Fluphenazine pharmacokinetics and therapeutic response

We conducted a double-blind study of therapeutic outcome versus mean steady-state levels in 29 newly admitted schizophrenic and schizoaffective patients who were treated with a constant dose of fluphenazine HCl over a 2-week period. Both an upper and lower end of the therapeutic window were suggested by three nonresponders whose plasma levels were above 2.8 ng per ml and by two nonresponders and one partial responder whose plasma levels were below 0.2 ng per ml. The mean terminal half-life of fluphenazine (±SD) was 16.4±13.3 h. We found that concomitant use of benztropin mesylate during the initial 4 weeks of fluphenazine treatment did not significantly alter fluphenazine plasma levels.     

Frequency response method in pharmacokinetics

The paper presents the demonstration of applicability of the frequency response method in a bioavailability study. The frequency response method, common in system engineering, is based on an approximation of the frequency response of a linear dynamic system, calculated from input-output measurements, by a frequency model of the system transfer function in the frequency domain. In general, the influence of the system structure on the form of the system frequency response is much more distinct than on the form of the system output. This is of great advantage in modeling the system frequency response instead of the system output, commonly used in pharmacokinetics. After a brief theoretical section, the method is demonstrated on the estimation of the rate and extent of gentamicin bioavailability after intratracheal administration to guinea pigs. The optimal frequency model of the system describing the gentamicin pathway into the systemic circulation and point estimates of its parameters were selected by the approximation of the system frequency response in the frequency domain, using a noniterative algorithm. Two similar estimates of the system weighting function were independently obtained: the weighting function of the selected frequency model and the weighting function estimated by the numerical deconvolution procedure. Neither of the estimates of the weighting function does decrease monotonously after the maximum of about 2.2–2.5 unit of dose·hr⁻¹ recorded approximately 0.1 hr after drug administration. Both estimates show a marked additional peak approximately at 0.3 hr after administration and possible peaks in the further time period. We hypothesized that the loop found in the frequency response calculated and in the selected optimal frequency model, the high-order of this model, and several peaks identified in the estimates of the system weighting function indicated the complexity of the system and the presence of time delays. Three estimates of the extent of gentamicin intratracheal bioavailability obtained by the three different ways: directly from the calculated frequency response, calculated using the selected frequency model, and by the deconvolution method were 0.950, 0.934, and 0.907 respectively. Thus the conclusion can be made that gentamicin injected intratracheally to guinea pigs is almost completely available. This work was supported in part by Grant 283 from the Slovak Grant Agency, 814 38 Bratislava, Slovak Republic.     

Exenatide effects on statin pharmacokinetics and lipid response

OBJECTIVE: Exenatide is an adjunctive treatment for type 2 diabetes. Many patients with type 2 diabetes have dyslipidemia, which requires treatment with three hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitors (statins), hence, concurrent use of exenatide and statins is likely. Exenatide slows gastric emptying, which may alter the absorption rate of co-administered oral medications. Thus, the potential interaction between exenatide and statins was evaluated in two study settings. METHODS: In an open-label, fixed-sequence, clinical pharmacology study, the plasma pharmacokinetics of lovastatin (40 mg after breakfast) in the presence and absence of exenatide (10 microg before breakfast and dinner) was evaluated in 21 healthy subjects. In a second clinical setting, changes in lipid profiles and statin dosage over 30 weeks in patients with type 2 diabetes were retrospectively compared (n = 180 exenatide 10 microg twice daily (BID), n = 168 placebo BID) in a combined analysis of three placebo-controlled, randomized exenatide Phase 3 trials. RESULTS: In healthy subjects, exenatide decreased mean lovastatin area under the plasma concentration time curve from zero to infinity (AUC0-infinity) and maximum plasma concentration (Cmax) by 40 and 28%, respectively, and increased median time to maximum plasma concentration (tmax) by 4 hours. In the exenatide Phase 3 trials, 30-week changes from baseline for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides and statin dosage were not significantly different between the exenatide and placebo groups treated with statins. CONCLUSIONS: Despite observed changes in lovastatin bioavailability in the pharmacokinetic drug interaction study, exenatide did not negatively affect long-term lipid profiles or statin dosage in patients with concurrent statin therapy. Thus, co-administration of exenatide does not require adjustment in statin dosage.     

