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Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited lysosomal storage disorder caused by mutations in the N-sulfoglucosamine sulfohydrolase gene that result in deficient enzymatic degradation of heparan sulfate (HS), resulting in progressive neurodegeneration in early childhood and premature death. A chemically modified variant of recombinant human sulfamidase, SOBI003, has shown to cross the blood-brain barrier (BBB) in mice and achieve pharmacologically relevant levels in cerebrospinal fluid (CSF). We report on a phase 1/2, open-label, first-in-human (FIH) study (NCT03423186) and its extension study (NCT03811028) to evaluate the long-term safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and clinical efficacy of SOBI003 in patients with MPS IIIA for up to 104 weeks.Six patients aged 1-6 years with confirmed MPS IIIA with developmental age ≥ 12 months received weekly intravenous injections of SOBI003 at 3 mg/kg (Cohort 1, n = 3) or 10 mg/kg (Cohort 2, n = 3). During the extension study, the individual dose of SOBI003 could be adjusted up to 20 mg/kg at the discretion of the investigator.SOBI003 was generally well tolerated. Serum concentrations of SOBI003 increased in proportion to dose, and presence in CSF confirmed that SOBI003 crosses the BBB. Anti-drug antibodies (ADA) were detected in serum and CSF in all patients, with subsequent reductions in serum SOBI003 exposure at high ADA titers. SOBI003 exerted a clear PD effect: a mean reduction in HS levels in CSF of 79% was recorded at the last assessment, together with reductions in HS levels in serum and urine. Neurocognitive development age-equivalent scores showed a stabilization of cognition for all patients, whereas no clear overall clinical effect was observed on adaptive behavior, sleep pattern or quality of life.SOBI003 was well tolerated when administered as weekly intravenous infusions at doses of up to 20 mg/kg for up to 104 weeks. ADA development was common and likely affected both PK and PD parameters. SOBI003 crossed the BBB and showed pharmacological activity on HS in CSF.

Nitisinone inhibits the cytochrome P450 (CYP) subfamilies CYP2C9, CYP2D6, and CYP2E1 and the organic anion transporter (OAT) isoforms OAT1 and OAT3 in vitro. Since the effect of nitisinone on these enzymes and transporters in humans is still unknown, the purpose of this study was to evaluate the effect of nitisinone on these CYP subfamilies and OAT isoforms. This was an open-label, nonrandomized, two-arm, phase 1 study (EudraCT: 2016-004297-17) in healthy volunteers. The substrates (tolbutamide, metoprolol, and chlorzoxazone for the respective CYPs and furosemide for the OATs) were administered as single doses, before and after 15 days of once daily dosing of 80 mg nitisinone, to determine the AUC∞ ratios ([substrate+nitisinone]/[substrate]). Nitisinone pharmacokinetics, safety, and tolerability were also assessed, and blood and urine were collected to determine substrate and nitisinone concentrations by LC-MS/MS. Thirty-six subjects were enrolled with 18 subjects included in each arm. The least square mean ratio (90% confidence interval) for AUC∞ was 2.31 (2.11–2.53) for tolbutamide, 0.95 (0.88–1.03) for metoprolol, 0.73 (0.67–0.80) for chlorzoxazone, and 1.72 (1.63–1.81) for furosemide. Clinically relevant nitisinone steady-state concentrations were reached after 12 days: mean Cav,ss of 94.08 μM. All treatments were well tolerated, and no safety concerns were identified. Nitisinone did not affect CYP2D6 activity, was a weak inducer of CYP2E1, and was a weak inhibitor of OAT1 and OAT3. Nitisinone was a moderate inhibitor of CYP2C9, and treatment may therefore result in increased plasma concentrations of comedications metabolized primarily via this enzyme. EudraCT 2016-004297-17.

