Differences In Route Of Administration Research Articles

Semaglutide use in people with obesity and type 2 diabetes from real-world utilization data: An analysis of the All of US Program.

To analyse data from the All of Us Research Program to evaluate the real-world application and long-term effectiveness of semaglutide in treating type 2 diabetes and obesity patients in a large population. We identified patients prescribed semaglutide and analysed differences in route of administration and the time on semaglutide. For individuals diagnosed with obesity, we measured changes in body mass index (BMI) and weight from baseline, while measured changes in HbA1c for those patients with type 2 diabetes. We also examined the occurrence of newly diagnosed common adverse events from taking semaglutide. For 3739 semaglutide patients, those on injectable semaglutide (3364 patients) averaged 301.54 days on the medication, with 20.36% having no end date, while those on oral semaglutide (435 patients) averaged 172.48 days, with 24.60% having no end date. We found average decreases of 1.54 kg/m2 in BMI, 4.65 kg in weight and 0.75% in HbA1c for semaglutide users. The decreases were larger in participants taking injectable formulation, probably because of higher starting values. Over time, improvements in these outcomes diminished, but the values remained significantly lower than baseline levels. Approximately only 1.0% of patients reported newly diagnosed common adverse events. Consistent with clinical trial findings, this real-world data analysis showed that semaglutide was well tolerated and that, for a large population, it effectively reduced BMI, body weight and HbA1c, albeit to smaller magnitudes than observed in clinical trials. These findings provide valuable insights into real-world experience and the long-term effectiveness of semaglutide.

PCR58 Comparing Adherence in Patients with Type 2 Diabetes Initiating Glucagon-like Peptide-1 Receptor Agonists or Sodium-Glucose Cotransporter-2 Inhibitors

Non-adherence to antidiabetic medications is associated with worse clinical outcomes including poorer hemoglobin A1c (HbA1c). Both sodium-glucose cotransporter 2 (SGLT2I) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate clinical benefits in type 2 diabetes (T2DM) patients with an increased risk for cardiovascular disease. However, differences in route of administration and side effect profile may affect adherence. Therefore, the objective of this study is to evaluate and compare medication adherence among new adult users of SGLT2I and GLP-1 agonists.

Perceptions on handling of opioids: focus COVID-19 : A survey among anesthesiologists via the specialist societies DGAI/BDA

HintergrundOpioide gehören zum Klinikalltag in Anästhesiologie, Intensivmedizin und Palliativmedizin. Hinsichtlich der Behandlung von Dyspnoe mit Opioiden finden sich in Leitlinien jedoch unterschiedliche Gewichtungen. Dies kann zu Unsicherheiten bezüglich Indikationsstellung und ethischer Implikationen im Umgang mit Opioiden – auch bei COVID-19 – führen.Ziel der ArbeitErfassung der Wahrnehmung bezüglich Umgang mit Morphin/Opioiden (M/O) zur Symptomkontrolle inner- und außerhalb der Palliativmedizin, auch bei COVID-19-Erkrankten.Material und MethodenMittels SurveyMonkey® (Momentive Inc., San Mateo, CA, USA) wurden Mitglieder der Deutschen Gesellschaft für Anästhesiologie (DGAI) und des Berufsverbands Deutscher Anästhesisten (BDA) im Oktober 2020 anonymisiert nach ihrer eigenen Wahrnehmung zum Umgang mit M/O zur Symptomkontrolle befragt.Ergebnisse und DiskussionVon N = 1365 teilnehmenden Anästhesist:innen beschrieben 88 % den Umgang mit M/O innerhalb der Palliativmedizin als „sicher und vertraut“ bzw. 85 % als „klar geregelt“, während dies für die Bereiche außerhalb der Palliativmedizin deutlich seltener angegeben wurde (77 %/63 %). Bei der Betreuung COVID-19-Erkrankter wurde der Umgang mit M/O außerhalb der Palliativmedizin noch seltener als „sicher und vertraut“ (40 %) oder „klar geregelt“ (29 %) wahrgenommen. Dyspnoe (95 %/75 %), Erleichterung des Sterbeprozesses (84 %/51 %), Unruhe (59 %/27 %) und Angst/Panik (61 %/33 %) wurden häufiger innerhalb als außerhalb der Palliativmedizin als allgemeine Indikationen genannt. Von den Befragten wünschten sich 85 % die Einbindung eines palliativmedizinischen Konsilteams.FazitAnästhesist:innen nahmen deutliche Unsicherheiten im Umgang mit M/O wahr, insbesondere außerhalb der Palliativmedizin. Einheitliche, interdisziplinäre Leitlinien zur Symptomkontrolle etwa bei Dyspnoe, mehr Lehre und die Einbindung eines palliativmedizinischen Konsilteams sollten zukünftig intensiver bedacht werden.

