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Biomedical subjects

Johan Ahlner

Publications and source records attributed to Johan Ahlner.

At least 19 recordsLinked to original sources

Cause of death and drug use pattern in deceased drug addicts in Sweden, 2002-2003.

Compared with their contemporaries, individuals abusing illicit drugs suffer a higher risk of premature death. In Sweden, a simple protocol for registration of fatalities among abusers of alcohol, pharmaceuticals, illicit drugs, or other substances, has been used by the forensic pathologists since 2001. This routine was introduced to allow for an evaluation of the cause and manner of death, and patterns of abuse among different groups of abusers. We explored the data on drug abusers (i.e. abusers of illicit drugs) subjected to a forensic autopsy 2002-2003. The Swedish forensic pathologists examined 10,273 dead victims during the study period and 7% (743/10,273) of the cases were classified as drug abusers. Toxicological analyses were carried out in 99% (736/743) and illicit drugs were detected in 70% (514/736) of these. On average, 3.8 substances (legal or illegal) were found per case. The most common substances were ethanol and morphine, detected in 43 and 35% of the cases, respectively. When exploring the importance of the different substances for the cause of death, we found that the detection of some substances, such as fentanyl and morphine, strongly indicated a poisoning, whereas certain other substances, such as benzodiazepines more often were incidental findings. In total, 50% (372/743) died of poisoning, whereas only 22% (161/743) died of natural causes. Death was considered to be directly or indirectly due to drug abuse in 47% (346/743), whereas evidence of drug abuse was an incidental finding in 21% (153/743) or based on case history alone in 33% (244/743). We believe that this strategy to prospectively categorize deaths among drug addicts constitutes a simple means of standardizing the surveillance of the death toll among drug addicts that could allow for comparisons over time and between countries.

Accidents↗

Mirtazapine naturalistic depression study (in Sweden)--MINDS(S): clinical efficacy and safety.

OBJECTIVE: To study how implementation of a naturalistic trial design for mirtazapine treatment in major depressive disorder for six (up to 12) months could be used and evaluated by means of clinical efficacy and safety. METHOD: An open-labelled, prospective, multicenter, non-comparative trial was conducted during a 2-year period in patients with major depression according to DSM-IV treated in psychiatric departments and primary care in Sweden. Minimal inclusion and exclusion criteria were used in order to diminish the potential patient selection bias. Maximum flexibility of the dosage of mirtazapine was allowed, and clinical assessments included MADRS, CGI, vital signs and spontaneous reporting of adverse events. RESULTS: 192 patients were found eligible and enrolled in the study. A significant improvement in depressive symptoms according to MADRS and CGI was observed including particularly marked sleep improvement early in the treatment. Slight increases in body weight and BMI were observed. The investigational drug was well tolerated overall. CONCLUSION: The clinical efficacy and safety of mirtazapine found in this naturalistic setting is in line with previously reported data on mirtazapine in traditional controlled clinical trials. The results confirm that the naturalistic study design facilitated conduct of the trial. The authors suggest that this type of study design should also be applied to other antidepressant drugs that are frequently prescribed in the general population.

Adolescent↗

Sustained citalopram treatment in experimental hepatic encephalopathy: effects on entrainment to the light-dark cycle and melatonin.

Patients with chronic hepatic encephalopathy often display altered diurnal rhythm as well as other affective disturbances which motivate treatment with antidepressants. We investigated the effects of sustained treatment with citalopram (10 mg/kg daily, 10 days) on 24-hr behavioural open-field activities in portacaval-shunted (PCS) rats and sham-operated control rats. In addition, the daytime and nighttime serum melatonin levels, as well as the serum concentrations of the enantiomers of citalopram and its metabolites, were analyzed. Untreated PCS rats showed reduced locomotor and rearing activities during nighttime. Citalopram treatment resulted in elevated behavioural activity in the PCS rats during night, indicative of an improved entrainment to the light-dark cycle, whereas no behavioural effect could be observed in sham rats. Higher melatonin levels in both PCS and sham rats were observed during nighttime compared with daytime, but the untreated PCS rats also showed higher daytime melatonin level than the corresponding sham group. Citalopram treatment seemed not to have any major effect on the melatonin levels. Higher serum levels of both citalopram and metabolites were observed in PCS rats as compared to sham rats. An altered ratio between the S- and R-enantiomers could also be observed in the PCS rats. In conclusion, the present data support the contention of a disturbed diurnal rhythm, and that the melatonin activity may be altered, in chronic hepatic encephalopathy. The citalopram treatment resulted in similar behavioural performances and daytime serum melatonin levels in PCS rats and controls, although pharmacokinetic differences were present between the groups.

