Total spinal anaesthesia following obstetric neuraxial blockade: a narrative review.

BACKGROUND: Total spinal anaesthesia (TSA) is an emergency caused by high neuraxial blockade. It is a recognised complication of all neuraxial techniques in obstetric anaesthesia. Its incidence and outcomes have not been evaluated. There is compelling evidence that TSA continues to be a problem in contemporary practice, having the capacity to cause significant morbidity and mortality if not recognised early and promptly treated. This review based on a literature search aims to clarify the epidemiology of TSA, summarise its pathophysiology, and identify risk factors and effective treatments. METHODS: We performed a literature search using PubMed, Web of Science and Google Scholar databases using specified search terms for materials published using search terms. For each case, the type of block, the difficulty of the procedure, the dose of local anaesthetic, positivity of aspiration before and after the event, maternal outcome, Apgar score, onset of symptoms, cardiorespiratory and neurological manifestations, cardiorespiratory support employed, admission to an intensive care unit, cardiac arrest events and duration of mechanical ventilation were extracted. RESULTS: A total of 605 cases were identified, of which 51 were sufficiently detailed for analysis. Although TSA is described after all neuraxial techniques, spinal after epidural was a particular concern in recent reports. Respiratory distress was universal but apnoea was not. The onset of apnoea was variable, ranging from 1 to 180 min. Hypotension was not invariable and occurred in approximately half of cases. Multiple fatalities and neurological injuries were reported, often in under-resourced areas when providers were not skilled in airway management or when recognition and intervention were delayed. In the most recent reports good outcomes were achieved when effective treatments were rapidly provided. CONCLUSIONS: The available literature confirms that TSA remains an active clinical problem and that with prompt recognition and treatment good outcomes can be achieved. This requires anticipation and preparedness in all clinical areas where neuraxial techniques are performed.

Assessment of the latest prescribed drug-related problems.

OBJECTIVE: Drug-related problems (DRPs) could affect patient care and lead to deleterious manifestations, therefore, this investigation aimed to review the recently published studies concerning DRPs to improve their availability to clinical pharmacists, hoping that this information will be supportive and relevant to their practice settings. MATERIALS AND METHODS: A search of Elsevier, Sage, Springer/Nature, and Wiley online libraries on Egyptian Knowledge Bank (EKB) was limited to the cumulative period from 1/1/2015 to 20/10/2020. The abstracts of 156 articles were critically reviewed and 50 articles were included based on relevance while excluding books. The selected articles reported DRPs and different strategies to reduce them. Moreover, drug-drug interactions (DDIs) in various patient populations were confirmed by many articles. Additionally, potential drug-drug interactions (pDDIs) predisposing factors were reported by others. RESULTS: 24 articles (48%) illustrated DDIs, 5 articles (10%) demonstrated ADRs, 4 articles (8%) showed medication errors (MEs), and 25 articles (50%) revealed efforts to reduce DRPs. The psychiatric population is at the utmost risk of pDDIs. Polypharmacy was the furthest recurrently reported risk factor related to DDIs. Adverse drug events (ADEs) increased healthcare costs. Different strategies to avoid DRPs were published through the stated period. CONCLUSIONS: Our findings can be supportive to healthcare professionals in enhancing their patients' quality of care by reducing the exposure to ADEs.

Physiological and behavioral responses of land molluscs as biomarkers for pollution impact assessment: A review.

Environmental pollution caused by human activities is a global public health concern. This review discusses the impact of different types of pollutants such as pesticides, metals, nanoparticles and others on land molluscs. These molluscs are of great interest as good model organisms for studying biomarker responses in ecotoxicological monitoring programs. Several biomarkers are utilized to characterize and quantify the exposure and harmful impacts of various pollutants. In this review, we have identified physiological and behavioral endpoints (feeding, growth, avoidance, mucus secretion, locomotion and reproductive behavior) for the diagnosis of environmental pollution. The present review displays that all types of pollutants can disturb physiological and behavioral endpoints of gastropods, and these impacts depend on the matrix, exposure time and route as well as the type and concentration of the pollutants in the environment. We have also confirmed that terrestrial gastropods particularly snails as sentinel species could be used as potential bioindicator organisms for environmental quality assessment and thus for predicting potential hazards to human health.

Biomarker responses in terrestrial gastropods exposed to pollutants: A comprehensive review.

