RESUMEN
BACKGROUND & AIMS: Potassium-competitive acid blockers have documented efficacy for erosive esophagitis. We performed a randomized trial in United States subjects diagnosed with non-erosive reflux disease of vonoprazan vs placebo for 4 weeks, followed by a 20-week active-treatment extension. METHODS: Adult subjects with heartburn ≥4 days/week during screening without erosive esophagitis on endoscopy were randomized to placebo, vonoprazan 10 mg, or vonoprazan 20 mg. After 4 weeks, subjects on placebo were re-randomized to vonoprazan 10 mg or 20 mg, and those already on vonoprazan continued at the same dose for 20 weeks. Electronic diaries were completed twice daily. The primary endpoint was percentage of days without daytime or nighttime heartburn (24-hour heartburn-free days). RESULTS: Among 772 randomized subjects, the percentage of 24-hour heartburn-free days was 27.7% for placebo vs 44.8% for vonoprazan 10 mg (least squares mean difference, 17.1%; P < .0001) and 44.4% for vonoprazan 20 mg (least squares mean difference, 16.7%; P < .0001). Differences in percentage of subjects with a 24-hour heartburn-free day for vonoprazan 10 mg vs placebo and vonoprazan 20 mg vs placebo were 8.3% and 11.6% on day 1 and 18.1% and 23.2% on day 2. The mean/median percentages of 24-hour heartburn-free days over the extension period were similar across the 4 study arms: 61%-63%/76%-79%. CONCLUSIONS: Vonoprazan reduced heartburn symptoms in subjects diagnosed with non-erosive reflux disease, with the benefit appearing to begin as early as the first day of therapy. Treatment effect persisted after the initial 4-week placebo-controlled period throughout the 20-week extension period. The 2 vonoprazan doses (10 mg and 20 mg) were similar in efficacy. (ClinicalTrials.gov: NCT05195528).
RESUMEN
BACKGROUND: Non-erosive reflux disease (NERD) symptoms are often episodic, making on-demand treatment an attractive treatment approach. AIMS: We compared the efficacy and safety of on-demand vonoprazan versus placebo in patients with NERD. METHODS: Patients with NERD, defined as heartburn for ≥6 months and for ≥4/7 consecutive days with normal endoscopy, received once-daily vonoprazan 20 mg during a 4-week run-in period. Patients without heartburn during the last 7 days and with ≥80% study drug and diary compliance were randomised 1:1:1:1 to vonoprazan 10, 20, 40 mg or placebo on-demand for 6 weeks. The primary endpoint was the percentage of evaluable heartburn episodes completely relieved within 3 h of on-demand dosing and sustained for 24 h. RESULTS: Of 458 patients in the run-in period, 207 entered the on-demand period. In the vonoprazan 10 mg group, 56.0% (201/359) of evaluable heartburn episodes met the criteria for complete and sustained relief; 60.6% (198/327) in the 20 mg group; and 70.0% (226/323) in the 40 mg group, compared with 27.3% (101/370) in the placebo group (p < 0.0001 versus placebo for each vonoprazan group). By 1 h post-dose, vonoprazan was associated with complete relief of significantly more heartburn episodes compared with placebo. No serious treatment-emergent adverse events were reported. CONCLUSION: On-demand vonoprazan may be a potential alternative to continued daily acid suppression therapy for the relief of episodic heartburn in patients with NERD. CLINICALTRIALS: gov: NCT04799158.
