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We have recently discovered that peptides are absorbed biologically intact from the rat uterus. The purpose of this investigation was to assess whether EPO, a large polypeptide hormone (34.5 kDa), can be absorbed from the uterus into the systemic blood circulation in a biologically active form, and to compare the biological effects of continuous transendometrial (TE) administration of EPO with those of the pulsatile mode. Sprague-Dawley rats with gentamicin-induced anemia were treated with recombinant human erythropoietin (r-HuEPO) 200 U/kg per day for 5 days as follows: (1) the daily dose was instilled as a bolus through an indwelling cannula in the uterus; (2) the daily dose was continuously delivered into the uterus at a constant rate of 2 U /h by mini-osmotic pump connected to a similar cannula; (3) the third group received the daily r-HuEPO dose through the jugular vein; and (4) a control group treated with normal saline solution instilled in the uterus (as in group 1). The hematological parameters were measured for 53 days following initiation of r-HuEPO treatment. It was found that the biological effects following bolus daily transendometrial (TE) administration of EPO, expressed by red blood cell count and hematocrit levels, were equipotent to i.v. injection. On the other hand, the biological response following continuous TE EPO administration was significantly better than that observed following pulsatile administration. It is concluded that r-HuEPO is absorbed from the uterus in its bioactive form, with no deleterious effects on the uterine tissue. Slow release of EPO from a TE device may induce a beneficial biological response in comparison to pulsatile delivery.

The purpose of the present investigation was to evaluate whether antiinflammatory drugs affect the pharmacodynamics of theophylline-induced seizures. Adult male Lewis rats were treated with either dexamethasone (DEX), hydrocortisone (HYD), ibuprofen (IBU), or mefenamic acid (MFA), for 4 consecutive days. On the fourth day they received a constant infusion of theophylline (2 mg/min IV) until the onset of maximal seizures. Then, blood and cerebrospinal fluid (CSF) were obtained for theophylline concentration determinations by HPLC. It was found that pretreatment with the corticosteroids DEX and HYD elevated the CSF theophylline concentration required to induce maximal seizures in comparison to the untreated rats (242 +/- 6, 232 +/- 6, and 203 +/- 10 mg/l, respectively, n = 10, p0.05). MFA also increased the CSF theophylline concentration at that end-point in comparison to the controls (p0.01), whereas pretreatment with IBU had no effect (280 +/- 10 MFA, 225 +/- 9 IBU vs. 220 +/- 8 controls, n = 12). The data suggests that concomitant treatment with antiinflammatory drugs, together with theophylline, do not increase the risk for theophylline-induced seizures. Moreover, in certain cases they may elevate the seizure threshold and protect against these hazardous episodes.

The purpose of this investigation was to determine whether paraplegia induced by neoplastic cord compression affects the pharmacodynamics of phenobarbital general anesthesia or of pentylenetet-razol (PTZ)-induced convulsions. Paraplegic rats harboring a thora-columbar epidural tumor, or an identical hindlimb tumor mass, received an i.v. infusion of phenobarbital until the onset of anesthesia. At that point, the phenobarbital concentrations in the CSF and serum were measured. Similarly, PTZ was infused until the onset of maximal seizures. It was found that changes related to systemic tumor growth and newly developed paraplegia due to neoplastic spinal cord compression did not attenuate the pharmacodynamics of phenobarbital. However, sustained paraplegia of 4 days’ duration reduced CNS sensitivity to the hypnotic action of the barbiturate as evidenced by the higher cerebrospinal fluid phenobarbital concentration required to induce anesthesia (170 ± 31 vs 125 ± 20 mg/L; P < 0.05). On the other hand, sustained paraplegia did not affect brain threshold concentration for PTZ-induced seizures.

The aim of this investigation was to assess whether immunosuppression induced by total-body irradiation (TBI) affects the pharmacodynamics of centrally acting drugs. Female Sabra rats were exposed to a single dose of gamma irradiation (5.3 Gy). Four days later, when both the cellular and the humoral immune responses were impaired, they received an i.v. infusion of either phenobarbital (0.8 mg/min), ethanol (16.3 mg/min), pentylenetetrazol (PTZ; 0.618 mg/min), or theophylline (as aminophylline; 2 mg/min). The infusion was stopped at the onset of the pharmacologic end point—loss of righting reflex for the depressant agents or maximal seizures for the stimulant drugs—and the concentrations of the neuroactive drugs at that point were determined. In the ethanol experiment, blood samples were also taken upon awakening. The radiation-induced immunosuppression significantly decreased the CNS sensitivity to the depressant action of both phenobarbital and ethanol as indicated by the higher CSF phenobarbital concentrations required to induce sleep in the irradiated rats versus controls (156±4 vs 133 ±5 mg/L, respectively; P < 0.05), and the higher serum ethanol concentrations at the onset and offset of sleep in the immunosuppressed group versus control values (4.6±0.2 and 1.68±0.01 vs 3.79±0.17 and 1.32±0.9 mg/mL, respectively; P < 0.04). Exposure to TBI did not alter the pharmacodynamics of the two convulsant drugs (theophylline andPTZ).

Among numerous reported biochemical effects the lithium-inhibitable enzyme inositol-monophosphatase (IMPase) remains a viable target for lithium's therapeutic mechanism of action. Calbindin-D28k (calbindin) interacts with IMPase enhancing its activity. In the present study in silico modeling of IMPase-calbindin binding using the program MolFit indicated that the 55-66 amino acid segment of IMPase anchors calbindin via Lys59 and Lys61 with a glutamate in between (Lys-Glu-Lys motif). The model further suggested that the Lys-Glu-Lys motif interacts with residues Asp24 and Asp26 of calbindin. Indeed, we found that differently from wildtype calbindin, IMPase was not activated by mutated calbindin in which Asp24 and Asp26 were replaced by alanine. Calbindin's effect was significantly reduced by a peptide with the sequence of amino acids 58-63 of IMPase (peptide 1) and by six amino-acid peptides including at least part of the Lys-Glu-Lys motif. The three amino-acid peptide Lys-Glu-Lys or five amino-acid peptides containing this motif were ineffective. Intracerebroventricular administration of peptide 1 resulted in a significant antidepressant-like reduced immobility in the Porsolt forced swim test (FST) compared with mice treated with a scrambled peptide or artificial cerebrospinal fluid. Based on the sequence of peptide 1, and to potentially increase the peptide's stability, cyclic and linear pre-cyclic analog peptides were synthesized. One cyclic and one linear pre-cyclic analog peptides exhibited an inhibitory effect on calbindin-activated brain IMPase activity in vitro. These findings may lead to the development of molecules capable of inhibiting IMPase activity at an alternative site than that of lithium.