他汀类药物与冠心病

高脂血症是罹患冠心病的独立危险因子 ,也是冠心病急性事件的重要诱发因素。大量研究证实 ,调脂治疗可明显降低冠心病的发病率及死亡率。在调脂治疗中 ,他汀类药物具有无可替代的主导作用 ,近几年来广泛应用于冠心病的一、二级预防 ,可以说调脂治疗已进入了他汀类时代。1　概况他汀类药物是羟甲基戊二酰辅酶Ａ(ＨＭＧ ＣｏＡ)还原酶抑制药的总称 ,因其药名均以 ｓｔａｔｉｎ结尾被统称为他汀类。最早于1976年从霉菌培养液中提取 ,1987年开始应用于临床。目前市场共有 6种药物 ,依上市先后为 :洛伐他汀 (ｌｏｖａｓｔａｔｉｎ ,美降之 )、氟…     

Statin therapy and myocardial no-reflow

HMG-CoA reductase inhibitors (statins) have now become one of the most powerful pharmacological strategies in the treatment of cardiovascular diseases. Originally, the cardioprotective effects of statins were thought to be mediated through lipid lowering actions. However, it has now become increasingly clear that the beneficial effects of statins are not related to the lipid lowering effects, but rather to a number of pleiotropic actions. Of particular interest, statins have been shown to increase bioavailability of nitric oxide and protect against vascular inflammation and cardiac cell death in a number of cardiovascular disease states. In this present issue of the British Journal of Pharmacology, Zhao and colleagues provide a novel mechanism of action for statins with the observation that simvastatin reduces myocardial 'no-reflow' after ischemia and reperfusion by activating the mitochondrial K(ATP) channel. The findings of the present study have very profound implications for the treatment of cardiovascular disease. This commentary discusses the implications of these findings and how they relate to the established cardioprotective actions of statins.     

Statin Adverse Effects

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.     

The pharmacokinetics of some psychoactive drugs and relationships to clinical response

Over the past decade a variety of studies have been carried out in the Department of Psychiatry and Human Behavior at the University of California, Irvine, investigating the pharmacokinetics of some psychoactive pharmacological agents and the relationships of these pharmacokinetics to certain clinical responses. This report summarizes and provides an overview of these studies.     

Cardiac pharmacokinetics and inotropic response of verapamil in rats with endotoxemia

The present study evaluated the effect of endotoxin-induced systemic inflammation on cardiac uptake and negative inotropic response to verapamil in isolated rat hearts. Rats received an i.p. dose of 4 mg/kg Escherichia coli lipopolysaccharide (LPS) or saline. After 5.5 h the outflow concentration-time curve and inotropic response data were measured following a 1.5 nmol dose of [(3)H]-verapamil (infused within 1 min) in Langendorff-perfused hearts and analyzed by pharmacokinetic/pharmacodynamic modeling, where the inotropic effects at individual time points were evaluated in relation to outflow concentrations at corresponding times. Endotoxemia decreased the rate of cardiac verapamil uptake and the maximal negative inotropic effect E(max) to 78% and 55%, respectively, of the values estimated in the control group (p < 0.01). The reduction in E(max) was correlated with the increase in body temperature. With verapamil as a model drug, the results give some information about potential effects of endotoxemia on the cardiac kinetics and dynamics of calcium antagonists.     

Relationship of pharmacokinetics to pharmacological response for acetazolamide.

