therefore, analogs that are less lipophilic and contain a metabolically labile group should result in a Class III antiarrhythmic agent with significantly lower toxicity. Simple modification of the n-butyl group of amiodarone to incorporate an ester gave 28, which was speculated to be quickly metabolized to a water-soluble compound resulting in a safer antiarrhythmic agent.
Many adverse events that occur during the course of a trial are expected. Some may be due to the disease itself. Others may be caused by the product under study, by comorbidities, or by drug interactions. For studies of drugs or biolog-icals, sometimes a particular class of product may be known to cause specific adverse events. Early phase studies should have already elucidated the mechanism of action of the drug and its pharmacokinetics, so that common adverse events attributable to the drug should have already been identified. In Phase 3 trials of diseases that are not life-threatening, serious adverse events will usually occur only rarely. In life-threatening disease, adverse experiences that reflect
Evaluations of either efficacy or safety involve large numbers of comparisons that may then identify either real differences, or chance findings. There are multiple dimensions of concern, multiple outcomes, and possibly multiple comparison groups. A single study may simultaneously evaluate multiple outcomes, for example, EKG and clinical lab data, or liver enzymes, nausea, and jaundice. Occasionally, there is the need for a no treatment (or placebo) comparison as well as an active comparator, in order to provide estimates addressing different risk benefit questions. Multiple comparisons also occur in assessing drug-drug interactions where either efficacy or safety evaluations may differ by drug-drug combinations. Adverse reactions to an intervention may not be distinguishable from events in the natural course of the disease under study, or the target study population may have extensive comorbidities so that the cause of the event is unclear. A variety of comparisons may help...
Evaluating the tumor response, 2 of sorafenib-treated patients had a confirmed partial response while no patients in the placebo group experienced a partial response, suggesting that the gain in PFS for the drug-treated group is primarily a reflection of stable disease. In this Phase III study, 30 of sorafenib-treated patients reported adverse events compared to 22 for placebo with the primary complaints in both groups including rash, diarrhea, hand-foot skin reaction, fatigue, and hypertension. Most of the observed laboratory abnormalities were comparable for sorafenib and placebo with the exception of hypophosphatemia (45 versus 11 with placebo). Regarding drug-drug interactions, caution should be exercised in coadministering drugs that inhibit CYP3A4 and UGT1A9 although limited data suggests that concomitant use of ketoconazole, an inhibitor of both CYP3A4 and UGT1A9, did not lead to an increase in the mean AUC of a 50 mg dose of sorafenib. Conversely, since sorafenib has been...
Side effect that can lead to swallowing difficulty, thereby, necessitating total paren-teral nutrition in severe cases. Other complications include potential infections, overuse of opioid analgesics to treat the pain, and extended hospitalization. Palifer-min, a recombinant human keratinocyte growth factor (KGF), has been approved as a novel agent to treat this condition. As a member of the heparin-family of fibroblast growth factors, palifermin provides protection from the damaging effects of chemotherapy and radiation by selectively promoting epithelial cell proliferation, leading to an increased rate of healing. Palifermin is produced by recombinant DNA technology utilizing an expression vector encoding KGFdes1_23. As an N-terminal, truncated version of endogenous KGF having amino acids 1-23 deleted, palifermin has greater stability while retaining biological activity. In Phase I studies, i.v. administration of palifermin generated linear pharmacokinetic parameters with no...
The activity of TPMT is inhibited in vitro by sulfasalazine and related mesalamine compounds (see Figure 69-1) (Szumlanski et al, 1995). A recent nonrandomized 8-week drug interaction study showed that the coadministration of AZA with either mesalamine or sulfasalazine led to leukopenia, and a significant increase in erythrocyte 6-TG metabolite levels, as a result of decreased 6-MP catabolism (Lowry et al, 2001).