Objective. The aim was to characterize the transfer of the insulin analog glargine across the placenta using the placental perfusion model. Methods. Placentas were obtained and selected cotyledons were cannulated and dually perfused. Glargine, 50 mU/L (n = 2) and 200 mU/L (n = 1), and a reference marker, antipyrine (50 μg/mL), were added to the maternal circulation. Samples were taken from the maternal and fetal compartments. Results. Glargine was not detected in the fetal compartment. In the maternal compartment, the steady state concentration was 50% lower than the starting concentration. Conclusions. Glargine probably does not cross the human placenta. Reduced maternal steady state concentrations may suggest insulin uptake by the placenta.

Seizures, often with fatal outcome, are a manifestation of pronounced theophylline toxicity. Prodromal symptoms are not always apparent, and the seizures are reported to be, in certain cases, refractory to treatment with anticonvulsant drugs. The purpose of this investigation was to examine, by an established animal model, which of the commonly used anticonvulsants can reduce the central nervous system sensitivity to theophylline neurotoxicity and what should be the preferred treatment in cases in which theophylline toxicity is anticipated. The anticonvulsant agents in doses that are found to be effective in other types of experimentally induced seizures in rats, clonazepam 5 mg/ kg, diazepam 5 mg/kg, phenytoin 8 mg/kg, phenobarbital 100 mg/kg, valproic acid 150 mg/kg, and magnesium sulphate 300 mg/kg, or the vehicle (controls) were administered intravenously to Lewis female rats. Thirty minutes later, theophylline was infused at a constant rate of 1.3 mg/min until onset of maximal seizures. Theophylline concentrations in the cerebrospinal fluid, brain, and serum were assayed by a high-performance liquid chromatography method. It was found that pretreatment with either clonazepam, diazepam, phenobarbital, or valproic acid increased the central nervous system thresholds to the theophylline-induced seizures, whereas phenytoin and magnesium sulphate did not attenuate the sensitivity of the brain to the stimulatory action of this widely used bronchodilator. Therefore, whenever theophylline toxicity is suspected, treatment with either diazepam, clonazepam, phenobarbital, or valproic acid can reduce the hazard associated with theophylline-induced seizures.

Certain irregularities in calcium metabolism such as Paget's disease, osteoporosis, as well as osteolysis in bone cancer, are characterized by excessive destruction of the bone by resorption. In contrast, a number of clinically important diseases, for example, atherosclerosis, kidney and renal calculu8, arthritis, and bioprosthetic heart valve calcification are characterized by the deposition of calcium phosphate. nis~hosphonates are a relct3vely new class of drugs, that have been used in these diseases to inhibit both mineralization and bone resorption, following the recognition, that they are stable analogs of endogenous pyrophosphate, which is a physiological inhibitor of calcification and bone resorption. A number of geminal bisphosphonates, namely, Pamidronate (ABP), Etidronate (HEBP), and Clodronate (ClMBP), have been approved for clinical use.

High molecular weight drugs in general, and peptides in particular, are usually delivered by parenteral route because they are poorly absorbed or degraded in the gastrointestinal tract. To optimize therapy, it is desirable to search for nonparenteral routes of administration and to deliver the drug in a controlled-release fashion. We report here on the absorption and the systemic biological effect of two peptides, insulin and calcitonin, after instillation into the uterus of the rat. Intrauterine delivery was compared to subcutaneous injections in intact and ovariectomized rats. In addition, we describe results of a preliminary study on calcitonin absorption from controlled-release matrices inserted in the rat uterus. The amount and duration of the hypoglycemic and the hypocalcemic effects induced by intrauterine delivery of insulin and calcitonin, respectively, were equivalent to those obtained after subcutaneous injections. The results were similar in intact and ovariectomized rats. It is concluded that the intrauterine administration of both insulin and calcitonin is bioequivalent to subcutaneous injection. The therapy of a number of clinically important diseases could benefit from this discovery.

International audience; Rational conversion of noncontinuous active regions of proteins into a small orally bioavailable molecule is crucial for the discovery of new drugs based on inhibition of protein-protein interactions. We developed a method that utilizes backbone cyclization as an intermediate step for conversion of the CD4 noncontinuous active region into small macrocyclic molecules. We demonstrate that this method is feasible by preparing small inhibitor for human immunodeficiency virus infection. The lead compound, CG-1, proved orally available in the rat model.

P-Glycoprotein (PGP) is nonuniformly distributed along the gastrointestinal (GI) tract; however, the data regarding regional differences in PGP function in the intestine are controversial. The aim of this work was to investigate the role of PGP efflux in region-specific absorption of talinolol from the GI tract in rats. Plasma talinolol concentrations were measured after several modes of administration, including high (40 mg/kg) and low (4 mg/kg) dose levels, to different segments of the GI tract (stomach versus colon), and codosing with PGP inhibitors (verapamil or cyclosporine). The bioavailability (F) of talinolol after high-dose administration to the stomach was significantly greater than that achieved by the low dose (approximately 18 versus 2%). Coadministration of low-dose talinolol with cyclosporine increased F by approximately 5-fold (p < 0.01). For the high dose, codosing with PGP inhibitors did not increase the extent of absorption. Talinolol demonstrated poor colonic absorption that was significantly increased by coadministration with cyclosporine (F = 0.76 versus 8.1%). Oral verapamil significantly increased systemic clearance and the steady state volume of distribution of intravenous talinolol. A semiphysiological model was developed that successfully captured the pharmacokinetic profiles of talinolol after various modes of administration. PGP-mediated efflux appears to be a major factor responsible for GI region-specific absorption of talinolol in rats, and gastroretentive dosage forms may provide an advantage in the delivery of talinolol and PGP substrate drugs.

The [3H]tetracycline ([3H]TC) model is based on the observation that TC is released from the bones of rats prelabeled with [3H]TC via first-order kinetics, a factor directly reflecting the kinetics of bone resorption. In the present paper we applied the [3H]TC elimination model to rats treated with antiresorptive drugs. The validity of this model was evaluated by examining the effect of the bisphosphonate, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (ABP), and a novel bisphosphonate, dihydrogen disodium adipoylbisphosphonate (AdBP), on serum TC levels and the elimination rate constant. ABP and AdBP significantly inhibited the TC elimination rate. However, ABP treatment caused impairment of bone mineralization, renal dysfunction, and inhibition of somatic growth. It is concluded that antiresorptive effects of bisphosphonates could be evaluated by the [3H]TC model, but this model is limited to animals with normal kidney function. The experimental conditions provide a technically simple method which is sensitive enough to examine antiresorptive properties in a healthy animal and to detect adverse effects on the kidney. The activity of the novel bisacylphosphonate, AdBP, and lack of its adverse effects indicate the potential of this drug for clinical applications.