Animals↗

To follow or not to follow dermatological treatment--a review of the literature.

Creams, ointments and solutions applied to the skin surface by patients as part of a daily routine might be expected to provide a more variable dosage than do standard tablets. However, adherence to treatment in dermatology has been little studied. This article reviews recent publications in the field. These are dominated by questionnaire-based studies, which tend to over-estimate adherence. Reduced adherence to dermatological treatment is noted in 34-45% of patients. It is likely that the percentage of patients who practice truly optimal treatment in their daily life is even lower considering the variable practice of self-treatment. Self-reported psychiatric morbidity contributes to poor adherence to dermatological treatment, while a well-functioning doctor-patient interaction is a major determinant of good adherence, as is patient satisfaction. In conclusion, adherence to dermatological treatment is unsatisfactory and there is a need for intervention and change in clinical routines. The therapeutic and economic benefits may be considerable. The immediate challenge is to stimulate a change in patient behaviour and improve self-treatment at home.

Administration, Cutaneous↗

Alcohol and drugs in drivers fatally injured in traffic accidents in Sweden during the years 2000-2002.

During the years 2000-2002, alcohol, pharmaceuticals and illicit drugs were analysed in blood samples from fatally injured drivers in Sweden. The total number of drivers was 920 and in 855 of these, corresponding to 93%, a toxicological investigation was performed. About 85% of the drivers were men and 15% were women. All but three women (96%) were car drivers while the corresponding figure for men was about 78% and about 13% were motorcyclists. The number of positive cases increased from 38.9% in year 2000 to 45.9% in year 2002 and alcohol was the most common drug with frequencies of 19.8%, 25.0% and 21.8% for the studied years 2000, 2001 and 2002, respectively. The median blood alcohol concentration ranged from 1.6 to 2.0mg/mL for men and from 1.2 to 1.8 mg/mL for women. There was a decrease in cases where alcohol was the only drug detected, from 52 out of 58 cases (90%) in year 2000 to 41 out of 61 cases (67%) in 2002. At the same time there was an increase, from 5.4% to 10.0% of illicit drugs, mainly amphetamine, and the cases with multiple drug intake increased from 10% to 26%. The prevalence of pharmaceuticals as the only drug or drugs detected decreased from 14.0% to 10.4% and in the majority of these cases the drug concentrations were within the therapeutic range.

Accidents, Traffic↗

Hormone replacement therapy in the menopause. Structure and content of risk talk.

OBJECTIVE: To investigate how risks and benefits of hormone replacement therapy (HRT) are communicated to women in clinical practice. To evaluate the usefulness of a risk classification based on context framing, i.e. whether the risk is discussed for one or several alternative treatments, and/or in the same context as possible benefits. DESIGN: Analysis of structure and content of transcribed consultations (n = 20) from first-time visits for discussion of climacteric discomfort and/or HRT with five physicians at three different out-patient clinics of gynecology. RESULTS: All women received a prescription of HRT. An alternative to HRT was discussed in seven of the consultations. No decision aids were used. Risk discussion was dominated by the physicians giving information about long-time risk and benefits. The decision to prescribe was made either before the risk discussion was initiated, or before it was finished, in 8 of the 18 consultations where risk discussion was present. Risk classification according to context framing was performed and indicated use of different communication strategies by the physicians. CONCLUSIONS: The perspective of the physicians was mainly on prevention while the women were more focused on symptom alleviation. Each physician had a strategy of his/her own for the risk discussion. Thus, the major differences found between the consultations were between physicians, and not between the women. Risk discussion seemed to be aimed at motivating the woman to follow the physician's decision rather than to help her participate in the decision-making process.

