Molecular modelling of mammalian CYP2B isoforms and their interaction with substrates, inhibitors and redox partners.

1. The construction of three-dimensional models of CYP2B isozymes from rat (CYP2B1), rabbit (CYP2B4) and man (CYP2B6), based on a multiple sequence alignment with CYP102, a unique eukaryotic-like bacterial P450 (in terms of possessing an NADPH-dependent FAD- and FMN-containing oxidoreductase redox partner) of known crystal structure, is reported. 2. The enzyme models described are shown to be consistent with experimental evidence from site-directed mutagenesis studies, antibody recognition sites and amino acid residues identified as being associated with redox partner interactions, together with the location of a key serine residue (Ser-128) likely to be involved in protein kinaseA-mediated phosphorylation. 3. A substantial number of known substrates and inhibitors of CYP2B isozymes are shown to fit the putative active sites of the enzyme models in agreement with their reported position of metabolism or mode of inhibition respectively. In particular, there is complementarity between the characteristic non-planar geometries of CYP2B substrates and key groups in the enzymes' active sites. 4. Molecular modelling of CYP2B isozymes appears to rationalize a number of the reported findings from quantitative structure-activity relationship investigations on series of CYP2B substrates and inhibitors.

Opçöes para a utilizaçåo dos antiinflamatórios nåo-esteróides no manejo da psoríase artropática / The management of arthropatic psoriasis with nonsteroidal antiinflammatory

Os antiinflamatórios nåo-esteróides såo fármacos nåo-esteroidais que inibem a via da ciclooxigenase no metabolismo do ácido aracdônio, suprimindo a síntese das prostaglandinas. Algumas destas drogas exacerbam as lesöes cutâneas da psoríase (indometacina, ácido acetilsalicílico). Outros antiinflamatórios nåo-esteróides apresentam uma boa açåo farmacológica sem exacerbarem o quadro dermatológico da moléstia (naproxeno, ibuprofeno e fenilbutazona). Estas drogas proporcionaråo novas opçöes na terapêutica da psoríase artropática. Os autores relatam sua experiência no manejo da psoríase artropática com os antiinflamatórios nåo-esteróides

Genetic susceptibility to fixed drug eruption: evidence for a link with HLA-B22.

BACKGROUND: Our observation of familial cases of fixed drug eruption (FDE) prompted us to consider a genetic predisposition to this disease. OBJECTIVE: Our purpose was to determine whether there is any association between FDE and any of the major histocompatibility complex class I or II alleles. METHODS: HLA class I and II typing was performed by lymphocytotoxicity assay in 36 unrelated patients with FDE. RESULTS: Significantly higher (p < 0.0001) frequencies of the B22 and Cw1 antigens were found in the 36 patients with FDE. CONCLUSION: Our data are the first to suggest a genetic predisposition to FDE.

Pharmacokinetics of single oral doses of feprazone in patients with rheumatoid arthritis or with impaired renal clearance.

1. The pharmacokinetics of feprazone have been studied in 10 patients with rheumatoid arthritis (RA), and in a further six patients with renal impairment (RI) who were not suffering from rheumatoid disease. 2. For RA patients, the mean elimination half-life (t1/2) of feprazone after a single oral dose was 21 +/- 5 h (SD), the mean apparent clearance (Cl) was 0.012 +/- 0.009 l/h per kg, and the mean apparent volume of distribution (Vd) was 0.33 +/- 0.17 l/kg. Corresponding values for RI patients were 25 +/- 13 h, 0.016 +/- 0.011 l/h per kg, and 0.46 +/- 0.24 l/kg, respectively. 3. These results show no impairment of the elimination of feprazone in RA or RI patients; Vd and Cl are greater than in healthy young volunteers or elderly subjects, the AUC values are lower, but t1/2 values are similar in all groups. 4. It is suggested that the greater Cl and Vd, and lower AUC, in RA and RI patients may be due to renal insufficiency and decreased plasma protein binding of feprazone and its metabolite, or to induction of glucuronyl transferase activity by the prior medication, thus enhancing the formation of the major metabolite, the C(4)-glucuronide, and increasing drug elimination.

Cutaneous reactions to analgesic-antipyretics and nonsteroidal anti-inflammatory drugs. Analysis of reports to the spontaneous reporting system of the Gruppo Italiano Studi Epidemiologici in Dermatologia.