Asunto(s)
Reflujo Gastroesofágico , Pirosis , Humanos , Pirosis/tratamiento farmacológico , Pirosis/diagnóstico , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/diagnóstico , Pirroles/efectos adversos , Sulfonamidas/efectos adversos , Resultado del Tratamiento , Inhibidores de la Bomba de Protones/efectos adversosRESUMEN
Background: Helicobacter pylori eradication rates achieved with clarithromycin-based triple therapies are declining due to antibiotic resistance, but data regarding temporal changes in efficacy with these eradication therapies are scarce. Objective: To evaluate the efficacy of clarithromycin-based triple eradication regimens over time. Design: A comprehensive literature review and time-trend analysis. Data sources and methods: Bibliographies of recently published systematic literature reviews were searched and supplemented with a targeted literature review conducted using Medline and Embase databases and ProQuest from conception to May 2021. Studies reporting H. pylori eradication rates of clarithromycin-based triple therapies were included and temporal trends were estimated using a random-effects model. Results: Eradication rates for triple therapies containing proton pump inhibitors (PPIs), clarithromycin, and amoxicillin showed a significant decline over the past 23 years (p = 0.0315). However, this decline was not significant when eradication rates achieved with vonoprazan-based triple therapy were included (p = 0.3910). Conclusion: Vonoprazan-based triple therapy partially mitigated the decline in eradication rates seen with PPI-based triple therapy, likely due to more powerful acid suppression of vonoprazan.
RESUMEN
BACKGROUND: Treatment of acid-related disorders relies on gastric acid suppression. The percentage of time intragastric pH is >4 (pH >4 holding time ratio [HTR]) is important for healing erosive oesophagitis; and the pH >6 HTR is critical for eradication of Helicobacter pylori infection, as bacterial replication is active and antibiotic effectiveness is optimised. Vonoprazan, a potassium-competitive acid blocker approved in the USA and other countries, suppresses gastric acid secretion in a predictable, rapid and consistent manner, extended over prolonged periods. AIM: To explore the relationship between vonoprazan exposure and pH HTR through a pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: We pooled data from Phase 1 studies with intragastric pH measurements. Pharmacokinetic profiles were predicted for study participants using an existing population pharmacokinetic model. Pharmacokinetic and pharmacodynamic data were merged, and three direct-link PK/PD models were derived and used to simulate pH HTRs with between-participant variability for pH >4, >5 and >6, for vonoprazan doses of 20 mg once and twice daily. RESULTS: We used data from five Phase 1 studies to derive the PK/PD model. These included 245 participants (95.1% male, 50.6% Japanese and 49.4% non-Asian). Pre-dose, the mean pH >4 HTR was 6.4%, pH >5 3.2% and pH >6 1.2%. After 7 days of dosing, simulations predicted pH >4 HTRs of 89.7% and 98.1%, and pH >6 HTRs of 53.1% and 75.3%, for vonoprazan 20 mg once and twice daily, respectively. CONCLUSIONS: Vonoprazan 20 mg once- and twice-daily dosing demonstrated high, dose-dependent, 24-hour intragastric acid control in this PK/PD model, supporting clinical efficacy data in patients with acid-related disorders.
Asunto(s)
Esofagitis , Infecciones por Helicobacter , Helicobacter pylori , Úlcera Péptica , Humanos , Masculino , Femenino , Infecciones por Helicobacter/tratamiento farmacológico , Inhibidores de la Bomba de Protones/uso terapéutico , Pirroles/uso terapéutico , Esofagitis/tratamiento farmacológicoRESUMEN
Vonoprazan is metabolized extensively through CYP3A and is an in vitro time-dependent inhibitor of CYP3A. A tiered approach was applied to understand the CYP3A victim and perpetrator drug-drug interaction (DDI) potential for vonoprazan. Mechanistic static modeling suggested vonoprazan is a potential clinically relevant CYP3A inhibitor. Thus, a clinical study was conducted to evaluate the impact of vonoprazan on the exposure of oral midazolam, an index substrate for CYP3A. A physiologically-based pharmacokinetic (PBPK) model for vonoprazan was also developed using in vitro data, drug- and system-specific parameters, and clinical data and observations from a [14 C] human absorption, distribution, metabolism, and excretion study. The PBPK model was refined and verified using data from a clinical DDI study with the strong CYP3A inhibitor, clarithromycin, to confirm the fraction metabolized by CYP3A, and the oral midazolam clinical DDI data assessing vonoprazan as a time-dependent inhibitor of CYP3A. The verified PBPK model was applied to simulate the anticipated changes in vonoprazan exposure due to moderate and strong CYP3A inducers (efavirenz and rifampin, respectively). The clinical midazolam DDI study indicated weak inhibition of CYP3A, with a less than twofold increase in midazolam exposure. PBPK simulations projected a 50% to 80% reduction in vonoprazan exposure when administered concomitantly with moderate or strong CYP3A inducers. Based on these results, the vonoprazan label was revised and states that lower doses of sensitive CYP3A substrates with a narrow therapeutic index should be used when administered concomitantly with vonoprazan, and co-administration with moderate and strong CYP3A inducers should be avoided.