The chemical contamination of terrestrial ecosystems is a great concern as these ecosystems are the target of most of the pollutants derived from anthropogenic activities such as pesticides, heavy metals, nanoparticles, and others. Terrestrial gastropods are considered to be excellent sentinel organisms for biological monitoring of environmental pollution, as they have the ability to accumulate chemicals in their tissues and exhibit a great potential to evaluate the ecological effects of pollutants in terrestrial ecosystems. The use of biomarkers as sensitive parameters to estimate the exposure or resulting effects of chemicals have received considerable attention. The successful biomarker must be applicable in the laboratory and field conditions. Many biomarkers have been examined to understand the adverse effects of pollutants. In this review, we shed light on different types of biomarkers, such as oxidative stress, genotoxicity and immunotoxicity as diagnostic tools for monitoring the impacts of pollution. These biomarkers can provide information about early detection and quantification of these impacts during their initial manifestations and can facilitate the implementation of a rapid preventive and/or restorative responses in the affected ecosystems, as well as single or multiple biomarkers can be integrated into routine monitoring programs.

Use of multiple endpoints to investigate the ecotoxicological effects of abamectin and thiamethoxam on Theba pisana snails.

The ecotoxicological effects of dietary exposure to sublethal concentration (1/20 LC50) of abamectin (ABM) and thiamethoxam (TMX) for two weeks exposure and one week recovery on oxidative stress parameters; lipid peroxidation (LPO), reduced glutathione (GSH), catalase (CAT) and glutathione S-transferase (GST), Deoxyribonucleic acid (DNA) damage as well as immunological parameters; cell death, phagocytosis, lysosomal membrane stability (LMS), lectins, superoxide anion (O2-) generation, phenoloxidase (PO), peroxidase (POD) and hemocyanin (Hc) of the land snail, Theba pisana were examined. The results showed that both tested compounds significantly increased DNA damage, LPO content, the activity of CAT and GST, cell death, POD activity, Hc level, whereas, significantly declined in phagocytic activity, LMS, lectins level, O2- generation, PO activity, and GSH content compared to the controls after two week exposure. After one week of recovery, the measured biochemical parameters of treated snails were slightly repaired but their levels were still less than that of the level of untreated animals. Overall, based on acute toxicity endpoints, ABM appeared to be more harmful than TMX against this animal. Indeed, the different patterns of endpoint responses could represent a useful picture to characterise exposure to these pesticides in the land snail, T. pisana. This battery of snail endpoints might be a promising option to biomonitor the health of the terrestrial ecosystem and to offer valuable insights to the pesticides toxicity mechanisms.

Imidacloprid induced alterations in enzyme activities and energy reserves of the land snail, Helix aspersa.

The in vivo sublethal toxic effects (0.2 and 0.6 LD50) of topically applied imidacloprid on biochemical biomarkers in the land snail, Helix aspersa was examined. Biochemical perturbations were assessed by measuring the three enzymatic (Acetylcholinesterase, AChE; catalase, CAT and glutathione-S-transferase, GST) activities and three energy reserves (protein, glycogen and lipids) in the snails. Snail samples were taken from each sublethal dose and control groups at 1, 3 and 7 days after treatment. The results revealed that there were overall decrease in AChE activity as well as depletion of lipids and glycogen contents in the imidacloprid-treated snails compared to control groups. The CAT and GST activities of treated snails with the sublethal doses of imidacloprid were significantly higher than those of untreated controls along the three times of exposure. Moreover, an increase in the level of total proteins was observed in animals treated with 0.6 LD50 imidacloprid compared to control groups. The alterations in all tested biochemical perturbations were most pronounced with the 0.6 LD50 than 0.2 LD50. This study suggests that alterations of the enzyme activities and energy reserves in this species that could be useful as biomarkers of imidacloprid exposure in the evaluation of terrestrial impacts of this insecticide.

Pharmacokinetics and cardiovascular effect of etoricoxib in the absence or presence of St. John's Wort in rats.

The effect of chronic administration of etoricoxib (EXB), in the absence or presence of St. John's Wort (SJW), on its pharmacokinetic parameters and blood pressure was investigated in rats.Rats were divided into 3 groups, each group received daily different oral treatment for 3 weeks. Rats' blood pressures were monitored initially, after 1 and 3 weeks of treatment, and after 1 week of discontinuing dosing of both drugs. EXB pharmacokinetic parameters in the absence or presence of SJW were calculated after 3 weeks.SJW was significantly affected EXB pharmacokinetic parameters. The steady state peak plasma concentration and terminal half-life were reduced by 32% and 91%, respectively, due to a > 3 fold increase in its apparent clearance which is a concentration and time dependent effect. EXB was significantly increased (P<0.001) Rats' blood pressure while, co-administration of EXB and SJW was not significantly affect (P>0.05) rats' blood pressure as compared to the control.Monitoring blood pressure of patients anticipated taking EXB for extended period should be advised. The co-administration of SJW with EXB should be avoided since SJW would greatly reduce EXB concentrations by inducing its metabolism.

Feeding and growth responses of the snail Theba pisana to dietary metal exposure.

