N-acetyltransferases: Pharmacogenetics and clinical consequences of polymorphic drug metabolism

Since the discovery of polymorphicN-acetylation of drugs nearly 40 years ago, great progress has been made in understanding the molecular genetics of acetylation as well as the clinical consequences of being a rapid or slow acetylator. Inborn errors (several different alleles) at the NAT2 locus are responsible for the traditional acetylator polymorphism. Studies have revealed variant alleles at the NAT1 locus as well. The consequences of pharmacogenetic variation in these enzymes include (i) altered kinetics of specific drug substrates; (ii) drug-drug interactions resulting from altered kinetics; (iii) idiosyncratic adverse drug reactions. The latter have been extensively investigated for the arylamine-containing sulfonamide antimicrobial drugs. Individual differences in multiple metabolic pathways can increase the likelihood of covalent binding of reactive metabolites of the drugs to cell macromolecules with resultant cytotoxicity and immune response to neoantigens. This can result clinically in an idiosyncratic hypersensitivity reaction, manifested by fever, skin rash, and variable toxicity to organs including liver, bone marrow, kidney, lung, heart, and thyroid. Slow acetylation by NAT2 is a risk factor for such reactions to sulfonamides. Given the incidence of these severe adverse drug reactions (much less than 1/1000), slow acetylation cannot be the sole mechanism of predisposition in the population. Differences in rates of production of hydroxylamine metabolites of the drugs by cytochrome P450 (CYP2C9), myeloperoxidase, and thyroid, roxidase, along with an inherited abnormality in detoxification of the hydroxylamines are critically important in determining individual differences in adverse reaction risk. Both NATs, particularly NAT1, also can further metabolize hydroxylamine metabolites toN-acetoxy derivatives. Intensive investigation of patients with these rare adverse reactions using a variety of tools fromin vitro cell toxicity assays through molecular genetic analysis will help elucidate mechanisms of predisposition and ultimately lead to diagnostic tools to characterize individual risk and prevent idiosyncratic drug toxicity.     

Antimicrobial selection in the penicillin-allergic patient

Patients frequently state that they have a penicillin allergy that often presents a therapeutic problem in treating a variety of infectious disorders. Penicillin and beta-lactam allergic reactions should be determined by a careful history. Many patients who say they have a penicillin allergy, in fact do not. If it is determined that the patient has a penicillin allergy, then the clinician should determine whether it is of an anaphylactic or nonanaphylactic variety. Most reactions to beta-lactams are of the nonanaphylactic variety and are usually manifested clinically as a mild maculopapular rash or drug fever. Uncommonly, penicillin allergies are clinically manifested as anaphylactic reactions, e.g., bronchospasm, laryngospasm, hypotension or hives. Patients' hypersensitivity reactions tend to be stereotyped on rechallenge, which make the reactions predictable. Patients who have a questionable penicillin allergy, or have had only fever or rash, may be safely given beta-lactam antibiotics without fear of anaphylaxis. Patients with a documented history of anaphylactic reactions should receive non-beta-lactam antibiotics. Although monobactams and carbapenems are structurally related to beta-lactams, they are unrelated in terms of allergic potential. There is no cross-reactivity between mono-bactams or carbapenems with beta-lactams, and these drugs may be used safely in patients with anaphylactic reactions to beta-lactams. Because so many antibiotics are available that are allergically unrelated to beta-lactams, beta-lactam desensitization procedures are rarely necessary. (c) 2001 Prous Science. All rights reserved.     

Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine

Sulfonamides are oxidized to protein reactive cytotoxic metabolites by murine hepatic microsomes. Mononuclear leukocytes from patients with idiosyncratic reactions to sulfonamides were more susceptible to toxicity from these metabolites than were leukocytes from a control population, suggesting that these metabolites play a role in the pathogenesis of such reactions. Here we have shown that murine hepatic microsomes oxidize sulfamethoxazole at the N4-position to form the hydroxylamine. Formation of the hydroxylamine was dependent on the presence of microsomes, NADPH, and oxygen. The addition of SKF 525-A, cimetidine, or gassing with carbon monoxide inhibited formation. The enzymic activity was stable at 37 degrees C in the absence of NADPH. Ascorbic acid, N-acetylcysteine, and reduced glutathione significantly increased the yield of hydroxylamine, presumably by decreasing further oxidation and covalent binding. Microsomes prepared from mice treated with phenobarbital or beta-naphthoflavone catalyzed the formation of the hydroxylamine more readily than did microsomes from untreated mice. These results demonstrate that cytochrome P-450-mediated oxidation of sulfamethoxazole results in the formation of hydroxylamines, which can be further oxidized to more reactive intermediates. These metabolites are likely involved in the pathogenesis of idiosyncratic reactions.     

