Effect of ultrasound on transdermal drug delivery to rats and guinea pigs.

The effect of therapeutic range ultrasound (1 MHz) on skin permeation of D-mannitol, a highly polar sugar alcohol, inulin, a high molecular weight polysaccharide and physostigmine, a lipophilic anticholinesterase drug was studied in rats and guinea pigs. D-Mannitol and inulin are totally and rapidly excreted, once they have penetrated through the skin into the blood stream, permitting direct in vivo monitoring. For evaluating skin penetration of physostigmine the decrease of whole blood cholinesterase was measured. Ultrasound nearly completely eliminated the lag time usually associated with transdermal delivery of drugs. 3-5 min of ultrasound irradiation (1.5 W/cm2 continuous wave or 3 W/cm2 pulsed wave) increased the transdermal permeation of inulin and mannitol in rats by 5-20-fold within 1-2 h following ultrasound application. Ultrasound treatment also significantly increased (P less than 0.05) the inhibition of cholinesterase during the first hour after application in both physostigmine treated rats and guinea pigs: while in control guinea pigs no significant inhibition of cholinesterase could be detected during the first 2 h after application of physostigmine, the ultrasound treated group showed a 15 +/- 5% (mean +/- SEM) decrease in blood cholinesterase 1 h after ultrasound application. For physostigmine-treated rats the level of cholinesterase inhibition 1 h after ultrasound application was 53 +/- 5% in the ultrasound-treated group and 35 +/- 5% in the controls.     

Liquid crystalline pharmacogel based enhanced transdermal delivery of propranolol hydrochloride.

A novel pharmacogel was developed for the enhanced transdermal delivery of propranolol hydrochloride (PH). The synthesized prodrugs, propranolol palmitate hydrochloride (PPH) and propranolol stearate hydrochloride (PSH) self-assembled to form gel simply upon mixing alcoholic solution of prodrug with an aqueous solution in a specified ratio. By varying the ratio of prodrug, alcohol and water, three-component phase diagram was constructed which revealed isotropic-gel-vesicular dispersion regions, respectively concomitant to increasing the ratio of water. The gel phase is termed 'Pharmacogel' and exhibits birefringence under plane-polarized light corroborating the presence of lamellar liquid crystals. The pharmacogel by virtue of high chemical potential gradient and improved physicochemical properties showed the enhanced in-vitro skin permeation flux of 51.5+/-3.7 and 42.5+/-3.1 microg/cm(2)/h from PPH and PSH gel, respectively, as compared to 1.9+/-0.1 microg/cm(2)/h for control; and decrease in lag time (1.8 and 2.8 h for PPH and PSH gel, respectively) compared to control (7.6 h) was observed. The admixing of egg lecithin (EL) in increasing ratio concomitantly decreased the flux values to 31.7+/-2.1 microg/cm(2)/h (at a mole ratio of 50:50 PPH:EL) and increased the lag time. In the gel containing 50% EL, the addition of span 40 and cholesterol slightly reduced the permeation while sodium deoxycholate and Tween-80 improved it. The plasma drug levels following transdermal application of control were low (C(max)=23 ng/ml) while in PPH gel, it increased with time reaching C(max) of 94 ng/ml at 8 h post-application of PPH gel (C(max) of 75 ng/ml at 12 h post application of PL5 gel) and maintained for longer times. The AUC(0-32 h) for PPH gel was much higher (1968 ng h/ml) than control (AUC(0-18 h) was 239 ng h/ml), while EL mixed gel also showed better absorption (AUC(0-32 h) was 1707 ng h/ml). The gel formulations also caused less irritation than control, while mixed gel showed least irritation. This novel self-assembled pharmacogel providing high transdermal permeation with many variables to regulate the delivery is therefore having a great potential in percutaneous delivery.     