We analyzed the cutaneous reactions to systemic analgesic-antipyretics and non-steroidal anti-inflammatory drugs reported to the spontaneous reporting system of the Gruppo Italiano Studi Epidemiologici in Dermatologia (GISED). The system has been active since 1988, with periodic intensive surveillance exercises, and 202 dermatologists have collaborated. Up to December 1991, 2,137 reactions had been collected, of which 713 were reactions to systemic analgesic-antipyretics and nonsteroidal anti-inflammatory drugs. A general profile of the reactions was identifiable. It included, in order of frequency, urticaria/angioedema, fixed eruptions, exanthemas, erythema multiforme and Stevens Johnson syndrome. Fixed eruptions and Stevens Johnson syndrome were reported with exceedingly high frequency in association with feprazone. Our system also revealed previously unreported reactions, including fixed eruption to nimesulide, fixed eruption to piroxicam and fixed eruption to flurbiprofen.

Familial occurrence of fixed drug eruptions.

Fixed drug eruptions following the use of pyrazolone derivatives occurred in 4 members of the same family: a 12-year-old girl, her grandmother, and two of her great aunts. Although the pathophysiologic events leading to this type of reaction are unknown, these cases of familial occurrence suggest that genetic predisposition might be an important causal factor.

Drug-triggered pemphigus in a predisposed woman.

A 31-year-old woman with three pemphigus-prone antigens in her HLA haplotype (B7, DR4, DQw7) developed the disease soon after taking a pyrazolone derivative, viz. feprazone. The pemphigus lesions persisted despite withdrawal of the drug and worsened appreciably when she used ceftriaxone (a new cephalosporin with three sulphur atoms) for a bout of acute pharyngitis. Thiol groups formed from the metabolic breakdown of ceftriaxone are thought to have promoted acantholysis via a biochemical route. Genetic predisposition alone ('the soil') may be essential, though not per se sufficient for outbreak of pemphigus; the intervention of exogenous, heterogeneous factors ('the seed') often seems decisive in triggering full-blown disease.

The pharmacokinetics of single oral doses of feprazone in healthy volunteers and elderly patients.

1. The pharmacokinetics of feprazone were studied in nine healthy volunteers and 10 elderly patients. 2. The mean elimination half-life of feprazone after a single oral dose in the healthy volunteers was 22.3 h, the mean apparent clearance 0.0051 1/h per kg and the mean volume of distribution 0.1681/kg. Corresponding values for the elderly patients were 22.6 h, 0.00561/h per kg and 0.1651/kg, which are not different from those for the volunteers. Thus, we were unable to detect any changes in feprazone pharmacokinetics which are related to age, or to the concurrent use of chronic medications, such as digoxin, diuretics, or hormones.

Feprazone: an inducer of the P450 II B family of proteins in the rat.

The ability of feprazone to induce the hepatic microsomal mixed-function oxidases was investigated in the rat, with emphasis being placed on the nature of the cytochrome P-450 family induced. Treatment with feprazone enhanced the p-hydroxylation of aniline and the dealkylations of benzphetamine and pentoxyresorufin but had no effect on the O-deethylation of ethoxyresorufin. The same treatment had no major effect on total cytochrome P-450 levels but increased the spectral interaction of metyrapone with reduced cytochrome P-450. Immunoblots employing monospecific polyclonal antibodies revealed that feprazone induces the apoprotein levels of the P450 II B, but not of the P450 I, family. It is concluded that feprazone is an inducer of the rat hepatic mixed-function oxidase system showing selectivity toward the P450 II B family.

[Pharmacological and clinical profile of tiaprofenic acid]. / Profilo farmacologico e clinico dell'acido tiaprofenico.

Tiaprofenic acid is a new generation anti-inflammatory drug synthesized to be a valid alternative to both cortisone preparations and other NSADs since it is less toxic yet equally effective. Its anti-inflammatory, analgesic, antipyretic activity is due to a particular interference mechanism active in the early phases of the inflammatory process (PG synthesis inhibition, stabilization of lysosomal membranes). Thanks to its good trophism toward tissues in the otolaryngological area and its tolerability this drug would appear particularly suited for the treatment of inflammatory E.N.T. pathologies.