Hypersensitivity reactions to drugs: evaluation and management

Most hypersensitivity reactions to drugs occur within several weeks of administration; signs and symptoms are often consistent with known immune-mediated reactions, including anaphylaxis, rashes, fever, cytopenias and vasculitis. The culprit immune mechanisms range from immunoglobulin E antibody to T cells inducing apoptosis of keratinocytes, in the case of bullous exfoliative rashes. Many drugs induce reactions via altered hepatic metabolism, with production of reactive intermediates which induce a common syndrome of rash and fever plus variable types of other signs. Examples of this reactive metabolite syndrome include the rash and fever in HIV-positive patients given sulfamethoxazole and reactions to the aromatic anticonvulsants. With the notable exception of anaphylaxis and severe bullous exfoliative rashes, most immune reactions to drugs are not life-threatening and generally resolve once the drug is discontinued. The key is prevention. Specific immune testing is standardized only for penicillin. If test results are negative, however, the patient can tolerate all beta-lactam antibiotics. Of those patients with a positive penicillin skin test, only 2% develop reactions when given cephalosporins. Sulfa and quinolone antibiotics, and muscle relaxants, also frequently induce reactions. If there is a history of bullous rash, the patient should never again receive sulfa or quinolone, or related drugs. In other cases, a cautious graded challenge or desensitization can be done. Vancomycin, protamine, and radiocontrast media induce non-immune reactions secondary to their irritant effects on vascular endothelium. Narcotic pain medications cause histamine release by binding to a specific receptor on mast cells in sensitive patients. In contrast to true immune reactions, most patients can receive these medications again, if they are pretreated and the drugs are given slowly. Angiotensin-converting enzymes, aspirin, and non-steroidal anti-inflammatory drugs induce adverse reactions by their effect on enzymes. Readministration usually results in repeat symptoms. It is possible to desensitize patients to aspirin. Some patients appear to develop similar adverse symptoms with multiple unrelated drugs. Although these cases present management problems, most patients can complete a therapeutic course of a vital drug, after careful review of the history, immune testing when possible, and graded challenge or desensitization.     

Cutaneous drug reactions

Cutaneous drug reactions are the most frequently occurring adverse reactions to drugs. Among hospitalized patients, the incidence of these reactions ranges from 1 to 3%. The frequency of cutaneous reactions to specific drugs may exceed 10%. These reactions may range from mildly discomforting to those that are life-threatening. Anti-infective and anticonvulsant agents are among the drugs most commonly associated with adverse reactions in the skin. We describe and illustrate the clinical morphology of the most common cutaneous drug reactions, as well as drugs that most commonly precipitate specific reactions. The varied nature of the reactions that do occur, even with specific agents, indicates a multiplicity of mechanisms available whereby cutaneous drug reactions may be initiated. Although a variety of terms have been proposed for categorizing cutaneous drug reactions, we propose that reactions are best defined based upon mechanisms, where known. In this review, we assess the current knowledge of four categories of cutaneous drug reactions: immediate-type immune-mediated reactions, delayed-type immune-mediated reactions, photosensitivity reactions, and autoimmune syndromes. Moreover, we describe evidence that viral infection is an important predisposing factor for the development of cutaneous drug reactions upon drug administration. Finally, we review the current knowledge of the type and mechanisms of cutaneous drug reactions to several categories of drugs.     

HMG CoA reductase inhibitors and impotence: two case series from the Spanish and French drug monitoring systems.

OBJECTIVE: HMG CoA Reductase inhibitors, more commonly called statins, are used in the pharmacological management of hyperlipidaemia. At present, the use of these drugs is increasing worldwide. They have been linked to certain adverse drug reactions, including impotence. The aim of the present study is to explore the basis of the association between statin use and impotence using data from spontaneous reports. METHOD: We analysed the cases of impotence associated with statins that were collected by the Spanish and French pharmacovigilance systems. We used cases of impotence as a numerator and consumption data as a denominator to estimate the cumulative reported incidence of impotence. RESULTS: Thirty-eight cases of impotence associated with statins have been identified in the database of the Spanish pharmacovigilance system; overall, there was a temporal sequence of events in all cases and the adverse reaction disappeared after drug withdrawal in 93% of the cases. Sixteen patients had also been treated with other drugs. In France, 37 cases were collected. In 85% of these cases recovery from the adverse reaction was observed after drug withdrawal; there was a positive rechallenge in five cases, and 15 patients were receiving other drugs at the same time. No significant differences among reported incidences with different statins were found. CONCLUSION: Considering the widespread use of this drug class and the under-reporting of this particular reaction it could affect a large number of patients. The reaction seems to be reversible in most of the cases after drug withdrawal. Doctors should be aware of this potential adverse reaction when prescribing statins to their patients.     