Protective effects of specific platelet-activating factor receptor antagonists in experimental glomerulonephritis

The present study was undertaken to evaluate the hypothesis that enhanced production of platelet-activating factor (PAF) contributes to the renal hemodynamic alterations and impaired glomerular permselectivity that characterize the heterologous phase of nephrotoxic serum nephritis. Intravenous administration of nephrotoxic gamma globulin to normal rats led to a rapid decline in glomerular filtration rate within 60 min from 1.08 +/- 0.08 to 0.45 +/- 0.12 ml/min/100 g b.wt., P less than .001, and in effective renal plasma flow rate from 2.56 +/- 0.15 to 1.35 +/- 0.21 ml/min/100 g b.wt., P less than .02. Concomitantly, the fractional excretion of protein rose from 3.4 +/- 0.6 X 10(-5) to 11.6 +/- 2.3 X 10(-5), P less than .03. Pretreatment with the specific PAF receptor antagonists WEB 2086 or WEB 2170 significantly ameliorated the impairment in glomerular filtration rate and in effective renal plasma flow rate induced by nephrotoxic globulin. Filtration rate declined by 0.63 +/- 0.12 ml/min/100 g b.wt. 60 min after administration of nephrotoxic globulin, but fell only 0.30 +/- 0.14 ml/min/100 g b.wt. in rats pretreated with WEB 2086, P less than .05 and 0.34 +/- 0.11 ml/min/100 g b.wt. in rats pretreated with WEB 2170, P less than .01. The decline in effective renal plasma flow rate 60 min after administration of nephrotoxic globulin was 1.21 +/- 0.30 ml/min/100 g b.wt., but only 0.86 +/- 0.23 ml/min/100 g b.wt. in rats pretreated with WEB 2086, NS, and 0.52 +/- 0.21 ml/min/100 g b.wt. in rats pretreated with WEB 2170, P less than .003.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transdermal delivery of fentanyl: rapid onset of analgesia using skin electroporation

Skin electroporation has recently been shown to increase transdermal transport of small-size drugs as well as considerably larger molecules by up to 4 orders of magnitude in vitro. Nevertheless, no in vivo studies have proven that high-voltage pulses can induce therapeutic plasma levels of drug. The aim of the present report was precisely to study the potential of skin electroporation in transdermal delivery of fentanyl in vivo. Fentanyl was transdermally delivered to hairless rats using high-voltage pulsing. Following the administration, the pharmacokinetics and pharmacodynamics were assessed. Significant fentanyl plasma concentrations were rapidly achieved using skin electroporation. Immediately after the 5 min pulsing, fentanyl plasma levels reached one third of the maximal plasma concentration of 30 ng/ml, the peak occurring 30 min after the electroporation. Deep analgesia and supraspinal effects were achieved, antinociception lasting for an hour. The magnitude of the effects was, however, dependent on the electrical parameters of the pulses.     

Transdermal delivery of regular insulin to chronic diabetic rats: effect of skin preparation and electrical enhancement

The efficacy of passive transdermal versus electrically-enhanced, or iontophoretic delivery of insulin was studied. The effect of skin pre-treatment on iontophoretic delivery of insulin was also investigated. Rectangular pulses of 0.25 mA/cm² current amplitude, 2 kHz frequency, and 50% duty cycle were used as anodal stimulation for electrically enhanced transdermal delivery of insulin. Twenty (20) BB/Wor chronic diabetic adult male rats were shaved 48 h prior to the study, and some experimental groups had hair stubble removed with a depilatory lotion. The iontophoretic drug-containing electrode was filled with 3 ml of porcine regular insulin (100 IU/ml) which had been adjusted to an acidic pH of 3.68 using 0.1 M HCl. The iontophoretic electrodes were then adhered to the abdomen of the alert rat. Results of the iontophoretic procedure were quantified by monitoring changes in blood glucose levels. When insulin was placed on the shaved skin, blood glucose levels fell in the chronic diabetic rat. In general, glucose levels fell more quickly and more profoundly using an iontophoretic enhancement of transdermal insulin delivery. However, some skin preparations facilitated movement of insulin more efficiently. The most profound effect of lowered blood glucose occurred when a depilatory lotion was used on the day of the study in conjunction with iontophoresis, where blood glucose levels fell by 61% after 1 h of iontophoretic treatment. Results indicate that insulin was delivered passively at therapeutic levels when the skin had been treated with the depilatory lotion on the same day as the study, as measured through a reduction in blood glucose levels of 29% after 1 h of passive delivery. When the depilatory lotion was used 24 h prior to iontophoresis, blood glucose remained near initial blood glucose levels. In the groups that did not have the depilatory lotion applied, blood glucose levels fell by 8% after 1 h of iontophoretic insulin delivery. The experimental evidence indicates a substantial increase in the penetration of insulin with the same-day application of a depilatory lotion in conjunction with iontophoretic enhancement.     