Asunto(s)
Inductores del Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Humanos , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacocinética , Midazolam/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Modelos BiológicosRESUMEN
INTRODUCTION: Guidelines recommend that proton pump inhibitor-based triple regimens with clarithromycin not be used for Helicobacter pylori infection in areas where clarithromycin resistance is ≥15%, or in patients with prior macrolide use. Up-to-date information on local resistance patterns is limited, especially in the US. Here, we report resistance rates to antibiotics commonly used to treat H. pylori from a large study conducted in the US and Europe (pHalcon-HP). METHODS: Gastric mucosal biopsies were collected from adult participants with H. pylori infection during screening. Minimum inhibitory concentrations were determined via agar dilution for clarithromycin, amoxicillin, and metronidazole, with breakpoints ≥1 µg/mL, >0.125 µg/mL, and >8 µg/mL, respectively. Resistance rates were obtained for the US and Europe, and also for US subregions and participating European countries. RESULTS: Resistance rates were established in isolates from 907 participants. Overall, 22.2% were resistant to clarithromycin, 1.2% to amoxicillin, and 69.2% to metronidazole. Resistance in the US and Europe was similar; metronidazole resistance was the most prevalent (50%-79%) and amoxicillin the least (≤5%). In all subregions, ≥15% of isolates were resistant to clarithromycin, except the UK (0/8 isolates). Among clarithromycin-resistant isolates, 75% were also metronidazole-resistant. Two US isolates were resistant to clarithromycin and amoxicillin; one of these was also metronidazole-resistant. DISCUSSION: The resistance rates observed in this study argue against the continued empiric use of proton pump inhibitor-based triple therapy containing clarithromycin, per treatment guidelines, and highlight the need for antibiotic resistance surveillance and novel treatment strategies for H. pylori infection in the US and Europe.
Asunto(s)
Infecciones por Helicobacter , Helicobacter pylori , Adulto , Humanos , Antibacterianos/uso terapéutico , Antibacterianos/farmacología , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/diagnóstico , Metronidazol/uso terapéutico , Claritromicina/farmacología , Claritromicina/uso terapéutico , Inhibidores de la Bomba de Protones/uso terapéutico , Inhibidores de la Bomba de Protones/farmacología , Farmacorresistencia Bacteriana , Amoxicilina/uso terapéutico , Pruebas de Sensibilidad Microbiana , Europa (Continente)/epidemiologíaRESUMEN
INTRODUCTION: We assessed pharmacodynamics and pharmacokinetics of a potassium-competitive acid blocker and proton pump inhibitor in US subjects. METHODS: Healthy adults were randomized to 7-day periods of vonoprazan 20 mg once daily followed by lansoprazole 30 mg once daily or the reverse order, separated by ≥ 7 days of washout. RESULTS: Vonoprazan (N = 40) had higher proportions of 24-hour periods with intragastric pH > 4 than lansoprazole (N = 41,38) on day 1 (62.4% vs 22.6%, P < 0.0001) and day 7 (87.8% vs 42.3%, P < 0.0001). Separation in pH started â¼2.5 hours after the first dose. DISCUSSION: Vonoprazan provided more rapid and potent inhibition of intragastric acidity than lansoprazole in US subjects.