Adult↗

Quantitation of R-(-)- and S-(+)-amphetamine in hair and blood by gas chromatography-mass spectrometry: an application to compliance monitoring in adult-attention deficit hyperactivity disorder treatment.

Amphetamine has been used in Attention Deficit Hyperactivity Disorder (ADHD), narcolepsy, and as an appetite suppressant either as the racemate or in different proportions of its enantiomers. In Linköping, Sweden, the Department for Drug Dependence has successfully treated drug abusers also diagnosed with Adult ADHD with Metamina [S-(+)-amphetamine]. Because of the high risk of relapse into drug abuse, a strategy involving the analysis of amphetamine enantiomers in blood and hair was investigated for the assessment of compliance as well as abstinence from street amphetamine. Four patients were included: one patient was treated with racemic amphetamine, and three with Metamina. Blood and hair samples were obtained as a part of the treatment. A basic extraction of the analytes into iso-octane was used. Hair was dissolved in sodium hydroxide before extraction. Chiral derivatization was performed by reaction with S-(-)-N-(trifluoroacetyl)prolyl chloride. Quantitation of R-(-)- and S-(+)-amphetamine was performed by gas chromatography-mass spectrometry in selected ion monitoring. Both blood and hair sample results showed good compliance for patients 1 and 2. Patient 3 and 4 showed different percentages of S-(+)-amphetamine in hair together with varying total concentrations, suggesting intake of additional racemic illicit amphetamine. During treatment, these patients also showed other signs of noncompliance, and one was temporarily withdrawn from treatment. We conclude that the method is suitable to detect therapeutic concentrations of R-(-)- and S-(+)-amphetamine in both blood and hair and that hair reveals noncompliance not shown by concentrations or enantiomer ratios in blood.

Adult↗

Inter- and intraindividual pharmacokinetic variations of mirtazapine and its N-demethyl metabolite in patients treated for major depressive disorder: a 6-month therapeutic drug monitoring study.

Mirtazapine pharmacokinetic (PK) data from patients on long-term treatment for major depression have never been investigated. For this reason, in a large naturalistic outpatient study (prospective, multicenter, open-labeled, and noncomparative) conducted in Sweden in the period 2000-2002, one of the main objectives was to outline the inter- as well as intraindividual PK variance of mirtazapine and demethylmirtazapine serum concentrations in a patient cohort treated up to 6 (optionally 12) months. A total of 192 male and female outpatients aged 18 years or older were included. Serum samples of mirtazapine and demethylmirtazapine were collected, by the means of therapeutic drug monitoring, at weeks 1, 4, 8, and 24 (52). Altogether 683 serum samples were analyzed. A pronounced interindividual variability of mirtazapine and demethylmirtazapine, and the demethylmirtazapine/mirtazapine ratio was seen. The coefficient of variation was about 38%, 33%, and 36%, respectively. The intraindividual variation over time was low, about 20% on all variables. At the population level, no accumulation of mirtazapine, demethylmirtazapine, or change of the demethylmirtazapine/mirtazapine ratio was observed over time. Women had significantly higher dose-corrected concentrations of mirtazapine and demethylmirtazapine and demethylmirtazapine/mirtazapine ratio than men. Patients above 65 years of age had higher concentrations than their younger counterparts. Among patients with adverse events, lower demethylmirtazapine concentrations were observed than in patients with no adverse events. Patients on multiple drug treatment had higher dose-corrected mirtazapine and demethylmirtazapine serum concentrations than patients taking only mirtazapine. Weight and BMI had a significant negative correlation with demethylmirtazapine concentrations and with the demethylmirtazapine/mirtazapine ratio. Continued efforts are warranted to perform PK studies in a natural clinical setting to learn and understand inter- and intraindividual PK variances in real patients treated for longer periods of time. For mirtazapine as well as for most antidepressant drugs only relatively short term PK is available. To help clinicians improve their treatment of patients with major depressive disorder, the possible implications on the PK with a long-term treatment are important to study.