Chemotherapy with high-dose methotrexate (HD-MTX) is often associated with acute neurotoxicity. We determined whether the altered neuronal function after HD-MTX [such as the reduced regional cerebral metabolic glucose rate (rCMRGlc) and slow electroencephalographic pattern] affects the sensitivity of the CNS to centrally acting drugs: the depressant phenobarbital, which reduces rCMRGlc, and the analeptic agent pentylenetetrazol (PTZ), which elevates rCMRGlc. Adult male Sabra rats received an i.v. infusion of MTX, 0.51 mg/min, to induce neurotoxicity or saline solution for 24 hr. Subsequently, MTX-treated and control groups were infused in one experiment with phenobarbital until loss of the righting reflex and in the second experiment with PTZ until the onset of maximal seizures. HD-MTX did not affect the infused hypnotic dose or serum, brain, and cerebrospinal fluid concentrations of phenobarbital at the onset of anesthesia. The convulsive dose and PTZ concentrations in the serum and brain at the onset of maximal seizures were significantly higher in the HD-MTX-treated animals. These outcomes indicate that HD-MTX and the reduced rCMRGlc that follows this treatment do not contribute to the hypnotic action of phenobarbital. On the other hand, treatment with HD-MTX exhibited anticonvulsant properties as evidenced by the reduced CNS sensitivity to PTZ-induced seizures.

The potential of peptides as drug candidates is limited by their poor pharmacokinetic properties. Many peptides have a short half-life in vivo and a lack of oral availability. Inspired by the excellent pharmacokinetic profile of cyclosporine, a natural, multiply N-methylated cyclic peptide, we envisioned multiple N-methylation as a promising way to rationally improve key pharmacokinetic characteristics. In this Account, we summarize our efforts toward modulating the properties of peptides by multiple N-methylation. As a first step, we simplified the synthesis of N-methylated amino acids in solution, by employing very mild conditions that could be tolerated by the diverse protecting groups required when working with naturally occurring amino acids. We also report the rapid and inexpensive syntheses of N-methylated peptides on a solid support; this facilitated the N-methyl scanning of bioactive peptides. Because of a lack of information regarding the conformational behavior of multiply N-methylated peptides...

Although abdominal surgery is a routine procedure in clinical practice and in preclinical investigation, little is known regarding its effect on the intestinal absorption of drugs. The aim of this study was to investigate the effect of abdominal surgery on the intestinal absorption of highly lipophilic compounds with different absorption mechanisms following oral administration. The 2 compounds that were tested were biopharmaceutical classification system (BCS) class 2 model lipophilic cannabinoid derivatives, dexanabinol and PRS-211,220. Although dexanabinol is mostly absorbed via passive diffusion to the portal blood, PRS-211,220 is absorbed mostly via lymphatic transport. In this work, we compared the absorption of these compounds after abdominal surgery in rat with the absorption data obtained from naive animals. The outcomes of this investigation showed that the abdominal surgery mostly affected the absorption process on the preenterocyte level, as indicated by the 2-fold increase in the extent of intestinal absorption of dexanabinol, which is a compound with a low degree of intestinal lymphatic transport. However, the lymphatic transport was not affected by the surgical procedure as evident by the absence of change in the extent of absorption of PRS-211,220, which is transported to the systemic circulation mainly by intestinal lymphatics. In conclusion, abdominal surgery can significantly affect the intestinal absorption of lipophilic drugs; however, intestinal lymphatic transport seems to be less affected by the abdominal surgery.

Objectives The uptake of drugs by chylomicrons is a key element in both intestinal lymphatic transport and postprandial alterations in the disposition profile of lipophilic drugs. The aim of this article was to elucidate the factors that affect this phenomenon. Methods The degree of association of 22 model lipophilic molecules with rat chylomicrons was assessed and correlated in silico with calculated physicochemical properties. The in-silico model was then validated using an external set of molecules. The uptake by chylomicrons was also compared to the association with a marketed artificial emulsion. Key findings The most important physicochemical property that affects the affinity to chylomicrons was found to be LogD7.4; however, a multiparameter model was required to describe properly the uptake process. The in-silico model (R2Y = 0.91, R2X = 0.91 and Q2 = 0.82) that was created using a combination of eight molecular descriptors enabled successful prediction of the affinity of the external set of molecules to chylomicrons. The association with the artificial emulsion was statistically different from the uptake by chylomicrons for four (out of nine) molecules. Conclusions The association of drugs with chylomicrons is a complex process, which involves the lipophilic core as well as surface apoproteins. The in-silico model based on multiple physicochemical properties of the drugs is able to predict successfully the degree of association with chylomicrons.

Increased life expectancy is associated with an increased prevalence of chronic diseases and drug consumption. Changes often occur in the medication regimen after hospitalization. The extent and nature of these changes and the adherence of elderly patients have not yet been fully investigated.To investigate the extent and reasons for modifications to the medication regimens of elderly patients and their adherence to treatment during the first month following hospital discharge.This was a prospective cohort study of 198 patients agedor=65 years in the Acute Geriatric Ward, Beilinson Hospital, Rabin Medical Center, Israel. Clinical, demographic and medication regimen data were recorded for all patients at an interview conducted prior to discharge. After 1 month, the patient, caregiver or general practitioner (GP) were interviewed regarding the extent and reasons for modifications to the medication regimen and adherence to treatment.At 1-month post-discharge, on average, 36.7% of patient medications had been modified compared with the discharge prescription. No modification was found in 16% of patients. During the observation month, 62% of prescribed long-term medications were taken without modification as recommended at discharge and during follow-up, 50% of all changes were characterized by the addition of a drug or an increase in dosage, and 26%, 16% and 8% consisted of cancelling, omission or switching within the same medication type, respectively. Seventy percent of medication regimen changes were based on specialists' recommendations or secondary to a change in the patients' medical state, and 13%, 8%, 3% and 6% were as a result of poor adherence, adverse effects, administrative restrictions and other reasons, respectively. There was no correlation between medication regimen change and age, gender, physical function, cognitive function and length of hospital stay. Patients discharged home experienced less regimen modification than those discharged elsewhere (p=0.02). Patients who visited their GP only once experienced less regimen modification (p=0.03). Regression analysis showed that the only factors affecting medication regimen changes were GP visits and chronic diseases (p0.01, R2=0.09). The overall mean adherence among 145 home-dwelling patients was 96.7%. Twenty-seven percent and 6% were under- and over-adherent, respectively, to at least one drug; under-adherence was more widespread than over-adherence. No correlation was found between the overall mean adherence and other clinical parameters or regimen change. However, non-adherence to at least one drug was associated with more medication regimen changes (p=0.001), was more common in patients discharged with prescriptions for seven or more drug types per day (p=0.01) and was associated with failing to visit the patient's GP 1 month after discharge (p=0.02).The majority of elderly patients experienced modifications in their medication regimen during the first month following hospital discharge. Thirty percent of patients were non-adherent to at least one drug. To improve adherence to a hospital medication regimen, patients should be encouraged to visit their GP and the number of long-term drugs should be reduced.

