Declining trend in valproate use in Finland among females of childbearing age in 2012-2016 - a nationwide registry-based outpatient study.

BACKGROUND AND PURPOSE: Documented teratogenic effects of valproate (VPA) prompted restrictions of its use in females of childbearing age in 2014. We investigated possible annual changes in the outpatient use of VPA in Finland during 2008-2016 with a special focus on women. METHODS: We identified all outpatients with VPA purchases between 2008 and 2016 categorizing users due to epilepsy, bipolar disorder or miscellaneous indications. Temporal trends in the annual prevalence rates of VPA use were estimated using Poisson regression analyses. RESULTS: Between 2012 and 2016, the prevalence of VPA use among women aged 15-44 years decreased by 19%, from 50/10 000 to 40/10 000 (prevalence rate ratio, 0.81; 95% confidence intervals, 0.77-0.91; P < 0.001). The use of VPA due to epilepsy decreased significantly in females aged 15-24 and 25-34 years and that due to bipolar disorders decreased significantly in females aged 25-34 and 35-44 years. The use of VPA in the miscellaneous indication group decreased by 32% after 2014 in females aged 15-44 years and, most strikingly, by 56% among those aged 15-25 years. In women with epilepsy, the use of VPA increased among those over the age of 44 years. CONCLUSIONS: The rates of female VPA users with childbearing potential have decreased in all three major indication groups in Finland during recent years, especially after the European Medicines Agency restrictions were published in 2014. However, it still remains open to question as to whether the practice of VPA use follows current guidelines. A special concern is the relatively high prevalence of off-label use of VPA in fertile-aged females.

The absolute bioavailability of clodronate from two different oral doses.

Clodronate (disodium clodronate tetrahydrate) is a bisphosphonate used in the treatment of hypercalcemia and osteolysis due to malignancy. Like all bisphosphonates, clodronate has low and variable oral bioavailability. The purpose of this study was to examine the absolute bioavailability of clodronate from two different oral doses. Thirty-one healthy young volunteers participated in this open, randomized, three-period, single-dose, cross-over study. The absolute bioavailability was calculated from the area under the serum clodronate-time curve in 48 h (AUC(0-48 h)) after administration of 800 or 1600 mg (Bonefos 400 mg capsules) of oral clodronate, or 30 mg (Bonefos 60 mg/mL infusion concentrate) of intravenous clodronate. The maximum concentration of clodronate in serum (C(max)), the time to maximum concentration (t(max)), the elimination half-life (t(1/2)), and the cumulative amount of clodronate excreted into urine in 48 h (Ae(0-48 h)) were also determined. The geometric mean of the absolute bioavailability of 800 mg of clodronate was 1.9% and that of 1600 mg 2.1%. The difference in the absolute bioavailability of these two doses was statistically nonsignificant. All treatments were well tolerated, and the AE profiles were similar in the different treatment groups. There were no serious adverse events during the study.

Effect of methylprednisolone on CYP3A4-mediated drug metabolism in vivo.

OBJECTIVE: To study the effects of methylprednisolone on the pharmacokinetics and pharmacodynamics of triazolam. METHODS: In this three-phase cross-over study, ten healthy subjects received 0.25 mg oral triazolam on three occasions: on day 1 (no pretreatment, control), on day 8 (1 h after a single dose of 32 mg oral methylprednisolone) and on day 18 (after further treatment with 8 mg oral methylprednisolone daily for 9 days). The plasma concentrations of triazolam were determined up to 10 h, and its effects were measured using four psychomotor tests up to 6 h. RESULTS: The single dose of methylprednisolone showed no significant effects on the pharmacokinetics of triazolam. However, the Digit Symbol Substitution Test result was better (P < 0.05) during the single-dose methylprednisolone phase than during the control phase, the other three tests showing no differences between the phases. The multiple-dose treatment with methylprednisolone reduced the mean peak plasma concentration (Cmax) of triazolam by 30% (P < 0.05) but had no significant effects on the time to Cmax (tmax), elimination half-life (t 1/2), area under the plasma concentration-time curve from 0 h to 10 h (AUC(0-10 h)) and AUC(0-infinity) and did not alter the effects of triazolam. CONCLUSION: A single, relatively high dose of methylprednisolone (32 mg) did not affect cytochrome P450 (CYP)3A4 activity, and treatment with 8 mg methylprednisolone daily for 9 days did not result in clinically significant induction of CYP3A4.

Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors.