Steady-state plasma and bronchopulmonary concentrations of intravenous levofloxacin and azithromycin in healthy adults

The purpose of this study was to compare the concentrations of levofloxacin and azithromycin in steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) after intravenous administration. Thirty-six healthy, nonsmoking adult subjects were randomized to either intravenous levofloxacin (500 or 750 mg) or azithromycin (500 mg) once daily for five doses. Venipuncture and bronchoscopy with bronchoalveolar lavage were performed in each subject at either 4, 12, or 24 h after the start of the last antibiotic infusion. The mean concentrations of levofloxacin and azithromycin in plasma were similar to those previously published. The dosing regimens of levofloxacin achieved significantly (P < 0.05) higher concentrations in steady-state plasma than azithromycin during the 24 h after drug administration. The respective mean (+/- standard deviation) concentrations at 4, 12, and 24 h in ELF for 500 mg of levofloxacin were 11.01 +/- 4.52, 2.50 +/- 0.97, and 1.24 +/- 0.55 micro g/ml; those for 750 mg of levofloxacin were 12.94 +/- 1.21, 6.04 +/- 0.39, and 1.73 +/- 0.78 micro g/ml; and those for azithromycin were 1.70 +/- 0.74, 1.27 +/- 0.47, and 2.86 +/- 1.75 micro g/ml. The differences in concentrations in ELF among the two levofloxacin groups and azithromycin were significantly (P < 0.05) higher at the 4- and 12-h sampling times. The respective concentrations in AM for 500 mg of levofloxacin were 83.9 +/- 53.2, 18.3 +/- 6.7, and 5.6 +/- 3.2 micro g/ml; those for 750 mg of levofloxacin were 81.7 +/- 37.0, 78.2 +/- 55.4, and 13.3 +/- 6.5 micro g/ml; and those for azithromycin were 650 +/- 259, 669 +/- 311, and 734 +/- 770 micro g/ml. Azithromycin achieved significantly (P < 0.05) higher concentrations in AM than levofloxacin at all sampling times. The concentrations in ELF and AM following intravenous administration of levofloxacin and azithromycin were higher than concentrations in plasma. Further studies are needed to determine the clinical significance of such high intrapulmonary concentrations in patients with respiratory tract infections.     

Ocular distribution of intravenously administered lipid formulations of amphotericin B in a rabbit model

Little is known about the ocular penetration of amphotericin B (AMB) and its lipid formulations, the current drug of choice in fungal endophthalmitis. The ocular distribution of AMB lipid complex (ABLC), liposomal AMB (L-AMB), and AMB deoxycholate (D-AMB) was studied in a rabbit model. D-AMB (1 mg/kg of body weight/day), ABLC (5 mg/kg/day), or L-AMB (5 mg/kg/day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 consecutive days after induction of unilateral uveitis by intravitreal injection of endotoxin. AMB concentrations in aqueous humor, vitreous humor, and plasma were determined by high-pressure liquid chromatography 16 h after administration of a single dose or 24 h after the last of seven doses. After single-dose administration, L-AMB achieved at least eightfold-higher AMB concentrations in the aqueous of inflamed eyes than ABLC or D-AMB (1.21 +/- 0.58 micro g/ml versus 0.14 +/- 0.04 and 0.11 +/- 0.09 micro g/ml, respectively). At that time point no drug was detectable in the vitreous. After 7 days of treatment, the concentration of AMB in the vitreous was higher after treatment with L-AMB (0.47 +/- 0.21 micro g/ml) than after treatment with ABLC (0.27 +/- 0.18 micro g/ml) and D-AMB (0.16 +/- 0.04 micro g/ml). Similarly, AMB concentration in the aqueous was higher after repeated doses of L-AMB (0.73 +/- 0.43 micro g/ml) than after repeated doses of ABLC (0.03 +/- 0.02 micro g/ml) or D-AMB (0.13 +/- 0.06 micro g/ml). No AMB was detected in noninflamed eyes. Following systemic administration, AMB distribution to the eye is inflammation dependent and occurs sequentially, first to the aqueous and then to the vitreous. Compared to D-AMB and ABLC, L-AMB reaches higher drug concentrations in both ocular compartments.     

