Hypothalamic antihypertensive effect of metoprolol in chronic aortic coarctated rats

1. The aim of the present study was to investigate the possible hypothalamic antihypertensive effect of metoprolol and its action on aminergic neurotransmission in sham-operated (SO) rats and aortic coarctated (ACo) rats at a chronic hypertensive stage using the microdialysis technique. 2. Hypothalamic metoprolol concentrations and their cardiovascular effects were measured after the intravenous administration of 3 mg/kg metoprolol. Based on metoprolol concentrations reached in the anterior hypothalamus, in a second experiment the anterior hypothalamus of SO and ACo animals was perfused with Ringer's solution containing approximately 7.5 microg/mL metoprolol. The cardiovascular effects of metoprolol perfusion and changes in hypothalamic dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindol acetic acid (5-HIAA) levels were measured during the perfusion. 3. After i.v. administration of metoprolol, a greater hypotensive effect was observed in ACo rats than in SO animals (Delta mean arterial pressure (MAP) -23.8 +/- 2.1 vs-13.8 +/- 1.3 mmHg, respectively; n = 5 for both groups). Metoprolol rapidly reached the central nervous system (CNS) in both groups of rats and its levels were similar in SO and ACo rats. Intrahypothalamic perfusion with metoprolol induced a significative decrease in blood pressure in ACo animals (DeltaMAP -13.3 +/- 1.5 mmHg; n = 5; P < 0.05 vs Ringer perfusion), but not in SO rats (DeltaMAP 3.4 +/- 2.7 mmHg; n = 5). Metoprolol perfusion reduced hypothalamic levels of DOPAC in ACo rats (65 +/- 7% of basal levels; n = 5; P < 0.05 vs Ringer perfusion), but not in SO animals (87 +/- 5% of basal levels; n = 5). There were no changes in hypothalamic concentrations 5-HIAA observed in either experimental group. 4. In conclusion, metoprolol exerts a greater hypotensive effect in chronic ACo animals, suggesting a participation of beta-adrenoceptors in the maintenance of the hypertensive stage. Metoprolol distribution in the CNS is not affected by ACo. The hypotensive effect of metoprolol perfusion in ACo rats suggested that hypothalamic beta-adrenoceptor blockade is part of the antihypertensive effect of metoprolol in chronic ACo rats. The effects of metoprolol on DOPAC levels suggest a reduction of dopamine turnover in hypertensive animals, but not in SO rats.     

Population pharmacokinetic–pharmacodynamic modelling to describe the effects of paracetamol and N‐acetylcysteine on the international normalized ratio

Paracetamol is one of the most common pharmaceutical agents taken in self‐poisonings, and can increase the prothrombin time (PT) through liver injury, and in overdose without hepatic injury by reducing functional factor VII. PT is a measure of hepatic injury used to predict and monitor hepatotoxicity, reported as the international normalized ratio (INR). The antidote for paracetamol poisoning, N‐acetylcysteine (NAC), has been reported to have an effect on the PT. This analysis included patients from a retrospective case series, a prospective inception cohort of paracetamol and psychotropic (control) overdoses, and a cross‐over clinical trial. A population pharmacokinetic–pharmacodynamic model describing the pharmacodynamic effects of paracetamol and NAC on the INR was developed in Phoenix NLME. The dataset included 172 patients; the median age was 22 years (range 13–71 years). A one‐compartment model with first‐order input and linear disposition best described paracetamol pharmacokinetics. The population mean estimate of the concentration that induced a response halfway between the baseline and maximal pharmacological effect of paracetamol was 1302 μmol/L (242), the maximum effect of paracetamol was 0.534 (202; from baseline) and the maximum effect of NAC was 0.325 (9.03; from baseline). Both paracetamol and NAC contributed a pharmacological effect to the elevation of INR. The estimated paracetamol concentration that induced a response halfway between the baseline and maximal pharmacological effect was within the range of plasma paracetamol values studied, fivefold greater than the maximum therapeutic concentration, suggesting that an elevated INR would not be expected within the therapeutic range. Simulated 24 and 48 g paracetamol overdoses with NAC administration produced INR values (50th percentile) that reached the upper limit of, or exceeded, the reference range.     