Preoperative Testosterone Therapy Prior to Surgical Correction of Hypospadias: A Review of the Literature.

Hypospadias is a congenital anomaly of the male urethra that causes significant morbidity in the pediatric male population. The mainstay of treatment is hypospadias repair surgery. However, given the common co-occurrence of microphallus in these patients, surgery remains difficult without adequate tissue for proper reconstruction of the urethra. The use of preoperative testosterone therapy, parenterally or topically, has been a topic of study for several years in urologic literature. This literature review aims to summarize the different studies that have been conducted to address whether preoperative testosterone therapy is beneficial, inconsequential, or detrimental to the surgical and cosmetic outcomes of hypospadias repair as well as to address the differences in routes of administration.

MSC therapy attenuates obliterative bronchiolitis after murine bone marrow transplant.

RationaleObliterative bronchiolitis (OB) is a significant cause of morbidity and mortality after lung transplant and hematopoietic cell transplant. Mesenchymal stromal cells (MSCs) have been shown to possess immunomodulatory properties in chronic inflammatory disease.ObjectiveAdministration of MSCs was evaluated for the ability to ameliorate OB in mice using our established allogeneic bone marrow transplant (BMT) model.MethodsMice were lethally conditioned and received allogeneic bone marrow without (BM) or with spleen cells (BMS), as a source of OB-causing T-cells. Cell therapy was started at 2 weeks post-transplant, or delayed to 4 weeks when mice developed airway injury, defined as increased airway resistance measured by pulmonary function test (PFT). BM-derived MSC or control cells [mouse pulmonary vein endothelial cells (PVECs) or lung fibroblasts (LFs)] were administered. Route of administration [intratracheally (IT) and IV] and frequency (every 1, 2 or 3 weeks) were compared. Mice were evaluated at 3 months post-BMT.Measurements and Main ResultsNo ectopic tissue formation was identified in any mice. When compared to BMS mice receiving control cells or no cells, those receiving MSCs showed improved resistance, compliance and inspiratory capacity. Interim PFT analysis showed no difference in route of administration. Improvements in PFTs were found regardless of dose frequency; but once per week worked best even when administration began late. Mice given MSC also had decreased peribronchiolar inflammation, lower levels of hydroxyproline (collagen) and higher frequencies of macrophages staining for the alternatively activated macrophage (AAM) marker CD206.ConclusionsThese results warrant study of MSCs as a potential management option for OB in lung transplant and BMT recipients.

Powder and crack cocaine use among opioid users: is all cocaine the same?

Problematic cocaine use is highly prevalent and is a significant public health concern. However, few investigations have distinguished between the 2 formulations of cocaine (ie, powder and crack cocaine) when examining the characteristics of cocaine use. Moreover, research has yet to assess the patterns of powder and crack cocaine use among opioid users, a clinical population in which problematic cocaine use is increasingly common. Using a within-subjects design, this study examined whether opioid users reported different patterns and features of powder and crack cocaine use, along with distinct trajectories and consequences of use. Seventy-three clients enrolled in a low-threshold methadone maintenance treatment were interviewed regarding their lifetime use of powder and crack cocaine. Compared with crack cocaine, initiation and peak use of powder cocaine occurred at a significantly younger age. In relation to recent cocaine use, participants were significantly more likely to report using crack cocaine than using powder cocaine. Differences in routes of administration, polysubstance use, and criminal activity associated with cocaine use were also found between the 2 forms of cocaine. Results suggest that it may not be appropriate to consider powder and crack cocaine as diagnostically and clinically equivalent. As such, researchers may wish to distinguish explicitly between powder and crack cocaine when assessing the characteristics and patterns of cocaine use among substance users and treat these 2 forms of cocaine separately in analyses.