低频超声波对双氯芬酸钠体外经皮渗透的影响

背景：双氯芬酸钠是临床上常用的强效非类固醇抗炎镇痛药物,经皮渗透可以避免肝的首过作用和胃肠道破坏,但受角质层影响,渗透量小;低频超声波能够改善皮肤通透性,促进药物经皮吸收。目的：通过对低频超声对促进双氯芬酸钠药物经皮的吸收效果研究,确定适合该类药物的低频超声经皮渗透物理参数。方法：30只大鼠随机均分为10组,9组用于正交试验,1组用于不加超声波时的对照试验。取大鼠背部皮肤进行透皮实验,以超声波的频率、强度及作用时间为影响因素,渗透量为指标,采用正交试验法,对双氯芬酸钠进行大鼠离体皮肤体外渗透试验,考察双氯芬酸钠渗透效果最好时,低频超声波各个参数值最优配比,并与空白组对比,观察其显著意义。结果与结论：渗透量随着超声波的作用时间的延长而增加,且超声波频率和强度都对渗透量有一定的影响。正交试验筛选的低频超声波最佳配比的参数为频率20kHz,强度0.75W/cm2,作用时间15min。结果提示,低频超声波频率、强度、作用时间均对渗透量的影响显著（P〈0.01）,三者相比较,作用时间对双氯芬酸钠渗透性的影响最大。     

Pharmacokinetics and tissue penetration of tazobactam and piperacillin in patients undergoing colorectal surgery.

The pharmacokinetics of tazobactam and piperacillin in plasma and different tissues after a 30-min intravenous infusion of 4 g of piperacillin and 0.5 g of tazobactam were investigated in 18 patients who underwent elective colorectal surgery. Serial blood samples were collected for up to 6 h after the initiation of the infusion. The types of tissue collected were fatty tissue, muscle, skin, appendix, and intestinal mucosa (proximal and distal). On the basis of concentrations in plasma, the following pharmacokinetic parameter values were obtained (values are means +/- standard deviations): maximum concentration of drug in serum, tazobactam, 27.9 +/- 7.67 micrograms/ml; piperacillin, 259 +/- 81.8 micrograms/ml; time to maximum concentration of drug in serum, tazobactam, 0.51 +/- 0.03 h; piperacillin, 0.51 +/- 0.03 h; area under the concentration-time curve, tazobactam, 47.6 +/- 13.3 micrograms.h/ml; piperacillin, 361 +/- 80.3 micrograms.h/ml; clearance, tazobactam, 188 +/- 52.3 ml/min; piperacillin, 194 +/- 42.9 ml/min; half-life, tazobactam, 1.42 +/- 0.32 h; piperacillin, 1.27 +/- 0.24 h; apparent volume of distribution, tazobactam, 0.31 +/- 0.07 liter/kg of body weight; piperacillin, 0.29 +/- 0.06 liter/kg; volume of distribution at steady state, tazobactam, 0.28 +/- 0.04 liter/kg; piperacillin, 0.25 +/- 0.05 liter/kg. The concentrations of tazobactam and piperacillin in fatty tissue and muscle tissue were 10 to 13 and 18 to 30% of the levels in plasma, respectively. In skin, the concentrations of piperacillin were 60 to 95% of the levels in plasma, whereas the concentrations of tazobactam in plasma were 49 to 93% of the levels in skin tissue. The mean concentration of tazobactam in the investigated gastrointestinal tissues (appendix, proximal and distal mucosa) exceeded levels in plasma after 1 h, while piperacillin showed a mean penetration into these tissues of 43 and 53%. The mechanisms that can be used to explain the extent of penetration of piperacillin and tazobactam are discussed. Simple diffusion may take place in fatty and muscle tissue, while penetration into skin and gastrointestinal tissue is governed by more complex mechanisms which lead to differences in penetration between piperacillin and tazobactam. For all tissues investigated (except fatty tissue), the time course of the concentrations of both compounds was similar, with a peak in concentration at between 1 and 2 h after the start of infusion followed by a decline of concentrations that were almost parallel to the curves of the drug concentrations in plasma. In plasma and in all investigated tissues, piperacillin as well as tazobactam reached or exceeded the concentrations found to be effective in vitro.     