Adolescent↗

Glyceryl trinitrate-induced angiotensin-converting enzyme (ACE) inhibition in healthy volunteers is dependent on ACE genotype.

Evidence concerning the importance of angiotensin-converting enzyme (ACE) genotype in cardiovascular diseases is accumulating. The aim of this study was to investigate if nitric oxide (NO), generated from glyceryl trinitrate (GTN), affects human serum ACE activity in vivo, and if so, whether this effect was dependent on ACE genotype and (or) reflected in blood pressure reduction. A tablet containing 5 mg GTN was bucally administered for 5 minutes to 17 healthy volunteers. Blood pressure (BP) was recorded, and serum ACE activity, ACE genotype, and plasma cGMP was analyzed. GTN administration significantly reduced BP only in individuals with the deletion/deletion (DD) genotype. Sixty minutes after GTN administration, serum ACE activity was reduced in individuals with the insertion/insertion (II) and insertion/deletion (ID) genotypes, but not the DD genotype. Comparing the change in ACE activity over time between the genotypes resulted in the following: II vs. DD, p < 0.01; II vs. ID, p < 0.05; and ID vs. DD, p < 0.05. There was no significant difference in plasma cGMP content neither between the ACE genotypes nor before and after GTN administration. In conclusion, GTN inhibits serum ACE in vivo in individuals with the II and ID, but not the DD genotype.

Adult↗

Fatal intoxications in a Swedish forensic autopsy material during 1992-2002.

Compilations of substances detected in fatal intoxications are important in order to observe changes in intoxication patterns, to monitor effects of preventive work and to discover new trends in drug usage. The aim of the present study was to describe the current pattern of substances detected in fatal intoxications in Sweden. Fatal intoxications investigated at the Department of Forensic Chemistry, Linköping, Sweden, during 1992-2002, were analysed. All suicides, uncertain cases and accidents where the cause of death were fatal intoxications (ICD-9: E950, E980 and E859) were included and substances detected in more than 50 fatal intoxications (in femoral blood) were listed. For each substance, a cut off value was set, above which concentrations were considered toxic. Fatal intoxications were detected by forensic-chemical analyses in 12% (6998/60,314) of the forensic autopsies during the study period. Among the suicides, an average of 3.8 substances were detected per case, the corresponding figure for uncertain cases and accidents were 3.5 and 4.1 substances, respectively. Ethanol was by far the most frequently detected substance, detected in 43% (3039) of the fatal intoxications, of which 32% (960) had toxic concentrations, followed by propoxyphene, detected in 27% (1863) of the fatal intoxications of which 74% (1370) had toxic concentrations. The number of cases where ethanol and propoxyphene were detected decreased during the study period. Moreover, other CNS-active drugs such as antidepressants, analgesics and anxiolytics were also frequently detected. The drugs with high proportions of cases with toxic concentrations detected were propoxyphene, amitriptyline, zolpidem, carisoprodol, alprazolam, thioridazine, methadone and ketobemidone. Selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) were detected in 12% (833) and 10% (665), respectively. A significantly (P <0.001) higher proportion of cases where TCA were detected had toxic concentrations when compared with cases where SSRI were detected (64% versus 31%).

Adolescent↗

Caffeine fatalities--four case reports.

Four cases of fatal intoxications with caffeine are described. Caffeine is widely available in beverages and in different OTC-products, in many of them in combinations with other drugs like ephedrine. Caffeine is not as harmless as one might believe. An overdose of caffeine alone, intentional or not, might be deadly. It seems to be warranted to include caffeine in the drug-screening of forensic autopsy cases. It is not motivated from a medical point of view to sell pure caffeine over the counter.

Adult↗

Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYD2D6 and CYP2C19.