Enduring Effects of Adolescent Drug Exposure

Enduring Effects of Adolescent Drug Exposure

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial

Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or capecitabine significantly improves progression-free survival and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus capecitabine has not been investigated. We compared the efficacy of the two regimens. In this open-label, non-inferiority, phase 3 trial, patients with HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease were randomised (by computer-generated sequence; 1:1 ratio; block size six; stratified by hormone receptor status, country, and menopausal status) to receive either intravenous bevacizumab (10 mg/kg on days 1 and 15) plus intravenous paclitaxel (90 mg/m(2) on days 1, 8, and 15) repeated every 4 weeks (paclitaxel group) or intravenous bevacizumab (15 mg/kg on day 1) plus oral capecitabine (1000 mg/m(2) twice daily on days 1-14) repeated every 3 weeks (capecitabine group) until disease progression or unacceptable toxic effects. Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel. We report results of an interim overall survival analysis, which was planned for after 175 deaths in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00600340. Between Sept 10, 2008, and Aug 30, 2010, we randomised 564 patients (paclitaxel group n=285; capecitabine group n=279) from 51 centres in 12 countries. The per-protocol population consisted of 533 patients (paclitaxel group n=268; capecitabine group n=265). After median follow-up of 18·6 months (IQR 14·9-24·7), 181 patients in the per-protocol population had died (89 [33%] in the paclitaxel group; 92 [35%] in the capecitabine group). The hazard ratio [HR] for overall survival was 1·04 (97·5% repeated CI -∞ to 1·69; p=0·059); the non-inferiority criterion of the interim analysis (interim α=0·00105) was not met. More patients who received bevacizumab plus paclitaxel had an objective response than did those who received bevacizumab plus capecitabine (125 [44%] of 285 patients vs 76 [27%] of 279; p<0·0001). Similarly, progression-free survival was significantly longer in the paclitaxel group than in the capecitabine group (median progression-free survival 11·0 months [95% CI 10·4-12·9] vs 8·1 months [7·1-9·2]; HR 1·36 [95% CI 1·09-1·68], p=0·0052). The most common adverse events of grade 3 or higher were neutropenia (51 [18%]), peripheral neuropathy (39 [14%]), and leucopenia (20 [7%]) in the paclitaxel group and hand-foot syndrome (44 [16%]), hypertension (16 [6%]), and diarrhoea (15 [5%]) in the capecitabine group. One treatment-related death occurred in the paclitaxel group; no deaths in the capecitabine group were deemed to be treatment-related. In this planned interim analysis, the non-inferiority criterion was not met and overall survival results are inconclusive. Final results are expected in 2014. Progression-free survival was better, and more patients achieved an objective response, with bevacizumab plus paclitaxel than with bevacizumab plus capecitabine. Efficacy results in both groups were consistent with previous reports. Central European Cooperative Oncology Group; Roche.

Comparing Injection and Non-Injection Routes of Administration for Heroin, Methamphetamine, and Cocaine Users in the United States

ABSTRACT Research examining the demographic and substance use characteristics of illicit drug use in the United States has typically failed to consider differences in routes of administration or has exclusively focused on a single route of administration—injection drug use. Data from National Survey on Drug Use and Health were used to compare past-year injection drug users and non-injection drug users' routes of administration of those who use the three drugs most commonly injected in the United States: heroin, methamphetamine, and cocaine. Injection drug users were more likely than those using drugs via other routes to be older (aged 35 and older), unemployed, possess less than a high school education, and reside in rural areas. IDUs also exhibited higher rates of abuse/dependence, perceived need for substance abuse treatment, and co-occurring physical and psychological problems. Fewer differences between IDUs and non-IDUs were observed for heroin users compared with methamphetamine or cocaine users.

