1 Theophylline metabolism was studied using seven human cytochrome P-450 isoforms (CYPs), namely CYPlAl, 1A2, 2A6, 2B6, 2D6, 2E1 and 3A4, and microsomal epoxide hydroxylase (EH), expressed in human B-lymphoblastoid cell lines. 2 At a high theophylline concentration of 10 mm four CYPs (lAl, 1A2, 2D6, 2E1) catalyzed the metabolism of theophylline. 3 Theophylline had the highest affinity (apparent Km range 0.2-1.0 mM) for the CYPIA subfamily and the kinetics of metabolic formation mediated by CYP1A2indicated substrate-inhibition (K1 range 9-16 mM). 4 CYP1A2 catalyzed the demethylation of theophylline as well as its hydroxylation, and was associated with the highest intrinsic clearance (1995 1 h-' per mol CYP) to 1,3-dimethyluric acid (DMU). Therefore, this isoform can be considered to be the most important enzyme involved in theophylline metabolism in vitro. 5 CYP2El was responsible for a relatively high intrinsic clearance by 8-hydroxylation (289 1 h-' per mol CYP). The apparent Km value of this reaction was about 15 mm, suggesting that CYP2E1 may be the low-affinity high-capacity isoform involved in theophylline metabolism. 6 The affinity of theophylline for CYPlAl was comparable with that of its homologue 1A2. When induced, the participation of CYPlAl in theophylline metabolism may be important. 7 CYP2D6 played only a minor role and CYP3A4 was not active in the in vitro metabolism of theophylline. 8 Our findings confirm the major role of CYP1A2 in theophylline metabolism and explain why in vivo the elimination kinetics of theophylline are non-linear and in vitro theophylline metabolism by human liver microsomes does not obey monophasic kinetics. 9 The data suggest also that not only tobacco smoking but also chronic alcohol intake may influence theophylline elimination in man as ethanol induces CYP2E1.Keywords theophylline metabolism CYP1A2 CYP2E1 in vitro cDNA expressed microsomes

The efficacy of long-term chemotherapy in nonresectable alveolar echinococcosis is debated, particularly because of the difficulty in defining therapeutic success. In this study the effect of chemotherapy on the parasitic mass was evaluated in a series of 37 patients. The patients had larval lesions documented by serial computed tomography studies at least 1.5 yr after chemotherapy (mean = 6.4 yr, range = 1.5 to 10.7 yr). The therapeutic regimen consisted of mebendazole (n = 34) or albendazole (n = 3) as previously described. The maximal areas of the parasitic lesions were assessed morphometrically by means of digital image analysis, utilizing the point-integration method, before and after chemotherapy. Marked regression of larval tissue occurred in 18 patients (group A; 48.6%), stationary lesions were noted in 13 patients (group C; 35.1%) and progression was found in 6 patients (group B; 16.2%). The three groups did not differ significantly with regard to age, plasma drug levels, duration of chemotherapy or initial size and composition of lesions (e.g., cystic cavities, degree of calcification). Despite morphologically successful chemotherapy in moist patients (e.g., 84%; groups A and C), late cholestatic complications after 1.5 to 11 yr of chemotherapy occurred in 10 patients (group A, n = 7; group C, n = 3; 4 of them died) and esophageal variceal bleeding occurred in 3 patients (relieved by sclerotherapy). These late complications were probably mainly due to posttherapy fibrosis of hilar structures. In conclusion, our data support the efficacy of chemotherapy. However, chemotherapy is not curative, and severe late complications were observed in patients with hilar (fibrotic) involvement.

Controversies in the literature regarding definition, diagnosis, and therapy of chronic pancreatitis may be related in part to differences in the natural history of alcoholic and idiopathic (nonalcoholic) chronic pancreatitis. In order to evaluate this problem the long-term course of 205 patients with alcoholic (85.4% with calcifications) (group A) and 82 patients with idiopathic (nonalcoholic) chronic pancreatitis (76.8% with calcifications) (group B) has been analyzed prospectively since 1963. The patients were studied at regular intervals with particular regard to pain, pancreatic exocrine, and endocrine function and calcifications. The observation time was 2 years or longer in 230 patients with a median observation time of 6.7 years from diagnosis in group A and 10.6 years in group B. In group B over 50% of the cases had primary painless chronic pancreatitis. Progressive deterioration of exocrine and endocrine function was observed in both groups. However, in group A the rate of progression of exocrine dysfunction after diagnosis was more rapid and the incidence of diabetes in relation to marked exocrine insufficiency was much higher than in group B. Steatorrhea preceded diabetes in 56% (group A) and 80% (group B), respectively. Onset of pancreatic calcifications was closely associated with pancreatic exocrine insufficiency in group A in contrast to group B. In addition lasting pain relief occurred spontaneously in about 30% of patients in group B despite a normal exocrine function for 6 years or longer which is in disaccord with the results in alcoholic chronic pancreatitis. In conclusion group A and B have many features in common, in particular the high incidence of pancreatic calcifications and the progressive pancreatic dysfunction. However, the long-term profile of both groups differs in some important aspects, particularly in the clinical pattern and in the rate of progression of pancreatic dysfunction and morphology. These differences should be appreciated in the discussion of problems regarding definition, diagnosis, and surgical therapy of chronic pancreatitis.The natural history of chronic pancreatitis (CP) is not well defined. Many controversies regarding definition, diagnosis, and therapy result mainly from the limited knowledge of the long-term course of CP. Clinically relevant problems of CP are still debated such as the relationship between pancreatic morphology and function (1-6), the rate of progression of exocrine dysfunction ( 4 3 , the interaction Of exocrine and endocrine insufficiency (7-9)9 the correlation of pain and exocrine insufficiency

Allergen-specific immunotherapy (AIT) is the only allergy treatment that confers long-term symptom amelioration for patients suffering from allergy. The most frequently used allergen application route is subcutaneous injection (SCIT), commonly taken as the gold standard, followed by sublingual (SLIT) or oral (OIT) application of allergen preparations. This is an up-to-date review of the clinical evidence for a novel route of allergen application, i.e., directly into lymph nodes – intralymphatic immunotherapy (ILIT). The major advantages of ILIT over the current AIT approaches are its short duration and the low allergen doses administered. The whole treatment consists of merely 3 ultrasound-guided injections into inguinal lymph nodes 1 month apart. While the number of patients included in randomised controlled trials is still limited, the clinical results for ILIT are encouraging, but more clinical trials are needed, as well as more preclinical work for optimising formulations.

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