DRUG INTERACTIONS WITH LITHIUM Drug interactions with lithium 24 . Acute renal failure, with or without oliguria, can be associated with lithium treatment, and with severe dehydration. In this case, acute renal failure can be considered a prerenal type consequently, it resolves rapidly with appropriate fluid therapy. Indeed, the histologic appearance in such cases is remarkable for its lack of significant abnormalities. Conditions that stimulate sodium retention and consequently lithium reabsorption, such as low salt intake and loss of body fluid by way of vomiting, diarrhea, or diuretics, decreasing lithium clearance should be avoided. With any acute illness, particularly one associated with gastrointestinal symptoms such as diarrhea, lithium blood levels should be closely monitored and the dose adjusted when necessary. Indeed, most episodes of acute lithium intoxication are largely predictable, and thus avoidable, provided that precautions are taken 25 .
The PIs were introduced in 1995 as a promising new category of antiretrovirals that work by a different mechanism than the reverse transcriptase inhibitors (192). These compounds block a separate virus-specific enzyme known as HIV protease. Mechanism of action. Inhibition of the protease enzyme prevents the cleavage of viral polyproteins in the final stage of viral protein processing (See Fig. 2.2 for site of action.). Without the HIV protease activity, mature HIV virions cannot be assembled and released from infected cells, which results in the production of defective, noninfectious viral particles (193). While the reverse transcriptase inhibitors prevent replication only in newly infected cells, PIs block enzyme activity in both newly infected and chronically infected cells (194). Adverse events. When compared to the nucleoside analogues, the PIs are more potent in reducing viral load (126,195), but are associated with the major morbidity of lipodystrophy as well as possible...
Ritonavir is associated with numerous drug interactions and adverse effects, which have limited its widespread use. It is a considerably strong inhibitor of the cytochrome P450 system, which leads to increased serum levels of other hepatically metabolized drugs. Therefore, coadministration with carbam-azepines should not occur. Ritonavir has been associated with carbamazepine toxicity (243).
In a phase I trial, ISIS 3521 was delivered over a period of 21 d by continuous iv infusion followed by a 7-d rest period (39). Doses were increased from 0.5 to 3.0 mg kg d. Twenty-one patients with incurable malignancies were treated in five patient cohorts. The maximum tolerated dose was 2.0 mg kg d, equivalent to pharmacologically active doses against human xenografts in mice. The dose-limiting toxicities were thrombocytopenia and fatigue at a dose of 3.0 mg kg d. Evidence of tumor response lasting up to 11 mo was observed in three of four patients with ovarian cancer. Another phase I study analyzed the combination of ISIS 3521 with 5-fluorouracil and leukovorin (5-FU LV) in patients with advanced cancer. ISIS 3521 was tolerable when given with 5-FU LV. Partial remission was seen in 2 of 14 patientsp however, it is uncertain whether clinical activity is a result of enhanced drug interaction (40).
Patients with neuropathic pain should have a trial of a tricyclic antidepressant or venlafaxine or an anticonvulsant. The choice of drug should be based on relative contraindications, possible drug interactions, and risk of side effects for each patient. Antidepressants and anticonvulsants may occasionally be prescribed simultaneously, though it is good clinical practice to introduce only one drug at a time.
- Knowledge Rules - provides real-time decision support for medication errors, dosage error, and adverse drug interactions, known patient allergies, calculate dosages based on the patient, and standardized care. It also provides links to alternative, complementary supporting knowledge.
Antimicrobials often fail to cure the infection. Some of the reasons they do not work are the development of bacterial resistance, achievement of insufficient tissue levels, incompatible drug interaction, and the development of an abscess. The environment of an abscess is detrimental for many antimicrobials. The abscess fibrotic capsule interferes with the penetration of antimicrobial agents, and the low pH and the presence of binding proteins or inactivating enzymes (i.e., beta-lactamases) may impair the activity of many antimicrobials. The low pH and the anaerobic environment within the abscess are especially deleterious toward the aminoglycosides (10). It should be remembered that an acidic environment, high osmolarity, and presence of an anaerobic environment can develop in an infection site without the presence of an abscess (11).
Erythromycin was the first macrolide to be developed, and has been a mainstay of treatment for many infections for the last forty years. More recently clarithromycin and azithromycin have become available in the UK. Their main benefits are that they offer easier dosing, are more tolerable to take and do not have as many drug interactions.
