Genetic effects on sperm design in the zebra finch.

Sperm design and function are important determinants of male reproductive success and are expected to be under strong selection. The way that spermatozoa phenotypes evolve is poorly understood, because there have been few studies of the quantitative genetics of sperm. Here we show, in the zebra finch Taeniopygia guttata, an extraordinary degree of inter-male variation in sperm design that is independent of sperm swimming velocity. A quantitative genetics study using data from over 900 zebra finches in a complex breeding experiment showed that sperm head, mid-piece and flagellum length are heritable, that negative genetic correlations exist between sperm traits, and that significant indirect (maternal) genetic effects exist. Selection on the zebra finch sperm phenotype may be low because sperm competition is infrequent in this species, and this, in combination with negative genetic correlations and maternal genetic effects, may account for the variation in sperm phenotype between males. These results have important implications for the evolution of sperm in other taxa.

Development of a model based on body composition to predict drug kinetics-1 evaluation in healthy volunteers.

A kinetic model for widely used drugs, based on body composition analysis, was developed and evaluated in young and elderly healthy individuals. Body composition was studied by body impedance analysis (BIA). Antipyrine, amlodipine, digoxin and tobramycin kinetics, liver microsomal activity enzyme (lidocaine/MEGX test), and appropriate clinical and laboratory tests were carried out. Major variables (V(d), AUC, t(1/2), C(max), Cl) for these drugs were calculated, and the possible relationships with the other clinical and biochemical data were analyzed by the Pearson's moment correlation, forecasting models being then obtained by a multiple linear regression method. Major kinetic parameters, particularly for the mixed elimination drugs (liver/renal), i.e. digoxin and amlodipine, proved to be well correlated to data collected during the study, in particular with body structure parameters. Results were less satisfactory in the case of the mainly renally handled tobramycin. Mathematical models to forecast the kinetic behaviors of the three chosen drugs, using readily accessible data, showed both in the young and the elder, as well as in the whole examined population, very satisfactory correlations in the case of digoxin (R(2) ranging from 0.89 to 0.85) and amlodipine (R(2) between 0.81 and 0.91), less satisfactory (with a wide range of R(2), from 0.65 to 0.94), in the case of tobramycin.

Accumulation of fluconazole in sebum.

Concentrations of fluconazole in sebum and plasma were determined in 2 parallel groups, each consisting of 8 healthy subjects. Group 1 received a 150 mg fluconazole capsule once weekly over a period of 4 weeks, Group 2 was administered 2 capsules/week, corresponding to 300 mg fluconazole/week for 4 weeks. Sampling was performed immediately before and 5 hours after dosing, and at intervals up to 2 weeks after the last dose. Fluconazole concentrations were determined by a specific and highly sensitive gas chromatographic method. Both treatments were well tolerated. Maximum fluconazole concentrations (mean +/- SD) in plasma were 3.5 +/- 1.0 microg/ml (Group 1) and 5.5 +/- 1.0 microg/ml (Group 2); maximum sebum concentrations were 11.0 +/- 8.4 microg/g (Group 1) and 48.4 +/- 37.0 microg/g (Group 2). Significant accumulation of fluconazole in sebum relative to plasma was observed. Sebum/plasma ratios ranged from 1.6 to 6.5 (Group 1) and from 4.3 to 27.9 (Group 2), with median ratios of 2.4 and 9.1, respectively. The overall accumulation factor was 7. The findings may be of particular relevance for the treatment of dermal mycoses involving the sebaceous glands, especially those associated with hair, such as tinea capitis.

A qualitative and quantitative study of the incidence, features and aetiology of near death experiences in cardiac arrest survivors.