Dexmecamylamine (TC-5214) is a nicotinic channel modulator that was evaluated as a potential adjunct treatment to an antidepressant for patients with major depressive disorder. Dexmecamylamine is almost completely eliminated via the kidneys, with more than 90 % of a given dose excreted unchanged in urine. The aim of this study was to assess the single-dose pharmacokinetics of dexmecamylamine in subjects with various degrees of renal impairment and subjects undergoing hemodialysis. A single-dose, open-label, parallel-group study was conducted at two study centers in the USA. There were four treatment groups with eight subjects in each, receiving a single dose of dexmecamylamine 8 mg (subjects with normal renal function and mild renal impairment) or TC-5412 2 mg [subjects with moderate renal impairment and end-stage renal disease (ESRD)]. The pharmacokinetics of dexmecamylamine in plasma, urine, and dialysate were evaluated using non-compartmental analysis. The plasma pharmacokinetics of dexmecamylamine were influenced by renal function. The increase in dose–normalized area under the plasma concentration–time curve (AUC) was statistically significant with an approximately doubled exposure in subjects with moderate renal impairment compared with subjects with normal renal function. The maximum plasma concentration was not impacted by renal function. Plasma clearance of dexmecamylamine in ESRD subjects appeared negligible, with flat plasma concentration–time profiles. Hemodialysis had a relatively modest effect on reduction of dexmecamylamine plasma concentrations. There was no discernable relationship between renal clearance and urinary pH. Renal impairment increased the AUC, prolonged the elimination half-life, and decreased the clearance of dexmecamylamine following administration as a single oral dose. It is likely that renal function would need to be taken into account when setting the dose. Dexmecamylamine administration should be avoided or the dose significantly reduced in patients with severe renal impairment and ESRD.

A 57-year-old man and a 70-year-old woman with relapsing polychondritis are reported. The man, suffering from arthralgias, respiratory obstruction, external ear and sanddle-nose deformities, conjunctivitis and irido-cyclitis, died after 4 years from airway obstruction because of tracheal and bronchial collapse. The woman is alive 8 months after the development of respiratory obstruction, probably caused by radiographically demonstrated tracheal obstruction, a saddle-nose deformity and hearing impairment. Microscopically, the involved cartilages showed degenerative and slight inflammatory changes and were eventually replaced by fibrous tissue. Histochemical studies, utilizing staining with Alcian blue at controlled electrolyte concentrations (Scott technique) and at controlled pH:s, with or without digestion with bacterial chondroitinase ABC; and staining with the PAS-method, with or without diastase digestion, revealed a complete or relative loss of glucosaminoglycans and glycogen. A biosynthetic defect is considered unlikely to be the primary pathogenetic mechanism of relapsing polychondritis. Histological and histochemical examination of biopsies from involved cartilages contribute to a definite diagnosis.

Objectives: Our objectives were (1) to determine whether the drugs caffeine, losartan, omeprazole, debrisoquin (INN, debrisoquine), and quinine can be given simultaneously in low doses as a cocktail for the phenotyping of cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4, respectively, and (2) to design an administration schedule to give as few sampling occasions as possible. Methods: Twenty-four subjects were given oral doses of 100 mg caffeine, 25 mg losartan, 20 mg omeprazole, 10 mg debrisoquin, and 250 mg quinine on separate days. After a washout period of at least 4 days, all drugs were given simultaneously except for quinine, which was given 8 hours after the other drugs. Blood and urine samples were collected to determine parent drug and metabolite concentrations for assessment of phenotyping indices. Any difference between both single and cocktail doses was tested on a log-normal distribution. Results: The phenotypic indices of CYP1A2 (paraxanthine/caffeine in 4-hour plasma), CYP2C9 (losartan/E-3174 [metabolite of losartan] in 0- to 8-hour urine), CYP2C19 (omeprazole/5-hydroxyomeprazole in 3-hour plasma), and CYP3A4 (quinine/3-hydroxyquinine in 16-hour plasma) were not significantly changed when probe drugs were administered alone compared with together, although a tendency toward higher concentrations of losartan was seen during simultaneous administration (95% confidence interval, 0.51–1.002; P = .051). The CYP2D6 phenotypic index (debrisoquin/4-hydroxydebrisoquin in 0- to 8-hour urine) was significantly changed when drugs were given together (95% confidence interval, 0.45–0.87; P = .007), indicating an inhibition of the debrisoquin metabolism. The within-subject coefficients of variation (8%-25%) were much lower than the between-subject coefficients of variation (34%-79%). Conclusions: The administration of drugs together suggests an inhibition of debrisoquin metabolism caused by the concurrent drugs given. By separating debrisoquin from the other cocktail drugs, this method is likely to be used as a tool to phenotype the enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 with only 2 urinary collections and 2 blood-sampling occasions. Clinical Pharmacology & Therapeutics (2003) 73, 517–528; doi: 10.1016/S0009-9236(03)00050-X