低频超声波对双氯芬酸钠体外经皮渗透的影响

背景:双氯芬酸钠是临床上常用的强效非类固醇抗炎镇痛药物,经皮渗透可以避免肝的首过作用和胃肠道破坏,但受角质层影响,渗透量小;低频超声波能够改善皮肤通透性,促进药物经皮吸收。目的:通过对低频超声对促进双氯芬酸钠药物经皮的吸收效果研究,确定适合该类药物的低频超声经皮渗透物理参数。方法:30只大鼠随机均分为10组,9组用于正交试验,1组用于不加超声波时的对照试验。取大鼠背部皮肤进行透皮实验,以超声波的频率、强度及作用时间为影响因素,渗透量为指标,采用正交试验法,对双氯芬酸钠进行大鼠离体皮肤体外渗透试验,考察双氯芬酸钠渗透效果最好时,低频超声波各个参数值最优配比,并与空白组对比,观察其显著意义。结果与结论:渗透量随着超声波的作用时间的延长而增加,且超声波频率和强度都对渗透量有一定的影响。正交试验筛选的低频超声波最佳配比的参数为频率20kHz,强度0.75W/cm2,作用时间15min。结果提示,低频超声波频率、强度、作用时间均对渗透量的影响显著(P<0.01),三者相比较,作用时间对双氯芬酸钠渗透性的影响最大。     

Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans.

It is known that the ingestion of glucose alone causes a greater increase in plasma glucose levels than ingestion of the same amount of glucose given with other nutrients. Since physiological plasma concentrations of cholecystokinin (CCK) prolong gastric emptying, it is proposed that after a meal, CCK may modify plasma glucose levels by delaying glucose delivery to the duodenum. To evaluate the effect of CCK on oral glucose tolerance, plasma CCK, insulin, and glucose levels and gastric emptying rates were measured in eight normal males before and after the ingestion of 60 g glucose with the simultaneous infusion of either saline or one of two doses of CCK-8 (12 or 24 pmol/kg per h). Gastric emptying rates were measured by gamma camera scintigraphy of technetium 99m sulfur colloid and plasma CCK levels were measured by a sensitive and specific bioassay. Basal CCK levels averaged 1.0 +/- 0.1 pM (mean +/- SEM, n = 8) and increased to 7.1 +/- 1.1 pM after a mixed liquid meal. After glucose ingestion, but without CCK infusion, CCK levels did not change from basal, and the gastric emptying t1/2 was 68 +/- 3 min. Plasma glucose levels increased from basal levels of 91 +/- 3.9 mg/dl to peak levels of 162 +/- 11 mg/dl and insulin levels increased from 10.7 +/- 1.8 microU/ml to peak levels of 58 +/- 11 microU/ml. After glucose ingestion, with CCK infused at 24 pmol/kg per h, plasma CCK levels increased to 8 pM and the gastric emptying t1/2 increased to 148 +/- 16 min. In concert with this delay in gastric emptying, peak glucose levels rose to only 129 +/- 17 mg% and peak insulin levels rose to only 24.2 +/- 4.2 microU/ml. With CCK at 12 pmol/kg per h, similar but less dramatic changes were seen. To demonstrate that endogenous CCK could modify the plasma glucose and insulin responses to oral glucose, oral glucose was given with 50 g of lipid containing long-chain triglycerides. This lipid increased peak CCK levels to 3.7 +/- 0.9 pM. Concomitant with this rise in CCK was a delay in gastric emptying and a lowering of plasma glucose and insulin values. To confirm that CCK reduced hyperglycemia by its effect on gastric motility, 36 g glucose was perfused directly into the duodenum through a nasal-duodenal feeding tube in four subjects. With duodenal perfusion of glucose, there was no change in plasma CCK levels, but plasma glucose levels increased from basal levels of 93+/-5 to 148+/-6 mg/dl and insulin levels rose from 10.6+/-3.5 to 29.5+/-5.2 microU/ml. When CCK was infused at 24 pmol/kg per h, neither the plasma glucose nor insulin responses to the duodenal administration of glucose were modified. Thus we conclude that CCK, in physiological concentrations, delays gastric emptying, slows the delivery of glucose to the duodenum, and reduces postprandial hyperglycemia. These data indicate, therefore, that CCK has a significant role in regulating glucose homeostasis in human.     

