Relationship between oral contraceptives and cervical cancer-a meta-analysis

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Phase I trial and pharmacokinetic study of intravenous and oral α-Difluoromethylornithine

Eflornithine-HCl (-difluoromethylornithine or DFMO), an irreversible inhibitor of ornithine decarboxylase, blocks polyamine synthesis and has demonstrated antitumor activity in cell culture and animal tumor models. This phase I study was designed to determine and compare toxicity and the maximally tolerated dose of a 4-day course of DFMO given to patients in oral, continuous intravenous infusion or pulse intravenous infusion forms. Twenty-four patients were entered into this study: 8 received intravenous pulse drug, 10 intravenous continuous infusion of drug, and 6 oral DFMO. The most frequent toxicity was nausea and vomiting which occurred in 9 courses of oral drug. Only two patients receiving intravenous DFMO had nausea and vomiting. Clinically significant thrombocytopenia and audiometric abnormalities were not encountered in contrast to previous experience with 28-day courses of oral DFMO. The maximally tolerated dose of a four-day course of oral DFMO was 3.75 gm/M² every 6 hours. The maximally tolerated dose of intravenous pulse and continuous infusion DFMO was not attained. Pharmacokinetic studies demonstrated that the intravenous schedules achieved higher plasma levels of DFMO than those previously obtained with chronic oral dosing.Presented in part at the 20th Annual Meeting of the American Society of Clinical Oncology, May 1984, Toronto, Ontario, Canada     

Bioavailability and pharmacokinetics of β- methyldigoxin after multiple oral and intravenous doses

Summary To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of -methyldigoxin 0.3 mg. After oral or intravenous administration of -methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.Supported by the Deutsche Forschungsgemeinschaft     

Can oral midazolam predict oral cyclosporine disposition?

Effective cyclosporine therapy is confounded by large interindividual differences in oral bioavailability and a narrow therapeutic window. Because cytochrome P450 (CYP) 3A-mediated first-pass metabolism contributes to this unpredictable bioavailability, an in vivo oral CYP3A phenotyping probe could be a valuable tool in optimizing cyclosporine therapy. Based on similarities in the metabolic kinetics of cyclosporine and midazolam by the liver and intestinal mucosa, we evaluated whether midazolam oral clearance would predict cyclosporine oral clearance when the two drugs were administered to 20 medically stable kidney transplant recipients. Despite earlier findings in liver transplant recipients who displayed a strong correlation between the systemic clearances of midazolam and cyclosporine, there was a weak correlation between their oral clearances in the current group of subjects (r(s)=0.50, P=0.03). Differing extents of intestinal first-pass metabolic extraction between the two drugs, inhibition of midazolam metabolism by cyclosporine at the level of the intestine, and/or P-glycoprotein-mediated intestinal efflux of cyclosporine (but not midazolam) may account for this poor correlation. We conclude that although oral midazolam is unlikely to be clinically useful as a probe for cyclosporine disposition, its utility in the prediction of other orally administered CYP3A substrates cannot be out ruled.     

Comparison of zopiclone concentrations in oral fluid sampled with Intercept(®) oral specimen collection device and Statsure Saliva Sampler™ and concentrations in blood

A clinical study of zopiclone was performed using doses of 5 and 10 mg. Samples of oral fluid were collected using the Statsure and Intercept devices, and blood samples were collected simultaneously. Concentrations of zopiclone in samples of oral fluid and blood were determined with liquid chromatography-mass spectrometry, and concentrations in undiluted oral fluid were calculated. The concentrations of zopiclone in oral fluid were generally higher when using the Intercept compared to the Statsure device; the median oral fluid/whole blood concentration ratios were 3.8 (range 1.5-15.9) and 1.9 (range 1.2-4.6), respectively (n = 21). The correlation between zopiclone concentrations in oral fluid collected with the two devices was fairly poor, r(2) = 0.35. The results indicate that the type of sampling device may significantly affect the analytical result for zopiclone in sampled oral fluid.     

Does prolonged oral exposure to cyanide promote hepatotoxicity and nephrotoxicity?