Oral administration of (±)3,4-methylenedioxymethamphetamine and (+)methamphetamine alters temperature and activity in rhesus macaques

Rationale Emergency Department visits and fatalities in which (±)3,4-methylenedioxymethamphetamine (MDMA) or (+)methamphetamine (METH) are involved frequently feature unregulated hyperthermia. MDMA and METH significantly elevate body temperature in multiple laboratory species and, most importantly, can also produce unregulated and threatening hyperthermia in nonhuman primates. A majority of prior animal studies have administered drugs by injection whereas human consumption of “Ecstasy” is typically oral, an important difference in route of administration which may complicate the translation of animal data to the human condition. Objective To determine if MDMA and METH produce hyperthermia in monkeys following oral administration as they do when administered intramuscularly. Methods Adult male rhesus monkeys were challenged intramuscularly (i.m.) and per os (p.o.) with 1.78 or 5 mg/kg (±)MDMA and with 0.1 or 0.32 mg/kg (+)METH. Temperature and activity were monitored with a radiotelemetry system. Results Oral administration of either MDMA or METH produced significant increases in body temperature. Locomotor activity was suppressed by MDMA and increased by METH following either route of administration. Conclusions The data show that the oral route of administration is not likely to qualitatively reduce the temperature increase associated with MDMA or METH although oral administration did slow the rate of temperature increase. It is further established that MDMA reduces activity in monkeys even after relatively high doses and oral administration.

Pharmacotherapy for patellofemoral pain syndrome.

Patellofemoral pain syndrome (PFPS) is common among adolescents and young adults. It is characterised by pain behind or around the patella and crepitations, provoked by ascending or descending stairs, squatting, prolonged sitting with flexed knees, running and cycling. The symptoms impede function in daily activities or sports. Pharmacological treatments focus on reducing pain symptoms (non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticosteroids), or restoring the assumed underlying pathology (compounds containing glucosamine to stimulate cartilage metabolism, anabolic steroids to increase bone density of the patella and build up supporting muscles). In studies, drugs are usually applied in addition to exercises aimed at building up supporting musculature. This review aims to summarise the evidence of effectiveness of pharmacotherapy in reducing anterior knee pain and improving knee function in people with PFPS. We searched the Cochrane Musculoskeletal Injuries Group and Cochrane Rehabilitation and Related Therapies Field trials registers, the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2003), PEDro (up to January 2004), MEDLINE (1966 to January 2004), EMBASE (1988 to January 2004), and CINAHL (1982 to January 2004). Controlled trials (randomised or not) comparing pharmacotherapy with placebo, different types of pharmacotherapy, or pharmacotherapy to other therapies for people with PFPS. The literature search yielded 780 publications. Eight trials were included, of which three were of high quality. Data were analysed qualitatively using best evidence synthesis, because meta-analysis was impeded by differences in route of administration of drugs, care programs and outcome measures. Four trials (163 participants) studied the effect of NSAIDs. Aspirin compared to placebo in a high quality trial produced no significant differences in clinical symptoms and signs. Naproxen produced significant short term pain reduction when compared to placebo, but not when compared to diflunisal. Laser therapy to stimulate blood flow in tender areas led to more satisfied participants than tenoxicam, though not significantly. Two high quality RCTs (84 participants) studied the effect of glycosaminoglycan polysulphate (GAGPS). Twelve intramuscular injections in six weeks led to significantly more participants with a good overall therapeutic effect after one year, and to significantly better pain reduction during one of two activities. Five weekly intra-articular injections of GAGPS and lidocaine were compared with intra-articular injections of saline and lidocaine or no injections, all with concurrent quadriceps training. Injected participants showed better function after six weeks, though only the difference between GAGPS injected participants and non-injected participants was significant. The differences had disappeared after one year. One trial (43 participants) found that intramuscular injections of the anabolic steroid nandrolone phenylpropionate significantly improved both pain and function compared to placebo injections. There is only limited evidence for the effectiveness of NSAIDs for short term pain reduction in PFPS. The evidence for the effect of glycosaminoglycan polysulphate is conflicting and merits further investigation. The anabolic steroid nandrolone may be effective, but is too controversial for treatment of PFPS.