Cellular tests in the diagnosis of drug hypersensitivity

The application of flowcytometry in the study of basophil activation for the diagnosis of allergic diseases has given interesting results in recent years. The quantification of basophil activation by flowcytometry has been proven to be a useful tool for the assessment of the immediate-type response to allergens mediated by IgE or by other mechanisms in drug allergic patients. Up to now, most basophil activation test studies reported in the literature have used CD69 or CD203c as markers to quantify basophil activation after antigen-specific stimulation. Some technical variations such as the use of whole blood or isolated leukocytes, the addition of IL-3, the conditions of storage of the blood sample, the time of incubation with allergens and their concentration can affect the results of the basophil activation tests. The basophil activation test is more sensitive and specific than other in vitro diagnostic techniques in drug allergy. In various studies, its sensitivity in allergy to muscle relaxant drugs ranges between 36 and 97.7%, with a specificity around 95%. For betalactam antibiotics, basophil activation test sensitivity is 50% and its specificity 90%. For NSAIDs, sensitivity varies between 66% and 75%; specificity is about 93%. Basophil activation test reproduces in vitro hypersensitivity mechanisms involved in immediate-type allergic reactions, allows the diagnosis of allergic and pseudo-allergic reactions particularly for drugs, which are often not detectable by serological techniques, such as determination of specific IgE.     

Hypersensitivity to antineoplastic agents

The need to offer first line therapy for primary and recurrent cancers has spurred the clinical development of rapid desensitizations for chemotherapy and monoclonal antibodies. Rapid desensitizations allow patients to be treated with medications to which they have presented with hypersensitivity reactions (HSRs), including anaphylaxis. Rapid desensitization achieves temporary tolerization to full therapeutic doses by slow administration of incremental doses of the drug inducing the HSR. Protocols are available for most chemotherapy agents, including taxanes, platins, doxorubicin, monoclonal antibodies, and others. Candidate patients include those who present with type I HSRs, mast cell/IgE dependent, including anaphylaxis, and non-IgE mediated HSRs, during the chemotherapy infusion or shortly after. Idiosyncratic reactions, erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis are not amenable to rapid desensitization. The recommendation for rapid desensitization can only be made by allergy and immunology specialists and can only be performed in settings with one-to-one nurse-patient care and where resuscitation personnel and resources are readily available. Repeated desensitizations can be safely performed in outpatient settings with similar conditions, which allow cancer patients to remain in clinical studies. We have generated a universal 12-step protocol that was applied to 413 cases of intravenous and intraperitoneal rapid desensitizations using taxanes, platins, liposomal doxorubicin, doxorubicin, rituximab, and other chemotherapy drugs. Under this protocol all patients were able to complete their target dose, and 94% of the patients had limited or no reactions. No deaths or codes were reported, indicating that the procedure was safe and effective in delivering first line chemotherapy drugs.     

Drug-induced hypersensitivity: role in drug development

Drug-induced hypersensitivity is an adverse reaction, characterised by damaging immune-mediated responses, initiated by medicine given at therapeutic doses for prevention, diagnosis or treatment. Immune-mediated drug hypersensitivity accounts for 6-10% of the adverse drug reactions, which rank between the fourth and sixth leading causes of death in the US. With <10% of all adverse drug reactions reported, the magnitude of the problem is significant, with estimates of costs >$US30 billion annually in the US (1995 value). In addition, the costs of not determining the potential of a drug to produce hypersensitivity in the pre-clinical phase of drug development can be substantial. It has been estimated that the pre-clinical phase and clinical phase I, phase II and phase III costs are approximately $US6 million, $US12 million, $US12 million and $US100 million per drug, respectively (1999 values). It is important that investigational drugs with the potential to produce hypersensitivity reactions be identified as early in the development process as possible. Some adverse reactions to drugs can be avoided if drug-drug interactions are known or if there is a structure-activity relationship established. However, these methods are inadequate. Appropriate animal models of drug-induced hypersensitivity are needed, especially because hypersensitivity has been cited as the leading reason for taking drugs off the market.It is of critical importance to be able to predict hypersensitivity reactions to drugs. Most anaphylactic reactions occur in atopic individuals. Similarly, patients who have experienced other hypersensitivity reactions are more likely to have recurrent reactions. Therefore, animal models should be considered that predispose the animal to the reaction, such as the use of appropriate adjuvants and species. Using known positive controls of varying strengths, the investigator can rank the reaction against the positive controls as standards. This approach might yield greater results in a shorter period of time than using novel models. For the greatest safety, use of well understood models that have been thoroughly validated is imperative.     

