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PubMed1976

Observations in man on some pharmacologic features of cefamandole.

Comparative studies of cefamandole and cephalothin were carried out in 32 cancer patients. After rapid intravenous injection of 1 gm cefamandole or cephalothin, the peak mean serum concentrations in 11 patients achieved at 0.25 hr were 103.4 mcg/ml and 56.7 mcg/ml, respectively. Except at 6 hr, the serum concentration of cefamandole was higher (p less than 0.05) at all times. The terminal half-lives (t 1/2) were similar, being 1.2 hr for cefamandole and 1.0 hr for cephalothin. Cefamandole, 1 gm intramuscularly, induced a peak mean serum concentration of 26.6 mcg/ml at 1 hr, with a slow decay. Intermittent cefamandole (2 gm intravenously every 6 hr) induced very high mean serum concentrations (7 patients), but at 4 hr the concentrations were similar to those after 1 gm intravenously. Per cent of urinary excretion was similar for both drugs regardless of dose and mode of administration. Continuous-infusion cefamandole or cephalothin (2 gm loading followed by 2 gm every 6 hr) in 14 patients showed consistently higher serum concentrations for cefamandole (p less than 0.05) over a 5-day period. There was no evidence of drug accumulation in the multiple-dose studies. Both the single- and multiple-dose schedules were well tolerated.

Adolescent↗
PubMed2005

Complexes of thiomandelate and captopril mercaptocarboxylate inhibitors to metallo-beta-lactamase by polarizable molecular mechanics. Validation on model binding sites by quantum chemistry.

Using the polarizable molecular mechanics method SIBFA, we have performed a search for the most stable binding modes of D- and L-thiomandelate to a 104-residue model of the metallo-beta-lactamase from B. fragilis, an enzyme involved in the acquired resistance of bacteria to antibiotics. Energy balances taking into account solvation effects computed with a continuum reaction field procedure indicated the D-isomer to be more stably bound than the L-one, conform to the experimental result. The most stably bound complex has the S(-) ligand bridging monodentately the two Zn(II) cations and one carboxylate O(-) H-bonded to the Asn193 side chain. We have validated the SIBFA energy results by performing additional SIBFA as well as quantum chemical (QC) calculations on small (88 atoms) model complexes extracted from the 104-residue complexes, which include the residues involved in inhibitor binding. Computations were done in parallel using uncorrelated (HF) as well as correlated (DFT, LMP2, MP2) computations, and the comparisons extended to corresponding captopril complexes (Antony et al., J Comput Chem 2002, 23, 1281). The magnitudes of the SIBFA intermolecular interaction energies were found to correctly reproduce their QC counterparts and their trends for a total of twenty complexes.

Algorithms↗
PubMed2001

A semiparametric deconvolution model to establish in vivo-in vitro correlation applied to OROS oxybutynin.

In vitro-in vivo correlation (IVIVC) models may be used to predict in vivo drug concentration-time profiles given in vitro release characteristics of a drug. This prediction is accomplished by incorporating in vitro release characteristics as an input function (A(vitro)) to a pharmacokinetics model. This simple approach often results in biased predictions of observed in vivo drug concentrations, and it can result in rejecting IVIVC. To solve this problem we propose a population IVIVC model that incorporates the in vitro information and allows one to quantify possibly changed in vivo release characteristic. The model assumes linear kinetics and describes the in vivo release as a sum of A(vitro) and a nonparametric function (A(d), a spline) representing the difference in release due to in vivo conditions. The function A(vitro) and its variability enter the model as a prior distribution. The function A(d) is estimated together with its intersubject variability. The number of parameters associated with A(d) defines the model: no parameters indicates perfect IVIVC, a large number of parameters indicates poor IVIVC. The number of parameters is determined using statistical model selection criteria. We demonstrate the approach to solve the IVIVC problem of an oral extended release oxybutynin form (OROS), administered in three pharmacokinetic studies. These studies present a particular challenging case; that is, the relative bioavailability for the OROS administration is >100% compared with that of the immediate-release form. The result of our modeling shows that the apparent lack of IVIVC can be overcome: in vivo concentration can be predicted (within or across data sets) based on in vitro release rate together with a simple form of systematic deviation from the in vitro release.