BACKGROUND: Vincristine is at least partly metabolized by CYP3A4. We have studied the possible effect of the CYP3A4-inducing antiepileptic agents carbamazepine and phenytoin on the pharmacokinetics of vincristine. METHODS: Fifteen adult patients with brain tumors receiving combination chemotherapy with procarbazine, lomustine, and vincristine volunteered for this open parallel-group study. Nine of the patients used either carbamazepine or phenytoin and six of the patients used no obvious CYP3A4-inducing medication. After intravenous infusion of 2 mg vincristine, timed blood samples were collected up to 24 hours. Plasma vincristine concentrations were measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of vincristine were compared between the two patient groups. RESULTS: The systemic clearance of vincristine was 63% higher (925 +/- 61 versus 569 +/- 76 mL/min [mean +/- SEM]; P = .004), the elimination half-life was 35% shorter (12.7 +/- 0.6 versus 19.4 +/- 3.6 hours; P = .13), and the total area under the plasma concentration-time curve was 43% smaller (37.3 +/- 2.4 versus 65.1 +/- 10.1 ng x h/mL; P = .04) in patients who were receiving carbamazepine or phenytoin than in the control group. CONCLUSIONS: Drugs that induce CYP3A4 can increase the elimination of vincristine. Further studies are needed to determine whether the increased clearance of vincristine by carbamazepine or phenytoin decreases the efficacy of vincristine.

The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron.

BACKGROUND: Ondansetron is an antiemetic agent metabolized by cytochrome P450 (CYP) enzymes. Rifampin (INN, rifampicin) is a potent inducer of CYP3A4 and some other CYP enzymes. We examined the possible effect of rifampin on the pharmacokinetics of orally and intravenously administered ondansetron. METHODS: In a randomized crossover study with 4 phases and a washout of 4 weeks, 10 healthy volunteers took either 600 mg rifampin (in 2 phases) or placebo (in 2 phases) once a day for 5 days. On day 6, 8 mg ondansetron was administered either orally (after rifampin and placebo) or intravenously (after rifampin and placebo). Ondansetron concentrations in plasma were measured up to 12 hours. RESULTS: The mean total area under the plasma concentration-time curve [AUC(0-infinity)] of orally administered ondansetron after rifampin pretreatment was reduced by 65% compared with placebo (P < .001). Rifampin decreased the peak plasma concentration of oral ondansetron by about 50% (from 27.2+/-3.0 to 13.8+/-1.5 ng/mL [mean +/- SEM]; P < .001]) and the elimination half-life (t1/2) by 38% (P < .01). The bioavailability of oral ondansetron was reduced from 60% to 40% (P < .01) by rifampin. The clearance of intravenous ondansetron was increased 83% (from 440+/-38.4 to 805+/-44.6 mL/min [P < .001]) by rifampin. Rifampin reduced the t1/2 of intravenously administered ondansetron by 46% (P < .001) and the AUC(0-infinity) by 48% (P < .001). CONCLUSIONS: Rifampin considerably decreases the plasma concentrations of ondansetron after both oral and intravenous administration. The interaction is most likely the result of induction of the CYP3A4-mediated metabolism of ondansetron. Concomitant use of rifampin or other potent inducers of CYP3A4 with ondansetron may result in a reduced antiemetic effect, particularly after oral administration of ondansetron.

The effect of dexamethasone on the pharmacokinetics of triazolam.

The effects of short-term use of a small dose of dexamethasone on the pharmacokinetics and pharmacodynamics of the CYP3A4 substrate, triazolam, were examined. In a randomized, double-blind cross-over study with two phases, ten healthy volunteers were given either 1.5 mg dexamethasone or placebo once a day for 4 days. On the 5th day, 0.5 mg triazolam was administered orally. Plasma triazolam concentrations and effects of triazolam were measured for 10 hr. Dexamethasone did not have statistically significant effects on the pharmacokinetics of triazolam. The mean total area under the plasma triazolam concentration-time curve was, however, 19% smaller during the dexamethasone phase than during the placebo phase (11.4 +/- 5.7 ng ml-1 hr versus 14.1 +/- 8.8 ng ml-1 hr (mean +/- S.D.); P = 0.09). The four psychomotor tests employed did not show significant differences in the effects of triazolam between the phases. Although dexamethasone had only small effects on the pharmacokinetics and pharmacodynamics of triazolam in the present study, higher doses or prolonged use of dexamethasone might cause a more pronounced induction of CYP3A4. Further studies on the effects of dexamethasone on the pharmacokinetics of CYP3A4 substrates in man are needed.

