Nikolas Klein

Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.

ObjectiveCurrent guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered &bgr;-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro. DesignProspective comparative study of two groups. SettingThe intensive care unit and research ward of an university hospital. SubjectsSix patients with septic shock and a control group of six gender- and age-matched healthy volunteers. InterventionsTo measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography. Measurements and Main Results In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p < .03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 &mgr;g/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock. ConclusionThe results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.

Reduced serotonin-1A receptor binding in social anxiety disorder.

BACKGROUND Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). METHODS Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. RESULTS We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). CONCLUSIONS The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.

Plasma and tissue pharmacokinetics of cefpirome in patients with sepsis

Objective Broad initial antibiotic treatment is crucial for patients experiencing septic shock or severe sepsis. Fourth-generation &bgr;-lactam antibiotics, such as cefpirome, are frequently favored in these conditions because of their low toxicity and wide antimicrobial coverage. From recent data, however, there is circumstantial evidence that one reason for the high mortality rate of patients with sepsis might be an impaired penetration of antimicrobial agents from the central compartment to the infectious focus. Thus, the present study aimed at describing penetration properties of cefpirome to the target site of many bacterial infections, which is the extracellular space fluid of soft tissues. Design Prospective comparative study of two groups. Setting An intensive care unit and research ward in a university hospital. Subjects The study population included 12 patients with septic shock or severe sepsis and a control group of six overall age-matched healthy volunteers. Interventions To measure cefpirome penetration into the interstitial space fluid of skeletal muscle, we employed microdialysis after single intravenous administration of 2.0 g of cefpirome to patients and healthy volunteers. Measurements and Main Results Maximum concentration and area under the concentration vs. time values in interstitium were significantly lower in patients compared with the control group (p < .004). Cefpirome area under the concentration time values for plasma were 16.0 ± 1.1 mg·min/mL (mean ± sem) and 18.8 ± 1.1 mg·min/mL in patients and healthy volunteers, respectively (p = .075, not significant). In both study groups, mean cefpirome concentrations in interstitium and plasma exceeded 28 &mgr;g/mL throughout the observation period of 240 mins and covered completely minimal inhibitory concentration values for a range of clinically relevant pathogens. Conclusion Cefpirome concentrations reached in tissue interstitium and plasma exceeded minimal inhibitory concentrations of most clinically relevant pathogens in patients with sepsis. Thus, cefpirome exhibits a tissue pharmacokinetic profile, which seems to be particularly valuable for the empirical therapy of patients with sepsis.

Effects of Olanzapine and Ziprasidone on Glucose Tolerance in Healthy Volunteers

Atypical antipsychotics have been linked to a higher risk for glucose intolerance, and consequentially the development of type 2 diabetes mellitus (DM2). We have therefore set out to investigate the acute effects of oral administration of olanzapine and ziprasidone on whole body insulin sensitivity in healthy subjects. Using the standardized hyperinsulinemic euglycemic clamp technique we compared whole body insulin sensitivity of 29 healthy male volunteers after oral intake of either olanzapine 10 mg/day (n=14) or ziprasidone 80 mg/day (n=15) for 10 days. A significant decrease (p<0.001) in whole body insulin sensitivity from 5.7 ml/h/kg (=mean, SM=0.4 ml/h/kg) at baseline to 4.7 ml/h/kg (=mean, SM=0.3 ml/h/kg) after oral intake of olanzapine (10 mg/day) for 10 days was observed. The ziprasidone (80 mg/day) group did not show any significant difference (5.2±0.3 ml/h/kg baseline vs 5.1±0.3 ml/h/kg) after 10 days of oral intake. Our main finding demonstrates that oral administration of olanzapine but not ziprasidone leads to a decrease in whole body insulin sensitivity in response to a hyperinsulinemic euglycemic challenge. Our finding is suggestive that not all atypical antipsychotics cause acute direct effects on glucose disposal and that accurate determination of side effect profile should be performed when choosing an atypical antipsychotic.