Transdermal delivery of timolol by electroporation through human skin.

The purpose was to achieve therapeutic fluxes of timolol by transdermal delivery using skin electroporation. The transdermal transport of timolol through human stratum corneum was studied in three compartment diffusion cells. The electrodes, buffer composition and pulse conditions were optimized. Timolol maleate concentration in the donor compartment was 40 mg/ml. Square wave pulses were applied. Electroporation enhanced the transdermal transport of timolol by 1-2 orders of magnitude as compared to passive diffusion. Even though the current application lasted for only 10 s, the transdermal transport remained high after pulsing for at least 6 h. Higher fluxes were obtained with Pt electrodes close to the skin and a phosphate buffer. 10 pulses of 400 V-10 ms were more efficient than 10 low voltage-long duration pulses. Therapeutic fluxes of timolol (>50 microg/cm(2) per h) through human stratum corneum were achieved by electroporation.     

Bioavailability of nerodilol-based transdermal therapeutic system of nicorandil in human volunteers.

The objective of the present investigation was to design and evaluate a nerodilol-based transdermal therapeutic system (TTS) for finding its ability in providing the desired steady-state plasma concentration of nicorandil in human volunteers. The influence of EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825-rat skin composite on the in vitro permeation of nicorandil from a nerodilol-based HPMC gel drug reservoir was studied against a control (excised rat skin alone). The flux of nicorandil from the nerodilol-based HMPC drug reservoir across excised rat skin (control) was 384.0+/-4.6 microg/cm2 h and this decreased to 222.7+/-7.1 microg/cm2 h when studied across EVA2825 membrane indicating that EVA2825 membrane was effective as rate controlling membrane. The flux of the drug decreased to 183.8+/-5.7 microg/cm2 h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat to EVA2825 membrane. However, the flux of nicorandil across adhesive-coated EVA2825-membrane-rat-skin composite was 164.8+/-1.8 microg/cm2 h, which was 1.74-times of the required flux that prompted for preparation of TTS. The nerodilol-based drug reservoir system was sandwiched between a composite of adhesive-coated EVA2825 membrane-release liner and a backing membrane. The resultant sandwich was heat-sealed to produce circle-shaped TTS (20 cm2) that were subjected to bioavailability study in human volunteers against immediate release nicorandil tablet. The nerodilol-based TTS provided a steady-state plasma concentration of 25.5 ng/ml for 24 h in human volunteers. It was concluded that the nerodilol-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations.     

Reduced blood-to-tissue albumin movement after plasmapheresis

We tested the hypothesis that a decrease in the blood-to-tissue movement of albumin contributes to the recovery of plasma albumin and plasma volume after acute plasma protein depletion (plasmapheresis). Awake and unrestrained male Sprague-Dawley rats (220-320 g) fitted with jugular catheters were plasmapheresed, and plasma volume, plasma albumin, and total plasma protein content were measured at 1, 5, 24, and 48 h postplasmapheresis. Plasma volume recovered to baseline within 1 h (4.6 +/- 0.42 vs. 4.7 +/- 0.46 mL/100 g body weight (bw), remained at baseline from 5 h to 24 h but increased to 5.5 + 0.57 mL/100 g bw at 48 h (P < 0.05). Plasma albumin and total protein content recovered rapidly but remained below baseline levels at 1 h (10.05 +/- 0.98 vs. 12.33 +/- 1.29 and 19.75 +/- 1.75 vs. 24.73 +/- 2.56 mg/100 g bw, respectively). Plasma protein content retumed to baseline by 5 h of recovery. Tissue uptake of I125-labeled albumin decreased in the heart, skin, skeletal muscle, and small Intestines of plasmapheresed rats (P < 0.05). These data support the hypothesis that a reduction in albumin efflux from the vascular space contrlbutes to the recovery of plasma albumin and total protein content during plasma volume recovery and eventual expansion after plasmapheresis.     

Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment.