Aims To study the influence of the CYP2D6*10 allele on the disposition of debrisoquine and nortriptyline. Methods The pharmacokinetics of debrisoquine and nortriptyline and their main metabolites were determined in ten Koreans with the CYP2D6*1/*1 (n = 5) and CYP2D6*1/*10 (n = 5) genotypes after single oral doses of 20 mg debrisoquine and 25 mg nortriptyline, respectively. The data were compared with previously published findings from 21 Caucasians with 0, one, two, three, four or 13 functional CYP2D6 genes. Results The AUC0−8 of 4-hydroxydebrisoquine was significantly lower in Koreans with CYP2D6*1/*10 genotype compared with CYP2D6*1/*1[95% confidence interval (CI) for the ratio between means 1.17, 1.85]. No other genotype-related differences were found in the plasma kinetics of nortriptyline and debrisoquine, or their hydroxy metabolites. The AUCnortriptyline/AUC10-hydroxynortriptyline ratio did not differ between the *1/*1 and *1/*10 genotype groups (95% CI for the ratio of means 0.60, 1.26). Similarly, there was no difference between these genotypes with respect to the AUCdebrisoquine/AUC4-hydroxydebrisoquine ratio (95% CI for the ratio of mean values 0.38, 1.46). Both Korean genotype groups had similar AUCs and parent compound/metabolite AUC ratios of debrisoquine and nortriptyline to Caucasians with two functional CYP2D6 genes. Conclusions Heterozygosity for CYP2D6*10 decreases the CYP2D6-dependent elimination of nortriptyline and debrisoquine to only a limited degree. Further studies in subjects homozygous for CYP2D6*10 are required to elucidate fully the pharmacokinetic consequences of this CYP2D6 genotype in Orientals.

Cytochrome P450 CYP2D6 is the most extensively characterized polymorphic drug-metabolizing enzyme. A deficiency of the CYP2D6 enzyme is inherited as an autosomal recessive trait; these subjects (7% of Caucasians, about 1% of Orientals) are classified as poor metabolizers. Among the rest (extensive metabolizers), enzyme activity is highly variable, from extremely high in ultrarapid metabolizers, to markedly reduced in intermediate metabolizers. The CYP2D6 gene is highly polymorphic, with more than 70 allelic variants described so far. Of these, more than 15 encode an inactive or no enzyme at all. Others encode enzyme with reduced, "normal" or increased enzyme activity. The CYP2D6 gene shows marked interethnic variability, with interpopulation differences in allele frequency and existence of "population-specific" allelic variants, for instance among Orientals and Black Africans. The CYP2D6 enzyme catalyses the metabolism of a large number of clinically important drugs including antidepressants, neuroleptics, some antiarrhythmics, lipophilic beta-adrenoceptor blockers and opioids. The present-day knowledge on the influence of the genetic variability in CYP2D6 on the clinical pharmacokinetics and therapeutic effects/adverse effects of psychotropic drugs is reviewed.