Review of cimetidine drug interactions

The literature on cimetidine drug interactions has been thoroughly reviewed. Several different mechanisms have been proposed for cimetidine-related drug interactions. These mechanisms include: (1) impaired hepatic drug metabolism due to inhibition of hepatic microsomal enzymes, (2) reduced hepatic blood flow, resulting in decreased clearance of drugs that are highly extracted by the liver, (3) increased potential for myelosuppression when administered concurrently with other drugs capable of causing myelosuppression, and (4) altered bioavailability of acid-labile drugs. Cimetidine binds reversibly to the hepatic cytochrome P-450 and P-448 systems, resulting in decreased metabolism of drugs that undergo Phase I reactions (e.g., dealkylation and hydroxylation). In contrast, glucuronidation pathways are unaffected. The rapid onset and reversal of cimetidine's inhibition of hepatic metabolism indicates an effect on hepatic enzyme systems. Cimetidine also has been reported to decrease hepatic blood flow. Drugs that are highly extracted by the liver, such as propranolol, lidocaine, and morphine, may be postulated to have a decreased hepatic clearance. Cimetidine, through its effect on gastric pH, may increase the absorption of acid-labile drugs or may decrease the absorption of drugs. There have been reports of increased potential for myelosuppression when cimetidine is administered concurrently with drugs capable of causing bone marrow suppression. An understanding of the mechanisms involved in cimetidine drug interactions allows the clinician to prevent and predict these interactions.     

Rapid desensitization of hypersensitivity reactions to chemotherapy agents

All chemotherapy agents can cause hypersensitivity reactions, which have limited the used of critical drugs in very sick patients for fear of inducing a more severe reaction and possibly death. The choice of an alternative chemotherapy regimen is often limited by tumor sensitivity and, because of the increasing number of cancer survivors, exposure to multiple courses of the same or similar chemotherapy agents. Increased exposures lead to sensitization and to hypersensitivity reactions in an increasing patient population. The need to offer first line therapy after cancer recurrence has spurred the clinical development of rapid desensitizations, which allow patients to be treated with medications to which they have presented hypersensitivity reactions. Desensitization protocols are available to treat hypersensitivity reactions to most chemotherapy agents including taxenes, platinums, doxorubicin, monoclonal antibodies and others, by gradual re-introduction of small amounts of drug antigens up to full therapeutic doses. Candidate patients include those who present mild to severe type I hypersensitivity, mast cell/IgE dependent, reactions during the chemotherapy infusion or shortly after. Symptoms include pruritus, flushing, urticaria, angioedema, respiratory and gastrointestinal distress, changes in blood pressure including hypotension, and shock with anaphylaxis. Associated musculoskeletal symptoms and pain can be present in patients reacting to taxenes as in anaphylactoid reactions, in which mast cell/IgE mechanisms cannot be demonstrated. There is now strong evidence that anaphylactoid reactions are amendable to treatment with the same rapid desensitization protocols as for type I hypersensitivity reactions. Initial rapid desensitizations should only be performed in settings with one on one nurse-patient care and where resuscitation personnel and resources are readily available. Temporary tolerization is achieved in a few hours. After the first desensitization, standard protocols are available for safe, repeated desensitizations in outpatient settings with similar conditions, which not only provides flexibility, but allows patients to remain in clinical studies. Breakthrough symptoms are less severe than the initial hypersensitivity reaction in all series reviewed, and deaths have not been reported. The aim of this review is to familiarize the medical community with the type of hypersensitivity reactions amendable to rapid desensitization and to review protocols for chemotherapy desensitization that can be used for most chemotherapy agents. Few studies have measured the cancer response to the chemotherapy agents delivered through rapid desensitizations. One patient population in which 26 patients were desensitized to carboplatin and 16 to paclitaxel had similar rates of remission as for non-desensitized patients. Education of nurses, pharmacists, oncology and allergy specialists will lead to the universal use of rapid desensitization protocols for all cancer patients with hypersensitivity reactions to chemotherapy agents. Basic research is needed to uncover the cellular and molecular mechanisms underlying the temporary tolerization induced by rapid desensitization, so that pharmacological interventions can improve its safety and efficacy.     