Backbone cyclization (BC) and N-methylation have been shown to enhance the activity and/or selectivity of biologically active peptides and improve metabolic stability and intestinal permeability. In this study, we describe the synthesis, structure-activity relationship (SAR) and intestinal metabolic stability of a backbone cyclic peptide library, BL3020, based on the linear alpha-Melanocyte stimulating hormone analog Phe-D-Phe-Arg-Trp-Gly. The drug lead, BL3020-1, selected from the BL3020 library (compound 1) has been shown to inhibit weight gain in mice following oral administration. Another member of the BL3020 library, BL3020-17, showed improved biological activity towards the mMC4R, in comparison to BL3020-1, although neither were selective for MC4R or MC5R. N-methylation, which restrains conformational freedom while increasing metabolic stability beyond that which is imparted by BC, was used to find analogs with increased selectivity. N-methylated backbone cyclic libraries were synthesized based on the BL3020 library. SAR studies showed that all the N-methylated backbone cyclic peptides demonstrated reduced biological activity and selectivity for all the analyzed receptors. N-methylation of active backbone cyclic peptides destabilized the active conformation or stabilized an inactive conformation, rendering the peptides biologically inactive. N-methylation of backbone cyclic peptides maintained stability to degradation by intestinal enzymes.

The potential of peptides as drug candidates is limited by their poor pharmacokinetic properties. Many peptides have a short half-life in vivo and a lack of oral availability. Inspired by the excellent pharmacokinetic profile of cyclosporine, a natural, multiply N-methylated cyclic peptide, we envisioned multiple N-methylation as a promising way to rationally improve key pharmacokinetic characteristics. In this Account, we summarize our efforts toward modulating the properties of peptides by multiple N-methylation. As a first step, we simplified the synthesis of N-methylated amino acids in solution, by employing very mild conditions that could be tolerated by the diverse protecting groups required when working with naturally occurring amino acids. We also report the rapid and inexpensive syntheses of N-methylated peptides on a solid support; this facilitated the N-methyl scanning of bioactive peptides. Because of a lack of information regarding the conformational behavior of multiply N-methylated peptides, a complete library of N-methylated cyclic alanine pentapeptides was synthesized. The library provided valuable insight into the conformational modulation of cyclic peptides by N-methylation. This information is extremely valuable for the design of bioactive peptides and spatial screening of cyclic N-methylated peptides. To demonstrate the applicability of N-methylation to highly active but poorly bioavailable peptides, we performed a full N-methyl scan of the cyclopeptidic somatostatin analog cyclo(-PFwKTF-), known as the Veber-Hirschmann peptide. We show here for the first time that the simple approach of multiple N-methylation can drastically improve the metabolic stability and intestinal permeability of peptides, for example, resulting in 10% oral bioavailability for a tri-N-methylated Veber-Hirschmann peptide analog. In addition, we also describe a designed approach to N-methylated peptide library synthesis, which can accelerate the screening of N-methylated bioactive peptides. Finally, we find that multiple N-methylation of a cyclic hexapeptide integrin antagonist of GPIIb-IIIa (alphaIIb beta3 integrin), cyclo(-GRGDfL-), increases the selectivity of this peptide toward different integrin subtypes. This result demonstrates the utility of multiple N-methylation in elucidating the bioactive conformation of peptides.

The design of a proper region-specific oral drug delivery system has to take into consideration the differences in anatomy, physiology and absorption characteristics that exist between segments within the gastrointestinal (GI) tract, as well as transit kinetics of the dosage form and the site of drug release within the GI tract.The aim of this review is to examine the various biopharmaceutical aspects of region-specific drug delivery in the GI tract.This review is mainly focused on pharmacokinetic and pharmacodynamic aspects of region-selective drug delivery with special emphasis on drug absorption pathways (para- and transcellular, absorption and efflux transporters, lymphatic uptake etc.). It includes a discussion of gastroretentive systems, colonic delivery, and lipid-based formulations. The review also addresses targeted therapy of local diseases within the GI tract.The advances in pharmaceutical technology allow for the development of a variety of region-specific drug delivery systems for oral administration to optimize local and systemic therapy.

The oral administration of insulin is difficult to achieve because the large peptide hormone is poorly absorbed and is subjected to enzymatic and acidic degradation in the stomach. Emisphere Technologies Inc is developing formulations of insulin co-administered with a drug delivery agent. With the proprietary Eligen technology employed, the carrier agent appears to form a conformational complex with insulin that can protect against degradation and facilitate the absorption of the hormone through the intestinal wall. In animal studies and phase I clinical trials, dosing with Eligen insulin led to a rapid elevation of plasma insulin and subsequent decrease in plasma glucose levels; the onset of activity was more rapid and insulin concentrations were higher with Eligen insulin than with injected insulin. Formulations of Eligen insulin have been well tolerated in all clinical trials performed to date. In a phase II clinical trial in patients with type 2 diabetes, Eligen insulin in combination with metformin failed to achieve significant superior glycemic control over treatment with metformin alone. Eligen oral insulin formulations may have potential as prandial insulin therapies in patients with either type 1 or type 2 diabetes; however, no clinical trials for such treatments appeared to be ongoing at the time of publication.

