Value of the vertebrogram in predicting cement filling patterns with unipedicular percutaneous vertebroplasty.

BACKGROUND: Unipedicular vertebroplasty can be successful in selected patients to decrease procedure time, sedation amounts, and cost. PURPOSE: To evaluate the value of the antecedent unipedicular vertebrogram in predicting patterns of cement deposition to decide whether unipedicular vertebroplasty will be successful, or if a bipedicular vertebroplasty is needed. MATERIAL AND METHODS: 75 fractured vertebral levels were injected by a unipedicle approach with iodinated contrast material (vertebrogram). This filling pattern was then compared to the cement deposition pattern, via the same pedicle, of the percutaneous vertebroplasty. RESULTS: 35 levels showed excellent cross-filling and matched pattern by vertebrogram and cement deposition (47%). Twelve levels (16%) showed cross-filling by both techniques, with less than 100% matched pattern, but cement deposition was considered adequate for fracture treatment. Four levels (5%) showed predominantly matched central filling, considered adequate for fracture treatment. Twenty-one levels (28%) showed only matched filling of half of the vertebral body with both techniques, necessitating a bipedicle approach for treatment with cement. The remaining three levels (4%) demonstrated mismatched patterns between the vertebrogram and the cement deposition, necessitating a bipedicular approach. CONCLUSION: The unipedicular vertebrogram was helpful in predicting adequate cement deposition, using a single pedicle, in 51 of 75 cases (68%). The vertebrogram was also accurate in predicting the need for a double-pedicle technique in an additional 21 cases (28%). Therefore, the vertebrogram was very helpful in predicting the route of cement deposition in 72 of 75 (96%) cases, and should be considered as an adjunct to percutaneous vertebroplasty.

Pelvic free fluid: clinical importance for reproductive age women with blunt abdominal trauma.

OBJECTIVE: To evaluate the importance of isolated pelvic free fluid (FF) detected by ultrasound examination in pregnant patients and in non-pregnant reproductive age women with blunt abdominal trauma (BAT). METHODS: Reproductive age women aged 10-50 years who presented with BAT and underwent focused abdominal sonography for trauma (FAST) from January 1995 to June 2002 at a Level 1 trauma center were included. Patients were assigned to four groups according to the location of FF detected by ultrasound (Group 1, no FF; Group 2, FF in pelvis; Group 3, FF in abdomen; Group 4, FF in abdomen and pelvis). Ultrasound findings were compared with intra-abdominal and pelvic injuries detected by computed tomography and/or laparotomy. Pair-wise comparison was performed using a Fisher's exact test. RESULTS: Ultrasound detection of FF in the abdomen alone or FF in the abdomen and pelvis was significantly associated with intra-abdominal injury (IAI) compared to those without FF (P < 0.001) for both pregnant and non-pregnant reproductive age women. FF isolated to the pelvis was also associated with a higher injury rate compared to no FF in pregnant women (30% vs. 3%, P = 0.005) and in non-pregnant reproductive age women (39.5% vs. 3.7%, P < 0.001). CONCLUSIONS: In reproductive age women with BAT, ultrasound detection of FF in the abdomen alone, in both the abdomen and pelvis, or isolated to the pelvis is associated with a higher IAI rate. Therefore, isolated FF in the pelvis should not necessarily be considered physiological in pregnant and non-pregnant patients with BAT.

Metered dose inhalers III: Metaproterenol sulphate; particle size distribution and dose uniformity.

Three American products and one Canadian product were examined for content uniformity and particle size distribution. The results showed that not all products performed equally well. Some of the products exhibited high sprays early in the canister lifetime and all products demonstrated loss of prime. The particle size distributions were determined using the Andersen cascade impactor (USP Induction Port) and the fine particle fraction was determined using the twin impinger. The results showed that three of the four products had similar particle size distribution profiles. Both the Andersen cascade impactor and the twin impinger yielded the same trends in the amount of drug substance delivered to the fine particle fraction.

Metered-dose inhalers, I: Drug content and particle size distribution of beclomethasone dipropionate.

Four commercially available beclomethasone metered dose inhalers were analyzed for both spray content uniformity and particle size. The drug contents of primed and unprimed sprays collected at the beginning of the lifetime of the canister were not significantly different from those collected throughout the experiment. Particle size analysis of the four products using the Andersen Cascade Impactor Mark II showed that the distribution profiles were not identical. An existing HPLC method was modified to quantitate single sprays for content uniformity and to measure the amount on an impactor stage for particle sizing.

