Milap C. Nahata

Cardiotoxicity of Chemotherapeutic Agents

Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide, the vinca alkaloids, fluorouracil, cytarabine, amsacrine, cladribine, asparaginase, tretinoin and pentostatin. Cardiotoxicity is rare with some agents, but may occur in >20% of patients treated with doxorubicin, daunorubicin or fluorouracil.Cardiac events may include mild blood pressure changes, thrombosis, electrocardiographic changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure) and congestive heart failure. These may occur during or shortly after treatment, within days or weeks after treatment, or may not be apparent until months, and sometimes years, after completion of chemotherapy.Anumber of risk factors may predispose a patient to cardiotoxicity. These are: cumulative dose (anthracyclines, mitomycin); total dose administered during a day or a course (cyclophosphamide, ifosfamide, carmustine, fluorouracil, cytarabine); rate of administration (anthracyclines, fluorouracil); schedule of administration (anthracyclines); mediastinal radiation; age; female gender; concurrent administration of cardiotoxic agents; prior anthracycline chemotherapy; history of or pre-existing cardiovascular disorders; and electrolyte imbalances such as hypokalaemia and hypomagnesaemia. The potential for cardiotoxicity should be recognised before therapy is initiated. Patients should be screened for risk factors, and an attempt to modify them should be made.Monitoring for cardiac events and their treatment will usually depend on the signs and symptoms anticipated and exhibited. Patients may be asymptomatic, with the only manifestation being electrocardiographic changes. Continuous cardiac monitoring, baseline and regular electrocardiographic and echocardiographic studies, radionuclide angiography and measurement of serum electrolytes and cardiac enzymes may be considered in patients with risk factors or those with a history of cardiotoxicity.Treatment of most cardiac events induced by chemotherapy is symptomatic. Agents that can be used prophylactically are few, although dexrazoxane, a cardioprotective agent specific for anthracycline chemotherapy, has been approved by the US Food and Drug Administration. Cardiotoxicity can be prevented by screening and modifying risk factors, aggressively monitoring for signs and symptoms as chemotherapy is administered, and continuing follow-up after completion of a course or the entire treatment. Prompt measures such as discontinuation or modification of chemotherapy or use of appropriate drug therapy should be initiated on the basis of changes in monitoring parameters before the patient exhibits signs and symptoms of cardiotoxicity.

Adverse Effects of Meperidine, Promethazine, and Chlorpromazine for Sedation in Pediatric Patients

A combination of meperidine (M) 25 mg/ml, promethazine (P) 6.5 mg/ml, and chlorpromazine (C) 6.5 mg/ml is widely used to produce sedation in pediatric patients. A dose of MPC 0.1 ml/kg is recommended for cardiac catheterization, but no specific guidelines for dosing or frequency of monitoring have been established for patients undergoing other types of procedures. The adverse effects of MPC were studied prospectively in 95 patients undergoing various procedures. MPC was given parenterally at a dose of 0.07-0.11 ml/kg. Four patients developed respiratory depression. In these patients, the lowest respiratory rate ranged from 12 to 20 per minute. The lowest pulse rate ranged from 92 to 102 per minute. Three patients had received recommended or lower than recommended doses of MPC. One who received MPC 0.07 ml/kg developed respiratory arrest within 30 minutes; another required naloxone, and all recovered within 10 hours. These cases suggest the need for frequent monitoring and specific dosing guidelines for MPC use in pediatric patients.