A review of animal model studies of tomato carotenoids, lycopene, and cancer chemoprevention.

There are relatively few reports on the cancer chemopreventive effects of lycopene or tomato carotenoids in animal models. The majority, but not all, of these studies indicate a protective effect. Inhibitory effects were reported in two studies using aberrant crypt foci, an intermediate lesion leading to colon cancer, as an end point and in two mammary tumor studies, one using the dimethylbenz(a)anthracene model, and the other the spontaneous mouse model. Inhibitory effects were also reported in mouse lung and rat hepatocarcinoma and bladder cancer models. However, a report from the author's laboratory found no effect in the N-nitrosomethylurea-induced mammary tumor model when crystalline lycopene or a lycopene-rich tomato carotenoid oleoresin was administered in the diet. Unfortunately, because of differences in routes of administration (gavage, intraperitoneal injection, intra-rectal instillation, drinking water, and diet supplementation), species and strain differences, form of lycopene (pure crystalline, beadlet, mixed carotenoid suspension), varying diets (grain-based, casein based) and dose ranges (0.5-500 ppm), no two studies are comparable. It is clear that the majority of ingested lycopene is excreted in the feces and that 1000-fold more lycopene is absorbed and stored in the liver than accumulates in other target organs. Nonetheless, physiologically significant (nanogram) levels of lycopene are assimilated by key organs such as breast, prostate, lung, and colon, and there is a rough dose-response relationship between lycopene intake and blood levels. Pure lycopene was absorbed less efficiently than the lycopene-rich tomato carotenoid oleoresin and blood levels of lycopene in rats fed a grain-based diet were consistently lower than those in rats fed lycopene in a casein-based diet. The latter suggests that the matrix in which lycopene is incorporated is an important determinant of lycopene uptake. A number of issues remain to be resolved before any definitive conclusions can be drawn concerning the anticancer effects of lycopene. These include the following: the optimal dose and form of lycopene, interactions among lycopene and other carotenoids and fat soluble vitamins such as vitamin E and D, the role of dietary fat in regulating lycopene uptake and disposition, organ and tissue specificity, and the problem of extrapolation from rodent models to human populations.

Routes of drug administration and multiple drug misuse: regional variations among clients seeking treatment at programmes throughout England

To investigate regional variations across England in routes of administration for heroin, non-prescribed methadone, non-prescribed benzodiazepines, cocaine powder, crack cocaine and amphetamines. A survey of 1053 clients recruited to 54 residential and community drug misuse programmes. Structured face-to-face interviews conducted with clients at admission to treatment. Routes of administration included injecting, smoking, snorting and oral use. For some drugs (methadone and benzodiazepines) one main route of administration was used. For other drugs (heroin, amphetamines and cocaine powder) there were marked variations in route. For all drugs except benzodiazepines, there were regional differences in routes of administration. Heroin injectors were more likely also to use other drugs by injection. The differences in routes of administration of different drugs, and the regional differences in routes of use, have implications for the provision of preventive and treatment services. Interventions to prevent transitions to injecting may be especially appropriate in areas where injecting is not prevalent. Hepatitis B vaccination continues to be advisable in both areas of high and low injecting prevalence. Needle exchange schemes and interventions targeted at drug overdose may be more suitable in areas of high injecting prevalence. Further research into regional differences in routes of drug use should be conducted with non-clinical samples.