Tamoxifen and toremifene concentrations in plasma are greatly decreased by rifampin.

BACKGROUND: Rifampin (INN, rifampicin) is a potent inducer of cytochrome P450 (CYP) enzymes involved in drug metabolism and therefore causes many drug interactions. METHODS: The effects of rifampin on the pharmacokinetics of tamoxifen (study I) and toremifene (study II) were examined in 2 randomized, placebo-controlled crossover studies. Ten (study I) or 9 (study II) healthy male volunteers took either 600 mg rifampin or placebo orally once a day for 5 days. On the sixth day, 80 mg tamoxifen or 120 mg toremifene was administered orally. Blood samples were collected up to 336 hours after drug administration. RESULTS: Rifampin reduced the area under the plasma concentration-time curve (AUC) of tamoxifen by 86% (P < .001), peak plasma concentration (Cmax) by 55% (P < .001), and elimination half-life (t1/2) by 44% (P < .001). The AUC of toremifene was reduced by 87% (P < .001), Cmax by 55% (P < .001), and t1/2 by 44% (P < .01) with rifampin. During the rifampin phase, the AUC of N-demethyltamoxifen was 38% (P < .001) and the AUC of N-demethyltoremifene was 20% (P < .01) of that during the placebo phase. CONCLUSIONS: Rifampin markedly reduces the plasma concentrations of tamoxifen and toremifene by inducing their CYP3A4-mediated metabolism. Concomitant use of rifampin or other potent inducers of CYP3A4 with tamoxifen and toremifene may reduce the efficacy of these antiestrogens.

Concentrations and effects of zopiclone are greatly reduced by rifampicin.

AIMS: The effects of rifampicin on the pharmacokinetics and pharmacodynamics of zopiclone, a non-benzodiazepine hypnotic, were studied. METHODS: In a randomized, placebo-controlled cross-over study with two phases, eight young healthy volunteers took either 600 mg rifampicin or placebo once daily for 5 days. On the 6th day, 10 mg zopiclone was administered orally. Plasma zopiclone concentrations and effects of zopiclone were measured for 10 h. RESULTS: The total area under the plasma zopiclone concentration-time curve after rifampicin was 18.0% (95% CI 13.5-22.5%) of that after placebo (86.1 +/- 34.5 ng ml(-1) h vs 473 +/- 114 ng ml(-1) h (mean +/- s.d.); P<0.001). Rifampicin decreased the peak plasma concentration of zopiclone from 76.9 +/- 27.2 ng ml(-1) to 22.5 +/- 6.0 ng ml(-1) (P<0.001) and the half-life from 3.8 +/- 0.6 h to 2.3 +/- 0.9 h (P<0.005). A significant (P<0.02) reduction in the effects of zopiclone was seen in three of the five psychomotor tests used (digit symbol substitution test, critical flicker fusion test and Maddox wing test) after rifampicin pretreatment. CONCLUSIONS: The strong interaction of rifampicin with zopiclone is due to enhanced metabolism of zopiclone. Zopiclone may show a reduced hypnotic effect when used concomitantly with rifampicin or other potent inducers of CYP3A4 such as phenytoin and carbamazepine.

Triazolam is ineffective in patients taking rifampin.

BACKGROUND: Triazolam is metabolized predominantly by cytochrome P450 3A4 (CYP3A4). Rifampin (rifampicin) is a potent inducer of CYP3A4 and it is known to markedly reduce plasma concentrations and effects of drugs such as midazolam. The possible interaction between rifampin and triazolam was examined in this study. METHODS: The pharmacokinetics and pharmacodynamics of triazolam were investigated in a randomized, double-blind crossover study with two phases. Ten young healthy volunteers took either 600 mg rifampin once daily or placebo for 5 days. On the sixth day, 0.5 mg triazolam was administered orally. Timed blood samples were collected and the effects of triazolam were measured with five psychomotor tests for 10 hours. RESULTS: The area under the plasma triazolam concentration-time curve in the rifampin phase was only 5.1% of that in the placebo phase (0.74 +/- 0.14 versus 14.8 +/- 1.0 ng.hr/ml [mean +/- SEM; p < 0.001]). Rifampin pretreatment decreased the maximum plasma concentration of triazolam to 12.4% of the control value (i.e., from 2.9 +/- 0.2 to 0.36 +/- 0.06 ng/ml [p < 0.001]) and the elimination half-life from 2.8 +/- 0.1 to 1.3 +/- 0.1 hours (p < 0.001). All psychomotor tests showed markedly reduced effects (p < 0.01) of triazolam after rifampin pretreatment. CONCLUSIONS: Triazolam is ineffective during rifampin treatment. This is most likely due to increased metabolism of triazolam after induction of CYP3A4 in the gut wall and liver by rifampin. It is advisable to use hypnotic agents that are not metabolized by CYP3A4 during treatment with rifampin or other potent inducers of CYP3A4.

