Diclofenac-Na gel is effective in reducing the pain and inflammation associated with exposure to ultraviolet light - results of two clinical studies.

The potential of a diclofenac-Na Emulgel (diclofenac gel) to alleviate the pain and associated symptoms caused by sunburn has been evaluated versus vehicle. Sunburn was induced on the buttock skin of healthy adult male subjects by irradiation with UVA + UVB rays. Investigational products were applied 6 and 10 h after irradiation, and efficacy was assessed on the basis of spontaneous and provoked pain, erythema, oedema, skin colour and temperature. The minimal efficacious concentration evaluated in an extension (0.1 vs. 0.25% diclofenac gel) of a previous concentration-finding study (1, 0.5 and 0.25% diclofenac gel) was 0.1% and was efficacious in alleviating pain (spontaneous and provoked) as well as reducing erythema, oedema and skin temperature. In a single- versus 2-application comparison study, a single application of 0.1% gel was sufficient to alleviate the pain and accompanying symptoms of sunburn with an onset of action 2 h after application. A second application of gel 4 h after the first maintained the analgesia and reduction of other symptoms for a period of up to 48 h after irradiation.

Diclofenac systemic exposure is not increased when topical diclofenac is applied to ultraviolet-induced erythema.

OBJECTIVES: Diclofenac is a non-steroidal anti-inflammatory drug used for a variety of painful and inflammatory conditions. A new low-dose, topical-gel form of diclofenac sodium (diclofenac-Na) has been developed for pain relief and redness reduction after sunburn. The objective was to compare exposure to oral diclofenac-Na with the systemic exposure to diclofenac after application of the new topical diclofenac-Na 0.1% Emulgel gel (diclofenac-Na gel) to normal skin and to that with ultraviolet-induced erythema relative. METHODS: This study was an open, single-centre, three-period, non-randomised trial in 18 healthy Caucasian subjects. During the first period, 12.5 g gel (12.5 mg diclofenac-Na) was applied twice on a single day to normal skin. During the second period, a 25-mg diclofenac-Na, enteric-coated tablet was given orally three times in a single day. During the third period, the diclofenac-Na gel was applied, as in the first period, but during the early phase of an erythema induced by three times the ultraviolet minimal erythema dose, i.e. a first-degree sunburn associated with pain. During each period, venous blood samples were collected over 24 h and urine was collected over 72 h after first administration for the determination of diclofenac in plasma and urine and of 4'-OH-diclofenac in urine. RESULTS: The systemic exposure after topical application of 25 mg diclofenac-Na on sunburned skin was less than 3% that of 75 mg oral diclofenac-Na and was not increased to that measured on normal skin. CONCLUSION: The diclofenac-Na 0.1% Emulgel gel can be applied safely to sunburned skin (superficial sunburn, i.e. first degree) as well as to normal skin.

Effect on compliance, acceptability of blood glucose self-monitoring and HbA(1c) of a self-monitoring system developed according to patient's wishes. The ACCORD study.

OBJECTIVES: To test a blood glucose monitor developed upon diabetic's recommendations (Glucotrend Premium). Self-monitoring of blood glucose (SMBG) generates hope when introduced, however several studies questioned its efficacy and many diabetics judge it too constraining. MATERIAL AND METHODS: Thirty diabetes centres in France, for 6 months in 179 insulin-treated diabetics, using SMBG but non optimally and with HbA(1c) (>=130% of the upper limit). Randomisation to 3 groups: either their previous system (Group A), or to the Glucotrend Premium monitor with a memory to assess compliance (Group B), or to another monitor, new for the patient, and with a memory too, the One Touch Profile (Group C). At entry, and then at 3 and 6 months, patients had an acceptability and compliance questionnaire, HbA(1c), count of weekly hypoglycaemia, record of insulin doses and an assessment of the key compliance factors. RESULTS: HbA(1c) improved significantly in the 3 groups, more markedly in groups B (Glucotrend) and C (One Touch), e.g. - 0.6 +/- 1.1% (group A), - 0.9 +/- 1.2% (group B) and - 1.0 +/- 0.9% (group C) at M6. Acceptability was judged better for groups B and C, an additional benefit for Glucotrend: better accuracy vs laboratory blood glucose (C/L) determinations and a lower utilisation cost. Intermediate (lente) and regular insulin doses only significantly decreased (26% and 10% respectively) in group B (Glucotrend) despite a decrease in HbA(1c). Compliance (defined as 75-150% of recommended self-monitoring) improved within the 3 groups (from 34% to 65%), this improvement was maintained after month 3 (M6: 76%) only in group B (Glucotrend), vs a worsening in groups A and C (M6: 62 and 57% respectively). A better accuracy of C/L was observed with Glucotrend at M0, M3 and M6. CONCLUSION: SMBG has limits due to various causes, and to specific difficulties of this invasive and repetitive technique. The development of a system based on advices formulated by patients themselves, Glucotrend Premium, has resulted in a marked improvement on acceptability, compliance and glucose control.