Asunto(s)
Potasio , Inhibidores de la Bomba de Protones , Adulto , Humanos , Concentración de Iones de Hidrógeno , Lansoprazol/farmacología , Inhibidores de la Bomba de Protones/farmacología , Pirroles/farmacología , SulfonamidasRESUMEN
Vonoprazan, a potassium-competitive acid blocker, is under investigation in the United States and Europe for the treatment of erosive esophagitis and Helicobacter pylori infection. Population pharmacokinetic (popPK) analysis allows the identification of factors that could affect drug exposure in population subgroups. Here, we report a popPK model based on pooled data sets of available pharmacokinetic (PK) studies in healthy volunteers and patients with gastroesophageal reflux disease, including erosive esophagitis, from Asia and Europe. This model was used to evaluate the impact of different covariates, including race and disease status, on vonoprazan exposure. We analyzed PK data from 746 patients and 410 healthy volunteers from 15 clinical trials using a nonlinear mixed-effects approach to develop the popPK model. Model development focused on characterizing and quantifying the effects of clinical covariates of race (Asian vs non-Asian) and disease status (gastroesophageal reflux disease vs healthy volunteers) on vonoprazan exposure. Identified clinical covariates included fed/fasting status, race, sex, disease status, weight, serum creatinine, and age. The impact of variations in these clinical covariates on exposure to vonoprazan was smaller than the effect of halving or doubling the dose. PK parameters were similar in Asian and non-Asian populations. Variations in weight, age, and race are not predicted to have a clinically relevant impact on vonoprazan exposure or safety and require no changes in vonoprazan dosing. The limited impact of race on exposure suggests that efficacy and safety data for vonoprazan in Asian populations are translatable to non-Asian populations.
Asunto(s)
Esofagitis , Reflujo Gastroesofágico , Infecciones por Helicobacter , Helicobacter pylori , Esofagitis/inducido químicamente , Esofagitis/tratamiento farmacológico , Reflujo Gastroesofágico/tratamiento farmacológico , Infecciones por Helicobacter/tratamiento farmacológico , Humanos , Inhibidores de la Bomba de Protones/uso terapéutico , Pirroles , SulfonamidasRESUMEN
Herein, we report a food-effect study of vonoprazan, an oral potassium-competitive acid blocker. In a phase 1, randomized, open-label, crossover study, healthy subjects received a single 20-mg dose of vonoprazan either following an overnight fast or 30 minutes after a high-fat breakfast. Plasma vonoprazan levels were determined at 0 hour and at 17 subsequent assessment points up to 48 hours after dosing. After a 5-day washout, subjects received a second 20-mg vonoprazan dose in the alternative fed/fasted state (identical process repeated). Twenty-four subjects completed the study. Vonoprazan exposure was not meaningfully affected by food. Geometric mean ratios for maximum concentration, area under the concentration-time curve from time 0 to 24 hours, and area under the plasma concentration-time curve extrapolated to infinity obtained under fed and fasting conditions were 1.05 (90% confidence interval, 0.98-1.12), 1.13 (1.09-1.18), and 1.15 (1.11-1.19), respectively. Four subjects experienced 6 adverse events that were all mild and considered unrelated to the study drug. Vonoprazan can be administered without regard to food intake.