Long-term exposure to cyanide and/or its main metabolite, thiocyanate, has been associated with goiter, pancreatic diabetes and several neurological disorders. However, very little is found in the literature relating the nephrotoxic and hepatotoxic effects of these substances. Thus, the objective of the present study was to verify the effects of prolonged exposure to potassium cyanide (KCN) in these organs. Forty-six male adults rats, weighing approximately 200 g at the beginning of the experiment, were distributed into five groups-four experimental and one control. Experimental groups were dosed with target doses of 0.3, 0.9, 3.0 or 9.0 mg KCN/kg per day, in the drinking water, during 15 days and the control groups received only tap water. At the end of this experiment, all rats were subjected to euthanasia and plasma samples were obtained in order to determine thiocyanate and thyroidal hormones levels and fragments of thyroid, kidney and liver were collected. Rats treated with the highest cyanide dose (9.0 mg KCN/kg per day) showed lower body weight gain. An increase in the thiocyanate levels was verified in all experimental groups. The histopathologic study revealed hydropic degeneration of the renal tubular epithelial cells in those animals, which received KCN at the dose of 3.0-9.0 mg/kg per day. This study also showed hydropic degeneration of the hepatocytes of those animals, which received KCN at a dose of 9.0 mg/kg per day, and in the thyroid gland an increase was observed in the number of reabsorption vacuoles on follicular colloid, in a dose-dependent manner, in all animals of the experimental groups.     

Is the oral route possible for peptide and protein drug delivery?

Oral delivery of peptides and proteins remains an attractive alternative to parenteral delivery and has challenged various attempts at delivery development. Incorporation of new tools into the delivery systems that can raise membrane permeability of macromolecules is essential to attain high oral bioavailability that is acceptable in clinical applications. In developing oral protein delivery systems with high bioavailability, three practical approaches might be most helpful: (1) modification of the physicochemical properties of macromolecules; (2) addition of novel function to macromolecules; or (3) use of improved delivery carriers. Clearly, it is essential that these approaches maintain the biological activity of the proteins.     

Bioavailability and pharmacokinetics of isradipine after oral and intravenous administration: half-life shorter than expected?

Isradipine is a calcium channel-blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half-life of 8-9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half-life was observed, and the present trial was therefore conducted in order to estimate the half-life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross-over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10-12 hr after administration and half-life and bioavailability were estimated. Mean terminal half-life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half-life of isradipine seems to be of much shorter than demonstrated in previous oral studies.     

In vitro and in vivo evaluation of oral tablet formulations prepared with ketoconazole and hydroxypropyl-β-cyclodextrin

The objective of this study was to enhance the solubility, dissolution rate, and oral bioavailability of a very poorly water-soluble anti-fungal agent, ketoconazole (KET), by inclusion complexation with a highly-soluble cyclodextrin derivative, hydroxypropyl-β cyclodextrin (HP-β-CD). Two groups of tablets containing KET alone and KET:HP-β-CD (1:2) kneaded product (KP) including magnesium stearate and lactopress (anhydrous and spray-dried) as excipients were prepared by direct compression method. After the characterization studies, the in vitro dissolution studies of these tablets in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were carried out. To evaluate the in vivo bioavailability, the tablets were administered orally to rabbits and drug levels in serum were determined by HPLC. Tablets containing the cyclodextrin complex showed a higher in vitro dissolution rate and bioavailability compared to the tablets containing KET alone.     

Sensory,perceptual, motor and cognitive functioning and subjective reports following oral administration ofΔ 9-Tetrahydrocannabinol

Three dose levels, 0.2, 0.4 and 0.6 mg/kg, of ⁹-tetrahydrocannabinol (THC) and a placebo were orally administered to 10 frequent and 10 occasional marijuana users. Following ingestion of each dose and the placebo, objective tests selected from a battery of sensory and perceptual motor tests routinely used to evaluate cerebral dysfunction in hospitalized patients were administered. The influence of ⁹-THC on proficiency and variability of performance was minimal. However, when individual test scores and variabilities were combined and converted to standard scores, allowing for analysis of overall performance, THC had a small but consistent detrimental effect on both proficiency and variability of performance. In contrast, THC exerted profound effects on the subjective experiences of the volunteers as assessed by the Subjective Drug Effects Questionnaire. Subjective changes in mood, feeling, perception and somatic sensations were reported by all subjects but were more pronounced in the occasional user group. It was proposed that the small impairment noted in objective test performance after ingestion of ⁹-THC as contrasted to the large effects on subjective responses suggests that the principal effects of marijuana are on the autonomic nervous system rather than on higher cortical functions.Veterans Administration approved Research Project 0864-03. Also supported by U.S. Public Health Service Research Grant No. DA000.56 from the National Institute of Mental Health.     