Biological Availability↗
PubMed1976

Conversion of cefamandole nafate to cefamandole sodium.

The rate of hydrolysis of the formyl moiety of cefamandole nafate was determined as a function of pH, temperature, and concentration of added sodium carbonate or tromethamine. The reaction rate was sensitive to hydroxide ion in the pH 5.5-8.0 range with half-life values of hours to minutes. Hydrolysis was rapid upon the addition of sodium carbonate or tromethamine. Chirality in the 7-D-mandelamido side chain was unaffected by hydrolysis.

Carbonates↗
PubMed1979

Oxybutynin influence on autonomic measures in dogs.

In the conscious dog, the most apparent oxybutynin effect was a dose-related tachycardia. Associated with this heart rate increase were a very slight, sometimes significant, elevation in diastolic pressure and an insignificant increase in systolic pressure. Under pentobarbital anesthesia, the systolic/diastolic arterial pressure oxybutynin responses were reversed and showed a dose-related systolic and diastolic hypotension. However, the tachycardic response to oxybutynin still appeared. The arterial pressure and heart rate responses produced by the autonomic agents were altered by the oxybutynin treatment in a pattern indicative of an anticholinergic mechanism of action. Differences in many response profiles were observed with either conscious or anesthetized dogs, but the statistically significant inhibition of the acetylcholine-induced systolic and diastolic arterial pressure and bradycardic responses were constant in both conditions. Oxybutynin is an anticholinergic agent with mild to moderate cardiovascular activity.

Anesthesia↗
PubMed2004

Acupuncture reflexotherapy in the treatment of sensory urgency that persists after transurethral resection of the prostate: a preliminary report.

AIMS: In this study, we wanted to evaluate whether acupuncture reflexotherapy is able to treat the sensory irritative components of LUTS (lower urinary tract symptoms) that persist after transurethral resection of the prostate. METHODS: We have evaluated 42 patients, randomly selected into three groups: 14 patients received placebo, 15 patients received oxybutynin, and 13 patient were treated with electrostimulation by acupuncture reflexotherapy. RESULTS: Before treatment, the mean maximum flow rate (Qmax) was 21.0 +/- 3.2 mL/sec, the mean International Prostate Symptom Score (I-PSS) score was 12.9 +/- 4.2, the mean I-PSS Quality of Life (IPSS QoL) score was 3.6 +/- 1.2. At the first check-up performed after 3 months, we could observe that the I-PSS and QoL scores were 12.6 +/- 4.3 and 3.8 +/- 1.3 in the group who received placebo; the scores decreased to 11.1 +/- 3.2 and to 3.1 +/- 1.0, respectively, in the 15 patients treated with oxybutynin and decreased to 6.1 +/- 2.6 and 1.3 +/- 1.1, respectively, in the 13 patients who underwent acupuncture reflexotherapy. At 1-year follow-up, these parameters were practically similar. The voiding diaries allowed us to deduce that the average number of daytime voidings decreased by 8% in patients who received oxybutynin and decreased by 20% in 13 patients who underwent reflexotherapy; the average number of nocturnal micturitions decreased by approximately 20% and 60%, respectively, in patients who received oxybutynin and reflexotherapy. CONCLUSIONS: This study has pointed out that acupuncture reflexotherapy has a real benefit in patients with sensory urgency that persists after transurethral resection of the prostate.

Acupuncture Therapy↗
PubMed1995

Intravesical oxybutynin in patients with posterior rhizotomies and sacral anterior root stimulators.