AIM: To carry out a prospective study of cardiac arrest survivors to understand the qualitative features as well as incidence, and possible aetiology of near death experiences (NDEs) in this group of patients. METHOD: All survivors of cardiac arrests during a 1 year period were interviewed within a week of their arrest, regarding memories of their unconscious period. Reported memories were assessed by the Greyson NDE Scale. The postulated role of physiological, psychological and transcendental factors were studied. Physiological parameters such as oxygen status were extracted from the medical notes. Patients' religious convictions were documented in the interviews and hidden targets were used to test the transcendental theories on potential out of body claims. Those with memories were compared to those without memories. RESULTS: 11.1% of 63 survivors reported memories. The majority had NDE features. There appeared to be no differences on all physiological measured parameters apart from partial pressure of oxygen during the arrest which was higher in the NDE group. CONCLUSIONS: Memories are rare after resuscitation from cardiac arrest. The majority of those that are reported have features of NDE and are pleasant. The occurrence of NDE during cardiac arrest raises questions about the possible relationship between the mind and the brain. Further large-scale studies are needed to understand the aetiology and true significance of NDE.

Fluconazole penetration into the pancreas.

Because of antibiotic prophylaxis for necrotizing pancreatitis, the frequency of fungal superinfection in patients with pancreatic necrosis is increasing. In this study we analyzed the penetration of fluconazole into the human pancreas and in experimental acute pancreatitis. In human pancreatic tissues, the mean fluconazole concentration was 8.19 +/- 3.38 microg/g (96% of the corresponding concentration in serum). In experimental edematous and necrotizing pancreatitis, 88 and 91% of the serum fluconazole concentration was found in the pancreas. These data show that fluconazole penetration into the pancreas is sufficient to prevent and/or treat fungal contamination in patients with pancreatic necrosis.

The pharmacokinetics of extended-release formulations of calcium antagonists and of amlodipine in subjects with different gastrointestinal transit times.

The influence of gastrointestinal (GI) transit times on the pharmacokinetics (PK) of three calcium channel blockers (CCBs), recommended for once-daily dosing, was investigated. In a three-way crossover design, the single-dose PK of a controlled-delivery formulation of 240 mg diltiazem (DIL), an extended-release formulation of 10 mg felodipine (FEL), and 5 mg amlodipine (AML) were compared in two groups of healthy subjects, with either slow (> 35 h) or rapid (< 15 h) GI transit, as assessed by the metal detector method (EAS II). GI transit significantly affected the PK of DIL. Mean PK parameters in the rapid versus slow transit group were the following: trough levels (C24 h): 22.8 +/- 8.3 versus 49.5 +/- 35.7 ng/ml, p < 0.05; AUC 1134.4 +/- 512.7 versus 1704.7 +/- 1185.6 hng/ml, p < 0.05 (one-sided). Neither AUC nor trough levels of FEL and AML were significantly influenced by transit times, nor was Cmax after any of the three treatments. Variations in PK parameters, as indicated by coefficients of variation, were about twofold higher for both DIL and FEL, compared to AML. Variations in mean residence times were significantly lower for AML compared to DIL and FEL (7% vs. 30% and 17%, p < 0.001 and p < 0.002, respectively). Peak-to-trough ratios (Cmax/C24 h mean) were 1.8 +/- 0.9 for DIL, 7.6 +/- 3.5 for FEL, and 1.7 +/- 0.2 for AML. In conclusion, the predictability of pharmacokinetic behavior both in conditions of rapid or slow GI transit is optimized in drugs with intrinsically slow elimination such as amlodipine. The pharmacokinetics of the CCBs with formulation-based once-a-day characteristics are sensitive to GI transit if these processes are rapid enough to interfere with the formulation-specific release profile.

The uptake of fluconazole in finger and toe nails.