芥子碱氯化盐的制备及其对自发性高血压大鼠的降压作用

目的利用菜籽粕制备芥子碱氯化盐,探讨其对自发性高血压大鼠(spontaneous hypertension rat,SHR)的降压作用。方法菜籽粕经水提法制备芥子碱硫氰酸盐,用氯型717阴离子交换树脂转换为芥子碱氯化盐,并通过理化性质和波谱数据对其进行结构鉴定。对随机分组的SHR大鼠连续给药28 d,间隔4 d测定其收缩压、舒张压、平均脉压和心率。结果采用1H-NMR、13C-NMR和IR法鉴定芥子碱硫氰酸盐与芥子碱氯化盐,HPLC归一化法测定芥子碱氯化盐纯度质量分数达99%。芥子碱氯化盐能显著降低SHR大鼠的收缩压、舒张压和平均脉压(P<0.05～0.01),但对心率无明显影响。结论该制备工艺简单,所得产品纯度高,对SHR大鼠降压作用显著,具备较好的药物开发前景。     

Different regulation of miR‐29a‐3p in glomeruli and tubules in an experimental model of angiotensin II‐dependent hypertension: potential role in renal fibrosis

The aim of this study was to evaluate the role of the angiotensin II (Ang II) induced‐differential miRNA expression in renal glomerular and tubulo‐interstitial fibrosis in an experimental model of Ang II‐dependent hypertension. To clarify this issue, Sprague Dawley rats were treated with Ang II (200 ng/kg per minute, n = 15) or physiological saline (n = 14) for 4 weeks. Systolic blood pressure and albuminuria were measured every 2 weeks. At the end of the experimental period, renal glomerular and tubulo‐interstitial fibrosis was evaluated by histomorphometric analysis, after Sirius‐Red and Masson's trichrome staining. Ang II increased systolic blood pressure (P < 0.0001), albuminuria (P < 0.01) and both glomerular and tubulo‐interstitial fibrosis (P < 0.01). Using laser capture microdissection and miRNA microarray analysis this study showed that miR‐29a‐3p was down‐regulated in renal tubules and up‐regulated in glomeruli. Real‐time polymerase chain reaction (PCR) experiments confirmed in Ang II‐treated rats a down‐regulation of miR‐29a‐3p in tubules (P < 0.01), while no significant changes were observed in glomeruli. Matrix metalloproteinase‐2 (MMP‐2) was identified as putative miR‐29a‐3p target (by TargetScan, miRanda, Tarbase software) and functionally confirmed by luciferase activity assay. These data demonstrate that the effects of Ang II on miR‐29a‐3p expression in renal tubules is different from the one exerted in the glomeruli and that miR‐29a‐3p targets MMP‐2. These results suggest that the development of renal fibrosis at glomerular and tubulo‐interstitial level depends on different molecular mechanisms.     

Response error in a transformation model with an application to earnings‐equation estimation*

Summary This paper considers estimation of a transformation model in which the transformed dependent variable is subject to classical measurement error. We consider cases in which the transformation function is known and unspecified. In special cases (e.g. log and square‐root transformations), least‐squares or non‐linear least‐squares estimators are applicable. A flexible approximation approach (based on Taylor expansion) is proposed for a parametrized transformation function (like the Box–Cox model), and a semi‐parametric approach (combining a semi‐parametric linear‐index estimator and non‐parametric regression) is proposed for the case of an unspecified transformation function. The methods are applied to the estimation of earnings equations, using wage data from the Current Population Survey (CPS).     

Detection of the recently emerged synthetic cannabinoid 5F–MDMB‐PICA in ‘legal high’ products and human urine samples