Aims To study whether the CYP2D6 capacity in ultrarapid metabolizers of debrisoquine due to duplication/multiduplication of a functional CYP2D6 gene, can be ‘normalised’ by low doses of the CYP2D6 inhibitor quinidine and whether this is dose-dependent. Methods Five ultrarapid metabolizers of debrisoquine with 3, 4 or 13 functional CYP2D6 genes were given single oral doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after quinidine intake, 10 mg debrisoquine was given. Urine was collected for 6 h after debrisoquine administration. Debrisoquine and its 4-hydroxymetabolite were analysed by h.p.l.c. and the debrisoquine metabolic ratio (MR) was calculated. Results Without quinidine the MR in the ultrarapid metabolizers ranged between 0.01 and 0.07. A dose-effect relationship could be established for quinidine with regard to the inhibitory effect on CYP2D6 activity. To reach an MR of 1–2, subjects with 3 or 4 functional genes required a quinidine dose of about 40 mg, while the sister and brother with 13 functional genes required about 80 mg quinidine. After 160 mg quinidine, the MRs, in the subjects with 3, 3, 4, 13 and 13 functional genes, were 12.6, 10.1, 9.2, 2.4 and 2.2, respectively. Conclusions A dose-effect relationship could be established for quinidine inhibition of CYP2D6 in ultrarapid metabolizers. The clinical use of low doses of quinidine as an inhibitor of CYP2D6 might be considered in ultrarapid metabolizers taking CYP2D6 metabolized drugs rather than giving increased doses of the drug. Normalizing the metabolic capacity of CYP2D6, by giving a low dose of quinidine, may solve the problem of ‘treatment resistance’ caused by ultrarapid metabolism.

Objectives To study the impact of the CYP2D6*10 allele on the disposition of nortriptyline in Chinese subjects. Methods A single dose of 25 mg nortriptyline was given orally to 15 healthy Chinese volunteers who were classified as extensive metabolizers after phenotyping with debrisoquin (INN, debrisoquine) and who were genotyped by allele-specific polymerase chain reaction. Five subjects were homozygous for CYP2D6*1, 5 subjects were homozygous for CYP2D6*10, and 5 subjects were heterozygous for these 2 alleles. Plasma concentrations of nortriptyline and its main metabolite 10-hydroxynortriptyline were measured by liquid chromatography-mass spectrometry, and the pharmacokinetics were studied during 168 hours after the dose. Results Subjects who were homozygous for CYP2D6*10 had significantly higher total areas under the plasma concentration-time curve (AUC), lower apparent oral clearances, and longer mean plasma half-life of nortriptyline than subjects in the CYP2D6*1/*1 and the heterozygous groups. For 10-hydroxynortriptyline, the AUC was lower and the plasma half-life was longer in subjects who were homozygous for CYP2D6*10 than in subjects in the other 2 groups. Conclusion The CYP2D*10 allele in Chinese subjects was associated with significantly higher plasma levels of nortriptyline compared with the CYP2D6*1 allele because of an impaired metabolism of nortriptyline to 10-hydroxynortriptyline, particularly in the subjects with the CYP2D6*10/*10 genotype. The results suggest that genotyping of CYP2D6 may be a useful tool in predicting the pharmacokinetics of nortriptyline. Clinical Pharmacology & Therapeutics (1998) 64, 384–390; doi

Objective To determine whether cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of tolterodine by investigating potential differences in pharmacokinetics and pharmacodynamics (heart rate, accommodation, and salivation) of tolterodine and its 5-hydroxymethyl metabolite between poor metabolizers and extensive metabolizers of debrisoquin (INN, debrisoquine). Methods Sixteen male subjects (eight extensive metabolizers and eight poor metabolizers) received 4 mg tolterodine by mouth twice a day for 8 days followed by a single intravenous infusion of 1.8 mg tolterodine for 30 minutes after a washout period. Doses were given as the tartrate salt. The pharmacokinetics of tolterodine and 5-hydroxymethyl metabolite were determined, and the pharmacodynamics were measured. Results The mean systemic clearance of tolterodine was significantly lower (p < 0.001) among poor metabolizers (9.0 ± 2.1 L/hr) compared with extensive metabolizers (44 ± 13 L/hr), resulting in a fourfold longer elimination half-life (p < 0.001). The terminal half-life of the 5-hydroxymethyl metabolite (2.9 ± 0.4 hours) was slightly longer than that of the parent compound (2.3 ± 0.6 hours) among extensive metabolizers, but the 5-hydroxymethyl metabolite was undetectable in the serum of poor metabolizers. Only minor differences in pharmacodynamic effects after tolterodine dosage were observed between the groups. Tolterodine caused a similar decrease in salivation in both panels. The decrease occurred when the concentration of unbound tolterodine and 5-hydroxymethyl metabolite among extensive metabolizers was comparable with that of tolterodine among poor metabolizers. Conclusions Tolterodine is extensively metabolized by CYP2D6 with high specificity. Despite the effect on pharmacokinetics, the CYP2D6 polymorphism does not appear to be of great importance in the antimuscarinic effect, probably because of the additive action of parent drug and active metabolite. Clinical Pharmacology & Therapeutics (1998) 63, 529–539; doi