Stage I non-Hodgkin's lymphoma treated with doxorubicin-containing chemotherapy with or without radiotherapy.

Seventy-six patients with stage I or IE intermediate-grade or immunoblastic non-Hodgkin's lymphoma were treated with a short course of doxorubicin-containing chemotherapy with (n = 58) or without (n = 18) involved field radiotherapy. Chemotherapy consisted of 3 or 4 cycles of M-BACOD or (bleo-)CHOP. Seventy-two (97%) of the 74 evaluable patients achieved a complete response. The 3-year overall survival was 89%, recurrence-free survival 94%, and lymphoma-specific survival 93%. Patients older than 60 years also had a 3-year lymphoma-specific survival rate of as high as 92%. The International Prognostic Index was associated with overall survival (p = 0.04), but not with lymphoma-specific survival (p = 0.18). We conclude that stages I and IE intermediate-grade or immunoblastic non-Hodgkin's Hodgkin's lymphoma is highly curable if treated with short doxorubicin-containing chemotherapy and involved field radiotherapy.

Rifampin reduces plasma concentrations and effects of zolpidem.

BACKGROUND: Zolpidem is a short-acting imidazopyridine hypnotic drug that is metabolized mainly by CYP3A4. Rifampin (INN, rifampicin) is a potent inducer of many cytochrome P450 enzymes, and it greatly reduces the plasma concentrations and effects of, for example, midazolam, triazolam, and zopiclone. In this study, the effects of rifampin on the pharmacokinetics and pharmacodynamics of zolpidem were studied. METHODS: In a randomized crossover study with two phases and a washout of 4 weeks, eight young healthy female volunteers took either 600 mg rifampin or placebo once a day for 5 days. On day 6, 20 mg zolpidem was administered orally. Plasma concentrations and effects of zolpidem were measured up to 10 hours. RESULTS: The total area under the plasma zolpidem concentration-time curve after administration of rifampin was 27% of that after administration of placebo (336 +/- 67 versus 1202 +/- 157 ng.hr/ml [mean value +/- SEM; p < 0.01]). Rifampin decreased the peak plasma concentration of zolpidem by 58%, that is, from 293 +/- 61 to 117 +/- 25 ng/ml (p < 0.01) and the elimination half-life from 2.5 +/- 0.2 to 1.6 +/- 0.1 hours (p < 0.01). A significant (p < 0.05) reduction in the effects of zolpidem was seen in all six pharmacodynamic tests after rifampin pretreatment. CONCLUSIONS: The effects of zolpidem are considerably reduced by rifampin because of enhanced metabolism of zolpidem. It is likely that zolpidem also shows a reduced hypnotic effect when used concomitantly with other potent inducers of CYP3A4, such as phenytoin and carbamazepine.

Cytokine therapy of malignant melanoma.

Melanoma is a malignant neoplasia of melanocyte origin appearing mainly in the skin. About one third of all melanomas detected disseminate, with the metastatic spread occurring either via lymphatic or blood vessels. In the treatment of advanced melanoma the conventional chemotherapy or radiotherapy has not been very successful. Melanoma is known to have immunologically provocative features. In recent years immunological therapies, mainly cytokines, have been applied in the treatment of melanoma. The most widely used cytokines are Interferons and interleukin-2. These agents are used either alone or in combination with each other or with chemotherapeutics. Interferon and interleukin-2 therapies have yielded response rates of 15-20% on average, whereas combinations of immunotherapy and chemotherapy offer response rates as high as 50-60%. Unfortunately, average survival of patients with disseminated melanoma has been short, from 6 to 12 months. The immunotherapy approach has yielded some long-term responses and probably even a cure for a small proportion of patients. Understanding of basic mechanisms of tumour destruction by cytokines and new agents coming into clinical use will undoubtedly further improve treatment results.