Citalopram, a selective serotonin reuptake inhibitor, is one of the most commonly found drugs in Swedish forensic autopsy cases. Citalopram is a racemic drug with 50:50 of the S- and R- enantiomers. Enantioselective analysis of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were performed in femoral blood from 53 autopsy cases by a chiral high-performance liquid chromatography (HPLC) method. The mean (+/- standard deviation) S/R ratio for citalopram was 0.67 +/- 0.25 and for desmethylcitalopram, 0.68 +/- 0.20. We found increasing S/R ratios with increasing concentrations of citalopram. We also found that high citalopram S/R ratios were associated with a high parent drug-to-metabolite ratio and may be an indicator of recent intake. Citalopram is metabolized by cytochrome P450 (CYP) 3A4, 2C19, and 2D6. Genotyping for the polymorphic CYP2C19 and CYP2D6 revealed no poor metabolizers regarding CYP2C19 and only 2 (3.8%) poor metabolizers regarding CYP2D6. The presence of drugs metabolized by and/or inhibiting these enzymes in several of the cases suggests that such pharmacokinetic interactions are a more important (practical) problem than metabolic deficiency. Enantioselective analysis of citalopram and its metabolites can provide additional information when interpreting forensic toxicology results and might be a necessity in the future.

Adult↗

Stability of drugs in stored postmortem femoral blood and vitreous humor.

The stability of 46 drugs in postmortem femoral blood stored for one year at -20 degrees C was investigated. The drugs included benzodiazepines, antidepressants, analgetics and hypnotics. For seven drugs we found a significant change in the concentration between the first and second analysis. Five substances; ethanol, desmethylmianserin, 7-amino-nitrazepam, THC and zopiclone showed a decrease in the concentration whereas the concentrations of two substances; ketobemidone and thioridazine increased. However, the changes observed were not of such an order that it would affect the interpretation in normal forensic casework. We also investigated the possible influence of potassium fluoride on the concentrations of the 46 drugs in vitreous humor after storage for one year. For two substances, ethanol and zopiclone, there were significantly lower concentrations in the samples without potassium fluoride. Furthermore, we also studied the correlation between the concentrations in femoral blood and vitreous humor. For 23 substances there was a significant difference between the concentrations in the vitreous humor and femoral blood. Significant correlations between the concentrations in these two specimens were found for 23 substances, indicating that vitreous humor can be an alternative specimen when blood samples are not available, provided that such correlation exists for the particular substance. Statistical analysis also revealed a correlation between the degree of protein binding of the different drugs and percentage of vitreous/femoral blood concentrations.

Drug Stability↗

Stereoselective single-dose kinetics of citalopram and its metabolites in rats.

The single-dose kinetics of the enantiomers of citalopram (CIT) and its metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT), were investigated after administration of 10, 20, or 100 mg/kg (s.c.) rac-CIT to rats. Samples from serum and two brain regions were collected 1, 3, 10, or 20 h postdose for HPLC analysis. In the 100 mg/kg rats, the enantiomeric (S/R) serum concentration ratios of CIT decreased during the study period (0.93 at 1 h vs. 0.59 at 20 h; P < 0.001). In the 10 and 20 mg/kg rats, the decrease in serum S/R CIT ratios was not so evident as in the 100 mg/kg rats. In all three groups the S/R CIT ratio was almost the same in the brain as in serum, although both CIT enantiomer levels in the brain were found to be 5-10 times higher than the levels in serum. The serum and brain metabolite levels were low in the 10 and 20 mg/kg rats, whereas the levels increased during the study period in the 100 mg/kg rats. In conclusion, the CIT enantiomers were shown for the first time to be stereoselectively metabolized after single-dose administration to rats, as previously shown in steady-state dosing studies in humans and rats.

Animals↗

Metabolism of salbutamol differs between asthmatic patients and healthy volunteers.

Patients with asthma are a target group for medication with beta2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries beta2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way. The group of asthma patients was then treated with budesonide inhalations 800 microg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R- and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons P<0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.

Adrenergic beta-Agonists↗

Use of morphine and 6-monoacetylmorphine in blood for the evaluation of possible risk factors for sudden death in 192 heroin users.