[Hypocholesterolemia during the acute phase of an inflammatory reaction of infectious origin. 120 cases]. / Hypocholestérolémie au cours de la phase aiguë de la réaction inflammatoire d'origine infectieuse. A propos de 120 cas.

OBJECTIVES: Transitory changes in the plasma levels of lipids, cholesterol and triglycerides have been observed since a long time by many authors, in the course of bacterial infections, with hypocholesterolemia, hypertriglyceridemia in the acute phase, increasing the third day of clinical evolution. Their decrease accompanies the return to normal. Lymphopenia is also observed during bacterial infections and as the very low level of cholesterol, is considered to be a factor of critical prognosis, predicting an unfavorable evolution, essentially in elderly people. C-reactive protein (CRP) proves to be a good marker protein in inflammation due to sepsis; its synthesis is directly influenced by the cytokines released during the acute phase response of inflammation in bacterial infection. The authors are researching a correlation between the intensity of the acute phase response represented by CRP levels, and a reduced cholesterol level, or a hypertriglyceridemia, or lymphocytopenia. METHODS: In this prospective study, blood samples at fasting state were obtained in 160 patients divided into four groups of 40 according to CRP levels, including a witness group (CRP levels lower than 10 mg/L) and three groups of patients presenting infectious diseases with acute phase response of different intensities. All patients were checked for cholesterol, triglyceride and CRP levels, blood cell count. The three pathologic groups were compared to the witness group and to each other. RESULTS: A significant correlation was established between the intensity of the acute phase response during sepsis and reduced levels of cholesterol. Cholesterolemia was reduced (P < 0.05) in all three pathologic groups when compared to the witness group; the difference existed when a low intensity inflammatory response was observed (mean CRP level 27.6 (10.5) mg/L in group 1). Moreover a significant response exists with reduced cholesterol levels between group 4 (mean CRP level 250 (73) mg/L) and group 1. Lymphocytopenia was observed in all three pathologic groups, without evident link with the CRP levels. No modification was observed concerning triglyceride levels. CONCLUSIONS: The authors report a negative correlation of total cholesterol to CRP levels at the early stage of infections diseases. Prior studies established a negative correlation between inflammatory parameters during bacterial infections and total cholesterol and HDL fraction. Considering the plasma lipid pathways, HDL fraction plays a major role in lipid transport and exchanges between lipoproteins, thanks to its apolipoproteins A1, A2 and C. IL-1 and TNF, two cytokines involved in the acute phase response, have metabolic functions which could possibly contribute to reduce plasma total cholesterol and HDL2 fraction. IL-1 also induces lymphocytopenia. The authors propose the hypothesis of a correlation between plasma cholesterol levels and the acute phase response during sepsis, which could be induced by the mediators or effectors of inflammation.

Intraindividual variability of paracetamol absorption kinetics after a semi-solid meal in healthy volunteers.