This report investigates the use of intravesical oxybutynin in spinal injury patients, who have had dorsal rhizotomies to abolish reflex detrusor activity and void with S2, S3, and S4 stimulation, done with the Brindley anterior root stimulator. Six male patients (age range 27 to 56, mean 36 years) who have had Brindley anterior root stimulators implanted were included in this study. Video urodynamic assessment was done and 10 mg of oxybutynin hydrochloride was instilled through the urethral catheter. This was left in the bladder for 60 minutes and video urodynamics were repeated. Voiding, both pre and post oxybutynin, was achieved with sacral root stimulation. Peak detrusor pressure (Pves) during voiding in the 6 patients before oxybutynin instillation was 89, 154, 90, 60, 56, and 80 (mean 88.2) cm of water. Post oxybutynin the pressures were 83, 163, 95, 40, 30, and 68 (mean 79.8) cm of water. The peak flow rate (Qmax) pre oxybutynin was 32, 24, 20, 20, 12, and 28 (mean 22.7) ml per second and this changed to 28, 31, 18, 24, 10, and 32 (mean 23.8) ml per second. This shows no difference in the detrusor pressure (P = 0.2) and flow rate (P = 0.54) pre and post oxybutynin instillation into the bladder. Effectiveness of oxybutynin is attributed to a combination of M3 receptor antagonism in the smooth muscle and direct spasmolytic, local anaesthetic and calcium channel blocking action. Its therapeutic benefit is limited by the anti cholinergic side effects (40-80%) and recent studies have shown the intravesical route to be effective and better tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intravesical↗
PubMed1995

Autonomic dysreflexia in a rat model spinal cord injury and the effect of pharmacologic agents.

The object of this study was to develop a spinal cord injury (SCI) rat model for autonomic dysreflexia (AD), assessing the effect of alpha-adrenergic and calcium channel blockade and to determine the relationship of detrusor-external sphincter dyssynergia (DESD) to the development of AD. A laminectomy was performed in male rats at the T4 or T10 level and a controlled 50 g cm blunt SCI was induced using an impounder. Four weeks after injury, changes in arterial blood pressure and heart rate were monitored while simultaneous cystometry (CMG) and pelvic floor electromography (EMG) were performed in vivo in sham (control) and spinal cord injured rats. The effects of terazosin (0.1 mg/kg), diltiazem (0.5 mg/kg), and oxybutynin chloride (0.1 mg/kg) on hemodynamic changes were assessed independently. Both T4 and T10 SCI rat displayed evidence of DESD (enhanced pelvic floor EMG activity at cystometric capacity) while control rats did not. Only T4 injured rats exhibited evidence of AD, with mean blood pressure elevations from 82.9 +/- 13.6 to 93.9 +/- 11.3 mm Hg (P < 0.01) and a mean heart rate decrease from 332.2 +/- 56.5 to 311.1 +/- 54.5 beats/min (P = 0.02) at cystometric capacity. The intravenous administration of terazosin or diltiazem abolished the AD response during CMG. The administration of oxybutynin exhibited the ability to increase bladder capacity and improve compliance in all 3 groups but did not blunt AD. The rat model of SCI effectively reproduced hemodynamic changes consistent with the AD complex in T4 level SCI but not T10 level SCI animals, despite incomplete lesions. Blockade with either an alpha-1 or a calcium channel antagonist effectively ablated the AD response to bladder distention. Anticholinergic agents had no effect on AD. DESD frequently accompanies autonomic dysreflexia, although the development of AD is not a prerequisite for DESD.

Adrenergic alpha-Antagonists↗
PubMed2004

Detrusor overactivity in spina bifida: how long does it need to be treated?

AIMS: To determine whether a lasting therapeutic effect can be expected from long-term antimuscarinic therapy for neurogenic detrusor overactivity in spina bifida and to answer the question whether detrusor overactivity in spina bifida children with detrusor/sphincter dyssynergia is primarily based on the neuropathy or, in part, can be a secondary detrusor reaction to the functional urethral obstruction. METHODS: Fifteen spina bifida patients, aged between 1 and 12 years, all on a regime of clean intermittent catheterisation (CIC) and oxybutynin since shortly after birth, underwent three consecutive urodynamic studies (UDS). One prestudy UDS for treatment control, one UDS after withdrawal of oxybutynin for 3-5 days and one UDS after reinstallment of oxybutynin treatment. Urodynamic results were compared concerning detrusor overactivity, cystometric bladder capacity, and compliance. RESULTS: Detrusor overactivity was seen in two patients on the prestudy UDS. After several days of withdrawal of oxybutynin overactivity was seen in 11 patients. After oxybutynin withdrawal, bladder compliance was within safe margins for two patients only, after reinstallment, safe vesical pressures were seen in 11 patients. CONCLUSION: The functional obstruction due to detrusor/sphincter dyssynergia has been by-passed chronically in all these children by CIC and oxybutynin. Due to the fact that detrusor overactivity recurs immediately after withdrawal of medication after long-term treatment with oxybutynin, one can conclude that there is no long-lasting therapeutic effect of pharmacological suppression. This suggests that in children with detrusor/sphincter dyssynergia, detrusor overactivity is primarily of neuropathic origin.

