Evidence has recently begun to accumulate that photoperiodic responses of mam mals and birds may affect the control of energy balance and thermoregulation. Exposure to short photoperiod can lower the set point for body temperature regulation in birds and mam mals, as well as the voluntarily selected body temperature in ectothermic lizards. This de crease is accompanied by a reorganization of circadian or ultradian rhythms of body temper ature, particularly an increase in periods spent at rest with minimum body temperatures. Short photoperiod is also used as an environmental cue for induction of seasonal torpor or facilita tion of hibernation. During winter, cold tolerance of small mammals is improved by an in crease of nonshivering thermogenesis in brown fat. Thermogenic capacity of brown fat (res piratory enzymes, mitochondria, uncoupling protein) is enhanced in response to short pho toperiod. This response is mediated via an increase in the activity of sympathetic innervation in brown fat. Moreover, an exposure to short photoperiod prior to low temperatures may act in preparing brown fat for facilitated thermogenesis during acclimation to cold. This shows that photoperiodic control not only affects energy balance indirectly via the control of repro duction or body mass, but may directly interact with central control of thermoregulation and may influence the process of acclimatization.

It is known that co‐administration of CYP3A inducers may decrease the effectiveness of oral contraceptives containing progestins as mono‐preparations or combined with ethinylestradiol. In a randomized clinical drug‐drug interaction study, we investigated the effects of CYP3A induction on the pharmacokinetics of commonly used progestins and ethinylestradiol. Rifampicin was used to induce CYP3A. The progestins chosen as victim drugs were levonorgestrel, norethindrone, desogestrel, and dienogest as mono‐products, and drospirenone combined with ethinylestradiol. Postmenopausal women (n = 12–14 per treatment group) received, in fixed sequence, a single dose of the victim drug plus midazolam without rifampicin, with rifampicin 10 mg/day (weak induction), and with rifampicin 600 mg/day (strong induction). The effects on progestin exposure were compared with the effects on midazolam exposure (as a benchmark). Unbound concentrations were evaluated for drugs binding to sex hormone binding globulin. Weak CYP3A induction, as confirmed by a mean decrease in midazolam exposure by 46%, resulted in minor changes in progestin exposure (mean decreases: 15–37%). Strong CYP3A induction, in contrast, resulted in mean decreases by 57–90% (mean decrease in midazolam exposure: 86%). Namely, the magnitude of the observed induction effects varied from weak to strong. Our data might provide an impetus to revisit the currently applied clinical recommendations for oral contraceptives, especially for levonorgestrel and norethindrone‐containing products, and they might give an indication as to which progestin could be used, if requested, by women taking weak CYP3A inducers—although it is acknowledged that the exact exposure‐response relationship for contraceptive efficacy is currently unclear for most progestins.

AIMSThe present study was conducted to investigate the influence of the strong CYP3A4 inhibitor ketoconazole (KTZ) on the pharmacokinetics of drospirenone (DRSP) administered in combination with ethinylestradiol (EE) or estradiol (E2). METHODSThis was a randomized, multicentre, open label, one way crossover, fixed sequence study with two parallel treatment arms. A group sequential design allowed terminating the study for futility after first study cohort. About 50 healthy young women were randomized 1 : 1 to 'DRSP/EE' or 'DRSP/E2'. Subjects in the 'DRSP/EE' group received DRSP 3 mg/EE 0.02 mg (YAZ®, Bayer) once daily for 21 to 28 days followed by DRSP 3 mg/EE 0.02 mg once daily plus KTZ 200 mg twice daily for 10 days. Subjects in the 'DRSP/E2' group received DRSP 3 mg/E2 1.5 mg (research combination) once daily for 21 to 28 days followed by DRSP 3 mg/E2 1.5 mg once daily plus KTZ 200 mg twice daily for 10 days. RESULTSOral co-administration of DRSP/EE or DRSP/E2 and KTZ resulted in an increase in DRSP exposure (AUC(0,24 h)) in both treatment groups: DRSP/EE group: 2.68-fold DRSP increase (90% CI 2.44, 2.95); DRSP/E2 group: 2.30-fold DRSP increase (90% CI 2.08, 2.54). EE and estrone (metabolite of E2) exposures were increased~1.4-fold whereas E2 exposure was largely unaffected by KTZ co-administration. CONCLUSIONSA moderate pharmacokinetic drug-drug interaction between DRSP and KTZ was demonstrated in this study. No relevant changes of medical concern were detected in the safety data collected in this study. WHAT IS KNOWN ABOUT THIS SUBJECT• Prior data indicate that the major plasma metabolites of drospirenone are formed without CYP enzymes. Thus, no major CYPmediated drug interactions were expected.• However, in a recent study with a drospirenone-containing combination oral contraceptive, it was observed that coadministration of boceprevir, a CYP3A4 inhibitor, led to an increase in drospirenone exposure. WHAT THIS STUDY ADDS• In this study, a moderate pharmacokinetic interaction between drospirenone and ketoconazole, a strong CYP3A4 inhibitor, was observed (2 to 3-fold increase in DRSP exposure with ketoconazole coadministration).• Ketoconazole also slightly increased the systemic exposure of ethinylestradiol and estrone.• Overall, safety data indicated that these pharmacokinetic interactions are without clinical relevance.