AIMS: To detect risk factors for sudden death from heroin injection. DESIGN: Evaluation of data from forensic investigations of all fatal cases of suspected heroin death in a metropolitan area. Only cases with detectable morphine and 6-monoacetylmorphine (6-MAM) in blood were included in order to select heroin intoxication cases. SETTING: Stockholm, Sweden. MEASUREMENTS: Autopsy investigation and toxicological analysis of blood and urine; and police reports. FINDINGS: In two-thirds of the 192 cases, death occurred in public places, and mostly without any time delay. Blood concentrations of morphine ranged from 50 to 1200 ng/g, and of 6-MAM from 1 to 80 ng/g. Codeine was detected in 96% of the subjects. In the majority of cases the forensic investigation indicated polydrug use, the most common additional findings being alcohol and benzodiazepines. However, in one-quarter of the cases other drug combinations were found. Previous abstinence from heroin and use of alcohol were identified as risk factors. For 6-MAM there was also a correlation with the presence of THC and benzodiazepines. Despite a high frequency of heart abnormalities (e.g. myocarditis and focal myocardial fibrosis), these conditions did not correlate with morphine or 6-MAM blood concentrations. CONCLUSIONS: We confirm that alcohol intake and loss of tolerance are risk factors for death from heroin use, whereas no connection to heart pathology was observed. Further, prospective, studies should focus on other possible risk factors.

Adolescent↗

Preserved bronchial dilatation after salbutamol does not guarantee protection against bronchial hyperresponsiveness.

Racemic salbutamol, a beta2-adrenoceptor agonist used for dilatation of airways, has recently been shown to induce lessened relaxation of bronchial smooth muscle and partial loss of bronchoprotection, seen as increased hyperresponsiveness, after regular treatment. The racemate undergoes stereo-selective disposition, giving higher plasma levels of S-salbutamol than that of bronchodilating R-salbutamol, thus raising S : R ratios after repeated administration. Our aim was to evaluate whether increased bronchial hyperresponsiveness (BHR) could be found even after 1 day of repeated salbutamol inhalations, with beta2-receptor-induced bronchial smooth muscle relaxation remaining and whether this would be associated with plasma levels of either enantiomer. Fifteen patients with stable asthma, aged 19-54 years, were included in a randomized, cross-over study. An indirect bronchial challenge method was used [voluntary isocapnic hyperventilation of cold air (IHCA)], and airway condition tested by means of impulse oscillometry. Racemic salbutamol was inhaled three times during a 6-h period. IHCA was performed and plasma concentrations of enantiomers were measured 4 h after the last dose. Tests were also performed without preceding drug treatment. beta2-Agonist-produced bronchial dilatation and protection persisted in the majority of the 15 patients 4 h after repeated inhalations of salbutamol during 1 day. In only two of the 15 patients we could trace increased BHR after salbutamol. Neither dilatation nor protection could be linked to plasma levels of either R- or S-salbutamol. The underlying mechanisms of BHR remain unknown and are dissociated from beta2-receptor-mediated dilatation.

Adrenergic beta-Agonists↗

Quantitative analysis of desmethylselegiline, methamphetamine, and amphetamine in hair and plasma from Parkinson patients on long-term selegiline medication.

Hair and plasma from patients on long-term selegiline medication were analyzed to evaluate the relationships between plasma and hair melanin concentrations and the incorporation of the selegiline metabolites methamphetamine and amphetamine in hair, and to evaluate hair analyses for determining compliance in medication. Analyses were performed on both the whole hairs, as well as pigmented and non-pigmented hairs from gray-haired patients. Melanin was quantitated by spectrophotometry, and metabolites were quantitated by gas chromatography-mass spectrometry. Concentrations in pigmented and non-pigmented hairs differed significantly for both methamphetamine (p < 0.01) and amphetamine (p < 0.02), with mean concentration ratios being 3.69 +/- 1.88 and 2.95 +/- 1.16 for methamphetamine and amphetamine, respectively. Segmental analysis indicated that some patients had not been compliant with medication. We concluded that the incorporation of methamphetamine and amphetamine into hair of single individuals shows a preference for pigmented hairs over white hairs and that segmental analysis of hair may be useful when measuring compliance with medication.

Aged↗