Asunto(s)
Interacciones Alimento-Droga , Potasio , Administración Oral , Estudios Cruzados , Humanos , Pirroles , SulfonamidasRESUMEN
Background and Aims: Effective acid suppression is a crucial component of Helicobacter pylori (H. pylori) eradication regimens. Approved treatments include dual, triple, and quadruple therapies composed of certain antibiotics in combination with proton pump inhibitors (PPIs). Vonoprazan, a potassium-competitive acid blocker, provides more potent and durable acid suppression than PPIs. We compared the efficacy of vonoprazan-based therapies vs approved standard regimens using new evidence from the phase 3 pHalconHP trial in North America and Europe. Methods: Studies reporting first-line H. pylori eradication rates from empiric treatment with Food and Drug Administration-approved therapies and vonoprazan-containing therapies were identified via bibliographic searches of systematic literature reviews and a subsequent MEDLINE/Embase search using index terms for H. pylori and eradication. Randomized controlled trials comparing 2 or more relevant comparators were included in Bayesian network meta-analyses for grouped and distinct therapies. Results: Twenty-three distinct regimens from 42 trials including 12,773 patients were identified. Vonoprazan-based triple therapy showed the highest relative efficacy (odds ratio: 2.73, 95% credible interval 2.11, 3.54) and 72.1% probability of being the best. North American, Western, and global scenarios were largely consistent. Vonoprazan-based therapies demonstrated higher odds of H. pylori eradication than each PPI-based triple therapy. Furthermore, vonoprazan-based triple therapy was superior to bismuth subcitrate quadruple therapy (odds ratio: 1.60, 95% credible interval: 1.07, 2.38). Conclusion: Vonoprazan-based eradication regimens represent novel treatments for H. pylori infection on a global scale, offering efficacy that, in this analysis, is superior to PPI-based triple therapy and comparable or better than bismuth quadruple therapy.
RESUMEN
BACKGROUND: Activation of free fatty acid receptor 1 (FFAR1; also known as G-protein-coupled receptor 40) by fatty acids stimulated glucose-dependent ß-cell insulin secretion in preclinical models. We aimed to assess whether selective pharmacological activation of this receptor by TAK-875 in patients with type 2 diabetes mellitus improved glycaemic control without hypoglycaemia risk. METHODS: We undertook a phase 2, randomised, double-blind, and placebo-controlled and active-comparator-controlled trial in outpatients with type 2 diabetes who had not responded to diet or metformin treatment. Patients were randomly assigned equally to receive placebo, TAK-875 (6·25, 25, 50, 100, or 200 mg), or glimepiride (4 mg) once daily for 12 weeks. Patients and investigators were masked to treatment assignment. The primary outcome was change in haemoglobin A(1c) (HbA(1c)) from baseline. Analysis included all patients randomly assigned to treatment groups who received at least one dose of double-blind study drug. The trial is registered at ClinicalTrials.gov, NCT01007097. FINDINGS: 426 patients were randomly assigned to TAK-875 (n=303), placebo (n=61), and glimepiride (n=62). At week 12, significant least-squares mean reductions in HbA(1c) from baseline occurred in all TAK-875 (ranging from -1·12% [SE 0·113] with 50 mg to -0·65% [0·114] with 6·25 mg) and glimepiride (-1·05% [SE 0·111]) groups versus placebo (-0·13% [SE 0·115]; p value range 0·001 to <0·0001). Treatment-emergent hypoglycaemic events were similar in the TAK-875 and placebo groups (2% [n=7, all TAK-875 groups] vs 3% [n=2]); significantly higher rates were reported in the glimepiride group (19% [n=12]; p value range 0·010-0·002 vs all TAK-875 groups). Incidence of treatment-emergent adverse events was similar in the TAK-875 overall (49%; n=147, all TAK-875 groups) and placebo groups (48%, n=29) and was lower than in the glimepiride group (61%, n=38). INTERPRETATION: TAK-875 significantly improved glycaemic control in patients with type 2 diabetes with minimum risk of hypoglycaemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes. FUNDING: Takeda Global Research and Development.