Gender differences in the psychopathology of depressed inpatients

Abstract.In the last few years there has been increased scientific effort to describe the gender–specific psychopathological features of depression. Until now these studies have not been entirely conclusive, which could be the result of methodological difficulties. This report investigates sex differences in the symptom presentation in an inpatient population: 104 female and 113 male patients suffering from a depressive episode according to ICD–10 were admitted to the inpatient treatment at the Department of General Psychiatry in Vienna. A psychopathological rating according to the standardized documentation system of the AMDP (Association for Methodology and Documentation in Psychiatry) was performed at admission and discharge. At admission into the hospital women tended to show more affective lability (p = 0.025), whereas men had higher scores in affective rigidity (p = 0.032), blunted affect (p = 0.002), decreased libido (p = 0.028), hypochondriasis (p = 0.016) and hypochondriac delusions (p = 0.039). At discharge from the hospital women had significantly higher scores in dysphoria (p = 0.010), while men were more prone to have compulsive impulses (p = 0.030). Although our results were obtained in a selected sample of inpatients at a university hospital, they are indicative of psychopathological differences between men and women in the core symptoms of depression. These differences may influence diagnostic practice and gender specific treatment of depression.

Differences in the dynamics of serotonin reuptake transporter occupancy may explain superior clinical efficacy of escitalopram versus citalopram

Escitalopram the S-enantiomer of the racemate citalopram, is clinically more effective than citalopram in the treatment of major depressive disorder. However, the precise mechanism by which escitalopram achieves superiority over citalopram is yet to be determined. It has been hypothesized that the therapeutically inactive R-enantiomer competes with the serotonin-enhancing S-enantiomer at a low-affinity allosteric site on serotonin reuptake transporters (SERTs), and reduces the effectiveness of the S-enantiomer at the primary, high-affinity serotonin-binding site. This study summarizes the results of two recent single-photon emission computerized tomography studies measuring SERT occupancy in citalopram-treated and escitalopram-treated healthy volunteers, after a single dose and multiple doses (i.e. under steady-state conditions). The single-dose study showed no attenuating effect of R-citalopram. After multiple dosing, however, SERT occupancy was significantly reduced in the presence of R-citalopram. Under steady-state conditions, R-enantiomer concentrations were greater than for the S-enantiomer because of slower clearance of R-citalopram. A pooled analysis suggests that build-up of the R-enantiomer after repeated citalopram dosing may lead to increased inhibition of S-enantiomer occupancy of SERT. This review adds to the growing body of evidence regarding differences in the dynamics of SERT occupancy, that is, molecular mechanisms underlying the often-observed superior clinical efficacy of escitalopram compared with citalopram in major depressive disorder.

Striatal D2 receptor occupancy in bipolar patients treated with olanzapine

We explored the relationship between striatal dopamine-2 (D(2)) receptor occupancy and extra-pyramidal symptoms (EPS) in bipolar patients receiving olanzapine. Seventeen patients with a DSM-IV diagnosis of bipolar disorder were treated with 5-45 mg/day olanzapine for at least 14 days. After that period, D(2) receptor occupancy was determined using Iodobenzamide (IBZM) and SPECT. EPS were assessed by the Simpson-Angus Scale (SAS) and Barnes-Akathisia Scale (BAS). We found a dose-dependent increase in occupancy: 5 mg led to 28-50%, 10 mg to 40-68%, 15 mg to 69%, 20 mg to 57-66%, 30 mg to 66% and 45 mg to 80% D(2) receptor occupancy; and a significant correlation between plasma levels and occupancy (R(2)=.55, P=.001). Similar to schizophrenic patients, bipolar patients did not exhibit EPS at D(2) occupancy levels of 28 to 80%. Although we did not find an increased vulnerability for acute EPS in bipolar patients receiving olanzapine at clinical relevant doses, this needs to be replicated with larger sample sizes.