Indole or indazole‐based synthetic cannabinoids (SCs) bearing substituents derived from valine or tert‐leucine are frequently abused new psychoactive substances (NPS). The emergence of 5F–MDMB‐PICA (methyl N‐{[1‐(5‐fluoropentyl)‐1H–indol‐3‐yl]carbonyl}‐3‐methylvalinate) on the German drug market is a further example of a substance synthesized in the context of scientific research being misused by clandestine laboratories by adding it to ‘legal high’ products. In this work, we present the detection of 5F–MDMB‐PICA in several legal high products by gas chromatography–mass spectrometry (GC–MS) analysis. To detect characteristic metabolites suitable for a proof of 5F–MDMB‐PICA consumption by urine analysis, pooled human liver microsome (pHLM) assays were performed and evaluated using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and liquid chromatography quadrupole time‐of‐flight mass spectrometry (LC‐QToF‐MS) techniques to generate reference spectra of the in vitro phase I metabolites. The in vivo phase I metabolism was investigated by the analysis of more than 20 authentic human urine specimens and compared to the data received from the pHLM assay. Biotransformation of the 5‐fluoropentyl side chain and hydrolysis of the terminal methyl ester bond are main phase I biotransformation steps. Two of the identified main metabolites formed by methyl ester hydrolysis or mono‐hydroxylation at the indole ring system were evaluated as suitable urinary biomarkers and discussed regarding the interpretation of analytical findings. Exemplary analysis of one urine sample for 5F–MDMB‐PICA phase II metabolites showed that two of the main phase I metabolites are subject to extensive glucuronidation prior to renal excretion. Therefore, conjugate cleavage is reasonable for enhancing sensitivity. Commercially available immunochemical pre‐tests for urine proved to be unsuitable for the detection of 5F–MDMB‐PICA consumption. Copyright © 2017 John Wiley & Sons, Ltd.     

Estimating the effect of a variable in a high‐dimensional linear model

Summary A problem encountered in some empirical research, e.g. growth empirics, is that the potential number of explanatory variables is large compared to the number of observations. This makes it infeasible to condition on all variables in order to determine whether a variable of interest has an effect. We assume that the effect is identified in a high‐dimensional linear model specified by unconditional moment restrictions. We propose a new method that provides a consistent estimator of the effect when the variable of interest is conditional mean independent of excluded variables. Existing methods are consistent when excluded variables do not explain the outcome, but not under the conditional mean independence assumption. We also demonstrate that the new method has good properties in a Monte Carlo study.     

Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in a NG‐nitro‐l‐arginine methyl ester rat model of secondary hypertension

Objectives The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in N^G‐nitro‐l ‐arginine methyl ester (L‐NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic–pharmacodynamic (PK‐PD) modelling. Methods Male Wistar rats were randomly divided into two groups: control rats received tap water to drink for 2 weeks while L‐NAME rats received L‐NAME solution to drink for 2 weeks. The effects of carvedilol (1 and 5 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics were studied by means of traditional blood sampling. The relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by means of PK‐PD modelling. Vascular sympatholytic activity of carvedilol was assessed by the estimation of drug effects on low frequency blood pressure variability by means of spectral analysis. Key findings A dose‐dependent increase in volume of distribution, as well as a greater volume of distribution and clearance of S‐carvedilol as compared with the R‐enantiomer was found in both experimental groups. Although the PK‐PD properties of the S‐carvedilol chronotropic effect were not altered in L‐NAME rats, hypertensive rats showed greater potency and efficacy to the carvedilol hypotensive response. Greater potency of carvedilol for inhibition of sympathetic vascular activity was found in L‐NAME rats. Conclusions Carvedilol showed enantioselective non‐linear pharmacokinetic properties in both groups. An enhanced hypotensive activity of carvedilol was found in L‐NAME hypertensive rats compared with control rats, which may be explained by the greater potency of carvedilol for sympathetic vascular tone inhibition.     

Assessment of CYP3A‐mediated drug–drug interaction potential for victim drugs using an in vivo rat model

The present study aims to determine if an in vivo rat model of drug–drug interaction (DDI) could be useful to discriminate a sensitive (buspirone) from a ‘non‐sensitive’ (verapamil) CYP3A substrate, using ketoconazole and ritonavir as perpetrator drugs. Prior to in vivo studies, ketoconazole and ritonavir were shown to inhibit midazolam hydroxylation with IC₅₀ values of 350 ± 60 nm and 11 ± 3 nm , respectively, in rat liver microsomes (RLM). Buspirone and verapamil were also shown to be substrates of recombinant rat CYP3A1/3A2. In the rat model, the mean plasma AUC_0‐inf of buspirone (10 mg/kg, p.o.) was increased by 7.4‐fold and 12.8‐fold after co‐administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. The mean plasma AUC_0‐inf of verapamil (10 mg/kg, p.o.) was increased by 3.0‐fold and 4.8‐fold after co‐administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. Thus, the rat DDI model correctly identified buspirone as a sensitive CYP3A substrate (>5‐fold AUC change) in contrast to verapamil. In addition, for both victim drugs, the extent of DDI when co‐administered was greater with ritonavir compared with ketoconazole, in line with their in vitro CYP3A inhibition potency in RLM. In conclusion, our study extended the rat DDI model applicability to two additional victim/perpetrator pairs. In addition, we suggest that use of this model would increase our confidence in estimation of the DDI potential for victim drugs in early discovery. Copyright © 2013 John Wiley & Sons, Ltd.     