Toxicodynamics and toxicokinetics of amikacin in the guinea pig cochlea.

An extensive overview of the relationship between cochlear toxicity and amikacin blood concentrations in the guinea pig is provided which should assist in the clinical application of this class of antibiotic. A data set previously used to relate the incidence of amikacin ototoxicity to dosing rates and blood concentrations was re-examined to assess the toxicodynamics of amikacin in terms of decibels of hearing loss across dosing rate, hearing frequency and time following drug exposure. Animals in this data set had received continuously i.v. infused amikacin over an 8-fold range of dosing rates. Preliminary analysis indicated that the data were consistent with a sigmoid relationship between hearing loss (decibels) and area under the amikacin plasma concentration vs time curve cumulated over the entire course of drug administration (cAUC). The sigmoid model was therefore used as the backbone of a far more comprehensive toxicodynamic model which described all the data with a single equation. Testing with this model showed that the cAUC required to produce half-maximum hearing loss (cAUC-1/2) was related to dosing rate (P < 0.01), to hearing frequency (P < 0.00001), and to post-drug interval (P < 0.00001). Maximum hearing loss (difference between upper and lower sigmoid asymptotes) was less than total and was significantly related to frequency (P < 0.00001). No effects could be detected on the sigmoid slope. Further modelling of the significant effects detected by the comprehensive toxicodynamic model was done to determine if they could be described by simple relationships or by biologically relevant sub-models. Modelling of maximum hearing loss (postulated to represent loss of mainly outer hair cell function) indicated that this parameter was constant at about 61 decibels for 2-12 kHz and linearly decreased with log frequency for frequencies > 12 kHz. Modelling of cAUC-1/2 on frequency indicated that there was a strong inverse linear relationship to log frequency. Modelling of cAUC-1/2 on post-drug interval indicated that delayed ototoxicity continued at progressively slower rates for at least 56 days after drug administration had ceased. Modelling of cAUC-1/2 on dosing rate showed an increased requirement for drug as the dosing rate decreased. However, cAUC-1/2 changed no more than 20% across the range of dosing rates compared to the 8-fold difference in mean steady-state plasma concentrations, suggesting that plasma concentration is not a primary determinant of ototoxicity. A toxicokinetic model was developed which explained the dosing rate effect on cAUC-1/2 very successfully.(ABSTRACT TRUNCATED AT 400 WORDS)

Relationship between body weight, body surface area and serum zidovudine pharmacokinetic parameters in adult, male HIV-infected patients.

OBJECTIVE: To determine whether there is a simple relationship between body weight or body surface area (BSA) and serum zidovudine pharmacokinetic parameters in patients receiving oral zidovudine. DESIGN: Single-dose, pharmacokinetic study. PATIENTS: Fifty-three asymptomatic and symptomatic HIV-infected men (CD4+ cell count < 500 x 10(6)/l) participated in the study. Results of renal function and haematology tests were within normal limits and all hepatic function tests were up to three times the upper limit of normal. Patients received 200 mg oral zidovudine and serial blood samples were collected for 4 h (18 patients) or 8 h (35 patients). Serum zidovudine concentrations were measured by high-performance liquid chromatography (12 patients) or radioimmunoassay (41 patients). Pharmacokinetic parameters were calculated by non-compartmental methods. The relationships between body weight or BSA and maximum serum concentration (Cmax), area under the concentration-time curve (AUC), apparent serum clearance (CL/F), and apparent terminal volume of distribution (Vz/F) were determined by simple least-squares linear regression. RESULTS: There were no significant relationships between either body weight or BSA and Cmax, AUC, Vz/F (corrected for weight), and clearance (P > 0.07; R2 < 0.06 for all comparisons). A significant positive association between Vz/F, uncorrected for weight, and either weight (P = 0.011; R2 = 0.121) or BSA (P = 0.022; R2 = 0.098) was observed. The interindividual coefficients of variation of CL/F and Vz/F values were only marginally reduced when the parameters were corrected for weight (31.3 versus 30.8% and 28.0 versus 26.0% respectively). CONCLUSIONS: There is little or no linear association between either body weight or BSA and observed serum zidovudine concentrations following administration of 200 mg zidovudine in adult male patients who are within 20% of their ideal weight.

Pharmacokinetics of zidovudine after the initial single dose and during chronic-dose therapy in HIV-infected patients.