Carisoprodol is a muscle relaxant analgesic, which has an active metabolite i.e. meprobamate. We conducted an open three-panel single-dose administration study with 15 healthy volunteers: five poor metabolizers of mephenytoin, five poor metabolizers of debrisoquine and five extensive metabolizers of both substrates. The aim was to investigate if the elimination of carisoprodol and meprobamate is dependent on the two metabolic polymorphisms of mephenytoin and debrisoquine. The subjects were given single oral doses of 700 mg carisoprodol and 400 mg meprobamate on separate occasions. The disposition of carisoprodol was clearly correlated to the mephenytoin hydroxylation phenotype. The mean serum clearance of carisoprodol was four times lower in poor metabolizers of mephenytoin than in extensive metabolizers, which confirms the hypothesis from our previous study that N-dealkylation of carisoprodol cosegregates with the mephenytoin hydroxylation polymorphism. However, mean serum clearance of meprobamate did not differ between the two groups. Also, polymorphic debrisoquine hydroxylation did not influence the elimination of carisoprodol or meprobamate. Poor metabolizers of mephenytoin thus have a lower capacity to metabolize carisoprodol and may therefore have an increased risk of developing concentration dependent side-effects such as drowsiness and hypotension, if treated with ordinary doses of carisoprodol.

When Kraepelin formulated the concept of dementia praecox, he lumped together a number of diagnostic categories. One of his reasons for doing so was that he had seen many patients who ended up in the same kind of demented state, even though their initial symptoms might have been quite different. He noted that even some cases presenting with mania, or melancholia, took the same downhill course as did the more classic cases of dementia praecox. Kraepelin, aware of the striking paradigm of general paresis, stated that “a single morbid process” explained the downhill course (Kraepelin, 1983, p. 68).

To investigate the disposition and effects of nortriptyline and its major metabolite 10-hydroxy-nortriptyline line in panels of white subjects with different CYP2D6 genotypes, including those with duplicated and multiduplicated CYP2D6*2 genes and to evaluate the contribution of the number of functional C gamma P2D6 alleles to the metabolism of nortriptyline, used here as a model drug for CYP2D6 substrates.Oral single doses of 25 to 50 mg nortriptyline were given to five poor metabolizers of debrisoquin (INN; debrisoquine) with no functional CYP2D6 gene, five extensive metabolizers with one functional CY2D6 gene, five extensive metabolizers with two functional CYP2D6 genes, five ultrarapid metabolizers with duplicated CYP2D6*2 genes, and one ultrarapid metabolizer with 13 copies of the CYP2D6*2 gene. Plasma kinetics of nortriptyline and 10-hydroxynortriptyline were analyzed. Anticholinergic effects (inhibition of salivation and accommodation disturbances), sedation, blood pressure, and effect on supine and erect pulse rate were measured.There was a clear relation between the C gamma P2D6 genotype and the plasma kinetics of nortriptyline and 10-hydroxynortriptyline. The proportion between the apparent oral clearances of nortriptyline in the groups with 0, 1, 2, 3, and 13 functional genes was 1:1:4:5:17. The proportions between AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratios in the groups with 0, 1, 2, 3, and 13 functional genes were 36:25:10:4:1. Oral plasma clearance of nortriptyline and AUC(nortriptyline) to AUC(10-hydroxynortriptyline) ratio both correlated significantly with the debrisoquin metabolic ratio (rS = -0.89, p = 0.0001; rS = 0.92, p = 0.0001). Although ultrarapid metabolizer subjects were given double the nortriptyline dose (50 mg), inhibition of salivation was not more pronounced compared with the other genotype groups given 25 mg nortriptyline.The results of this study show the quantitative importance of the CYP2D6 genotype, especially the presence of multiple functional CYP2D6 genes for the pharmacokinetics of nortriptyline and 10-hydroxynortriptyline. Genotyping of subjects with multiple copies of functional genes may be of great value for differentiating ultrarapid metabolizers from patients who do not comply with the prescription and for assuring adequate drug choice and dosage for these patients.

