Drug–drug interactions of new active substances: mibefradil example

Introduction: Mibefradil was approved as a novel calcium antagonist in Switzerland in 1996. Following its launch as an antihypertensive and anti-anginal agent, there were reports about serious pharmacokinetic and pharmacodynamic interactions occurring with other drugs frequently administered to patients with cardiovascular diseases. Despite appropriate modifications of the prescribing information, such interactions continued to occur. The drug was finally withdrawn after a study in patients with congestive heart failure showed a trend to higher mortality with mibefradil. This increase in mortality could again be due to multiple interactions between mibefradil and other drugs. In retrospect, it can be concluded that several of the interactions, including the theoretical risk of severe toxicity in some patients, could have been and in fact were predicted on the basis of the data available before introduction to the market. Depending on the benefits, these problems would however not necessarily represent an unacceptable risk for a new active compound. Results and conclusion: The most important points revealed by this analysis were: (1) when interpreting the results of interaction studies, it is important to consider not only the mean of the interaction effect but also the observed and the theoretically conceivable extreme effects in individual subjects and (2) a drug with a high interaction potential may represent a high risk even if an adequate warning is included in the product information. The need for specific pharmacokinetic and pharmacodynamic interaction studies with new drugs and the limitations of the pivotal clinical efficacy and safety studies during phase III in order to reveal such interactions are discussed. Received: 19 March 1999 / Accepted in revised form: 29 July 1999     

A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin.

Cytochrome P-450 (CYP) 2C19 is responsible for the metabolism of a number of therapeutic agents such as S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Genetic polymorphisms in this enzyme are responsible for the poor metabolizers (PM) of mephenytoin, which represent approximately 13-23% of Asians and 3-5% of Caucasians. Several polymorphisms contribute to this phenotype. We have isolated two new allelic variants that contribute to the PM phenotype in Caucasians. CYP2C19*7 contained a single T --> A nucleotide transversion in the invariant GT at the 5' donor splice site of intron 5. The second PM allele, CYP2C19*8, consisted of a T358C nucleotide transition in exon 3 that results in a Trp120Arg substitution. In a bacterial expression system, CYP2C198 protein exhibited a dramatic (approximately 90% and 70%) reduction in the metabolism of S-mephenytoin and tolbutamide, respectively, when compared with the wild-type CYP2C191B protein. Restriction fragment length polymerase chain reaction tests were developed to identify the new allelic variants.     

Belimumab treatment in rhupus: A case report with severe skin involvement

Patients with rhupus characteristically exhibit symmetric polyarthritis and clinical manifestations suggestive of systemic lupus erythematosus (malar rash, photosensitivity, hematological manifestations, serositis, and/or skin involvement) and positive anti‐dsDNA. Treatment is unclear and it can include disease‐modifying rheumatic drugs like hydroxyl chloroquine, or methotrexate or, in refractory cases, rituximab or abatacept. We report a case of 31‐year‐old female who present with rhupus with skin acute lesions treated with belimumab. This is the first case of rhupus treated with this drug described in the literature.     

Is there a rationale to using leflunomide in early rheumatoid arthritis?

The efficacy of leflunomide in the treatment of early rheumatoid arthritis (RA) patients might be attributed to the fact that it acts at several levels, including the anti-inflammatory and anti-destructive pathways. This is in addition to its inhibition of the L-dihydro-orotate dehydrogenase (DHOH) enzyme and pyrimidine de novo synthesis which decreases cell proliferation and more specifically early activated CD4+ T cells, as well as monocyte interaction with T cells leading to cytokine and anticytokine production. Recent studies clearly indicate the rationale of an early administration of leflunomide in RA patients, particularly in the light of the results of previously reported clinical studies showing its rapid onset of action when compared to other DMARDs. The early efficacy and safety of leflunomide in patients with early RA is sustained over a long period, and the long-term safety profile of leflunomide does not seem to be different from that observed in phase III trials.     

Systemic allergic reaction and diffuse bone pain after exposure to a preparation of betamethasone

Allergic reactions to corticosteroids are unexpected as they seem to contradict their pharmacodynamic action. Nevertheless, they are not infrequent, with an estimated incidence of up to 4% for cutaneous reactions. Systemic reactions are rarely reported, but their incidence might be underestimated. We report here an unusual allergic reaction to betamethasone presenting with diffuse bone pain, erythema, and bronchoconstriction, which was confirmed by a positive rechallenge in a double-blind procedure. This is the first case report of a systemic reaction to betamethasone confirmed by a positive rechallenge. An impurity in betamethasone diproprionate cannot be excluded. As this substance is frequently used in rheumatologic soft-tissue injections, it is important to recognize this potentially life-threatening side effect.     