After cold exposure, cytochrome c oxidase (COX) activity increased about 2.5-fold within 2 weeks in the brown adipose tissue (BAT) of Djungarian hamsters. The mRNAs for COX subunits I and III and the 12 S rRNA, encoded on mitochondrial DNA (mtDNA), as well as mRNAs for COX subunits IV, Va and mitochondrial transcription factor A, encoded in the nucleus, were unchanged when expressed per unit of total tissue RNA. However, since total tissue RNA doubled per BAT depot, while total DNA remained unchanged, the actual levels of these transcripts were increased within BAT cells. In contrast, the abundance of mRNA for uncoupling protein was increased 10-fold, indicating specific activation of this gene. In addition, the maximal rate of protein synthesis analysed in a faithful in organello system was increased 2.5-fold in mitochondria isolated from BAT after 7 days of cold exposure. We conclude from these data that the biogenesis of thermogenic mitochondria in BAT following cold adaptation is achieved by increasing the overall capacity for synthesis of mitochondrial proteins in both compartments, by increasing their mRNAs as well as the ribosomes needed for their translation. In addition, the translational rate for COX subunits as well as all other proteins encoded on mtDNA is increased. Thus the pool of subunits encoded on mtDNA required for assembly of respiratory chain complexes is provided. By comparison with other models of increased mitochondrial biogenesis, we propose that thyroid hormone (generated within BAT cells by 5'-deiodinase, and induced upon sympathetic stimulation), which is a well known regulator of the biogenesis of mitochondria in many tissues, is also the major effector of these adaptive changes in BAT.

Brown adipocytes from cold‐adapted guinea‐pigs (C‐cells) are more sensitive to uncoupling by exogenous palmitate than are cells from warm‐adapted animals (W‐cells) with much less uncoupling protein. Half‐maximal respiratory stimulation of C‐cells requires 80 nM free palmitate. Noradrenaline‐stimulated lipolysis is not rate‐limiting for the respiration of either C‐cells or W‐cells. Half‐maximal stimulation of fatty acid oxidation by mitochondria from warm‐adapted guinea‐pigs (W‐mitochondria) and cold‐adapted guinea‐pigs (C‐mitochondria) both require 12 nM free palmitate. Palmitate uncouples C‐mitochondria much more readily than M‐mitochondria, parallelling its action on the adipocytes. The uncoupling is partially saturable, about 100 nM free palmitate being required for half‐maximal response of C‐mitochondria. W‐ and C‐mitochondria show identical binding characteristics for palmitate. The respiratory increase of mitochondria is calculated as a function of bound palmitate. After correcting for the residual uncoupling protein present in W‐mitochondria, palmitate is estimated to be almost ineffective as an uncoupler of brown fat mitochondria in the absence of the protein. It is concluded that fatty acids display characteristics required of a necessary and sufficient physiological activator of the uncoupling protein.