Effects of sildenafil on nanostructural and nanomechanical changes in mitochondria in an ischaemia‐reperfusion rat model

Sildenafil exerts cardioprotective effects by activating the opening of mitochondrial ATP‐sensitive potassium channels to attenuate ischaemia–reperfusion (IR) injury. In the present study, we used atomic force microscopy (AFM) to investigate changes in mitochondrial morphology and properties to assess sildenafil‐mediated cardioprotection in a rat myocardial infarction model. To investigate the cardioprotective effects of sildenafil, we used an in vivo Sprague‐Dawley rat model of IR. Rats were randomly divided into three groups: (i) sham‐operated rats (control; n = 5); (ii) IR‐injured rats treated with vehicle (normal saline; IR; n = 10); and (iii) IR‐injured rats treated with 0.75 mg/kg, i.p., sildenafil (IR + Sil; n = 10). Morphological and mechanical changes to mitochondria were analysed by AFM. Infarct areas were significantly reduced in sildenafil‐treated rats (7.8 ± 3.9% vs 20.4 ± 7.0% in the sildenafil‐treated and untreated IR groups, respectively; relative reduction 62%; P < 0.001). Analysis of mitochondria by AFM showed that IR injury significantly increased the areas of isolated mitochondria compared with control (24 150 ± 18 289 vs 1495 ± 1139 nm², respectively; P < 0.001), indicative of mitochondrial swelling. Pretreatment with sildenafil before IR injury reduced the mitochondrial areas (7428 ± 3682 nm²; P < 0.001; relative reduction 69.2% compared with the IR group) and ameliorated the adhesion force of mitochondrial surfaces. Together, these results suggest that sildenafil has cardioprotective effects against IR injury in a rat model by improving the morphological and mechanical characteristics of mitochondria.     

Anti‐inflammatory effect of enzymatic hydrolysate of corn gluten in an experimental model of colitis

Objectives Intestinal bacteria are thought to be involved in the initiation and perpetuation of inflammatory bowel diseases. Prebiotics (non‐digestable dietary carbohydrate) have beneficial properties that alter the intestinal flora and contain glutamine‐rich protein. Glutamine significantly decreases indices of inflammation. In this study, an enzymatic hydrolysate of corn gluten (EHCG) was administered by gavage to Sprague‐Dawley rats fed an elemental diet to determine whether EHCG can ameliorate experi‐ mental colitis. Methods Colitis was induced by intrarectal administration of 2,4,6‐trinitrobenzene sulfonic acid after 10 days' daily oral administration of EHCG at 100 and 300 mg/kg. Macroscopic damage was assessed using a scoring system. The mucosa homogenate was sonicated and myeloperoxidase activity and histamine levels measured. Key findings Treatment with EHCG significantly decreased the severity of injury and reduced myeloperoxidase activity and histamine levels in the distal colon mucosa. Conclusions EHCG may have therapeutic benefit as a supplement in enteral nutrition for patients with inflammatory bowel diseases.     

Respiratory Arrest as Main Determinant of Toxicity due to Overdose with Different β–Blockers in Rats

Propranolol, timolol and sotalol were compared regarding their toxicological effects on the cardiovascular and respiratory system. Each drug was administered intravenously to anaesthetized spontaneously breathing and artificially ventilated rats. After the start of infusion in spontaneously breathing rats each drug induced an expected decrease in arterial blood pressure and heart rate. An increase in PQ, QRS and QT interval was observed. From 5/8 of the survival time onwards these changes were accentuated. PaO₂, pH and respiratory rate decreased and PaCO₂ increased. The rats died as a result of respiratory arrest. Artificial ventilation of rats infused with the same doses increased the survival time significantly. The total doses administered before the animals died as a result of cardiovascular failure were significantly higher for each drug. The initial decreases in arterial blood pressure and heart rate were similar to those in spontaneously breathing rats. Thereafter, significantly smaller decreases were observed. The increases in PQ, QRS and QT interval were significantly less than in spontaneously breathing rats. Blood gases remained unchanged except for a decrease in pH in case of timolol     