Conclusiveness of rechallenge in the interpretation of adverse drug reactions.

We here consider the extent to which the presumed correlation between an adverse event and the administration of a particular drug can be reinforced by rechallenge. At first question of terminology is: what is a rechallenge? Rechallenge is often accepted too readily as proof of a causal relationship and clinical examples give illustrations of common misinterpretations. Definitions are proposed to characterize: the outcome of rechallenge; the conditions under which rechallenge is performed. In discussing causality, a sharp distinction is drawn between the outcome per se and the establishment of a causal relationship. Finally, the simple concepts proposed here should permit to establish a typology of rechallenge and to assess, by further experimental or retrospective research, the conclusiveness of rechallenge in interpreting adverse drug reactions.     

Fixed drug eruption in hands caused by omeprazole.

OBJECTIVE: Omeprazole is one of the most widely prescribed gastric antisecretory drugs. It is generally well tolerated and significant adverse reactions occur rarely. The objective of this report is to describe a case of fixed drug eruption that occurred during omeprazole treatment. CASE REPORT: A 37-year-old white female patient admitted with epigastric pain and heartburn symptoms. An upper gastrointestinal endoscopy revealed reflux esophagitis and the patient was given 20 mg b.i.d. omeprazole. She developed dark-red coloration on her hands, at the fourth day of treatment, which has been defined as fixed drug eruption. These lesions were attributed to treatment and recurred soon after a rechallenge with omeprazole. CONCLUSION: Fixed drug eruption is associated with many drugs but this is the first such report with omeprazole. We suggest being aware of such reactions during omeprazole usage.     

Toxic Epidermal Necrolysis induced by rarely implicated drugs

Toxic Epidermal Necrolysis (TEN) and Steven-Johnson Syndrome (SJS) are serious disorders commonly caused as idiosyncratic reactions to drugs, the most common ones being oxicams, anticonvulsants, allopurinol, and sulfonamides. We present a case of TEN in a patient who developed the lesions after ingesting multiple drugs including paracetamol, metoclopramide, antihistamines, and multivitamins. These drugs have rarely been implicated in this disorder. The suspected drugs in this case were paracetamol and metoclopramide. However, the role of other drugs could not be ruled out definitely. The patient was managed with antibiotics, corticosteroids, and parenteral fluids and recovered well.     

Hypersensitivity reactions to last generation chimeric, humanized [correction of umanized] and human recombinant monoclonal antibodies for therapeutic use

A new class of drugs, produced with the hybridoma technique, has been introduced and employed to treat many immunological diseases. This class consists of recombinant monoclonal antibodies, which can be chimeric, humanized or human. Predictably, there has been a rise in adverse hypersensitivity reactions to these therapeutic agents, whose pathogenic mechanisms are not yet well understood. Specific IgE has been demonstrated in a very few cases, and only in some of these recombinant antibodies. Skin tests are not done as a clinical routine screening. In the present article the mechanisms underlying hypersensitivity reactions to these drugs are analyzed, also in the light of the personal experience and that reported in the literature, with the aim of identifying potential risk factors and means of prevention of these reactions. For some drugs, infusion reactions may be prevented thanks to the the use of premedication. Moreover, symptoms of acute hypersensitivity during infusion can be successfully managed in the majority of cases by slowing the speed of administration. All these findings seem to confirm that the pathogenesis is not related to a true immediate (IgE-mediated) hypersensitivity in most cases. When the substitution of the drug that has triggered a hypersensitivity reaction is required, this is only possible if such an alternative drug exists (i.e., replacement of a chimeric antibody with a humanized or human antibody sharing the same target). As an alternative, desensitization protocols have been employed to induce a state of temporary tolerance to the drug in some cases, yielding successful results for infliximab and trastuzumab.     