Chronic parenteral antidepressant treatment in rats: Unaltered levels and processing of neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH)

We have previously reported elevated brain tissue contents of neuropeptide Y-like immunoreactivity (NPY-LI) following 3 weeks of oral treatment with the antidepressants zimelidine and imipramine. Other studies have not reproduced this finding. To eliminate the possibility that this has been due to insufficient treatment duration, dosage, or differences in route of administration or assay specificity, we have administered the selective serotonin reuptake inhibitor citalopram and the preferential noradrenaline reuptake inhibitor desmethylimipramine parenterally for 6 weeks. NPY-LI was assayed using both the assay employed in the original study, and an assay based on a different antiserum which has been extensively examined for cross-reactivity. To exclude the possibility that differential processing rather than altered synthesis rate is responsible for apparent changes in NPY-LI, HPLC analysis of immunoreactive fragment profiles was used. No differences in NPY-LI levels were seen in the brain regions examined, and no differences in HPLC profiles of NPY-LI were present with either drug. We conclude that chronic parenteral administration of antidepressant drugs in naive (non-depressed) animals does not affect the synthesis or processing of NPY. Another neuropeptide implicated in mechanisms of depression, corticotropin-releasing hormone (CRH) was also found to be unaffected by a similar analysis.

Effect of chronic daily oral administration of 17 beta-oestradiol and norethisterone on the isoforms of serum gonadotrophins in post-menopausal women.

Chronic treatment with 17 beta-oestradiol (E2) implants has been found to counteract the formation of more acidic isoforms of the gonadotrophins in post-menopausal women. Oral medication with an oestrogen in combination with a progestagen is a common hormone replacement therapy (HRT) in post-menopausal women. The present study investigated the effect of such a therapy on the concentration and charge of the gonadotrophin isoforms in serum. Serum samples were obtained from 20 post-menopausal women, mean age 60 years (range 50-72 years), treated with continuous daily oral medication of 2 mg E2 combined with 1 mg norethisterone acetate (NETA). FSH, LH and E2 in the serum was measured with fluoroimmunoassays. The median charge and charge heterogeneity of the FSH and LH isoforms were determined for each serum by electrophoresis in 0.1% agarose suspension. Sera from 20 post-menopausal women without a history of HRT served as controls. The results were compared with those from previous studies on post-menopausal women treated with E2 implants and on women with normal menstrual cycles. The E2 level in the oral-E2 + NETA treated women was 198-610 pmol/l, within the range expected during the mid-luteal phase of the normal menstrual cycle and similar to that of the group of women with an E2 implant. The mean LH level was similar to that of the luteal phase of the cycle and significantly lower than that of the controls (P < 0.001), the E2 implant group (P < 0.001) and at the follicular phase of the cycle (P < 0.01). The mean FSH level was similar to that of the follicular phase and the E2 implant group but lower than that of the controls (P < 0.001) and higher than at the luteal phase of the cycle (P < 0.01). The mean values for median charge of both FSH and LH were less acidic than those of the controls (P < 0.001) but more acidic than those for the E2 implant group (P < 0.01; P < 0.001) and for different phases of the menstrual cycle (P < 0.05; P < 0.001). The mean degree of charge heterogeneity of FSH was larger (P < 0.01), while that of LH was smaller (P < 0.01), than for the controls. The mean concentrations of SHBG in the oral E2 + NETA group, the E2 implant group and the controls were similar. Chronic oral therapy with 2 mg 17 beta-oestradiol combined with 1 mg norethisterone in post-menopausal women efficiently decreased the serum gonadotrophin levels but only partly counteracted the formation of the more acidic isoforms of FSH and LH after menopause. The differences in the charge for both FSH and LH between the E2 implant and the oral E2 + NETA treated groups may be due to the differences in route of administration of E2 or to the effect of norethisterone or both.

Extent and nature of transitions of route among heroin addicts in treatment--preliminary data from the Drug Transitions Study.

Preliminary data are presented here from a study of drug transitions in the UK. These support the contention that differences in route of administration are likely to be reflected in differing patterns of drug use, and associated with differing health risks for the individual drug user. Heroin 'chasers' were found to have robust and long-term patterns of heroin use and could not merely be considered as pre-injectors. They were also younger. No differences were found in the typical daily doses prior to entering treatment between chasers and injectors. Subjects who usually 'chased the dragon' but who would also inject were less likely to have shared injecting equipment in the past. Transitions between different routes of use were found in most directions. However, changes from 'chasing' to injection were most common. Year of initiation into heroin use was also related to initial route of use.