Pharmacokinetics of zimelidine in humans — Plasma levels and urinary excretion of zimelidine and norzimelidine after intravenous and oral administration of zimelidine

Summary Five healthy adults were administered zimelidine orally (150 mg) and by intravenous infusion (20 mg) in a crossover design. Blood and urine samples were collected for a period of 28 hours after dosing and the concentrations of zimelidine and norzimelidine determined. There was no significant difference in terminal phase half-life of zimelidine after oral (4.7 h±1.3 SD) or intravenous dosing (5.1 h±0.7 SD). An average of 50% of the ingested oral dose reached the systemic circulation. Excretion of unchanged zimelidine in urine was on average 1.26% of the intravenous dose. In appears that zimelidine is completely absorbed from the gastrointestinal tract and first-pass metabolism in the liver reduces the bioavailability to 50%. The mean plasma half-life for norzimelidine was 22.8 h. The area under the plasma concentration time curve for norzimelidine after oral administration was 92% of that after intravenous administration. The plasma concentration of both zimelidine and norzimelidine are predicted to approach steady-state within 3–5 days.     

Pharmacokinetics of risperidone in different application forms – Comparing long-acting injectable and oral formulations

We aimed to explore the differences in the pharmacokinetics of risperidone between oral and long-acting injectable (LAI) formulations using a large database of therapeutic drug monitoring (TDM). Plasma concentrations of risperidone (RIS), its active metabolite (9-OH-RIS) and the active moiety (AM) (RIS+9-OH-RIS), their concentration-to-dose (C/D) ratios and ratio of RIS/9-OH-RIS (an index of CYP2D6 metabolic activity) were used to compare patients receiving risperidone orally (n = 851) and those treated with LAI RIS (n = 63). Patients taking CYP inducers or inhibitors or with liver/renal impairment were eliminated. Our study demonstrated that patients on LAI RIS, despite slightly higher RIS doses in the oral group, showed no significant differences in total AM or 9-OH-RIS. Conversely, RIS concentration, RIS C/D ratio and total C/D ratio were slightly higher in the LAI RIS group, reaching significance due to the large sample size. More importantly, the median ratio of RIS/9-OH-RIS was 0.52 in LAI RIS vs. 0.25 in the oral group, providing a significant difference (p < 0.001). After controlling for confounding factors, we replicated the RIS/9-OH–RIS ratio increases in patients with LAI RIS, probably reflecting a decrease in first-pass metabolism. More studies are required to establish the clinical use of TDM for patients on LAI RIS.     

Pharmacokinetic–pharmacodynamic modelling of intravenous and oral topiramate and its effect on phonemic fluency in adult healthy volunteers

Aims

The aim was to develop a quantitative approach that characterizes the magnitude of and variability in phonemic generative fluency scores as measured by the Controlled Oral Word Association (COWA) test in healthy volunteers after administration of an oral and a novel intravenous (IV) formulation of topiramate (TPM).

Methods

Nonlinear mixed-effects modelling was used to describe the plasma TPM concentrations resulting from oral or IV administration. A pharmacokinetic–pharmacodynamic (PK-PD) model was developed sequentially to characterize the effect of TPM concentrations on COWA with different distributional assumptions.

Results

Topiramate was rapidly absorbed, with a median time to maximal concentration of 1 h and an oral bioavailability of ∼100%. Baseline COWA score increased by an average of 12% after the third administration on drug-free sessions. An exponential model described the decline of COWA scores, which decreased by 14.5% for each 1 mg l⁻¹ increase in TPM concentration. The COWA scores were described equally well by both continuous normal and Poisson distributions.

Conclusions

This analysis quantified the effect of TPM exposure on generative verbal fluency as measured by COWA. Repetitive administration of COWA resulted in a better performance, possibly due to a learning effect. The model predicts a 27% reduction in the COWA score at the average observed maximal plasma concentration after a 100 mg dose of TPM. The single-dose administration of relatively low TPM doses and narrow range of resultant concentrations in our study were limitations to investigating the PK-PD relationship at higher TPM exposures. Hence, the findings may not be readily generalized to the broader patient population.     

Plasma concentration of α-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester

Summary The plasma concentrations of free -methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following -methyldopa (1 g) orally. Five of these patients subsequently received -methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of -methyldopa intravenously. After oral administration a large amount of total plasma -methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated -methyldopa in plasma (ratio at 4 hours ranged from 3.73 – 0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous -methyldopa than -methyldopate. The plasma concentration of -methyldopa (free and esterified) 60 minutes after i.v. -methyldopate was 1.7±0.3 µg/ml wile at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 µg/ml. Although small amounts of sulphate conjugate were detected after i.v. -methyldopate, insignificant quantities of conjugate were found after i.v. -methyldopa. The average fall in mean arterial pressure was 27 mm Hg following i.v. -methyldopa but only 2.7 mm Hg following -methyldopate. These results suggest that sulphate conjugation of -methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of -methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free -methyldopa have been demonstrated.     