Parkinson's disease (PD) is a progressive neurodegenerative, dopamine deficiency disorder. The main therapeutic strategies for PD treatment relies on dopamine precursors (levodopa), inhibition of dopamine metabolism (monoamine oxidase [MAO] B and catechol-O-methyl transferase inhibitors), and dopamine receptor agonists. Recently, a novel selective and irreversible MAO B propargylamine inhibitor rasagiline (N-propargyl-1-R-aminoindan, Azilect((R))) was approved for PD therapy. In contrast to selegiline, the prototype of MAO B inhibitors, rasagiline is not metabolized to potentially toxic amphetamine metabolites. The oral bioavailability of rasagiline is 35%, it reaches T(max) after 0.5-1 hours and its half-life is 1.5-3.5 hours. Rasagiline undergoes extensive hepatic metabolism primarily by cytochrome P450 type 1A2 (CYP1A2). Rasagiline is initiated at 1 mg once-daily dosage as monotherapy in early PD patients and at 0.5-1 mg once-daily as adjunctive to levodopa in advanced PD patients. Rasagiline treatment was not associated with "cheese effect" and up to 20 mg per day was well tolerated. In PD patients with hepatic impairment, rasagiline dosage should be carefully adjusted. Rasagiline should not be administered with other MAO inhibitors and co-administration with certain antidepressants and opioids should be avoided. Although further clinical evidence is needed on the neuroprotective effects of rasagiline in PD patients, this drug provides an additional tool for PD therapy.

The tetrapeptide sequence His-Phe-Arg-Trp, derived from melanocyte-stimulating hormone (alphaMSH) and its analogs, causes a decrease in food intake and elevates energy utilization upon binding to the melanocortin-4 receptor (MC4R). To utilize this sequence as an effective agent for treating obesity, we improved its metabolic stability and intestinal permeability by synthesizing a library of backbone cyclic peptidomimetic derivatives. One analog, peptide 1 (BL3020-1), was selected according to its selectivity in activating the MC4R, its favorable transcellular penetration through enterocytes and its enhanced intestinal metabolic stability. This peptide was detected in the brain following oral administration to rats. A single oral dose of 0.5 mg/kg in mice led to reduced food consumption (up to 48% vs the control group) that lasted for 5 h. Repetitive once daily oral dosing (0.5 mg/kg/day) for 12 days reduced weight gain. Backbone cyclization was shown to produce a potential drug lead for treating obesity.

The central nervous system (CNS) sensitivity to the hypnotic (general anesthetic) action of pheno-barbital and to the neurotoxic (convulsive) action of theophylline is greater in rats with acute renal failure than in normal animals, consistent with clinical observations. In the case of phenobarbital, this increased sensitivity can be produced in normal rats by infusion of a solution of the lyophilized dialysate of serum from rats with renal failure. It was hypothesized that the relevant constituent(s) of this dialysate may circulate between the blood and the intestinal lumen and that it (they) can be adsorbed by orally administered activated charcoal and thereby removed from the body. If so, treatment of renal failure rats with activated charcoal should partly reverse the increased CNS sensitivity to phenobarbital and to other drugs similarly affected. Accordingly, rats with renal failure produced by bilateral ligation of ureters were given an aqueous suspension of activated charcoal, about 1 g per kg body weight, orally every 8 hr for six doses. Uremic controls received equal volumes of water. About 2 hr after the last dose, the animals were infused i.v. with phenobarbital to onset of loss of righting reflex or with theophylline to onset of maximal seizures. In the phenobarbital study, charcoal treatment partly reversed the hypothermia associated with renal failure and caused a reduction of creatinine and total bilirubin concentrations in serum. The cerebrospinal fluid (CSF) concentration of phenobarbital at onset of loss of the righting reflex was significantly higher in charcoal treated rats than in their controls. In the theophylline experiment, charcoal treatment had no significant effect on the measured biochemical variables but caused a large increase in the dose and concentrations of theophylline required to produce maximal seizures. In both experiments, administration of activated charcoal caused a reversal of the hyperalgesia associated with renal failure, as determined before drug administration by tail flick latency. These results are consistent with the hypothesis that oral administration of activated charcoal can cause a reduction in the concentration of the circulating endogenous substance(s) that alters the pharmacodynamics of certain drugs in renal failure.

The mechanism by which microcapsule aggregation is diminished in the presence of low concentrations of adjunct non-walling polymers such as polyisobutylene (PIB) in organic solvents is uncertain. It is here investigated by phase separation studies employing the non-solvent addition method (cyclohexane) in parallel with microencapsulation experiments, using Eudragit wall polymers and tetrahydrofurane (THF) as solvent with and without PIB. Polymer incompatibility leads to formation of two dilute liquid phases and emulsification from the outset. Progressive solvent transfer to the PIB phase modulates the rate of wall polymer desolvation and maintains the concentrated wall polymer phase in a fluid state during the critical microencapsulation stages of wall polymer entrapment--and spreading. A three-phase system is formed when gelling ensues (L1 + L2 + gel). In the absence of PIB, phase separation leads immediately to deposition of the wall polymer in gel form (L1 + gel) leading to adhesion. Phase diagrams are presented.

As a consequence of modern drug discovery techniques, there has been a consistent increase in the number of new pharmacologically active lipophilic compounds that are poorly water soluble. A great challenge facing the pharmaceutical scientist is making these molecules into orally administered medications with sufficient bioavailability. One of the most popular approaches to improve the oral bioavailability of these molecules is the utilization of a lipid based drug delivery system. Unfortunately, current development strategies in the area of lipid based delivery systems are mostly empirical. Hence, there is a need for a simplified in vitro method to guide the selection of a suitable lipidic vehicle composition and to rationalize the delivery system design. To address this need, a dynamic in vitro lipolysis model, which provides a very good simulation of the in vivo lipid digestion process, has been developed over the past few years. This model has been extensively used for in vitro assessment of different lipid based delivery systems, leading to enhanced understanding of the suitability of different lipids and surfactants as a delivery system for a given poorly water soluble drug candidate. A key goal in the development of the dynamic in vitro lipolysis model has been correlating the in vitro data of various drug-lipidic delivery system combinations to the resultant in vivo drug profile. In this paper, we discuss and review the need for this model, its underlying theory, practice and limitations, and the available data accumulated in the literature. Overall, the dynamic in vitro lipolysis model seems to provide highly useful initial guidelines in the development process of oral lipid based drug delivery systems for poorly water soluble drugs, and it predicts phenomena that occur in the pre-enterocyte stages of the intestinal absorption cascade.