The objective of the present study is to evaluate the efficacy and the safety of transdermal iontophoretic delivery of R-apomorphine, a potent dopamine agonist, in combination with surfactant pretreatment in patients with advanced Parkinson's disease. Iontophoresis patches were applied in 16 patients for 3.5 h, with 0.5 h of passive delivery followed by 3 h of current application at a current density of 250 microA/cm2. Eight of these patients were treated with a surfactant formulation prior to iontophoresis. The pharmacokinetics, pharmacodynamic effects, systemic and local side effects of R-apomorphine were assessed. The plasma concentration vs. time profiles upon iontophoresis of R-apomorphine were described successfully by a novel pharmacokinetic model. The model suggests that only 1.9% of the dose that has been released from the patch accumulated in the skin. The patients treated with the surfactant formulations showed a statistically significant increase of bioavailability (from 10.6+/-0.8% to 13.2+/-1.4%) and of the steady state input rate (from 75.3+/-6.6 to 98.3+/-12.1 nmol/cm2 h) compared to the control patients (iontophoresis without absorption enhancers). In five out of eight patients in the study group and in three out of eight patients in the control group, clinical improvement was observed.     

Importance of Hepatic Portal Circulation for Insulin Action in Streptozotocin-Diabetic Rats Transplanted with Fetal Pancreases

The importance of the hepatic portal circulation in the response to insulin was assessed in streptozotocin-diabetic rats transplanted with syngeneic fetal pancreases. Partial reversal of diabetes was accomplished by transplantation of two or three fetal pancreases beneath the capsule of the kidney; complete reversal followed shunting of the venous drainage from the transplants to the liver. Plasma glucose after streptozotocin of 509+/-31 mg/dl (mean+/-SEM) fell after transplantation to 395+/-23 and after the shunt to 143+/-5 mg/dl. Urine volume fell from 84+/-4 to 50+/-5 ml/d and then to normal (17+/-1 ml/d) after the shunt. Glucose excretion which was 8.1+/-0.3 g/d after streptozotocin fell after transplantation to 4.8+/-0.3 g/d and after the shunt completely disappeared from the urine. The disappearance rate of glucose injected into the circulation, which was 0.50+/-0.07%/min in untreated diabetes, increased to 1.39+/-0.38%/min after transplantation and to 2.52+/-0.31%/min after the shunt, not different from normal controls (2.79+/-0.25). Plasma immunoreactive insulin (IRI) was below normal (25-35 muU/ml) and unresponsive to glucose in untreated diabetic rats. After transplantation IRI levels ranged from 73-223 muU/ml and there was no rise after glucose injection. After the shunt both the basal IRI (36+/-5 muU/ml) and the peak response to glucose at 10 min (58+/-7 muU/ml) were the same as in normal controls (42+/-4 and 62+/-7 muU/ml, respectively). The fall in IRI after the shunt is explained by increased extraction of insulin passing into the liver and also diminished secretion. After removal of the transplants plasma glucose and urine values returned almost to pretransplant levels.Secretion of insulin by transplanted pancreases into the liver enhances the effectiveness probably by increased extraction and action and reveals the importance of the normal route for insulin delivery.     

Use of intravenous microdialysis to monitor changes in serotonin release and metabolism induced by cisplatin in cancer patients: comparative effects of granisetron and ondansetron

Serotonin [5-hydroxytryptamine (5-HT)] is involved in the production of emesis associated with cisplatin treatment. Serotonin released from intestinal enterochromaffin cells may act either directly on vagal afferents and/or pass to the circulation and stimulate central emetic centers. However, the role for circulating 5-HT has not been determined. In this study, i.v. microdialysis probes were used to investigate 1) cisplatin-induced changes in 5-HT release and metabolism assessed through changes in blood dialysate levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA), 2) whether free 5-HT in blood increases after cisplatin, and 3) whether granisetron and ondansetron exert different effects on cisplatin-induced 5-HT release and metabolism. Control experiments conducted in 10 healthy volunteers revealed stable 5-HT and 5-HIAA dialysate levels for a period of 6 h. In patients with cancer (n = 16), baseline blood dialysate 5-HIAA concentrations averaged 2.98 +/- 0.38 ng/ml, which were equivalent to a total of 94 +/- 10 pg in the 30-min collection period at a flow rate of 1 microl/min. Cisplatin (89 +/- 2.9 mg of cisplatin/m(2)) produced a gradual increase in blood dialysate 5-HIAA levels (104 +/- 4% increase at 4 h). Increases in dialysate 5-HIAA were associated with increases in the urinary excretion of this metabolite. After cisplatin, dialysate 5-HIAA levels increased to 5.89 +/- 0.5 ng/ml in granisetron and to 5.27 +/- 0.9 ng/ml in ondansetron-treated patients (P >.1). Similar time courses and percentages of increase in blood dialysate and urinary 5-HIAA levels were observed in ondansetron- and granisetron-treated patients. Contrary to 5-HIAA, no significant increases in dialysate 5-HT were observed from 2 to 8 h after cisplatin either for the total group or for each of the groups separately. In conclusion, i.v. microdialysis probes coupled to HPLC-EC allowed the continuous monitoring of free-5-HT and 5-HIAA in blood. Cisplatin-induced increases in blood 5-HIAA were not associated with increases in 5-HT blood dialysates. These results argue against a possible action of free 5-HT in plasma on the chemoreceptor trigger zone (unprotected from the blood brain barrier) but support the view that 5-HT released within the intestinal wall triggers emesis after cisplatin. Our results argue against the view that at clinically effective doses, granisetron and ondansetron exert different actions on cisplatin-induced 5-HT release and metabolism.     

