Rifampin's acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug-drug interaction trial design.

We studied the time course for the reversal of rifampin's effect on the pharmacokinetics of oral midazolam (a cytochrome P450 (CYP) 3A4 substrate) and digoxin (a P-glycoprotein (P-gp) substrate). Rifampin increased midazolam metabolism, greatly reducing the area under the concentration-time curve (AUC(0-∞)). The midazolam AUC(0-∞) returned to baseline with a half-life of ~8 days. Rifampin's effect on the AUC(0-3 h) of digoxin was biphasic: the AUC(0-3 h) increased with concomitant dosing of the two drugs but decreased when digoxin was administered after rifampin. Digoxin was found to be a weak substrate of organic anion-transporting polypeptide (OATP) 1B3 in transfected cells. Although the drug was transported into isolated hepatocytes, it is not likely that this transport was through OATP1B3 because the transport was not inhibited by rifampin. However, rifampin did inhibit the P-gp-mediated transport of digoxin with a half-maximal inhibitory concentration (IC(50)) below anticipated gut lumen concentrations, suggesting that rifampin inhibits digoxin efflux from the enterocyte to the intestinal lumen. Pharmacokinetic modeling suggested that the effects on digoxin are consistent with a combination of inhibitory and inductive effects on gut P-gp. These results suggest modifications to drug-drug interaction (DDI) trial designs.

The value, qualification, and regulatory use of surrogate end points in drug development.

The acceptance and use of either surrogate end points (SEPs) or efficient clinical end points are associated with greater and more rapid availability of new medicines as compared with disease situations for which clinical end points are inefficient or no surrogates exist. This review of the history of the development, qualification, and acceptance of key SEPs shows that both successes and failures had three key characteristics: (i) apparent biologic plausibility, (ii) prognostic value for the outcome of the disease, and (iii) an association between changes in the SEP and changes in outcome with therapeutic intervention--the three factors recommended for SEPs in the International Conference on Harmonisation's "Statistical Principles for Clinical Trials." We recommend that only prognostic value be an absolute prerequisite for surrogacy, because therapeutic interventions may not exist a priori, and biological plausibility can be subjective. Ideally, all three of these factors would be traded off against one another in a consistent and transparent risk-management process.

Telenzepine-sensitive muscarinic receptors on rat pancreatic acinar cells.

To identify the muscarinic subtype present on the rat pancreatic acinar cell, we examined the effects of different muscarinic receptor antagonists on amylase secretion and proteolytic zymogen processing in isolated rat pancreatic acini. Maximal zymogen processing required a concentration of carbachol 10- to 100-fold greater (10(-3) M) than that required for maximal amylase secretion (10(-5) M). Although both secretion and conversion were inhibited by the M3 antagonist 4-diphenylacetoxy-N-methyl-piperidine (4-DAMP) (50% inhibition approximately 6 x 10(-7) M and 1 x 10(-8) M, respectively), the most potent inhibitor was the M1 antagonist telenzepine (50% inhibition approximately 5 x 10(-10) M and 1 x 10(-11) M, respectively). Pirenzepine, another M1 antagonist, and the M2 antagonist methoctramine did not reduce amylase secretion or zymogen processing in concentrations up to 1 x 10(-5) M. Analysis of acinar cell muscarinic receptor by PCR revealed expression of both m1 and m3 subtypes. The pancreatic acinar cell has a distinct pattern of muscarinic antagonist sensitivity (telenzepine >> 4-DAMP > pirenzepine) with respect to both amylase secretion and zymogen conversion.

[Diabetic foot syndrome in clinical practice. I. A model of a Diabetic Foot Consulting Unit]. / Zesp57ol stopy cukrzycowej w praktyce klinicznej. I. Model Gabinetu Stopy Cukrzycowej.

Complex pathogenesis of the foot syndrome involving a number of body system and tissues provided us with grounds for making multispecialistic assessment of its severity. Also a decision about the type and intensity of procedure should be multispecialistic. An interdisciplinary team consists of a diabetologist, diabetic educator, podiatrist, kinesitherapist, orthopedist, general and vascular surgeon and a consultant from manufacturing corrective shoes. The make-up of the team implies that the procedure includes education, metabolic normalization of diabetes mellitus, orthopedic correction, possible surgical intervention and rehabilitation. Results discussed in part II of the study indicate the effectiveness of such approach.

[Diabetic foot syndrome in clinical practice. II. Results after one year at the Diabetic Foot Consulting Unit]. / Zespól stopy cukrzycowej w praktyce klinicznej II. Wyniki rocznej dzialalnosci Gabinetu Stopy Cukrzycowej.

The study included 46 patients with the diabetic foot syndrome and ulcerations, and 40 patients with high-risk foot. Mean duration of hospitalization of the patients with ulcerations was 54 days, mean daily glycemia decreased from 162.5 mg% to 114.9 mg%. Ulcerations were completely healed in 93.5% of patients, whereas high and partial foot amputation was high and 3.2% of patients, respectively. The annual amputation rate was 2.3% in the entire group of diabetic foot patients (86). The present results indicate the necessity for adoption of a multidisciplinary approach to the problem of diabetic foot. It may be added that cooperation in glycemia normalization and patients education may decrease the number of amputations, and hence the degree of physical disability in diabetic foot patients.

[Induction of hematologic remission in a patient with acute promyelocytic leukemia through the therapeutic use of trans-retinoic acid]. / Indukcja remisji hematologicznej u chorej z ostra bialaczka promielocytowa przy pomocy kwasu trans-retinowego.

A case of 62-year-old female with acute promyelocytic leukemia is presented, in whom in poor general condition, and with symptoms of severe haemorrhagic diathesis and biochemical signs of coagulopathy a treatment with trans-retinoic acid was induced. After three weeks of treatment with t-RA complete hematological and clinical remission was achieved, without bone marrow aplasia, worsening of hemostatic parameters, or necessity of protective or therapeutic antibiotics administration typical of conventional chemotherapy. Apart from skin allergization and increase of transaminases other side effects of the t-RA treatment were not observed.