OBJECTIVE: The uptake of the antimycotic agent fluconazole in finger and toe nail following various treatment schedules was investigated in order to characterize the pharmacokinetic basis for the systemic treatment of onychomycosis with fluconazole. SUBJECTS: Between 8 and 12 healthy, male and female Caucasian subjects were included in four separate studies. Mean age of the subjects in the single studies ranged between 34 years (study 4, group 2; n = 4 male and 4 female) and 38 years (study 4, group 1; n = 4 male and 4 female). METHODS: Fluconazole was administered orally over 4 weeks in all studies. The treatment schedules were 150 mg once weekly (study 1), 300 mg once weekly (study 2), 50 mg once daily (study 3) and 150 or 300 mg once weekly in a parallel group study (study 4). At fixed times samples of blood, nail cuttings and nail dust were taken, up to two months after end of treatment. Fluconazole was analyzed in blood plasma and in the nail samples using a highly specific and sensitive gas chromatographic procedure. RESULTS: High concentrations of fluconazole were found in distal nail clippings with all three treatments. Mean maximum concentrations which occurred in the third or fourth week of treatment amounted to 2.1 microg/g (150 mg/w), 5.4 microg/g (300 mg/w) and 6.5 microg/g (50 mg/d) in finger nails and to 9.6 microg/g (150 mg/w), 12.3 microg/g (300 mg/w) and 12.2 microg/g (50 mg/d) in toe nails. The nail concentrations were 1-2 times (finger) and 2-3 times (toe) higher than the corresponding fluconazole plasma levels and were within the MIC range for dermatophytes and yeasts occurring commonly in onychomycosis. The residence times of fluconazole in the nail plate after the end of treatment was long, with approximate half-lives of 33 days in finger nail and 30 days in toe nail. In pharmacokinetic terms there was no evidence of advantages of the daily dosage (50 mg) over the once-weekly (300 mg) dosage. Fluconazole was found to penetrate into both finger and toe nails at a very fast rate. On the first two days of the 150 mg/w and 300 mg/w treatments, i.e. after the first dosage, fluconazole concentrations in the distal nail plates amounted to 50-80% of the later observed peak levels. The initial concentrations in the upper dorsal plate were particularly high, with mean peak concentrations of 11.9 microg/g (150 mg) and 33.7 microg/g (300 mg) in finger nails and 5.7 microg/g (150 mg) and 24.4 microg/g (300 mg) in toe nails. CONCLUSIONS: Fluconazole is rapidly and highly distributed into finger and foot nail, reaching there higher concentrations than in the plasma. The rapid initial uptake of fluconazole in nail, which is unlike the uptake of other antifungal agents, suggests the existence of special routes of access to the nail for fluconazole, possibly based on high diffusion rates.

Accumulation of fluconazole in scalp hair.

The accumulation in scalp hair of the antimycotic triazole, fluconazole, was studied during and after administration. Fluconazole 50 mg was administered to 12 healthy subjects as a single capsule each day for 28 days. The concentration of fluconazole 5 hours after administration was measured in different 1-cm sections of scalp hair at intervals during treatment and for 6 months after the end of treatment. In each section of scalp hair the concentration of fluconazole increased during treatment and was consistently higher than values found in plasma. For example, the mean concentration in the first hair section on day 28, 19.8 micrograms/g, corresponded to a mean penetration ratio relative to plasma of 9.42. During administration, the maximal concentration of fluconazole was found in the first hair section. After cessation of administration, the measured concentrations of fluconazole decreased and greater concentrations were found in the distal hair sections, presumably as a result of hair growth. Fluconazole was detectable, however, in the hair of 9 of the 12 subjects even 6 months after treatment. The mean concentration of fluconazole in hair bulbs on day 28 was 12.1 micrograms/g (n = 6), corresponding to a mean penetration ratio of 5.99. In a second study, fluconazole was administered as a single oral 150-mg capsule per week for 4 weeks to a group of 8 healthy subjects. The mean fluconazole concentration in whole scalp hair 5 hours after the last dose was 3.2 micrograms/g.

Fluconazole concentrations in pulmonary tissue and pericardial fluid.

In order to investigate the clinical efficacy of the triazole antifungal agent fluconazole (FCA) in the treatment of pulmonary mycosis, in the present study the concentrations of fluconazole in human pulmonary tissue, pericardial fluid and serum were determined at 1, 2, 12 and 13 h after intravenous administration of fluconazole 200 mg. The mean FCA concentrations in the serum were 4.04 mg/l (1 h), 3.82 mg/l (2 h), 2.35 mg/l (12 h) and 2.13 mg/l (13 h). The respective FCA levels in the pulmonary tissue were 4.64 mg/kg, 4.54 mg/kg; 3.50 mg/kg and 3.40 mg/kg and the concentrations in the pericardial fluid were 3.86 mg/l, 3.57 mg/l, 2.35 mg/l and 2.13 mg/l. The FCA concentrations in the pulmonary tissue that were statistically significant higher than the serum concentrations were found at 2 h, 12 h and 13 h after intravenous administration (p < 0.05).