Pharmacokinetics of nitroglycerin and its dinitrate metabolites over a thirtyfold range of oral doses

The pharmacokinetics of nitroglycerin and the formation of its dinitrate metabolites (1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate) were determined in six healthy volunteers after administration of six oral solution doses ranging from 0.4 mg to 13 mg. ANOVA analysis indicated significant differences between subjects for all Cmax/dose and AUC/dose measurements. No significant difference between doses were noted for these parameters except for AUC/dose for 1,3-glyceryl dinitrate. The ratio of metabolites (1,2-metabolite/1,3-metabolite) for the 0.4 mg dose was significantly different from the ratios for the doses of 1.6 mg or higher. Measurements of the combined residence time parameter suggest nonlinearity in nitroglycerin absorption and metabolism processes of AUMC/AUC between the 0.4 and the 13 mg doses. Consistent results were observed in the AUC ratios of metabolites for 0.4 mg doses of nitroglycerin between oral and sublingual administrations, suggesting that the increased metabolite ratio noted for sublingual nitroglycerin may reflect differences in dose, rather than differences in route of administration.

Effect of route of administration in the micronucleus test with potassium bromate

The effect of intraperitoneal injection (i.p.) versus oral gavage administration (p.o.) of potassium bromate was examined using the micronucleus test in 2 strains of male mice (MS/Ae and CD-1). First, a small acute toxicity test and a pilot micronucleus experiment were performed to determine the appropriate dose range and sampling time for the full-scale micronucleus test. The full-scale test was carried out using doses of 18.8, 37.5, 75, and 150 mg/kg in the i.p. test and of 37.5, 75, 150, and 300 mg/kg in the p.o. test. The sampling time was 24 h for both mouse strains. Potassium bromate induced micronucleated polychromatic erythrocytes (MNPCEs) dose-dependently by both routes of administration in both mouse strains. No distinct difference in route of administration was observed in the test with MS/Ae mice. In CD-1 mice more MNPCEs were induced by the i.p. route than by the p.o. route.

Metabolism of 3, 4-dihydroxyphenylalanine, its metabolites and analogues in vivo in the rat: urinary excretion pattern.

The metabolism and interrelationships of orally and intraperitoneally administered L-dopa, related amino acids and their metabolites have been studied 2. Amino acids were decarboxylated. N-Methyldopa formed dopamine but not epinine. D-Dopa was absorbed from the intestine and metabolized by a series of reactions which resulted in greater decarboxylation than was observed after L-dopa. Transamination was a minor pathway. 3. m-Hydroxylated phenylpyruvic acids were poorly reduced, but vanilpyruvic acid was reduced fairly readily. Lactic acids were largely unchanged. Lactic and pyruvic acids formed phenylethylamines and their metabolites. Small amounts of phenylpyruvic acids may be decarboxylated to phenylacetic acids. 4. Glycine conjugates were formed from phenylacetic acids, a partially reversible change 3,4-Dihydroxyphenylacetic acid was metabolized to homovanillic and m-hydroxyphenylacetic acids, especially when given orally. Little 3-hydroxy-4-methoxyphenylacetic acid was oxidized to 3,4-dihydroxyphenylacetic acid but some increase in m-hydroxyphenylacetic acid excretion was observed. 5. 2-Phenylethanol analogues were largely converted to the corresponding acids. 3,4-Dihydroxyphenylethanol was partially m-O-methylated before oxidation. 6. beta-Phenylethylamine analogues were oxidized mainly to phenylacetic acids. but a variable amount of analogous phenylethanol was also formed, especially from m-tyramine. Dopamine was O-methylated, a process not readily reversible. It was also p-dehydroxylated following oral and intraperitoneal administration but not after oral neomycin; biliary excretion of amines may be involved in this sequence of events. N-Methylated amines were oxidized less readily than the parent amine. 7. Differences in route of administration resulted in quantitative changes in degradation pathways, an effect deriving, to some extent, from p-dehydroxylation and O-methylation in the gut.