Asunto(s)
Benzofuranos/administración & dosificación , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Sulfonas/administración & dosificación , Compuestos de Sulfonilurea/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Benzofuranos/efectos adversos , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/diagnóstico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Medición de Riesgo , Sulfonas/efectos adversos , Compuestos de Sulfonilurea/efectos adversos , Resultado del TratamientoRESUMEN
TAK-875 is a selective G-protein-coupled receptor 40 agonist in development for the treatment of type 2 diabetes mellitus. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-875 following administration of a single oral dose of TAK-875 (25-800 mg) in 60 healthy volunteers. TAK-875 was eliminated slowly with a mean terminal elimination t(1/2) of approximately 28.1 to 36.6 hours. Systemic exposure of TAK-875 did not exhibit dose-proportional increases across the dose range evaluated due to a greater than proportional increase in exposure at doses greater than 200 mg. A preliminary food effect assessment indicated that coadministration of TAK-875 with a high-fat meal decreased C(max) of TAK-875 by 40% and AUC by 17%. Clinical adverse experiences were generally mild and transient. No dose-dependent pattern was observed. In healthy volunteers, no glucose-lowering effect and no increase in insulin or c-peptide secretion were evident following administration of TAK-875; the frequency of plasma glucose concentrations <70 mg/dL was similar in the TAK-875 and pooled placebo groups. TAK-875 was well tolerated in the study and has pharmacokinetic characteristics suitable for a once-daily regimen. The pharmacodynamic data support the notion that TAK-875, if effective in diabetic patients, may bear a low risk of hypoglycemia.
Asunto(s)
Benzofuranos/efectos adversos , Glucemia/efectos de los fármacos , Receptores Acoplados a Proteínas G/agonistas , Sulfonas/efectos adversos , Adolescente , Adulto , Área Bajo la Curva , Benzofuranos/farmacocinética , Benzofuranos/farmacología , Péptido C/metabolismo , Grasas de la Dieta/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Interacciones Alimento-Droga , Semivida , Humanos , Insulina/metabolismo , Secreción de Insulina , Masculino , Persona de Mediana Edad , Sulfonas/farmacocinética , Sulfonas/farmacología , Adulto JovenRESUMEN
BACKGROUND: In studies of premenstrual syndrome (PMS), a significant response to treatment is commonly defined as a 50% reduction in symptom scores, but empirical support for this definition is lacking. We compared healthcare utilization in women with and without PMS according to the Daily Record of Severity of Problems (DRSP) scores in order to determine the degree of symptomatic variation in premenstrual symptoms associated with differences in the burden of illness. METHODS: Participants were women aged 18-45 years enrolled in a medical group in southern California. Respondents completed the Medical Outcomes Study Short Form-36 (SF-36) at baseline and the DRSP symptom and occupational productivity items daily. Luteal phase DRSP scores were averaged over two consecutive cycles. Respondents were categorized as having mild/no and moderate/severe PMS or premenstrual dysphoric disorder (PMDD) using a previously published, validated algorithm. Medical costs were estimated from medical claims data over the 2 years prior to study entry. RESULTS: Compared with women with moderate/severe PMS/PMDD (n = 117), those with mild/no PMS/PMDD (n = 271) had 43% lower DRSP scores (29.7 and 52.4, p < 0.05), higher SF-36 mental component summary (49.9 and 40.5, p < 0.0001) and physical component summary (52.6 and 50.8, p = 0.04) scores, and fewer workdays per month with reduced productivity (13.3 and 22.0, p < 0.0001) and workdays missed due to health reasons (1.2 and 2.7, p = 0.001). Women with moderate/severe PMS/PMDD had greater odds of having >10 office visits (OR = 1.80, 95% CI 1.01, 3.22) and of accumulating >$500 in medical charges (OR = 1.9, 95% CI 1.2, 3.0). CONCLUSIONS: A 43% difference in premenstrual vs. postmenstrual symptom scores is associated with a significant difference in healthcare burden. These data support the use of a 50% reduction in symptom ratings as a clinically relevant improvement in PMS/PMDD treatment trials, although smaller differences may also be meaningful.