Fluconazole: comparison of pharmacokinetics, therapy and in vitro susceptibility.

Fluconazole shows good penetration into the tissues and body fluids examined and a rapid equilibrium is achieved between the concentrations in the various compartments. The pharmacokinetics of fluconazole after intravenous or oral administration are proportional to the dose. This finding, together with the slow elimination of the triazole (t1/2 30 h), makes it easier to forecast the therapeutically effective dosage. Measurements of fluconazole concentration in blood can be used to predict levels in some tissues (lung, brain, gynaecological samples), body fluids (sputum, saliva, vaginal secretions) or exudates. Concentrations in cerebrospinal fluid and vitreous humour of the eye reach approximately 80% of the levels found in blood. A very high proportion of fluconazole is excreted unchanged in the urine, where concentrations of the drug are 10-20-fold higher than in blood. Whilst this pharmacokinetic profile is valuable in the treatment of fungal infections of the urinary tract, it also means that the dosage may need to be decreased in patients with renal impairment. The susceptibility of fungi to fluconazole in vitro and in vivo correlates well with the concentrations of the drug measured in various compartments of the body.

Pharmacokinetic and pharmacodynamic interaction study between midazolam and the macrolide antibiotics, erythromycin, clarithromycin, and the azalide azithromycin.

This report includes a recalculation of the pooled data of 2 pharmacokinetic and pharmacodynamic studies of the interaction between the hypnotic midazolam and the antibiotics erythromycin, clarithromycin (macrolides), and azithromycin (an azalide). Erythromycin and clarithromycin similarly and strikingly impaired the metabolism of midazolam and enhanced its pharmacodynamic activity; little or no effect was found with azithromycin. It was concluded that coadministration of midazolam and azithromycin involves less clinical risk than with the 2 macrolides.

Screening for cytochrome P450 3A in man: studies with midazolam and nifedipine.

This report describes work directed towards the development of a screening technique for cytochrome P450 3A activity which should be valid for a variety of drugs metabolized by this enzyme. A significant correlation (P < 0.01) was found between the ratio of the plasma concentration of nifedipine to that of its oxidized metabolite and the area under the time curve for the plasma concentration of midazolam. It is suggested that the nifedipine: metabolite ratio might have general predictive value for the metabolism of orally administered cytochrome P450 3A substrates.

Interaction between midazolam and clarithromycin: comparison with azithromycin.

A comparative pharmacokinetic and pharmacodynamic investigation was carried out on the interaction between the hypnotic midazolam and 2 different macrolide-type antibiotics, clarithromycin and azithromycin. In an open randomized crossover study of 3 phases 12 healthy volunteers received either clarithromycin (250 mg twice a day for 5 days), azithromycin (500 mg once a day for 3 days) or no pretreatment. On the last day of antibiotic treatment they ingested 15 mg midazolam. Plasma samples were collected for midazolam analysis up to 24 h and pharmacodynamic performance measured by a series of tests up to 12 h. Pretreatment with clarithromycin caused large and statistically significant changes in both the pharmacokinetic and pharmacodynamic parameters of midazolam compared to control. For example, the AUC was increased from 248.84-888.75 hng/ml (factor of 3.57, p < 0.0001) and the mean duration of sleep increased from 135.4 min to 281.3 min (p < 0.05). No statistically significant effect was found with azithromycin in any test. It is concluded that a drug interaction exists between midazolam and clarithromycin which could be of clinical importance. No such effect is present with azithromycin.

A new pharmaceutical concept for the treatment of oropharyngeal and oesophageal candidosis with fluconazole.