Allylamines are antifungal agents targeted to squalene epoxidase, an enzyme necessary for ergosterol biosynthesis. Naftifine (12) was the first allylamine agent introduced in therapy in the early 1980s as 1 cream or gel for topical use. It has fungicidal activity against dermatophytes and fungistatic activity against Candida species. Its sensitizing capacity seems to be greater than in the commonly used azoles 58 . Terbinafine (13) was approved in 1990s in the UK and USA for the treatment of onychomycosis. It is the most frequently prescribed oral antifungal agent in North America, for onychomycosis. Eighteen randomized controlled trials have shown terbinafine to be highly effective with mycological cure of 76 . 13 has an established safety profile and very low occurrence of drug interactions 59 . An improved antifungal composition for topical application to the skin and nails has been developed for allylamines (naftifine or terbinafine) 60 . A formulation to provide a product having...
Methotrexate interacts with anti-inflammatory and antiepileptic drugs. A full list of drug interactions should be consulted before treatment is started. This drug has proved helpful in severe psoriasis within inflammatory lesions and, secondly, in the treatment of severe atopic dermatitis. There are a number of drug interactions and it is important to check renal function and monitor both blood urea and serum creatinine.
Professionals Handbook of Complementary and Alternative Medicines (C. W. Feltrow and J. R. Avila, Springhouse Publishers). This book describes the chemical components, actions, reported uses, and suggested doses of many herbs and alternative medicines. The authors also list potential adverse events and drug interactions. The book is less critical of claims made about the efficacy of the treatments than the above two books.
Acute renal failure, with or without oliguria, can be associated with lithium treatment, and with severe dehydration. In this case, acute renal failure can be considered a prerenal type consequently, it resolves rapidly with appropriate fluid therapy. Indeed, the histologic appearance in such cases is remarkable for its lack of significant abnormalities. Conditions that stimulate sodium retention and consequently lithium reabsorption, such as low salt intake and loss of body fluid by way of vomiting, diarrhea, or diuretics, decreasing lithium clearance should be avoided. With any acute illness, particularly one associated with gastrointestinal symptoms such as diarrhea, lithium blood levels should be closely monitored and the dose adjusted when necessary. Indeed, most episodes of acute lithium intoxication are largely predictable, and thus avoidable, provided that precautions are taken 25 .
Drug metabolism occurs primarily in the liver, by the cytochrome P450 (CYP450) enzyme system. When a drug is absorbed through the GI tract, it often undergoes first-pass metabolism. This is where the absorbed drug passes through the liver before being distributed throughout the rest of the body and whilst in the liver, it is metabolised. This process can either activate a drug, as is the case with valaciclovir, or form an inactive metabolite, as with the opioid analgesics. Some metabolites may be toxic and lead to adverse effects. If a drug is heavily metabolised in the liver, it can lead to poor oral bioavailablity, resulting in higher doses being required. Some drugs can inhibit or induce CYP450 enzymes, leading to drug-drug interactions. For example, ritonavir is a potent inhibitor of cytochrome isoenzyme 3A4 thus it can greatly affect the bioavail-ability of other drugs, such as sildenafil.
Clovir) or as high as almost 100 per cent (doxycycline). There are four main factors that affect gastrointestinal (GI) absorption. These are GI motility and blood flow, GI pH, particle size, and the formulation of the drug and various physiochemical factors (e.g. drug interactions). The fraction of the drug that is absorbed into the systemic circulation and is available at its site of action is known as the bioavailability.
Geriatric patients are often prescribed a large number of drugs to deal with the many disorders they suffer from. However, as indicated above, there are usually effective nonpharmacological therapies available that should be attempted before resorting to drugs. All geriatric patients need a careful and thorough review of the drugs they are prescribed to ensure they are necessary and that there is no change of potentially dangerous drug interactions. Effective drug therapy is often hampered by faulty diagnosis. Older patients may underreport symptoms, or their complaints may be vague and multiple. In addition, symptoms of physical diseases may overlap with psychological illness. Consequently, making the correct diagnosis and prescribing the appropriate drugs is a very difficult task in geriatric medicine. Finally, the aging process alters the elderly patient's ability to deal with drugs physiologically. This deficit occurs primarily at the liver and at the kidneys.