The New Macrolide Antibiotics: Azithromycin, Clarithromycin, Dirithromycin, and Roxithromycin

OBJECTIVE: To review the chemistry, antimicrobial spectrum, pharmacokinetics, clinical trials, adverse effects, and drug interactions of four new macrolide antibiotics: Azithromycin, clarithromycin, dirithromycin, and roxithromycin. DATA SOURCES: Information was obtained from comparative clinical trials, abstracts, conference proceedings, and review articles. Indexing terms included azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, and macrolide antibiotics. STUDY SELECTION: Emphasis was placed on comparative clinical trials involving the new macrolide antibiotics. DATA EXTRACTION: Data from human studies published in the English language were evaluated. Trials were assessed by sample size, macrolide dosage regimen, and therapeutic response. DATA SYNTHESIS: The erythromycins have gained widespread use in treating a variety of infections. Although they are effective, limitations include the need to administer four times a day and the intolerable adverse gastrointestinal effects. Four of the more extensively studied agents, azithromycin, clarithromycin, dirithromycin, and roxithromycin, are currently being studied in patients. Based on the studies to date, the newer macrolides may offer several advantages over erythromycin, including: (1) greater antimicrobial activity against certain organisms; (2) longer elimination half-life, thus allowing less frequent administration; and (3) lower incidence of adverse gastrointestinal effects. CONCLUSIONS: The new macrolide antibiotics appear to offer an improvement over erythromycin. Definitive conclusions about the role of these drugs should await completion of ongoing clinical studies.

Treatment of Listeriosis

OBJECTIVE: To review the most currently accepted treatment options for the treatment of listeriosis. DATA SOURCES: Clinical literature was accessed through MEDLINE (1966–October 1999). Key search terms included Li steria monocytogenes, food-borne illness, penicillins, fluoroquinolones, cephalosporins, and vancomycin. DATA SYNTHESIS: Listeriosis is mainly a food-borne illness caused by L. monocytogenes;people most prone to the disease are pregnant women, newborns, elderly, and those with HIV or other diseases compromising immunity. Listeria infections are associated with a high mortality rate, and thus effective antibiotic treatment is essential. Although a variety of antibiotics have activity against the organism, ampicillin alone or in combination with gentamicin remains the treatment of choice. Some patients may require alternative therapies due to allergies or certain disease states. Second-line agents for these cases include trimethoprim/ sulfamethoxazole, erythromycin, vancomycin, and the fluoroquinolones. Cephalosporins are not active against Listeria. CONCLUSIONS: Ampicillin is currently the drug of choice for treating L. monocytogenes infections. Many antibiotics have been shown to be effective and are used as second-line agents. However, further study is required for some of the most recently introduced antibiotics, such as the fluoroquinolones, to determine their place in the treatment of Listeriainfections.

Clinical Pharmacokinetics of Antibacterial Drugs in Neonates

SummaryNeonatal patients are surviving longer due to the rapid advances in medical knowledge and technology. Our understanding of the developmental physiology of both preterm and full term neonates has also increased. It is now apparent that differences in body composition and organ function significantly affect the pharmacokinetics of antibacterial drugs in neonates, and dosage modifications are required to optimise antimicrobial therapy.The penicillins and cephalosporins are frequently used in neonates. Although ampicillin has replaced benzylpenicillin (penicillin G) for empirical treatment of neonatal sepsis, many of the other penicillins may be used in neonates for the management of various infections. Increased volume of distribution (Vd) and decreased total body clearance (CL) affect the disposition of penicillins and cephalosporins. Decreased renal clearance (CLR) due to decreased glomerular filtration and tubular secretion is responsible for the decreased CL for most of the β-lactams.Aminoglycoside Vd is affected by the increased total body water content and extracellular fluid volume of neonates. The increased Vd, in part, accounts for the extended elimination half-life (t½) observed in neonates. Aminoglycoside CL is dependent on renal glomerular filtration which is markedly decreased in neonates, especially those preterm. These drugs appear to be less nephrotoxic and ototoxic in neonates than in older patients, and the role of serum concentration monitoring should be limited to specific neonatal patients.Other antibiotics such as vancomycin, teicoplanin, chloramphenicol, rifampicin, erythromycin, clindamycin, metronidazole and cotrimoxazole (trimethoprim plus sulfamethoxazole) may be used in certain clinical situations. The emergence of staphylococcal resistance to penicillins has increased the need for vancomycin. With the exceptions of vancomycin and chloramphenicol, the efficacy and safety of these other agents in neonates have not been established. The need for serum vancomycin concentration monitoring may be limited, as with aminoglycosides, while safety concerns warrant the routine monitoring of serum chloramphenicol concentrations in neonates.Dosing guidelines are provided, based on the pharmacokinetics of the drugs and previously published recommendations. These dosing guidelines are intended for initial therapy, and close therapeutic monitoring is recommended for maintenance dose requirements to optimise patient outcome.There has been an enormous increase in our knowledge of neonatal physiology and drug disposition. Fortunately, many of the antibacterial drugs used in neonates (e.g. penicillins and cephalosporins) are relatively safe. It will be important to evaluate all newly developed antibiotics in neonates to assure their maximum efficacy and safety.