Drug–drug interaction study to assess the effects of atorvastatin co‐administration on pharmacokinetics and anti‐thrombotic properties of cilostazol in male Wistar rats

Cilostazol (CLZ) and atorvastatin (ATV) are often co‐prescribed to treat conditions such as peripheral arterial disease. In the present study, the drug–drug interaction potential of multi‐dose ATV co‐administration with CLZ on both pharmacokinetics and the anti‐thrombotic property of CLZ is demonstrated. The pharmacokinetic parameters of CLZ (6 mg/kg, twice daily) were determined in male Wistar rats after 7 days co‐administration with ATV (5 mg/kg, once daily) in order to assess the interaction potential between CLZ and ATV on chronic treatment. In vitro metabolic inhibition and everted gut sac studies were conducted to elucidate the mechanism of this interaction. Pharmacodynamic drug–drug interaction was evaluated on anti‐thrombotic models including time to occlusion, platelet aggregation and rat tail bleeding time. A validated LC‐MS/MS method was employed simultaneously to quantify both ATV and CLZ in rat plasma matrix. A statistically significant increase in systemic exposure (Css_max by ~1.75 fold; AUC by ~3.0 fold) to CLZ was observed in ATV pre‐treated rats. In vitro metabolism studies using liver microsomes (RLM and HLM) demonstrated statistically significant inhibition of CLZ metabolism when co‐incubated with ATV. No change in apparent permeability of CLZ was observed in the presence of ATV. Atorvastatin showed a significant delay in artery occlusion time without altering CLZ's bleeding time and platelet aggregation profile. Collectively the results of these studies provide metabolic insight into the nature of drug–drug interaction between the selected drugs. Co‐administration with ATV influences the pharmacokinetics and anti‐thrombotic property of CLZ. A thorough clinical investigation is required before extrapolation of data to humans. Copyright © 2012 John Wiley & Sons, Ltd.     

Physiologically based modeling of p‐tert‐octylphenol kinetics following intravenous,oral or subcutaneous exposure in male and female Sprague–Dawley rats

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for p‐tert‐octylphenol (OP) for understanding the qualitative and quantitative determinants of its kinetics in Sprague–Dawley rats. Compartments of the PBPK model included the liver, richly perfused tissues, poorly perfused tissues, reproductive tissues, adipose tissue and subcutaneous space, in which OP uptake was described as a blood flow‐ or a membrane diffusion‐limited process. The PBPK model successfully simulated previously published data on blood and tissue OP concentrations in Sprague–Dawley rats following oral, intravenous (i.v.) or subcutaneous (s.c.) routes. The model predicted that OP concentrations would reach 6.8, 13.8 and 27.9 ng ml^?1 (male) and 7.2, 14.7 and 31.4 ng ml^?1 (female), 4 h after a single i.v. dose of 2, 4 and 8 mg kg^?1, respectively. The model also predicted that OP concentrations would reach 53.3, 134.8 and 271.2 ng ml^?1 (male) and 87.4, 221.4 and 449.7 ng ml^?1 (female) 4 h after a single oral dose (50, 125 and 250 mg kg^?1) and that, 4 h after a single s.c. dose (125 mg kg^?1), OP concentrations would reach 111.3 ng ml^?1 (male) and 121.6 ng ml^?1. A marked sex difference was seen in blood and tissue OP concentrations. This was reflected in the model by a gender‐specific maximal velocity of metabolism (V_max) that was higher (1.77×) in male than in female rats. Further studies are required to elucidate the mechanism underlying the gender differences and to evaluate whether that is also observed in humans. Copyright © 2010 John Wiley & Sons, Ltd.     