A library of 18 hexapeptide analogs was synthesized, including sub-libraries of N- or C-methylation of the parent hexapeptide Phe-Gly-Gly-Gly-Gly-Phe, as well as backbone cyclized analogs of each linear analog with various ring sizes. N- or C-methylation as well as cyclization (but not backbone cyclization) have been suggested to improve intestinal permeability and metabolic stability of peptides in general. Here we aimed to assess their applicability to hydrophilic peptides. The intestinal permeability (Papp) of the 18-peptide library was in the range of 0.2-6.8 x 10-6 cm/sec. Based on several tests, we concluded that the absorption mechanism of all tested analogs is paracellular, regardless of the structural or conformational modifications. In all cases, backbone cyclization increased Papp (5-fold) in comparison to the linear analogs due to the smaller 3D size and also dramatically decreased peptide proteolysis by brush border enzymes. N- or C-methylation did not enhance the permeability of the linear analogs in this series.

The purpose of this study was to evaluate the oral absorption characteristics of a phospholipid-drug conjugate, comprising direct conjugation between the lecithin and the drug moiety through the sn-2 position. We investigated the mechanisms involved with the trafficking of this conjugate following oral administration in the gastrointestinal (GI) lumen, within the enterocyte and further. A phospholipid-valproic acid conjugate (DP-VPA) was utilized as a model molecule. The oral absorption of this conjugate in rats was investigated following administration in long (LCT) vs. medium (MCT) chain triglyceride formulations, and in the postprandial vs. fasted state. Oral administration within the LCT solution caused more than a 3-fold increase in DP-VPA bioavailability in comparison to the MCT solution. Moreover, a significant food effect was evident for DP-VPA. Hence, we evaluated the lymphatic transport of DP-VPA in mesenteric lymph duct cannulated freely moving rats. Sixty percent of the absorbed DP-VPA was associated with lymphatic transport. Similar DP-VPA absorption was obtained in secretory type II PLA(2) knockout mice (C57BL/6) and in control mice (BALB/c). Moreover, nil DP-VPA degradation in serum and very low (4.8%) degradation by bee venom PLA(2)in vitro were obtained. In conclusion, direct conjugation between the drug and the phospholipid produces a complex having unique absorption properties that include: (1) a stable complex that does not undergo degradation in the GI tract; (2) permeation through the gut wall and entering intact to the enterocyte; and (3) association with chylomicron in the enterocyte and reaching the systemic circulation via the lymphatic route. These unique properties may be of interest in drug delivery.

DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A2 (PLA)(2) to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following indomethacin administration. The brain to serum ratio was 3.5 times higher for DP-155 than for indomethacin. In vitro studies demonstrated that DP-155 is a selective cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its indomethacin derivative nonselectively inhibits both COX-1 and -2. DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its indomethacin metabolite. DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while indomethacin caused gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with DP-155 compared to indomethacin. In addition to reduced toxicity, DP-155 had similar ameliorative effects to indomethacin in antipyretic and analgesia models. Moreover, DP-155 and indomethacin were equally efficacious in reducing levels of amyloid ss (Ass)42 in transgenic Alzheimer's disease mouse (Tg2576) brains as well as reducing Ass42 intracellular uptake, neurodegeneration, and inflammation in an in vitro AD model. The relatively high brain levels of indomethacin after DP-155 administration explain the equal efficacy of DP-155 despite its low systemic blood concentrations. Compared to indomethacin, the favored safety profile and equal efficacy of DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for analgesia.

An unselective cyclic peptide integrin ligand was sequentially N-methylated by a designed approach, where only the externally oriented (solvent exposed) amide bonds were N-methylated. The N-methylation resulted in tremendous enhancement in selectivity among the different integrin receptor subtypes (alpha5beta1, alphavbeta3, and alphaIIbbeta3). Conformational and docking studies were performed, which suggested that the receptor selectivity is principally caused by reduced backbone flexibility due to N-methylation.

Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel Psychiatry Research Unit, Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel

Cerebrotendinous xanthomatosis (CTX) is a rare neurodegenerative disorder with cholestanol accumulation resulting from mutations in the sterol 27-hydroxylase gene (CYP27A). Conventional treatment includes chenodeoxycholic acid and HMG-CoA reductase inhibitors. Mice with disrupted Cyp27A (Cyp27 KO) do not show elevated cholestanol levels nor develop CTX manifestations. This phenomenon was proposed to be due to murine CYP3A overexpression leading to an alternative pathway for degradation of bile alcohols including cholestanol. Our objective was to examine the influence of CYP3A4 induction on cholestanol elimination in CTX patients. Rifampicin (600 mg/day x 7 days), known to induce the PXR, and thereby to increase CYP3A activity, was used. The degree of CYP3A4 induction was assessed by comparing midazolam pharmacokinetics before and after rifampicin treatment. Cholestanol levels and cholestanol/cholesterol ratios were assayed during the experimental period and compared to a 3 weeks period without treatment. The results show that despite 60% increase in CYP3A4 activity following rifampicin treatment, there is no significant change in cholestanol levels. We conclude that up-regulated expression of CYP3A affects cholestanol elimination in mice differently as compared to its effect in CTX patients. Therefore, CYP3A4 inducers cannot replace chenodeoxycholic acid for the treatment of CTX.

The purpose of this study was to investigate the impact of different lipid based formulations of lipophilic drugs on in vitro solubilization and intestinal ex vivo permeability processes. Thereafter, to evaluate the ability of these in vitro and ex vivo results to predict the corresponding in vivo oral bioavailability data. The dissolution of dexamethasone and griseofulvin in long (LCT), medium (MCT) and short (SCT) chain triglyceride formulations was tested in a dynamic in vitro lipolysis model. Following the completion of the lipolysis, the permeability through the gut wall was tested in an ex vivo side-by-side diffusion chamber model. The absolute oral bioavailability of the drugs from the tested formulations was investigated in rats. The dynamic in vitro lipolysis experiments indicated an equivalent performance of the different formulations for dexamethasone, and a performance rank order of MCT>LCT>SCT>H(2)O for griseofulvin. In the subsequent ex vivo permeability studies, the SCT formulation caused enhanced permeation with doubled permeability coefficient for both drugs. The in vivo bioavailability of both drugs correlated well with the in vitro data, i.e., LCT=MCT=SCT for dexamethasone and MCT>LCT>SCT>H(2)O for griseofulvin, despite the significant augmented intestinal permeability produced by the SCT formulation. In conclusion, the in vitro lipolysis model was found to be useful in the intelligent optimization of oral lipid formulations for lipophilic drugs, even in the case where the intestinal permeability is enhanced by the formulation. The SCT vehicle showed to be a potential permeability enhancer; however, for class 2 compounds, the permeability does not correlate with in vivo bioavailability.

