The influence of the luteal and follicular phases on major pharmacokinetic parameters of blood and breath alcohol kinetics in women.

Drink tests involving 14 women were carried out to determine the effects of the menstrual cycle phases on the pharmacokinetics of ethanol. One experiment was carried out in the follicular phase of the cycle and another in the luteal phase, with the estradiol, progesterone, and testosterone levels being determined in both cases. The target concentration was a final blood alcohol concentration (BAC) of approximately 0.08g%. After drinking was completed, concurrent BAC and breath alcohol concentration (BrAC) measurements were carried out at intervals of 10-20min. The ethanol elimination rate was determined by calculating a linear function in the part of the slope that was clearly linear. In addition, the c(0) and Widmark factors r were calculated. In 10 of the volunteers, who had a normal increase in progesterone in the luteal phase, the average hourly elimination rate ss(60) in the follicular phase amounted to 0.0194+/-0.0020g%/h (BAC) and 0.0975+/-0.0068mg/L/h (BrAC), and in the luteal phase to 0.0193+/-0.0031g%/h (BAC) and 0.1026+/-0.0101mg/L/h (BrAC). There was no significant difference. Other pharmacokinetic parameters (c(0) concentrations, Widmark factors r, distribution volumes, maximal BAC, mean absorption rate, time until the peak concentrations were reached) also revealed no significant differences between the blood and breath alcohol levels of the luteal and follicular phases. In addition, no significant correlations were observed between the absolute progesterone level and the respective elimination rates ss(60).

Mycophenolate mofetil-based immunosuppression and cytokine genotypes: effects on monokine secretion and antigen presentation in long-term renal transplant recipients.

BACKGROUND: It has been suggested that increased monocyte responses might play a role in chronic allograft rejection. METHODS: We investigated in vitro monokine responses in 112 patients with long-term stable kidney graft function (ST patients; n=80, non-mycophenolate mofetil [MMF]; n=32, MMF) and 25 patients with chronic renal transplant rejection (CR patients; non-MMF). Interleukin 10 and tumor necrosis factor (TNF)-alpha promoter gene polymorphisms were tested by polymerase chain reaction and sequence-specific primers; antigen-presenting capacity (AC) of monocytes was tested by incubation with staphylococcal superantigens (SEA, SEE, SED). RESULTS: Although non-MMF-based immunosuppression in ST patients did not result in compromised AC or lipopolysaccharide (LPS)-stimulated monokine responses compared with healthy controls, we found MMF therapy to be associated with significantly reduced TNF-R1 expression on monocytes (P<0.001), suppressed AC (P<0.02, SED), and suppressed LPS-stimulated IL-1 beta, IL-10, and TNF-alpha secretion (P<0.01). Coinciding with a significantly higher steroid dosage in CR patients, IL-6 receptor and TNF-R1 expression on monocytes were down-regulated (P< or =0.02) and AC was suppressed in CR compared with ST (non-MMF) patients (P<0.01, SED; P<0.05, SEE). However, LPS-stimulated monokine secretion was not decreased or even enhanced (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]; P<0.05). Enhanced in vitro IL-10 responses (>500 pg/mL) were found predominantly in non-MMF-treated patients with the IL-10 genotype GCC (GCC: 23/62 [37%], non-GCC: 2/27 [7%], P<0.005; GCC and non-MMF: 22/47 [47%], GCC and MMF: 1/15 [7%], P<0.005]. CONCLUSION: Steroids and azathioprine did not sufficiently suppress monokine responses, whereas MMF treatment might inhibit chronic graft rejection because of suppression of TNF-R1 expression and vigorous inhibition of monokine secretion. MMF treatment may especially be indicated in patients with the IL-10 "high-producer" genotype GCC.

Polymorphisms of the tumor necrosis factor-alpha gene promoter predict for outcome after thalidomide therapy in relapsed and refractory multiple myeloma.

Thalidomide (Thal) is a drug with antiangiogenic, anti-inflammatory, and immunomodulatory properties that was found to inhibit the production of tumor necrosis factor-alpha (TNF-alpha) in vitro. We studied single nucleotide polymorphisms at positions -308 and -238 of the TNF-alpha gene promoter and measured the corresponding TNF-alpha cytokine levels in 81 patients (pts) with refractory and relapsed multiple myeloma (MM) who were treated with Thal. In myeloma pts carrying the TNF-238A allele (n = 8), we found a correlation with higher pretreatment TNF-alpha levels in peripheral blood (P =.047). After Thal administration, this TNF-238A group had a prolonged 12-month progression-free and overall survival of 86% and 100% versus 44% and 84% (P =.003 and P =.07) in pts with the TNF-238G allele, respectively. These findings suggest that regulatory polymorphisms of the TNF-alpha gene can affect TNF-alpha production and predict the outcome after Thal therapy, particularly in those MM pts who are genetically defined as "high producers" of TNF-alpha.