The pharmacokinetics of zidovudine in 10 symptomatic HIV-infected men were assessed after administration of the initial 200 mg oral dose at the start of therapy (day 1) and on one occasion during non steady-state conditions of chronic-dose therapy (200 mg every 4 h while awake on day 21-66; 5 doses per day). The following mean (+/- s.d.) pharmacokinetic parameters were determined on day 1 and during chronic therapy, respectively: Cmax (4.09 +/- 2.54 vs 3.82 +/- 1.03 mumol l-1), oral clearance (40.7 +/- 12.9 vs 41.1 +/- 8.4 ml min-1 kg-1) and terminal half-life (68.4 +/- 29.4 vs 65.1 +/- 13.1 min). Mean pharmacokinetic parameters on day 1 were < 10% different (P > 0.34) from those determined during chronic therapy. Differences in means of 21% for clearance and 36% for Cmax could be detected with a power of 80% at the 5% significance level. Intra-subject coefficients of variation were 17% for clearance and 32% for Cmax, respectively. This study suggests that within a group of patients whose stage of HIV infection and general health are relatively stable, first-dose pharmacokinetic parameters provide a good estimate of multiple-dose pharmacokinetic parameters.

Logarithmic transformation in bioequivalence: application with two formulations of perphenazine.

The rationale for using the logarithmic transformation on concentration-dependent pharmacokinetic parameters a priori is presented. This rationale is based on theoretical pharmacokinetic and statistical grounds, but is also applicable to the practice of physicians in dealing with variations of drug treatment within and between patients. The implications of the transformation on data analysis, specifically analysis of variance, and estimation and inference from the analysis as it pertains to bioequivalence decisions are explored. Implementation of the transformation is shown, with an example of two perphenazine formulations in a single-dose crossover study. It is concluded that the transformation has to be accepted on theoretical grounds because sample sizes are too small in bioequivalence studies and too susceptible to extreme values to state with any certainty the actual distribution of pharmacokinetic parameters or their differences within a subject.

In vitro assessment of cytotoxicity and biotransformation of propranolol in Cunninghamella echinulata.

1. Biotransformation studies with five concentrations of racemic propranolol were conducted using the filamentous fungus Cunninghamella echinulata ATCC 9244. 2. The rate of formation and subsequent disappearance of a new major metabolite, 8-hydroxypropranolol, was dose-dependent. Desisopropylpropranolol and 4-hydroxypropranolol were also formed. 4-Hydroxypropranolol was the major fungal metabolite in earlier studies. 3. Propranolol exerted a dose-dependent response on biotransformation, fungal growth, dextrose utilization, ammonia formation and incubation broth pH. Determination of dextrose utilization and incubation broth pH would provide reliable, cost-effective and convenient alternative methods for cytotoxicological evaluation.

Evidence that amikacin ototoxicity is related to total perilymph area under the concentration-time curve regardless of concentration.

Previous studies have failed to fully establish whether ototoxicity is related in any way to the levels of an aminoglycoside antibiotic in the perilymph. To study this we exposed guinea pigs to continuously infused amikacin at four different dosing rates under conditions parallel to those used in our previous study which related ototoxicity to total plasma area under the concentration-time curve regardless of the level in plasma. It was found that at all dosing rates, levels in the perilymph and ratios of levels in perilymph/plasma remained constant as the dosing duration increased from nonototoxic to strongly ototoxic. Plasma and perilymph amikacin levels were found to be linear functions of the dosing rate even at ototoxic dosing exposures, and ratios of levels in perilymph/plasma did not differ between dosing rates. The total perilymph area under the concentration-time curve was not different between dosing rates either for a total dose associated with threshold ototoxicity or for one associated with severe ototoxicity. The results suggest that amikacin ototoxicity is related to the integral of the concentration in the perilymph over the total time of amikacin exposure regardless of the level in the perilymph.

Harmonization of bioavailability and bioequivalence requirements.

Requirements for bioavailability (BA) and bioequivalence (BE) of drug products have evolved in different jurisdictions according to precedents established within the framework of existing laws. Thus, while the scientific principles behind the regulation and guidelines are common, it is often difficult for countries to agree on specific standards. This presentation examines some of the similarities and differences between European Community (EC) and North American requirements and indicates areas in which consensus may be achieved as well as those issues which may be more challenging.

Delay in hearing loss following drug administration. A consistent feature of amikacin ototoxicity.