OBJECTIVE: The absorption kinetics of paracetamol is dependent on gastric emptying and its measurement was proposed as a non-invasive method to estimate gastric emptying rate. The objective of this study was to evaluate the intraindividual variability of paracetamol absorption kinetics after a semi-solid meal. METHODS: The pharmacokinetics of paracetamol was studied on two occasions in 15 healthy volunteers without Helicobacter pylori antibodies. A 1-g dose of paracetamol was given as a solution together with a standardised semi-solid meal and the subjects stayed in the supine position. RESULTS: For most of the subjects, the time course of paracetamol concentrations was similar on the two occasions. The intraindividual variability was low, with coefficients of variation of 38.3%, 8.0% and 3.8% for time to maximum plasma concentration, maximum concentration and area under the plasma concentration - time curve until 6 h, respectively. CONCLUSION: The assessment of paracetamol absorption kinetics is reproducible when the drug is given together with a semi-solid meal in Helicobacter pylori-negative healthy subjects.

Inhibition of caffeine metabolism by 5-methoxypsoralen in patients with psoriasis.

Eight patients with psoriasis were given 200 mg caffeine orally with or without 1.2 mg kg-1 of 5-methoxypsoralen. Blood and urine samples were collected over a 2-day period. During 5-methoxypsoralen coadministration, the apparent volume of distribution of caffeine remained unchanged, but oral clearance (CLp.o.) decreased from 9.5 +/- 3.8 (mean +/- s.d.) to 3.2 +/- 0.51 h-1 (P < 0.01). The area under the plasma concentration-time curve (AUC) increased from 24 +/- 9 to 73 +/- 29 mg 1(-1) h (P < 0.001). This decrease in CLp.o. with increased AUC was consistent with a CYP1A2-dependent inhibition of caffeine N-demethylation which was further supported by significant decreases in the (AFMU+1U+1X)/17U and (AFMU+1U+1X)/17X urinary metabolic ratios.

A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients.

OBJECTIVE: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. METHODS: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. RESULTS: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng.h.ml-1, Cmax was 832 vs 871 ng.ml-1 and tmax was 2 vs 2 h, after ursodiol and placebo, respectively. CONCLUSION: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely.

Stability of debrisoquine (CYP2D6) phenotype in liver transplant patients.

Liver metabolism may be modified after liver transplantation according to the phenotype of the donor and may be influenced by posttransplantation complications. The CYP2D6 phenotype was assessed in 13 patients (group I) before and after liver transplantation using debrisoquine. CYP2D6 activity was also assessed in vitro on microsomes from the liver of the recipients and the donors, using dextromethorphan. Twelve patients were extensive metabolizers both before and after transplantation. One apparently poor metabolizer was transplanted with the liver of another poor metabolizer. The intrinsic clearance of dextromethorphan (CL(int)) measured on recipient liver microsomes was significantly lower than that on donor liver microsomes (p < 0.05). In extensive metabolizers, the debrisoquine metabolic ratio was correlated with CL(int) before (r = 0.78, p < 0.05) and after (r = 0.89, p < 0.0005) transplantation. Debrisoquine phenotype was measured repeatedly in nine additional patients (group II) up to 3 years after liver transplantation. Their phenotype was stable during the follow-up observation, although the variations observed may be clinically relevant. Therefore, no change in CYP2D6 phenotype (extensive/poor metabolizer) was observed because of the liver transplantation, and the debrisoquine log metabolic ratio was largely unaffected by the liver complications observed during the posttransplantation follow-up observation.

Cinchonine per os: efficient circumvention of P-glycoprotein-mediated multidrug resistance.

We have previously suggested that quinine and cinchonine could be good candidates for the clinical circumvention of multidrug resistance (MDR) in haematological malignancies because of their tolerance and their retained efficacy in serum. We have also shown that cinchonine was more efficient than quinine as an anti-MDR agent in vitro, ex vivo and in vivo after parenteral administration. Here, we report that cinchonine administered per os (po) is much more active than quinine po in circumventing MDR in rats bearing resistant colon tumours. The pharmacokinetics of cinchonine and quinine administered po in rat are shown to be very different. Cinchonine demonstrates a greater absolute bioavailability than quinine (44% versus 30%, respectively). Its serum concentration correlates with the anti-MDR activity measured ex vivo and in vivo. Cinchonine administered po does not significantly modify the pharmacokinetics of intravenous doxorubicin (DXR). However, cinchonine induces a significant increase of DXR uptake in organs which express the mdr1 gene (liver, kidney, lung). When associated with VAD (vincristine, adriamycin, dexamethasone) combined therapy in rats, cinchonine does not significantly increase the toxicity of the cytotoxic drugs. Based on these experimental data, a phase I clinical trial is currently in progress to test the tolerance of this potent MDR-reversing agent administered po.