Identification of sulfonamide-like adverse drug reactions to celecoxib in the World Health Organization database

BACKGROUND: The selective COX-2 inhibitor celecoxib has a sulfonamide structure and is contraindicated for patients with known sulfa allergy. However, there is currently no standard available for the identification of sulfonamide-related adverse drug reactions (ADRs) and the occurrence of such ADRs with celecoxib has not been established. THE AIMS OF THIS STUDY WERE: (1) to identify the typical pattern of sulfonamide ADRs from literature and verify this pattern in the World Health Organization (WHO) ADR database; and (2) to examine whether these sulfonamide ADRs occur more frequently with celecoxib than with the non-sulfonamide, COX-2 inhibitor rofecoxib. METHODS: A sulfonamide ADR pattern was derived from the most extensive textbook source of ADRs and applied to the WHO database for the three groups of sulfonamide drugs: short- and intermediate-acting sulfonamides, and sulfasalazine. ADRs reported three or more times for each of these groups were included in a 'sulfonamide template' comprising 19 ADRs relating to the skin, the blood, the liver, and anaphylaxis. This template was then applied to celecoxib and rofecoxib. RESULTS: Overall, the relative reporting rate of a sulfonamide-type ADR with celecoxib was 80% higher than with rofecoxib, whether this was based on total number of reports (RR 1.8, 95% Cl 1.6-1.9) or restricted to reports that listed coxibs as the sole suspected drugs (RR 1.8, 95% Cl 1.6-1.9). There were numerically more ADRs for celecoxib than for rofecoxib in 15 of the 19 terms. Within the ADRs in the sulfonamide template, relative reporting rate of fatal reactions was 80% higher with celecoxib (RR 1.8, 95% Cl 0.9-4.0). Even though serious sulfonamide reactions are rare, their clinical impact on patient safety warrants close monitoring as more data becomes available. Physicians should be aware of possible sulfonamide allergy when prescribing celecoxib.     

Adverse drug reactions and drug non-compliance as primary causes of admission to a cardiology department

Summary 426 consecutive patients admitted to a Danish University Department of Cardiology have been studied. Drug intake prior to admission by each patient was ascertained from medical records and personal interviews. Adverse drug reactions (ADR) were the primary cause of admission in 49 patients (11.5%), and 16 patients (3.8%) were admitted due to drug non-compliance (DNC).Thiazide diuretics, beta-adrenoceptor blocking agents and calcium antagonists accounted for almost 60% of all the ADR-related admissions. Patients admitted for ADR took significantly more drugs than patients admitted for other reasons. DNC was not correlated with the number of prescribed drugs.It is concluded that drug-related hospital admissions are an important medical and economic problem. Most of the ADRs were well-known and predictable actions of the drugs, and could have been avoided by more careful clinical and laboratory monitoring of the patients. Most of the DNC, too, could have been avoided by giving better information to the patients.     

Design of anti-bacterial drug and anti-mycobacterial drug for drug delivery system

Liposome-encapsulated drugs often exhibit reduced toxicity and have also been shown to enhance retention of drugs in the tissues. Thus, encapsulation of drugs in liposomes has often resulted in an improved overall therapeutic efficacy. The results of efficacy of liposome-encapsulated ciplofloxacin or azithromycin for therapy of intracellular M. avium infection show enhanced cellular delivery of liposome-encapsulated antibiotics and suggest that efficiency of intracellular targeting is sufficient to mediate enhanced antimycobacterial effects. The antitubercular drugs encapsulated in lung specific stealth liposomes have enhanced efficacies against tuberculosis infection in mice. These results from stealth liposome study indicate that antitubercular drugs encapsulated in liposome may provide therapeutic advantages over the existing chemotherapeutic regimen for tuberculosis. Liposomes with encapsulated amikacin are able to protect collagen almost completely from adherence of bacterial cells of all strains examined and prevent from invading of bacteria.     

Avoiding drug interactions

(1) Drug interactions potentiate or oppose the therapeutic or adverse effects of one or more co-administered drugs. (2) There are two mechanisms: pharmacodynamic interactions occur between drugs that have similar actions or adverse effects. The shared effect can potentiate or antagonise the actions of a physiological system such as clotting, or the parasympathetic nervous system. Pharmacokinetic interactions alter the metabolism of the relevant drug(s). (3) The clinical consequences of drug interactions are very variable. Most interactions with serious consequences involve either high risk drugs or high risk patients (such as older people). (4) The risk of interactions increases with the number of drugs taken, and with advancing age. (5) Some patients are at an increased risk of drug interactions because they have pathology that alters drug metabolism, such as renal failure, liver failure or malnutrition. Other patients are at risk because of the type and number of drugs they need (this is particularly true for patients with heart disease, HIV infection, epilepsy, tuberculosis and migraine). (6) In practice, patients must be questioned thoroughly about all the drugs they are taking, whether or not they have been prescribed.