Acetazolamide concentration values derived from a nonlinear model system were related to two pharmacological responses in the rabbit. Kidney response was measured by monitoring urine flow and sodium elimination. Ocular response was followed using an applanation tonometer. Maximum urine flow and sodium elimination occurring immediately after injection correlated with log dose. Urine flow dropped below control values along with a rise in osmolality, suggesting the involvement of antidiuretic hormone. Sodium elimination was correlated with plasma levels. Urine pH is thought to be involved in reducing accessibility of drug to carbonic anhydrase in the kidney. Maximum ocular response also was correlated with log dose. Ocular response was related to a protein fraction, which is believed to be mainly carbonic anhydrase. However, the duration of ocular response was related to the red blood cell protein fraction. Thus, drug activity could conceivably be regulated by monitoring a tissue that is not the site of action and can be sampled readily.     

长期他汀类药物的使用与冠心病患者心理障碍的关系

目的观察长期服用他汀药物对冠心病患者心理状态的影响。方法研究对象来自潍坊市人民医院心血管科及老年医学科,在入组时及随访中评价心理状况,干预因素为长期服用他汀药物,观察指标为抑郁、焦虑、敌对状态。计算优势比及95%置信区间代表他汀使用与异常心理评分的关联性。结果研究对象平均随访4年,最多随访7年,比较140例长期连续服用他汀药物患者的异常心理评分,在对基础状态进行校正后,优势比分别为抑郁（OR0.63,95%CI0.43～0.93）、焦虑（OR0.69,95%CI0.47～0.99）及敌对（OR0.77,95%CI0.58～0.93）。他汀药物的心理获益与胆固醇水平关系不大。结论冠心病患者长期他汀药物服用与抑郁、焦虑、敌对等心理状态好转有关。     

Statin therapy--what now?

In England, only 30% of patients with established coronary heart disease (CHD) and raised serum lipids, and fewer than 4% of individuals eligible for primary prevention, receive lipid-lowering therapy. Target total cholesterol concentrations are achieved in fewer than 50% of patients who do receive such treatment. Here, we review the use of statin therapy in the prevention of CHD events.     

Clinical response,plasma levels and pharmacokinetics of desiramine in depressed in-patients

• 1.1. Correlation between clinical response and plasma levels was investigated in seven patients with endogenous depression treated with 2×1 mg/kg/day of desipramine (DMI) for 21 days. Clinical response was measured by reduction in Hamilton Depression Rating Scale (HDRS) scores.
• 2.2. A beneficial effect of DMI was seen in five out of seven patients studied and was fully evident already one week after the beginning of treatment.
• 3.3. Great inter-individual differences were observed in DMI plasma levels both after a single dose and at ‘steady state’. The maximum plasma concentration after a single dose (C_max) ranged between 19 and 179 ng/ml and the mean ‘steady state’ concentration between 65 and 240 ng/ml.
• 4.4. No significant correlation was found between HDRS scores and plasma levels of DMI; however, a plot of plasma levels and amelioration scores at the end (22nd day) of treatment was suggestive of a curvilinear relationship.
• 5.5. Post ‘steady state’ plasma disappearance half-lives of DMI calculation in four patients ranged from 11.5 to 34.3 hr (mean ± S.E.M. = 26.2 ± 5.0).

     

Effect of viscosity on the pharmacokinetics and biological response to intranasal desmopressin

The effect of viscosity on the nasal absorption and biological response to desmopressin was studied in humans. Nasal solutions of desmopressin with and without the addition of 0.25% (w/v) methylcellulose were administered by a precompression nasal spray pump to 10 volunteers. Plasma levels of desmopressin were assayed by radioimmunoassay and the biological response was measured by determination of the antihemophilia factors (Factor VIII and von Willebrand factor). The results showed that the addition of methylcellulose produced a more sustained and slower absorption, with a longer time to maximum plasma concentration (tmax). However, the areas under the plasma concentration-time curve were not different, indicating a similar total bioavailability. The biological response showed a similar effect. Peak Factor VIII activity was not different, but the presence of methylcellulose produced a slower onset of activity. These findings indicate that although the addition of a viscous agent to nasal formulations may produce a more sustained effect, it delays the onset of activity and no enhancement is achieved in the total bioavailability.