Pharmacokinetics of a more reliable Chloraminophene formulation.

The pharmacokinetics of two formulations of chlorambucil, Chloraminophene capsules and Chloraminophene tablets, were compared in 12 patients in a randomized cross-over study. Chlorambucil concentrations in plasma were measured by HPLC over a period of 24 h after drug intake. The peak concentration (Cmax) occurred earlier after administration of capsules than after administration of tablets [median (range)]: 0.50 (0.33-0.66) h vs 2.00 (0.66-4.00) h (p < 0.01). Although values of Cmax and the area under the plasma concentration versus time curve (AUC) were not significantly different, the two formulations were not bioequivalent. Tolerance was in both cases acceptable, with only a transient decrease in haemoglobin one day after last drug intake. The variability of chlorambucil pharmacokinetics tended to be less important for capsules than for tablets: 38% vs 71% and 35% vs 113% for Cmax and AUC respectively. Capsules are therefore likely to be more reliable than tablets for clinical use.

Is debrisoquine hydroxylation modified during acute viral hepatitis?

Drug metabolism in the liver may be decreased during liver diseases. However, the extent of impairment of specific isozymes of cytochrome P450 is largely unknown. We have studied the debrisoquine hydroxylation capacity of 17 patients with acute viral hepatitis and 106 unrelated healthy subjects. Debrisoquine metabolic ratio was increased in extensive metabolizers (EM) with acute viral hepatitis as compared with healthy EMs (median metabolic ratio: 1.20 vs 0.84, P < 0.05). However, there was no difference in phenotype prevalence between patients and controls. Our results suggest that acute viral hepatitis only has a marginal effect on the activity of CYP2D6 and that substrates of this enzyme may be given in normal therapeutic doses to this category of patients.

A population and family study of N-acetyltransferase using caffeine urinary metabolites.

Population and family studies were undertaken to validate caffeine as a probe drug to establish the genetic status of rapid acetylators and slow acetylators. The acetylator status was established from the urinary metabolic ratio of 5-acetylamino-6-formylamino-3-methyluracil to 1-methylxanthine (AFMU/1X) after oral administration of caffeine. We confirmed a bimodal distribution (chi 2(1) = 229.48; p << 10(-9)) of the AFMU/1X ratio in 245 unrelated subjects. A third distribution did not significantly improve the fit to the data (chi 2(1) = 0.04; p = 0.84). Complex segregation analysis of 76 nuclear families confirmed the monogenic inheritance of N-acetyltransferase, with incomplete dominance of the rapid allele over the slow one. We observed a slight shift between the mean activities of heterozygous and homozygous rapid acetylators (t = 2.89; p < 0.01). However, the 30 obligate heterozygotes belonging to the 76 families were evenly distributed among the rapid acetylators and never located in a hypothetic intermediary group between slow acetylators and rapid acetylators.

Pharmacokinetic of a very low molecular weight heparin in chronic renal failure.

The pharmacokinetic characteristics of a low molecular weight heparin (LMWH) (Cy 222; mean mw: 2500 daltons) are studied in 24 patients with 3 degrees of chronic renal failure (CRF) stage I (creatinine clearance between 50 and 30 ml/mn), stage 2 (creatine clearance between 30 and 10 ml/mn), stage 3 (creatinine clearance below 10 ml/mn). Patients with CRF have significantly higher values of anti Xa activity at 3 hours (p less than 0.05), 5 hours (p less than 0.05), and at 8 hours (p less than 0.03) after injection than controls, CMAX values, VDSS and AUC do not differ, whereas patients with the highest stage of CRF are characterised by the most important t1/2 a (p less than 0.001) and the smallest total body clearance (p less than 0.01). Consequences of these disturbances of pharmacokinetic characteristics have to be evaluated before adequate posology of heparin fragments could be determined in patients with CRF.