The purpose of this study was to assess the contribution of lymphatics to the systemic bioavailability of macromolecules following SC administration in a rat model. The rat model included continuous lymph collection from the thoracic lymph duct and concurrent serial blood sampling from freely moving animals. A thoracic lymph duct-jugular vein shunt produced by an implanted connective cannula, and maintained during the recovery period, enabled superior rat survival and prevented lymphatic cannula occlusion. The SC absorption of three macromolecules (bovine insulin, bovine serum albumin, and recombinant human erythropoietin alpha) was assessed in comparison to the non-lymph cannulated control group. For all tested molecules, only minimal amounts (less than 3%) of the SC administered dose were detected in the collected lymph. In the rat model, following SC administration, the macromolecules were absorbed mainly through the blood capillaries with minimal contribution of the lymphatic system to systemic bioavailability. The relatively small elevation in the lymphatic concentration, which occurred in all molecules, may be attributed to the redistribution of the molecules from the blood to the interstitial fluid compartment. These findings are important since rodents are commonly used in preclinical evaluation of macromolecular drugs.

Purpose: To investigate a novel mechanism for oral controlled release of drugs involving a continuous degradation of a phospholipid prodrug along the intestine. An indomethacin–lecithin conjugate with the drug attached to the sn-2 position of the phospholipid through a 5-carbon linker (DP-155) was used as a model molecule. Methods: The pharmacokinetics of DP-155 and free indomethacin liberated from the prodrug following intravenous, oral or intra-colon administration was investigated in rats, and evaluated in comparison to free indomethacin administration. Degradation by phospholipase A2 (PLA2) enzymes was assessed in-vitro. The impact of the linker length was evaluated in comparison to an indomethacin–phospholipid conjugate with a shorter linker (2-carbons). Results: Following oral or intra-colon DP-155 administration, free indomethacin was liberated along the intestine and absorbed into the systemic circulation, resulting in a controlled release profile of indomethacin in the plasma. The shorter linker caused a 20-fold decrease in the subsequent indomethacin absorption. DP-155 in-vitro degradation by PLA2 was over 60%, while shorter linkers were profoundly less degradable. Conclusions: DP-155 caused a continuous input of free indomethacin into the plasma following degradation by PLA2 in the gut lumen. Since the rate of drug release is not formulation dependent, the prodrug can be compounded even in a liquid dosage form. The phospholipid–drug conjugate is thus a potential novel mechanism for oral controlled release of drugs. © 2007 Elsevier B.V. All rights reserved.

Association of a drug with chylomicrons in the enterocyte is an essential step in the lymphatic absorption pathway. In this article, the uptake of lipophilic compounds by chylomicrons ex vivo was compared to the corresponding intestinal lymphatic bioavailability reported in rats in order to elucidate the degree of correlation and to evaluate the utilization of this correlation as a predictive measurement of the lymphatic bioavailability potential of lipophilic drugs. Nine lipophilic compounds (Vitamin D(3), Vitamin E, halofantrine, probucol, diazepam, testosterone, cyclosporin A, benzo[a]pyrene and p,p'-DDT) at a concentration of 1.75 x 10(-6)M were incubated for 1h with chylomicron emulsion separated from rat blood. A strong linear correlation was found between the degree of association of compounds with chylomicrons ex vivo and the lymphatic transport reported in rats (r(2)=0.94, P

The pharmacokinetic characteristics and tissue distribution of a novel water-soluble, nontoxic amphotericin B-arabinogalactan (AMB-AG) conjugate exhibited distinct differences from those of micellar and liposomal amphotericin B formulations. These differences included extended persistence of drug in the body and its accumulation in the lungs; thus, the AMB-AG conjugate was highly effective in treating systemic murine aspergillosis.

To design novel expandable gastroretentive dosage form (GRDFs) and evaluate their gastroretentive properties. Then, to assess the pharmacokinetics of levodopa compounded in such a GRDF in healthy volunteers.Thin (0.07 cm), large-dimensioned (or = 5 x 2.1 cm), multi layer dosage forms (DFs) with different rigid polymeric matrices an mechanical properties were folded into gelatin capsules and wer administered to healthy volunteers with a light breakfast. GRDF unfolding and physical integrity were evaluated in vitro and in vivo (by gastroscopy and radiology). The pharmacokinetics of levodopa GRDF were compared to Sinemet CR in a crossover design.The combination of rigidity and large dimension of the GRDFs was a decisive parameter to ensure prolonged gastroretentivity (or = 5 h). Large-dimension DFs lacking rigidity had similar gastroretentivity as a nondisintegrating tablet (10 mm). The GRDF rapidly unfolded and maintained their mechanical integrity. The absorption phase of levodopa was significantly prolonged following GRDF administration in comparison to Sinemet CR.The combination of size and rigidity of the novel GRDF enables a significant extension of the absorption phase of a narrow absorption window drug such as levodopa. This approach is an important step toward the implementation of such GRDFs in the clinical setting.

‘Bone-seeking agents’ are drugs characterised by high affinity for bone, and are disposed in bone for prolonged periods of time while maintaining remarkably low systemic concentrations. As a consequence, the bone becomes a reservoir for bone-seeking agents, and a site of both desirable and adverse effects, depending on the pharmacological activities of the specific agent. For some agents, significant systemic effects may also be produced following their prolonged release from bone, a process that is governed mostly by the rate of bone remodelling. This review covers the pharmacokinetic and pharmacodynamic features of bone-seeking agents with different pharmacological properties, including drugs (bisphosphonates, drug-bisphosphonate conjugates, radiopharmaceuticals and fluoride), bone markers (tetracycline, bone imaging agents) and toxins (lead, chromium, aluminium). In addition, drugs that do not possess bone-seeking properties but are used for therapy of bone diseases (such as antibacterials for treatment of osteomyelitis) are discussed, along with targeting of these drugs to the bone by conjugation to bone-seeking agents, local delivery systems, and other approaches. The pharmacokinetic and pharmacodynamic behaviour of bone-seeking agents is extremely complex due to heterogeneity in bone morphology and physiology. This complexity, accompanied by difficulties in human bone research caused by ethical and other limitations, gave rise to modelling approaches to study bone drug disposition. This review describes the pharmacokinetic models that have been proposed to describe the pharmacokinetic behaviour of bone-seeking agents and predict bone concentrations of these agents for different doses and patient populations. Models of different types (compartmental and physiologically based) and of different complexity have been applied, but their relevance to drug effects in the bone tissue is limited since they describe the behaviour of the ‘average’ drug molecule. Understanding of the cellular and molecular processes responsible for the heterogeneity of bone tissue will provide better comprehension of the influence of microenvironment on drug bone disposition and the resulting pharmacological response.