A retrospective comparison of inpatients with mixed and pure depression

Some authors advocate a broadening of the narrow concept of mixed episodes in the direction of mania leading to the concept of mixed mania, and in the direction of depression leading to the concept of mixed depression. The latter has been little investigated so far. In the present article, we retrospectively compare 49 patients with pure depression with 51 patients with mixed depression in terms of socio-demographic and clinical variables in order to contribute to the validation of the distinction between mixed and pure depression. Supporting this distinction, we observed that mixed depressive patients more frequently had past histories of bipolar disorder and alcohol abuse and had longer durations of hospital stay. These last two points remain significant even when we control for the effect of the association with bipolarity.     

The molecular mechanisms of two common polymorphisms of drug oxidation--evidence for functional changes in cytochrome P-450 isozymes catalysing bufuralol and mephenytoin oxidation

Using the stereospecific metabolism of (+)- and (-)-bufuralol and (+)- and (-)-metoprolol as model reactions, we have characterized the enzymic deficiency of the debrisoquine/sparteine-type polymorphism by comparing kinetic data of subjects in vivo with their microsomal activities in vitro and with reconstituted activities of cytochrome P-450 isozymes purified from human liver. The metabolism of bufuralol in liver microsomes of in vivo phenotyped 'poor metabolizers' of debrisoquine and/or sparteine is characterized by a marked increase in Km, a decrease in Vmax and a virtual loss of the stereoselectivity of the reaction. These parameters apparently allow the 'phenotyping' of microsomes in vitro. A structural model of the active site of a cytochrome P-450 for stereospecific metabolism of bufuralol and other polymorphically metabolized substrates was constructed. Two cytochrome P-450 isozymes, P-450 buf I and P-450 buf II, both with MW 50,000 Da, were purified from human liver on the basis of their ability to metabolize bufuralol to 1'-hydroxy-bufuralol. However, P-450 buf I metabolized bufuralol in a highly stereoselective fashion ((-)/(+) ratio 0.16) as compared to P-450 buf II (ratio 0.99) and had a markedly lower Km for bufuralol. Moreover, bufuralol 1'-hydroxylation by P-450 buf I was uniquely characterized by its extreme sensitivity to inhibition by quinidine. Antibodies against P-450 buf I and P-450 buf II inhibited bufuralol metabolism in microsomes and with the reconstituted enzymes. Immunochemical studies with these antibodies with microsomes and translations in vitro of RNA from livers of extensive and poor metabolizers showed no evidence for a decrease in the recognized protein or its mRNA. Because the antibodies do not discriminate between P-450 buf I and P-450 buf II, both a decreased content of P-450 buf I or its functional alteration could explain the polymorphic metabolism in microsomes. The genetically defective stereospecific metabolism of mephenytoin was determined in liver microsomes of extensive and poor metabolizers of mephenytoin phenotyped in vivo. Microsomes of poor metabolizers were characterized by an increased Km and a decreased Vmax for S-mephenytoin hydroxylation as compared to extensive metabolizers and a loss of stereospecificity for the hydroxylation of S-versus R-mephenytoin. A cytochrome P-450 with high activity for mephenytoin 4-hydroxylation was purified from human liver. Immunochemical studies with inhibitory antibodies against this isozyme suggest the presence in poor-metabolizer microsomes of a functionally altered enzyme.     

Corticospinal control of respiratory muscles in chronic obstructive pulmonary disease

Patients with chronic obstructive pulmonary disease (COPD) face an increased respiratory load and in consequence have an elevated respiratory drive. We used transcranial magnetic stimulation (TMS) to investigate associated changes in corticospinal excitability both at rest and during voluntary facilitation at different levels of inspiratory effort. Diaphragm and abdominal motor thresholds were significantly lower in COPD than healthy controls, but the quadriceps response was the same. In patients there was a significant increase in diaphragm response from rest during 20% inspiratory efforts but no further increase with greater efforts. In controls there was a further stepwise increase at 40% and 60% of inspiratory effort. The cortical silent period was significantly shorter in COPD. Using paired stimulation to study intracortical inhibitory and excitatory circuits we found significantly less excitability of intracortical facilitatory circuits in patients at long (>7 ms) interstimulus intervals. These results suggest that there is a ceiling effect in motor control output to the respiratory muscles of patients with COPD.