The analyses of missing data, and particularly the assumptions about the mechanism of missingness, have been extensively addressed in the statistical literature Little and Rubin (1987) and Laird (1988) . Designations such as missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR) may apply differently to efficacy outcomes than to safety outcomes even for the same subject. Some analytic approaches utilize covari-ates related to missing (e.g., distance from residence to clinic) or to reasons for discontinuation of therapy (tolerance, toxicity, drug-drug interactions, etc.). Analytic approaches can contribute to and advance the identification of potential safety problems that might not rapidly come to light with less sensitive methods. In evaluating either efficacy or safety, the sensitivity of estimates and hypothesis tests to assumptions and to methods of estimation should be examined.
Emergence of chemical genomics 67,68 has brought additional dimensions to the information available to chemists, requiring further changes in the optimization philosophy. Traditionally, the structure-centric thinking has been natural for medicinal chemists trying to hit a specific molecular target. Most of the properties requiring optimization could be directly or indirectly related to the structure, and after all, it is the structure that chemists have control over and can change. In chemogenomics space, drug interactions with all components of the biological system are taken into account in order to understand the mechanism of drug's
Drug interactions can generally be classified as either pharmacokinetic or pharmacodynamic. Pharmacokinetic interactions result from processes that lead to a change in the disposition of one or more drugs and result in a change in clinical response. The most common form of a pharmacokinetic interaction occurs when one drug induces or inhibits the metabolism and or elimination of another, and the steady-state concentration of a drug is lowered or raised. Alcohol can affect many medications through competition for the same microsomal oxidase system, involved in the metabolism of various drugs 22 , Pharmacodynamic interactions result when drugs have separate actions that are either augmented or antagonized when the drugs are used together. Alcohol appears to enhance aspirin-induced gastric mucosal damage and aspirin-induced prolongation of the bleeding time. Alcohol-drug interaction varies greatly in the range between social drinkers and heavy chronic drinkers. This phenomenon is also...
Whether the underlying process is myopathic or neuropathic in nature, all patients with CIP have disordered GI tract motility. Multiple prokinetic agents have been used in an attempt to promote normal intestinal motility, however there are few investigational studies available to demonstrate the efficacy of any of these agents in CIP. Erythromycin, a macrolide antibiotic that acts as an agonist to the motilin receptor, can be given either orally or IV. Doses in the range of 50 to 200 mg orally, or 50 to 100 mg IV, approximately 30 minutes before meals, have been shown by Minami and colleagues (1996)to be effective in accelerating gastric emptying and improving the symptoms of CIP. Cisapride, a mixed 5-HT4 receptor agonist 5-HT3 receptor antagonist, is no longer routinely available for noninvestigational uses. Cisapride was found to improve symptoms of nocturnal acid reflux, and to increase gastric emptying and improve orocecal transit times. Cisapride was generally taken orally as a...
Coadministration with terfenadine, cisapide, triaz-olam, midazolam, or ergot derivatives. Coadministra-tion with terfenadine, cisapride, triazolam, midazolam, or ergot derivatives may cause potentially serious reactions. Several other drug interactions occur that may increase or decrease drug plasma concentrations of either compound, requiring dosage adjustments.
Gatifloxacin, 5, is another methoxyfluoroquinolone that is actually furthest along in clinical development for tuberculosis treatment. Like moxifloxacin, it is used to treat a variety of bacterial infections, has been used globally for many years, and has no interactions with ARV drugs. Gatifloxacin is a structurally similar to moxifloxacin and likely to have the same mechanism of action against bacterial DNA gyrase. This means cross-resistance is possible between these two drugs. Gati-floxacin's toxicity and drug-drug interaction profile is similar to moxifloxacin's.