Debrisoquine is a major prototypic in-vivo probe used to assess polymorphic CYP2D6 activity in humans, based on the 0-8 h urinary excretion of unchanged drug and its 4-hydroxy metabolite (the so-called metabolic ratio). The primary purpose of the study was to investigate further the relationship between genotype and phenotype by determining the overall disposition characteristics of the drug in selected groups of healthy Swedish Caucasian individuals. Debrisoquine (20 mg) was orally administered to five poor metabolizers with no functional CYP2D6 gene, five heterozygous extensive metabolizers, five homozygous extensive metabolizers, five ultrarapid metabolizers with duplicated/triplicated CYP2D6*2 genes and one individual with 13 copies of CYP2D6*2. Peak plasma levels of debrisoquine and 4-hydroxydebrisoquine were attained within 2-4 h and then declined in a multi-exponential fashion over 96 h. However, the post 8-h period of the elimination process was characterized by irregular fluctuations that prevented formal pharmacokinetic analysis. Nevertheless, marked differences were apparent in the compounds' plasma level-time profiles between the CYP2D6 genotypes. For example, in the case of debrisoquine, the mean ratio of the AUC(0-8) values was 22:22:7:6:1, corresponding to 0, 1, 2, 3/4 and 13 genes and, for 4-hydroxydebrisoquine, the respective values were 1:7:19:28:17. The 0-96 h urinary recovery of debrisoquine differed 100-fold between the genotypes, being essentially complete in poor metabolizers and zero in the individual with 13 CYP2D6*2 genes. 4-hydroxydebrisoquine excretion increased according to the number of functional CYP2D6 genes. A highly significant correlation (r(s) = 0.95, P < 0.001) was observed between the plasma AUC(0-8) ratio for debrisoquine to 4-hydroxydebrisoquine and the 0-8 h urinary metabolic ratio. This study demonstrates that the number of functional CYP2D6 alleles is critically important in the plasma concentration-time curves of debrisoquine and its CYP2D6-mediated 4-hydroxy metabolite. Concentration-related pharmacologic effects would be expected to be similarly affected by gene dosage and it is likely that the same situation also applies to other drugs whose elimination is importantly determined by this enzyme; for example, many antidepressants and neuroleptics, antiarrhythmic agents, beta-adrenoceptor antagonists and opiates.

Lewis (1989) has suggested that the effect of so-called age incidence on season-of-birth data may be a sufficient explanation of the anomalies found in many samples of schizophrenic patients. Various predictions made by Lewis do not agree, however, with data available from some of the sources he quoted. Age incidence can be a source of error when a small age difference has a considerable effect on the likelihood of being included in a sample. Depending on methods of ascertainment, this is unusual in empirical studies.

Maternal age is a neglected variable, with obvious implications for aetiology, in psychiatric research. In samples of schizophrenic patients, the distributions by month of birth and maternal age at birth show remarkable anomalies. These phenomena may be connected, because the seasonal distribution of births varies with maternal age, probably as a result of the age-dependent changes of fertility. Preliminary attempts to describe the seasonal effect in schizophrenia as a function of the shift in mean maternal age are not wholly successful at the quantitative level. Southern-hemisphere findings do not seem to fit the predicted pattern. Examples from other areas of research are discussed (sudden unexpected death in infants, congenital dislocation of the hip, and handedness) in which the seasonal distributions of births, and the findings on maternal age, conform to different varieties of the expected relationship.

The rules known as Koch's postulates have served as invaluable guides to the discovery of the specific causes of various infectious diseases. It may safely be assumed that their influence has also been great on the methods of study in the field of non-infectious diseases. For example, with slight modification Koch's postulates may be applied to the study of diseases caused by poisons. But can they be modified and applied with profit in psychiatric research? This is an important problem, and it cannot be discussed without reference, explicit or implicit, to philosophical assumptions. In this paper some consequences of the philosophy of science of Sir Karl Popper will be tentatively explored.