Administration of fluconazole in capsule form has proved effective in the prophylaxis and treatment of mucosal candidosis, particularly in immunosuppressed patients. An additional topical effect in oropharyngeal and oesophageal candidosis might be expected with a fluconazole suspension. This hypothesis was therefore tested in a crossover study in 12 healthy volunteers in whom the concentrations of the antimycotic were measured in saliva and plasma after oral administration of 100 mg fluconazole as either a capsule or a suspension. The time courses of the fluconazole concentrations were very similar with the two formulations in plasma, but significantly different in saliva. Thus, the mean Cmax for fluconazole in saliva of 551 micrograms ml-1 was reached 5 min after ingestion of the suspension, compared with a value of 3 micrograms ml-1 some 4 h after taking the capsule. The mean concentration of the antimycotic in saliva over the observation period (0-96 h) was more than 80% higher with the suspension than with the capsule.

Influence of the antibiotics erythromycin and azithromycin on the pharmacokinetics and pharmacodynamics of midazolam.

The pharmacokinetic and pharmacodynamic interaction between azithromycin (CAS 83905-01-5), an azalide antibiotic, and midazolam (CAS 59467-70-8), a short-acting hypnotic agent, was investigated in an open, three-way cross-over study, including erythromycin (CAS 114-07-8) as a positive control. Twelve healthy male and female subjects had standard doses of azithromycin (500 mg o.d. over 3 days), or erythromycin (500 mg t.i.d. over 5 days), or no pretreatment. On the day of the last dose, they ingested 15 mg midazolam. Blood samples were collected and psychometric tests performed. Erythromycin pretreatment (E) significantly changed the pharmacokinetics of midazolam compared to control (C), whereas azithromycin (A) had no such effect. The parameters are summarized as follows: area under the concentration-time curve, AUC (C) 173.8 h.ng.ml-1 vs. (E) 662.7 h.ng.ml-1*+ and (A) 220.0 h.ng.ml-1; concentration maxima (C) 67.2 ng.ml-1 vs. (E) 182.3 ng.ml-1*+ and (A) 86.7 ng.ml-1; elimination half-life (C) 2.21 h vs. (E) 4.85 h* and (A) 2.41 h (* p < 0.05 vs. (C), +p < 0.05 vs. (A)). Pharmacodynamic tests (digit symbol substitution test; critical flicker fusion test; subjective analog scale for rating of alertness; duration of sleep) consistently showed significant differences after erythromycin pretreatment compared to control, but not after azithromycin. Erythromycin, but not azithromycin, causes clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam.

[A new pharmaceutical concept for the therapy of oropharyngeal and esophageal candidiasis with fluconazole]. / Ein neues pharmazeutisches Konzept für die Therapie der oropharyngealen und oesophagealen Candidose mit Fluconazol.

Administration of fluconazole capsules is of proven worth in the treatment of candidosis of the mucous membranes, particularly in immunocompromised patients. An additional topical effect on the course of oropharyngeal and oesophageal candidosis can be expected when fluconazole is administered as a suspension. For this reason a crossover pharmacokinetic study with 12 healthy volunteers was carried out, in which the concentrations of the antimycotic were measured in saliva and plasma, after oral administration of 100 mg fluconazole as either a capsule or as a suspension. The time-courses of the concentration of fluconazole after the two formulations were very similar in plasma, but significantly different in saliva. The mean Cmax for fluconazole in saliva was 551 micrograms/ml 5 min after ingestion of the suspension and 3 micrograms/ml 4 h after taking the capsule. Over the observation time (0-96 h) the concentration of the antimycotic in saliva was more than 80% higher with the suspension than with the capsule.

[Fluconazole: comparison of pharmacokinetics, therapy and in vitro susceptibility of yeasts]. / Fluconazol: Vergleich von Pharmakokinetik, Therapie und Empfindlichkeit der Sprosspilze in vitro.