Interactions between oral contraceptives and antifungals/antibacterials. Is contraceptive failure the result?

The effectiveness of oral contraceptives may be impaired by concomitant treatment with antimicrobials. This may occur because of reductions in plasma concentrations of ethinylestradiol by the induction of hepatic metabolism, as for rifampicin (rifampin) and possibly griseofulvin, or in a small percentage of women because of interference with enterohepatic recirculation. There are no scientific data to support the anecdotal evidence that the concomitant use of combined oral contraceptives and antimicrobials reduces contraceptive efficacy in the majority of women. It has been postulated that there is a subset of women in whom the enterohepatic recirculation of ethinylestradiol plays an important role. In these women the action of an antimicrobial may reduce the efficacy of oral contraceptives by interfering with this mechanism. Studies that have quantitatively examined these effects may have failed to include women from this subset because of the small numbers involved in the studies. On the other hand, there are no good prospective studies comparing contraceptive failure rates between compliant women who use combined oral contraceptives with and without antimicrobials. All women using combined oral contraceptives should be informed of the very low level of risk of interactions with antimicrobials (probably about 1%) and that it is not possible to identify who may be at risk. Women concerned about this low level of risk should be given information about the use of barrier methods or avoidance of intercourse during the first 7 days of concomitant antimicrobial therapy and for 7 subsequent days. Women who have had previous contraceptive failures or developed breakthrough bleeding during concomitant antimicrobial use should be strongly advised to follow these precautions, as they may be part of the subset of women at higher risk of contraceptive failure.     

Accelerated stability and bioassay of a new oral α-ketoglutarate formulation for treating cyanide poisoning

Context: Due to several limitations of existing cyanide antidotes, α-ketoglutarate (α-KG) has been proposed as a promising treatment for cyanide.

Objective: This study reports the accelerated stability and bioassay of a new oral α-KG formulation.

Materials and methods: Amber-colored PVDF bottles containing 100?ml of 10% α-KG in 70% sorbitol, preservative (sodium methyl paraben and sodium propyl paraben), sweetener (sodium saccharine), flavor (American ice-cream soda and peppermint) and color (tartrazine), at pH 7.0–8.0 were stored in stability chamber (40?±?2?°C and 75?±?5% humidity) for 6?months in a GMP compliant facility. Various physical (pH, color, evaporation, extractable volume and clarity), chemical (identification and quantification of active ingredient) and microbiological (total aerobic count) analyses, together with protection studies were carried periodically in mice. Acute toxicity of the formulation and bioavailability of α-KG were assessed in rats at the beginning of the experiment.

Results: No physical changes and microbiological growth were observed in the formulation. After 6?months, α-KG content in the formulation diminished by ～24% but its protective efficacy against cyanide remained at 5.9-fold. Protection was further characterized spectrophotometrically by disappearance of α-KG spectrum in the presence of cyanide, confirming cyanohydrin formation. Oral LD₅₀ of α-KG formulation in rats was >7.0?g/kg body weight, and did not produce any acute toxicity of clinical significance. Also, an appreciable amount of α-KG was measured in blood.

Conclusion: As per the guidelines of International Conference on Harmonization, the new α-KG formulation exhibited satisfactory stability, bioefficacy and safety as cyanide antidote.     

Allopregnanolone concentration and mood—a bimodal association in postmenopausal women treated with oral progesterone

Rationale Allopregnanolone effects on mood in postmenopausal women are unclear thus far.Objectives Allopregnanolone is a neuroactive steroid with contradictory effects. Anaesthetic, sedative, and anxiolytic as well as aggressive and anxiogenic properties have been reported. The aim of this study is to compare severity of negative mood between women receiving different serum allopregnanolone concentrations during progesterone treatment.Materials and methods A randomized, placebo-controlled, double-blind, crossover study of postmenopausal women (n=43) treated with 2 mg estradiol daily during four treatment cycles. Oral micronized progesterone at 30, 60, and 200 mg/day, and placebo were added sequentially to each cycle. Participants kept daily symptom ratings using a validated rating scale. Blood samples for progesterone and allopregnanolone analyses were collected during each treatment cycle.Results During progesterone treatment, women had significantly higher negative mood scores when allopregnanolone serum concentration was in the range of 1.5–2 nmol/l compared to lower and higher concentrations. In addition, women displayed a significant increase in negative mood during the progesterone treatment period, compared to the estradiol-only period when 30 mg progesterone daily was used. On the other hand, treatment with higher doses of progesterone had no influence on negative mood.Conclusions Mood effects during progesterone treatment seem to be related to allopregnanolone concentration, and a bimodal association between allopregnanolone and adverse mood is evident.