Asunto(s)
Costo de Enfermedad , Indicadores de Salud , Estado de Salud , Síndrome Premenstrual/epidemiología , Salud de la Mujer/economía , Adulto , California/epidemiología , Estudios Transversales , Femenino , Humanos , Tamizaje Masivo/estadística & datos numéricos , Persona de Mediana Edad , Oportunidad Relativa , Síndrome Premenstrual/economía , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
BACKGROUND: A major event in the post-meiotic development of male germ cells is the formation of the acrosome. This process can be perturbed in C57BL/6 mice by administration of the small molecule miglustat (N-butyldeoxynojirimycin, NB-DNJ). The miglustat-treated mice produce morphologically abnormal spermatozoa that lack acrosomes and are poorly motile. In C57BL/6 mice, miglustat can be used to maintain long-term reversible infertility. In contrast, when miglustat was evaluated in normal men, it did not affect spermatogenesis. To gain more insight into this species difference we have now evaluated the reproductive effects of miglustat in rabbits, in multiple mouse strains and in interstrain hybrid mice. METHODS: Male mice of 18 inbred strains were administered miglustat orally or via miniosmotic pumps. Rabbits were given the compound in their food. Fourth-generation interstrain hybrid mice, bred from C57BL/6 and FVB/N mice (which differ in their response to miglustat), also received the drug. Data on fertility (natural mating), sperm motility and morphology, acrosome status, and serum drug levels were collected. RESULTS: In rabbits the drug did not induce aberrations of sperm shape or motility, although the serum level of miglustat in rabbits far exceeded the level in C57BL/6 mice (8.4 microM and 0.5 microM, respectively). In some strains of the Swiss and Castle lineages of inbred mice miglustat did not cause infertility, severe morphological sperm aberrations or reduced sperm motility. In these strains miglustat only had milder effects. However, miglustat strongly disturbed acrosome and sperm nucleus development in AKR/J and BALB/c mice and in a number of C57BL/6-related strains. The consequences of drug administration in the interstrain hybrid mice were highly variable. Judging by the number of grossly abnormal spermatozoa, these genetically heterogeneous mice displayed a continuous range of intermediate responses, distinct from either of their parental strains. CONCLUSION: The effects of miglustat on spermatogenesis in mice are strain-dependent, while in rabbits the drug is ineffective. Evaluation of interstrain hybrid mice indicated that the sensitivity of spermatogenesis to miglustat is a quantitative trait. These studies pave the way for identifying the genetic factors underlying the strain/species differences in the effect of miglustat.
Asunto(s)
1-Desoxinojirimicina/análogos & derivados , Inhibidores Enzimáticos/farmacología , Infertilidad Masculina/inducido químicamente , Espermatogénesis/efectos de los fármacos , Espermatogénesis/genética , 1-Desoxinojirimicina/sangre , 1-Desoxinojirimicina/farmacología , Acrosoma/efectos de los fármacos , Animales , Resistencia a Medicamentos/genética , Inhibidores Enzimáticos/sangre , Femenino , Masculino , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Ratones Endogámicos MRL lpr , Ratones Endogámicos NZB , Embarazo , Carácter Cuantitativo Heredable , Conejos , Conducta Sexual Animal , Especificidad de la Especie , Motilidad Espermática/efectos de los fármacosRESUMEN
For women at risk to develop schizophrenia, estradiol has been postulated to constitute a protective factor. Women suffering from psychotic disorders have accordingly been found to exhibit lower estradiol levels than controls. Our aim was to study gonadal function in psychotic men to determine the gender specificity of these observations, as available data in men are more scarce and conflicting and largely disregarded estradiol. Serum hormone levels were examined in 34 men admitted consecutively for an acute exacerbation or first onset of schizophrenia in a blinded prospective design. Subjects with current affective disorder including manic episode, concomitant substance abuse or severe medical illness were excluded. A control group of 34 healthy male blood donors was recruited. As compared to matched controls, acutely admitted men suffering from schizophrenia exhibited significantly lower serum levels of estradiol, oestrone, testosterone and free testosterone. Although results have to be regarded as preliminary, acute exacerbation of schizophrenia in men seems to be associated with low serum oestrogen and androgen levels. The oestrogen hypothesis postulating a protective action of estradiol concerning schizophrenia for women might well be valid for both genders. However, future research is needed before clinical applications are justified.