Extemporaneous drug formulations.

BACKGROUND Access to a special dosage form of a medication is essential when administration to infants and children and selected other populations is required. Some drugs necessary for pediatric patients are not commercially available in dosage forms appropriate for use in this population. These drugs may be prepared extemporaneously for use in individual patients. Physical and chemical properties of drugs and excipients should be considered when preparing extemporaneous formulations. These formulations, however, may lack studies to document stability, bioavailability, pharmacokinetics, pharmacodynamics, efficacy, and tolerability. OBJECTIVE The goal of this article was to discuss factors involved in extemporaneous compounding of pediatric dosage forms. METHODS The proceedings from a Pediatric Formulation Initiative workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, held December 6 and 7, 2005, in Bethesda, Maryland, were used as a source of information for this article. A literature search of PubMed/ MEDLINE (1966-October 2008) was also conducted, using the search terms extemporaneous, drug formulations, and pediatric. RESULTS Access to age-appropriate drug formulations is critical to provide effective and well-tolerated medications to patients. There continues to be a need for extemporaneous formulations of brand and generic drugs for neonates, infants, and children. Potential solutions to current limitations include the need to develop a prioritized list of essential formulations, increased funding of research, dissemination of data, and monitoring of clinical effectiveness and tolerability during use in various age groups of pediatric patients and the sharing of these clinical experiences. CONCLUSION To achieve desired therapeutic outcomes in pediatric patients, access to age-appropriate, stable, effective, and well-tolerated drug formulations is essential.

Glycerol: a review of its pharmacology, pharmacokinetics, adverse reactions, and clinical use.

Glycerol is a potent osmotic dehydrating agent with additional effects on brain metabolism. In doses of 0.25‐2.0 g/kg glycerol decreases intracranial pressure in numerous disease states, including Reyes syndrome, stroke, encephalitis, meningitis, pseudotumor cerebri, central nervous system tumor, and space occupying lesions. It is also effective in lowering intraocular pressure in glaucoma and shrinking the brain during neurosurgical procedures.

Gabapentin associated with aggressive behavior in pediatric patients with seizures

Gabapentin (GBP) is a new antiepileptic drug (AED) approved for adjunctive treatment of complex partial seizures with or without seizures secondarily generalization in adults. We report 2 children who received GBP for intractable seizures and who developed intolerable aggressive behavior requiring dose reduction or drug discontinuation. Behavioral changes should be recognized as a possible side effect of GBP, especially in mentally retarded children.

Oral Terbinafine: A New Antifungal Agent:

Objective To review the pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of terbinafine. Available comparative data of terbinafine and other antimycotic agents are described for understanding the potential role of terbinafine in patient care. Data Sources A MEDLINE search restricted to English language during 1966–1996 and extensive review of journals was conducted to prepare this article. MeSH headings included allylamines, terbinafine, SF 86–327, dermatophytosis, dermatomycosis. Data Extraction The data on pharmacokinetics, adverse effects, and drug interactions were obtained from open-label and controlled studies and case reports. Controlled single- or double-blind studies were evaluated to describe the efficacy of terbinafine in the treatment of various fungal infections. Data Synthesis Terbinafine is the first oral antimycotic in the allylamines class: a fungicidal agent that inhibits ergosterol synthesis at the stage of squalene epoxidation. Terbinafine demonstrates excellent in vitro activity against the majority of dermatophyte species including Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum; less activity is seen against Dematiaceae and the filamentous fungi. It is least active against the pathogenic yeast and this correlates with the relatively poor efficacy against these organisms in vivo. High concentrations of terbinafine are achieved in keratinous tissues, the site of superficial infections, and these concentrations are maintained for up to 3 months. The clinical efficacy of terbinafine against a number of dermatophyte infections exceeds that of the current standard of therapy, griseofulvin. The efficacy of terbinafine may be as good or better than that of the azole antifungals. Additional studies are required to confirm these observations. Terbinafine demonstrates a good safety profile, and relatively few drug interactions have been identified. Conclusions Terbinafine is more effective than the gold standard, griseofulvin, in the treatment of tinea pedis and tinea unguinum, with considerably shorter treatment duration in the latter. It has been proven as effective as griseofulvin in the treatment of tinea capitis, tinea corporis, and tinea cruris. Terbinafine does not appear to offer any advantage in the treatment of nondermatophyte infections; its utility in the treatment of systemic infections has yet to be established. Depending on individual institutional costs, terbinafine may be a front-line drug for some superficial infections responding poorly to the current standard of therapy.

Rimantadine: A Clinical Perspective

Objective: To provide a review of rimantadine, including its antiviral activity, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage and administration. Information on influenza A virus and clinical features of influenza disease are presented. Comparative data on rimantadine and amantadine are described. Data Sources: A MEDLINE search restricted to English-language literature published from 1966 through 1994 and an extensive review of journals was conducted. Data Extraction: The data on antiviral activity, pharmacokinetics, adverse effects, and drug interactions were obtained from various articles on rimantadine in open and controlled studies. Controlled double-blind studies were evaluated to assess the efficacy of rimantadine in prophylaxis and treatment of influenza A infection. Data Synthesis: Over 90% of a rimantadine dose was absorbed in 3–6 hours in healthy adults. Steady-state plasma concentrations have ranged from 0.10 to 2.60 μg/mL at doses of 3 mg/kg/d in infants to 100 mg twice daily in the elderly. Nasal fluid concentrations of rimantadine at steady-state were 1.5 times higher than plasma concentrations, which may explain the effectiveness of rimantadine despite a low plasma concentration. Over 75% of a rimantadine dose was metabolized in the liver, and the parent compound and metabolites were almost completely eliminated by the kidneys. The elimination half-life ranged from 24.8 to 36.5 hours, which allows once-daily dosing. Dosage adjustment is recommended for patients with severe renal impairment (creatinine clearance ≤ 0.17 mL/s), severe hepatic dysfunction, or elderly nursing home patients. Drug-resistant strains of influenza A virus to rimantadine occurred in several studies with children and/or adults. Clinical significance of drug-resistant strains has not been established. Rimantadine appeared to be effective in 85–90% of individuals for prevention of influenza A illness and in 50–65% for prevention of influenza A infection. Rimantadine reduced the time to a 50% reduction in symptoms by 1–3 days versus placebo. Differences in symptom reduction between rimantadine and placebo after the first 3 days of treatment was not generally clinically significant. The most common adverse effects of rimantadine administration were associated with the central nervous system (CNS) and the gastrointestinal (GI) tract. CNS-related adverse effects occurred in 3.2% of children younger than 10 years of age and 8.4% of adults. In elderly patients, the incidence of CNS-related adverse effects ranged from 4.9% at 100 mg/d to 12.5% at 200 mg/d. GI adverse effects occurred in 8.4% of children younger than 10 years of age, 3.1% of adults, and 2.9% at 100 mg/d and 17.0% at 200 mg/d in the elderly. Conclusions: Rimantadine offers some desirable features for the treatment and prophylaxis of influenza A infection. It appears to be an attractive choice in elderly patients with a history of CNS adverse effects from amantadine and in patients with mild or moderate renal impairment. Although approved for twice-daily dosing, rimantadine has a pharmacokinetic profile that would allow once-daily dosing. It is effective for prophylaxis (not postexposure prophylaxis) and treatment of influenza A virus. It also has a low incidence of adverse effects.