The time course of threshold increase in the VIII nerve compound action potential was studied in guinea pigs following amikacin administration at four different constant infusion rates. Despite the wide range of dosing durations required to achieve drug ototoxicity (2-24 days), the full development of both high and low frequency hearing loss was invariably found to be delayed with respect to the time of drug removal. The greatest degree of delayed hearing loss generally occurred within the first 7 days after drug removal, with smaller losses occurring during later time intervals. The delay showed a tendency to decrease as the ototoxic dose was increased. Using the data from the two highest dosing rates, it was estimated that a minimum of 4 days had to elapse before any hearing loss could be detected, once an ototoxic amount of drug had been administered. These data suggest that hearing loss is always substantially delayed with respect to the receipt of an ototoxic dose of amikacin, and that this must be taken into account when conducting animal experiments and when monitoring hearing in patients for the early detection of ototoxicity.

Incidence of amikacin ototoxicity: a sigmoid function of total drug exposure independent of plasma levels.

A sigmoid curve was found to closely describe the relationship between the incidence of amikacin ototoxicity (greater than or equal to 15 dB hearing loss at a given frequency) and either (1) total dose, or (2) the area under the curve (AUC) describing plasma drug concentration v time over the total period of amikacin administration (total AUC) in continuously infused guinea pigs. Total dose or total AUC estimates of the drug exposure required to produce ototoxicity in 50% of the animals (ED50s) were not significantly different over an eight-fold range of dosing rates or plasma concentrations. A theoretical explanation for this result is that ototoxicity occurs only when a critical amount of drug is accumulated at the ototoxic site by an essentially unidirectional process with a rate that is slow and linearly related to the extracellular drug concentration. The sigmoid relationships for pooled data were parallel in slope for all hearing frequencies from 2 to 32 kHz, and the ED50s showed a strong negative linear relationship to the log of the hearing frequency over this range. The magnitude of ototoxicity expressed as the number of octaves (frequency ratios of 2) for which hearing loss damage was continuous from 32 kHz downward, was correlated to both total dose (r = .605) and total AUC (r = 0.703). No relationship between ototoxicity and plasma level or dosing rate was found. The extreme steepness of the dose-effect curve for the incidence of ototoxicity greatly amplified the variability between individuals and offers an explanation for the unpredictability of aminoglycoside ototoxicity in human patients. The results indicate that either total dose or total AUC (in cases of highly unpredictable blood levels), and not peak or trough serum levels, should be used as an index of ototoxic risk and that the safety limits of drug exposure should be set conservatively.

Short-term pathological and proliferative effects of butylated hydroxyanisole and other phenolic antioxidants in the forestomach of Fischer 344 rats.

Food grade butylated hydroxyanisole (BHA) when incorporated in the diet and fed to male Fischer 344 rats for 9 or 27 days induced proliferative squamous epithelial changes in the lesser curvature of the forestomach proximate to the glandular stomach. These changes were assessed histopathologically and by [methyl-3H]thymidine radioautography. It was shown that BHA mixed dry into powdered diet, incorporated into the diet in corn oil, or in a pelleted diet, induced similar effects. When levels of 2%, 1%, 0.5%, 0.25%, 0.1% and 0% BHA were incorporated in rat diet for 9 days, the proliferative effect appeared to show a no effect level at 0.25% based on the [methyl-3H]thymidine-labelling index. Other food use antioxidants, namely butylated hydroxytoluene or tertiary butylhydroquinone, induced a lesser response than BHA at the maximum dose employed in the study. Propyl gallate was without effect. Propyl-4-hydroxybenzoate, a food use phenol, on the other hand, induced a less pronounced response than BHA but was more effective than the other antioxidants. Because increased cellular proliferation often provides an optimal milieu for tumor formation, it is suggested that these observations may be relevant to rat forestomach tumors induced by BHA.

Comparison of Fresh Feces with Lyophilized and Frozen Cultures of Feces as Inocula to Prevent Salmonella Infection in Chicks.

Mixed treatment cultures obtained by inoculating anaerobic medium with chicken feces were administered to 0 to 1 d-old chicks in their drinking water. Three types of treatment cultures (all fourth passage) were compared: FFC (fresh fecal cultures started with inocula of fresh feces followed by four daily, uninterrupted serial subcultures), LFC (cultures started with inocula obtained by lyophilizing third-passage cultures), and FrFC (cultures started with inocula obtained by freezing third-passage cultures). Protection of treated chicks against infection by Salmonella typhimurium was assessed by challenging the chicks via their drinking water 2 d after treatment and culturing their ceca 8 to 9 d later, or at weekly intervals for 7 weeks. FFC protected chicks against infection more consistently than LFC or FrFC. However, some LFC and FrFC were as protective as FFC (α= .05). Treatment with cultures did not increase mortality or decrease weight gain.