Extended acute toxicity study of 188Re‐liposome in Rats

Liposomes can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness as well as reducing toxicity. To evaluate therapeutic strategies, it is essential to use animal models reflecting important safety aspects before clinical application. As our previous study found that a high dosage (185 of MBq) of ¹⁸⁸Re‐N,N‐bis (2‐mercaptoethyl)‐N’,N’‐diethylethylenediamine‐labeled pegylated liposomes (¹⁸⁸Re‐liposome) induced a decrease in white blood cell (WBC) count in Sprague–Dawley rats 7 days postinjection, the objective of the present study was to investigate extended acute radiotoxicity of ¹⁸⁸Re‐liposome. Rats were administered via intravenous (i.v.) injection with ¹⁸⁸Re‐liposome (185, 55.5 and 18.5 MBq), normal saline as a blank control or non‐radioactive liposome as a vehicle control. Mortality, clinical signs, food consumption, body weights, urinary, biochemical and hematological analyzes were examined. In addition, gross necropsy and histopathological examinations were also performed at the end of the follow‐up period. None of the rats died and no clinical sign was observed during the 28‐day study period. Only male rats receiving ¹⁸⁸Re‐liposome at a high dosage (185 MBq) displayed a slight weight loss compared with the control rats. In both male and female rats, the WBC counts of both high‐dose and medium‐dose (55.5 MBq) groups reduced significantly 7 days postinjection, but recovered to the normal range on Study Day 29. There was no significant difference in urinary analyzes, biochemical parameters and histopathological assessments between the ¹⁸⁸Re‐liposome‐treated and control groups. The information generated from the present study on extended acute toxicity of ¹⁸⁸Re‐liposome will serve as a safety reference for radiopharmaceuticals in early‐phase clinical trials. Copyright © 2012 John Wiley & Sons, Ltd.     

Evaluation of species difference in peripheral lymphocyte reduction effect of CS‐0777, a sphingosine 1‐phosphate receptor modulator,based on a pharmacokinetic/pharmacodynamic model analysis

Pharmacokinetic (PK) and pharmacodynamic (PD) modeling was conducted for the reduction of peripheral lymphocytes after oral administration of CS‐0777 to healthy rats, monkeys and experimental autoimmune encephalomyelitis (EAE) induced rats. The phosphorylated active metabolite of CS‐0777, M1, is a selective sphingosine 1‐phosphate receptor‐1 modulator. A linear one‐ and two‐compartment model with a reversible metabolism process characterized the time courses of CS‐0777 and M1 concentrations in rats and monkeys, respectively. The relationship between lymphocyte counts and M1 concentrations in blood was well described by an indirect response model in all animals examined. An I_max of 0.815 and an IC₅₀ of 6.58 nM in healthy rats, an I_max of 0.807 and an IC₅₀ of 5.09 nM in the EAE rats, an I_max of 0.789 and an IC₅₀ of 0.484 nM in monkeys were estimated by the indirect PD model. Since the IC₅₀ values calculated in terms of the unbound plasma concentration in rats and monkeys were within a similar range, after correction of the IC₅₀ in blood described above with the blood to plasma concentration ratio and the plasma free fraction of M1, it was revealed that there is no species difference in the essential activity of M1 against lymphocyte reduction. The sensitivity of the lymphocytes to M1 was not affected by the EAE status. Comparison of the simulated lymphocyte reduction in EAE rats after multiple dosing with CS‐0777 and the actual EAE clinical scores implies that the significant suppressive effect on EAE did not require the elimination of all lymphocytes from the blood. Copyright © 2016 John Wiley & Sons, Ltd.     

A simple method for optimising transformation of non‐parametric data: an illustration by reference to cortisol assays

Neuroendocrine data are typically positively skewed and rarely conform to the expectations of a Gaussian distribution. This can be a problem when attempting to analyse results within the framework of the general linear model, which relies on assumptions that residuals in the data are normally distributed. One frequently used method for handling violations of this assumption is to transform variables to bring residuals into closer alignment with assumptions (as residuals are not directly manipulated). This is often attempted through ad hoc traditional transformations such as square root, log and inverse. However, Box and Cox (Box & Cox, 1964 ) observed that these are all special cases of power transformations and proposed a more flexible method of transformation for researchers to optimise alignment with assumptions. The goal of this paper is to demonstrate the benefits of the infinitely flexible Box–Cox transformation on neuroendocrine data using syntax in spss . When applied to positively skewed data typical of neuroendocrine data, the majority (~2/3) of cases were brought into strict alignment with Gaussian distribution (i.e. a non‐significant Shapiro–Wilks test). Those unable to meet this challenge showed substantial improvement in distributional properties. The biggest challenge was distributions with a high ratio of kurtosis to skewness. We discuss how these cases might be handled, and we highlight some of the broader issues associated with transformation. Copyright © 2016 John Wiley & Sons, Ltd.