Relationship between in vivo drug exposure of the tumor interstitium and inhibition of tumor cell growth in vitro: a study in breast cancer patients

A novel approach is described to simulate effect site pharmacodynamics of anticancer drugs. This approach is based on (i) the in vivo measurement of unbound, interstitial drug pharmacokinetics (PK) in solid tumor lesions in patients and (ii) a subsequent pharmacodynamic (PD) simulation of the time versus drug concentration profile in an in vitro setting. For this purpose, breast cancer cells (MCF-7) were exposed in vitro to the time versus interstitial tumor concentration profiles of 5-fluorouracil (5-FU) and methotrexate (MTX) from primary breast cancer lesions in patients. This led to a maximal reduction in the viable cell count of 69 on day 4, and of 71 on day 7 for 5-FU and MTX, respectively. This effect was dependent on the initial cell count and was characterized by a high interindividual variability. For 5-FU there was a significant correlation between the maximum antitumor effect and the intratumoral AUC (r = 0.82, p = 0.0005), whereas no correlation could be shown for MTX (r = 0.05, p = 0.88). We conclude, that the in-vivo-PK / in-vitro-PD model presented in this study may provide a rational approach for describing and predicting pharmacodynamics of cytotoxic drugs at the target site. Data derived from this approach support the concept that tumor penetration of 5-FU may be a response-limiting event, while the response to MTX may be determined by events beyond interstitial fluid kinetics.

Lipid-Induced Insulin Resistance Is Not Mediated by Impaired Transcapillary Transport of Insulin and Glucose in Humans

Increased lipid availability reduces insulin-stimulated glucose disposal in skeletal muscle, which is generally explained by fatty acid–mediated inhibition of insulin signaling. It remains unclear whether lipids also impair transcapillary transport of insulin and glucose, which could become rate controlling for glucose disposal. We hypothesized that lipid-induced insulin resistance is induced by inhibiting myocellular glucose uptake and not by interfering with the delivery of insulin or glucose. We measured changes in interstitial glucose and insulin in skeletal muscle of healthy volunteers during intravenous administration of triglycerides plus heparin or glycerol during physiologic and supraphysiologic hyperinsulinemia, by combining microdialysis with oral glucose tolerance tests and euglycemic-hyperinsulinemic clamps. Lipid infusion reduced insulin-stimulated glucose disposal by ∼70% (P < 0.05) during clamps and dynamic insulin sensitivity by ∼12% (P < 0.05) during oral glucose loading. Dialysate insulin and glucose levels were unchanged or even transiently higher (P < 0.05) during lipid than during glycerol infusion, whereas regional blood flow remained unchanged. These results demonstrate that short-term elevation of free fatty acids (FFAs) induces insulin resistance, which in skeletal muscle occurs primarily at the cellular level, without impairment of local perfusion or transcapillary transport of insulin and glucose. Thus, vascular effects of FFAs are not rate controlling for muscle insulin-stimulated glucose disposal.

Therapy of treatment resistant depression: focus on the management of TRD with atypical antipsychotics.

Treatment-resistant depression (TRD) represents a significant challenge for physicians. About one third of patients with major depressive disorder fail to experience sufficient symptom improvement despite adequate treatment. Despite this high occurrence of TRD there was no general consensus on diagnosis criteria for TRD until 1997 when researchers proposed a model of defining and staging TRD. In 1999, others defined operational criteria for the definition of TRD. Treatment of TRD is commonly separated into pharmacologic and nonpharmacologic methods. This review gives a short overview of these two methods. The nonpharmacologic methods include psychotherapy, electroconvulsive therapy, and vagus nerve stimulation. Pharmacologic methods include switching to another antidepressant monotherapy, and augmentation or combination with two or more antidepressants or other agents. This review especially focuses on the augmentation of the antidepressant therapy with atypical antipsychotics.