The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of furosemide following gastroretentive dosage from (GRDF) administration. A furosemide (60 mg) GRDF, releasing the drug during 6 hours in vitro, or an immediate-release tablet was administered to healthy male volunteers (N = 14) in a crossover design. Food and liquid intake were standardized; urine was collected, weighed, and assayed for furosemide and sodium concentrations. Pharmacokinetics of furosemide following the GRDF administration, as compared to the tablet, showed lower Cmax and indicated a prolonged absorption phase leading to longer mean residence time in the stomach. The sustained input of the drug significantly improved diuretic and natriuretic efficiencies during the first 5 hours and thereby increased the total effects measured over 24 hours. The unfolding controlled-release GRDF of furosemide improved the pharmacodynamic actions due to the sustained absorption in the stomach and jejunum, which delayed the body's counteractivity to the drug effect.

Due to its narrow absorption window, levodopa has to be administered continuously to the upper parts of the intestine in order to maintain sustained therapeutic levels. This may be achieved by a controlled release (CR) gastroretentive dosage form (GRDF). The aim of this work was to develop a novel GRDF, based on unfolding polymeric membranes, that combines extended dimensions with high rigidity, and to examine the pharmacokinetics of levodopa compounded in the GRDF. Levodopa CR-GRDFs were administered to beagle dogs pretreated with carbidopa. The CR-GRDF location in the gastrointestinal tract was determined by X-ray, and serial blood samples were collected and assayed for levodopa. Optimization of the pharmacokinetic profile of levodopa from the CR-GRDFs was carried out based on the in-vitro in-vivo correlation following modifications of the release rates (adjusted by various membrane thicknesses) and drug loads. The successful CR-GRDF maintained therapeutic levodopa concentrations (>500 ng ml −1 ) over 9 h. In comparison to non-gastroretentive CR-particles and oral solution, mean absorption time was significantly extended. These outcomes demonstrate that the CR-GRDF may be used to improve levodopa therapy and can be applied to extend the absorption of other narrow absorption window drugs that require continuous input.

We used a novel pharmacokinetic-pharmacodynamic (PK-PD) approach that had been applied for signal transduction kinetics to investigate the kinetics of the parasympathomimetic effect of scopolamine and atropine in rats. The parasympathetic tone was assessed by continuous measurement of the power of the high frequency band (HF) of electrocardiogram (ECG) R-R intervals obtained by power spectral analysis (PSA) of heart rate variability (HRV). To overcome the inherent noise of the HRV-HF data and to quantitatively identify temporal changes in the autonomic tone, a new approach of stepwise regression of the cumulative HF data was applied. The elevation of the parasympathetic tone occurred after a significant lag time (>70 min) following scopolamine administrations [0.25 and 0.5 mg/kg intravenous (iv) bolus or infusion over 100 min], followed by a gradual return to the baseline levels. A similar lag time in parasympathetic stimulation was observed following iv bolus administration of atropine (0.1 mg/kg). The plasma drug concentration versus time data were linked to the response versus time data using a signal transduction pharmacodynamic model that was fitted simultaneously to all four experimental data sets. This PK-PD model resolved the significant discrepancy between the concentration versus time and the response versus time patterns and successfully described the kinetics of the parasympathetic stimulation obtained for different drugs and different rates of administration. This work paves the way for further PK-PD preclinical investigations in this field.

[corrected] The purpose of this study was to design novel gastroretentive dosage forms (GRDFs) based on unfolding multilayer polymeric films, to investigate the mechanism of their gastroretentivity in dogs, and to assess the effect of compounding a narrow absorption window drug in a GRDF on the drug's absorption properties.Dosage forms (DFs) with different dimensions and mechanical properties were administered to beagle dogs with acidic buffer (pH = 1.5), whose gastric retention time (GRT) was then determined by X-ray pictures. Concurrent administration of radiopaque markers was used to assess the effect of the GRDF and/or acidic buffer on GRT. The absorption of riboflavin from a prototype GRDF was compared with a nongastroretentive controlled-release DF and to an oral solution of the drug.Large DFs (or = 2.5 x 2.5 cm) containing rigid frame had prolonged GRT (4 h). Administration of 400 mL of acidic buffer (or water) prolonged GRT whereas the GRDF did not cause additional prolongation. The extended absorption phase (48 h) of riboflavin administered in a GRDF led to 4-fold increased bioavailability.The combination of large dimensions with rigidity produce gastroretentivity that can be used to improve absorption properties of a model of narrow absorption window drugs in the gastrointestinal tract.

Controlled release gastroretentive dosage forms (CR-GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. CR-GRDF provide a means to utilize all the pharmacokinetic (PK) and pharmacodynamic (PD) advantages of controlled release dosage forms for such drugs. Thus, CR-GRDF may improve therapy with clinically used medications, as well as enable oral administration of drugs, or drug candidates, that hitherto had to be infused parenterally. This manuscript discusses the complexity of the PK and PD factors that influence the treatment benefits of CR-GRDF and summarizes the results of our recent in vivo investigations in animal models (rats and dogs) and in human subjects. We found that a CR-GRDF formulation was superior to the other modes of administration for levodopa and riboflavin, but not for metformin. The PK and PD rationales of GRDFs for the studied drugs are presented and discussed. We conclude that due to the complexity of the PK and PD factors for a certain drug, the rationale for continuous administration obtained by CR-GRDF should be assessed and established in vivo.

We studied heart rate variability in rats by power scaling spectral analysis (PSSA), autoregressive modeling (AR), and detrended fluctuation analysis (DFA), assessed stability by coefficient of variation between consecutive 6-h epochs, and then compared cross-correlation among techniques. These same parameters were checked from baseline conditions through acute and chronic disease states (streptozotocin-induced diabetes) followed by therapeutic intervention (insulin). Cross-correlation between methods over the entire time period was r = 0.94 (DFA and PSSA), r = 0.81 (DFA and AR), and r = 0.77 (AR and PSSA). Under baseline conditions the scaling parameter measured by DFA and PSSA and the high-frequency (HF) component measured by AR fluctuated around an average value, but these fluctuations were different for the three methods. After diabetes induction, a strong correlation was found between the HF power and the short-term scaling parameter. Despite their differences in methodology, DFA and PSSA assess changes in parasympathetic tone as detected by autoregressive modeling.