Fluconazole penetrates well into the tissues and body fluids which were examined and achieves rapid equilibration between the different compartments. The pharmacokinetics of fluconazole are independent of the dose after oral or intravenous administration. This finding, together with the drug's slow elimination (t1/2 30 h) facilitate the estimation of the therapeutically effective dosage. The concentrations of fluconazole measured in blood can be extrapolated to the concentrations in tissue (lung, brain, gynecological tissues), body fluids (sputum, saliva, vaginal secretions) and exudates. The concentration of fluconazole in cerebrospinal fluid and in the vitreous humour of the eye is ca. 80% of that in blood. Fluconazole is predominantly excreted in the urine in the unchanged form, which explains the 10 to 20 fold higher concentration of the drug in urine relative to blood. Although this pharmacokinetic profile favours the use of fluconazole in mycotic infections of the urinary tract it also means that the dose of the drug may have to be adapted to lower regimens in the systemic treatment of patients with restricted kidney function. The in vitro and in vivo susceptibility of the yeasts correlates with the concentrations of fluconazole measured in the different compartments of the body.

Single-dose pharmacokinetics of fluconazole in patients with liver cirrhosis.

The pharmacokinetics of a single 100 mg i.v. dose of fluconazole were studied in parallel groups of ten normal subjects and nine patients with liver cirrhosis, a condition with a high risk of life-threatening fungal infection. The following mean pharmacokinetic parameters were found for the patient group: terminal elimination constant 0.0101/h (normal 0.0214/h); mean residence time 134 h (normal 46.7h); area under the curve 200 h.mg/L(normal 69.4 h.mg/L); plasma clearance 0.96 L/h.kg(normal 2.16 L/h.kg). All these differences were statistically significant (P < 0.05). The majority of the patients were being concomitantly treated with duretics (frusemide and spironolactone). It is suggested that the known slight interaction between such drugs and fluconazole was intensified by the disease state. These results emphasize the need for caution in the treatment with fluconazole of patients with severe liver disease. Nevertheless, in view of the wide range of values found in the patients, and low toxicity of fluconazole, a dosage reduction in cirrhosis does not seem to be justified in the present state of knowledge.

Comparative pharmacokinetics of fluconazole and of itraconazole in Japanese and in German subjects.

In separate but identically designed studies the oral pharmacokinetics of 100 mg doses of the 2 antimycotics fluconazole and itraconazole were examined in Japanese and German subjects (both n = 12), both fasting and concomitant to a heavy breakfast. The results with the 2 races were compared. With fasting subjects no significant difference was found with either antimycotic for any parameter. With fluconazole the pharmacokinetic parameters after food were essentially the same for the 2 races. The only significant difference, a delay of 1.5 h in the median tmax in the Japanese relative to the Germans, should not be of practical importance. In contrast, the mean AUC for itraconazole in Japanese subjects after the meal was only 54.9% of the value with Germans (p < 0.05); the corresponding Cmax was only 54.7% (p < 0.01). As itraconazole is normally administered together with food, this suggests that there is a possibility of underdosage in Japanese subjects. There appears to be no such problem with fluconazole.

Pharmacokinetic optimization of the treatment of oral candidiasis with fluconazole: studies with a suspension.

An open crossover study was performed in 12 healthy subjects to investigate the pharmacokinetics in saliva and plasma of a 100 mg oral dose of fluconazole, administered as either a capsule or as a suspension, the latter being used to rinse the mouth and retained for 2 min before being swallowed. In terms of fluconazole plasma concentrations the capsule and the suspension were essentially bioequivalent. While the saliva concentrations of fluconazole after capsule administration reached their peak at 3.0 +/- 0.8 micrograms/ml 4 h after dosage, administration of the suspension resulted in a mean peak concentration of 551.1 +/- 425.6 micrograms/ml 5 min after ingestion. The saliva concentrations decreased gradually after ingestion of the suspension, but were higher for 4 h than the corresponding levels from the capsule. The area under the curve (AUC) from 0 to 96 h of fluconazole in saliva was 227.7 +/- 73.8 h micrograms/ml after the suspension, compared to 123.5 +/- 25.5 h micrograms/ml after the capsule, indicating that the total drug exposure to the oral mucosa by the salivary route was enhanced more than 80% with use of the suspension. Four h after administration of the suspension, saliva and plasma concentrations of fluconazole were in equilibrium, at a saliva: plasma ratio of around 1.2. Taken together, the present results suggest that the treatment of oral candidiasis with fluconazole may be optimized by use of an oral suspension, as this delivers pharmacologically active levels of the drug to the site of infection by both topical and systemic routes.