Oral solid gentamicin preparation using emulsifier and adsorbent.

Oral gentamicin (GM) therapy has been challenged by formulating GM in oral solid preparation. GM was dispersed with a surfactant used for the self-microemulsifying drug delivery system (SMEDDS), PEG-8 caprylic/capric glycerides (Labrasol), and the mixture was solidified with several kinds of adsorbents. The used adsorbents were microporous calcium silicate (Florite RE), magnesium alminometa silicate (Neusilin US2), and silicon dioxide (Sylysia 320). In vitro release study showed that the percentage released of GM from each preparation per 2 h was 99.8+/-0.06% for Florite RE 10 mg, 96.7+/-1.16% for Florite RE 20 mg, 98.3+/-0.32% for Neusilin US2, and 94.4+/-0.23% for Sylysia 320. The T50% values were 0.35+/-0.05 h for Florite RE 10 mg, 0.34+/-0.03 h for Florite RE 20 mg, 0.26+/-0.03 h for Neusilin US2, and 0.15+/-0.01 h for Sylysia 320. The in vivo rat absorption study showed that Florite RE 10 mg preparation had the highest C(max) (2.14+/-0.67 microg/ml) and AUC (4.74+/-1.21 microg h/ml). Other preparations had C(max) and AUC of 0.69+/-0.10 microg/ml and 1.56+/-0.43 microg h/ml for Florite RE 20 mg, 1.07+/-0.31 microg/ml and 1.80+/-0.33 microg h/ml for Neusilin US2, and 0.99+/-0.21 microg/ml and 1.77+/-0.50 micorg h/ml for Sylysia 320, respectively. The bioavailability (BA) of GM from the microporous calcium silicate preparation, Florite RE 10 mg, was 14.1% in rats, derived by comparing the AUC obtained after intravenous injection of GM, 1.0 mg/kg, to another group of rats. The microporous calcium silicate preparation using Florite RE 10 mg was evaluated in dogs after oral administration in an enteric capsule, Eudragit S100 (50 mg/dog). High plasma GM levels were obtained (i.e., the C(max) was 1.26+/-0.20 microg/ml and the AUC was 2.59+/-0.33 microg h/ml). These results suggest that an adsorbent system is useful as an oral solid delivery system of poorly absorbable drugs such as GM.     

Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study

Purpose  

A novel transdermal formulation of granisetron (the granisetron transdermal delivery system (GTDS)) has been developed to deliver granisetron continuously over 7 days. This double-blind, phase III, non-inferiority study compared the efficacy and tolerability of the GTDS to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV).     

Concentrations of cefmetazole in plasma and tissue resulting from peri-incisional administration before appendectomy.

The levels of cefmetazole in plasma and tissue were determined after injection of a dose of 30 mg/kg into the zone of the wound of each of 15 patients undergoing appendectomy. The mean plasma levels of cefmetazole at the start and end of surgery (8.9 +/- 2.4 and 31.7 +/- 6.4 min after dosage) were 21.1 and 59.0 micrograms/ml, respectively; concentrations of the drug were 14.6 and 4,486.9 micrograms/g in skin, 9,165.0 and 1,756.4 micrograms/g in subcutaneous tissue, and 8,669.6 and 2,022.9 micrograms/g in muscle.