[Use of nimesulide in inflammations of the upper respiratory tract]. / Impiego della nimesulide nelle flogosi delle vie respiratorie superiori.

In a controlled clinical study of 40 patients, aged 18 to 65, suffering from acute inflammatory pathology of the upper respiratory tract or from a chronic form flaring into acute crisis, without any general symptoms of infection, were assigned at random to treatment with nimesulide in tablet form (100 mg x 2/day), or with phenylprenazone in capsules (200 mg x 2/day) for a period of seven days. In both groups a clinically significant reduction of the symptoms was obtained (congestion and edema of the pharyngeal mucosa, cough) as well as an improvement in the values of conductance and MCTt. Epigastralgy was evidenced in three subjects treated with nimesulide and in four treated with phenylprenazone. No significant variations of the laboratory parameters were found in either treatment group.

The disposition of feprazone and its hydroxylated metabolite in human volunteers.

1. 14C-Feprazone administered as a single oral dose (17 mg/subject) to each of 3 human volunteers on the 6th day of repeated dosage with unlabelled feprazone (200 mg/subject, twice daily) was excreted slowly, with only 19-38% of the dose excreted in the urine in 8 days, with a further 27-49% of the dose in the faeces. 2. 14C-Feprazone had a half-life of 30-33 h, similar to that after single dosage of unlabelled feprazone (22-33 h). The half-life for total 14C was not significantly different from that for unchanged feprazone, indicating that no metabolite with a very long half-life was formed. 3. Only feprazone and 4'-hydroxyfeprazone were detected in the plasma of subjects dosed orally with feprazone, the metabolite being characterized by mass spectrometry. The time of peak plasma concentration of feprazone was 4-5 h after dosage, and of 4'-hydroxyfeprazone was approx. 25 h. The urine contained feprazone plus its C-glucuronide, and 4'-hydroxyfeprazone plus its conjugate (glucuronide), in the ratio of approx. 5:1. 4. When 4'-hydroxyfeprazone was administered as a single oral dose to a human volunteer the plasma elimination half-life of the metabolite was 18 h, but after administration of feprazone the half-life of 4'-hydroxyfeprazone was 45 +/- 29 h (10 subjects), indicating the slow hydroxylation of feprazone and the slow excretion of 4'-hydroxyfeprazone. The clearance of feprazone was 5.2 and of 4'-hydroxyfeprazone was 5.5 ml/kg/h. 5. These studies have shown that even though enterohepatic recirculation of the drug in man is indicated, the plasma half-life of feprazone is unchanged on repeated dosage, and accumulation of the drug at a daily dosage of 2 x 200 mg, does not occur.

Emprego clínico da feprazona em odontologia / Clinical use of feprazone in dentistry

Os autores trataram 35 pacientes em intervençoes odontológicas diversas. Estes casos foram divididos em três grupos, de acordo com as entidades clínicas tratadas. O grupo I incluiu 12 pacientes, nos quais foram realizados tratamentos endodônticos, sendo que em 2, simultaneamente, foram realizadas cirurgias (curetagem de bolsas periodontais e extraçoes múltiplas). O grupo II incluiu 9 pacientes, que foram submetidos a cirurgias bucais menores, tais como extraçoes múltiplas, epicetomias e devido a problemas periodontais. O grupo III era constituído por 12 pacientes de ambos os sexos, submetidos a cirurgias mais extensas. Sua idade variou entre 7 e 60 anos. A todos os pacientes foi administrada a feprazona, na dose de 1 cápsula de 12 em 12 horas, durante quatro dias. Efeitos colaterais surgiram em dois casos; foi necessário suspender o medicamento em apenas um paciente, que apresentou erupçao cutânea

Inducing effect of feprazone on hepatic drug-metabolizing enzymes in man.

The inducing effect of feprazone, a pyrazolone anti-inflammatory agent, on hepatic drug-metabolizing enzymes has been studied in healthy volunteers. The ratio of 6 beta-hydroxycortisol (6 beta-OHF) to 17-hydroxycorticosteroids (17-OHCS) in urine, used as an indicator of oxidative drug-metabolizing enzyme activity, was increased up to 1.6-times the original level after 5 days of oral treatment with feprazone 300 mg/day. This indicates that feprazone induces hepatic drug-metabolising enzymes in man as does phenylbutazone.