Child↗
PubMed2006

Minimal clinically important change in urinary incontinence detected by a quality of life assessment tool in overactive bladder syndrome with urge incontinence.

AIMS: The objective of this research was to detect a minimal clinically important change (MCIC) in frequency of incontinence episodes in Japanese patients with overactive bladder syndrome (OAB) based on the change in domain scores of health-related quality of life (HRQoL). METHODS: The patients (n = 659) enrolled for the 8 weeks, randomized, double-blind, placebo-controlled study of an oxybutynin transdermal patch were used for the analysis. The endpoints of the study were the change in frequency of incontinence episodes and the domain scores of King's health questionnaire (KHQ) from baseline to the end of treatment. To search a threshold of the change of incontinence frequency that apparently improves patient's quality of life (QOL), we calculated mean changes of selected five KHQ domain scores for nine patient groups divided by the amount of change of incontinence frequency. A minimum value of the change of incontinence frequency in the groups with apparent improvement in the QOL scores was defined as an MCIC of incontinence frequency. RESULTS: The apparent improvement of KHQ domain scores was seen in the patient groups whose incontinence episodes decreased more than three times per week (/w) after treatment. This result was common in almost all domain scores, but more relevant for the domains related to patients' life limitations. CONCLUSION: Japanese OAB patients can feel their QOL improved if their incontinence episodes decrease more than 3 times/w. This suggests that the reduction of '3 times /w' is an MCIC of incontinence frequency for Japanese OAB patients.

Administration, Cutaneous↗
PubMed2006

Systemic oxybutynin decreases afferent activity of the pelvic nerve of the rat: new insights into the working mechanism of antimuscarinics.

AIMS: In a rat model, intravesical oxybutynin was recently shown to suppress pelvic afferent nerves. This study evaluates if a similar effect exists after systemic administration of oxybutynin. METHODS: Twenty-four single afferent bladder nerves were identified in 15 rats. Based on their conduction velocities they were grouped as C or Adelta fibers. Bladder filling parameters and afferent nerve spike rate were simultaneously recorded 30 min before administration of saline (nine fibers) or oxybutynin (15 fibers, 1 mg/kg), and again 30, 60, 90, 120, and 150 min after systemic saline or drug administration. RESULTS: No change in C or Adelta afferent spike rate was observed after saline injection (P > 0.90). In the study group, a decrease in afferent activity was noted after systemic administration of oxybutynin for C fibers, which were statistically significant 90 (P < 0.004) and 120 min (P < 0.028) after drug delivery. After 150 min, the spike rate was still lower compared to the baseline filling, without reaching the level of significance (P > 0.09). For the Adelta fibers the decrease in afferent spike rate was already significant at 30 min (P < 0.005) and remained significant during all subsequent fillings (P < 0.012). To avoid a possible confounding influence of the bladder compliance, which increased significantly after injection of oxybutynin (P < 0.011), afferent activity during bladder filling was recalculated. Normalized afferent sensitivity of C and Adelta fibers decreased significantly after injection of oxybutynin. This means that the decrease in afferent spike rate is not the result of an increased compliance. CONCLUSIONS: The findings of this study strongly suggest that oxybutynin directly or indirectly influences bladder sensory nerves, inhibiting the afferent part of the micturition reflex.

Animals↗