The effects of dietary exposure to copper (Cu), lead (Pb), and zinc (Zn) on feeding activities, growth response, and mortality of Theba pisana snails were studied in 5-week feeding tests. Snails were fed on an artificial diet containing the following Cu, Pb, or Zn concentrations: 0, 50, 100, 500, 1000, 5000, 10,000, and 15,000 µg/g dry food. At the end of 5 weeks, the food consumption rate was decreased with increasinges in both metal concentrations and time of exposure. The estimated concentrations of metals that reduces food consumption to 50% (EC50) after 5 weeks were 56, 118, and 18 µg/g dry food for Cu, Pb, and Zn, respectively. All tested metals in the diet were found to inhibit growth of the snails in a dose-dependent manner. The toxic effect on growth of the tested metals could be arranged in the order Cu > Zn > Pb. The cumulative percentage mortality among snails fed a Cu- or Zn-contaminated diet was 73.3% and the respective value for a Pb-contaminated diet was 13.3%. There was a positive correlation between growth coefficient and food consumption for all tested metals.

Pharmacokinetics of ketorolac loaded to polyethylcyanoacrylate nanoparticles using UPLC MS/MS for its determination in rats.

Polyethylcyanoacrylate (PECA) nanoparticles (NPs) have been employed as biodegradable polymeric carriers for oral (PO) delivery of ketorolac. The nanoparticles were prepared by polymerization technique at room temperature in a continuous aqueous phase at pH 2.5. This polymerization technique was able to hold 76-96% of ketorolac and the drug loading was a monomer concentration dependent. The feasibility of PECA NPs as PO controlled drug delivery systems of ketorolac was investigated in two groups of rats which were given orally either ketorolac tromethamine solution (1.5 mg/kg) or the selected ketorolac NPs aqueous dispersion (1.6 mg/kg). Ketorolac plasma concentrations were measured by a new fully validated specific, precise and accurate ultra-performance liquid chromatography tandem mass spectrometry (UPLC MS/MS) assay. The detection was performed on Waters TQ detector via negative electrospray ionization in a multiple reaction monitoring mode. Linear response (r(2)> or =0.995) was observed over the range of 10-10,000 ng/ml of ketorolac, with the lower limit of quantification of 5 ng/ml with 1 microl injection volume. The intra- and inter-day precision (relative standard deviation, R.S.D.) values were <10% and the accuracy (relative error) was < or =8 for ketorolac concentrations. The drug solution is rapidly absorbed, distributed, and eliminated and shows a monophasic elimination phase. The assay was sensitive to follow pharmacokinetics of ketorolac in rats up to 24 h after a PO dose of its aqueous solution or NPs suspension. After NPs administration the mean Cmax, 5.0+/-1.3 mg/l, was attained at 1 h. The drug was successfully maintained around this elevated plasma drug concentration up to 6h (>2t(1/2)), in rats. The AUC was significantly higher after the NPs suspension than the solution of ketorolac. This present study provides evidence that the sorption of ketorolac to PECA NPs could control the drug release/elimination in rats.

Biomarkers of oxidative stress in the land snail, Theba pisana for assessing ecotoxicological effects of urban metal pollution.

This study investigates the biomarkers of oxidative stress and heavy metal accumulation for assessing ecotoxicological effects of urban metal pollution in Alexandria city, Egypt. This investigation was performed in the digestive gland of roadside Theba pisana snails obtained from six different sites in the city. Relationships between heavy metal (Zn, Cu, Pb and Cd) concentrations and oxidative stress indicators were also examined. The results showed that mean concentrations of the measured elements (mugg(-1) dry weight) were higher in polluted sites when compared to the background levels of the reference site. The pattern of metals accumulation at all sites was Zn>Cu>Pb>Cd. In the metal polluted sites, snails displayed higher mean of catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities, lower reduced glutathione (GSH) content and higher levels of lipid peroxidation (LPO) compared to snails from the reference site. All oxidative stress parameters were positively correlated to heavy metal concentrations except GSH content which exhibits negative correlation with the concentrations of these metals. Our results suggest that the tested antioxidant defenses are sensitive parameters that could be useful as oxidative stress biomarkers in snails exposed to the actual metals in the environment. These biomarkers when complemented with metal accumulation in the digestive gland of snails may provide a powerful biomonitor for the assessment of environmental metal pollution.

Oxidative stress biomarkers in the digestive gland of Theba pisana exposed to heavy metals.

The in vivo toxic effects of sublethal treatment of 40 and 80% of 48-h LD(50) of topically applied trace metals [copper (Cu), lead (Pb), and zinc (Zn)] on oxidative stress biomarkers in the digestive gland of Theba pisana were examined. Oxidative individual perturbations were assessed by measuring nonenzymatic (glutathione; GSH) and enzymatic (catalase, CAT; glutathione peroxidase, GPx; and glutathione-S-transferase, GST) antioxidants in digestive gland of the snails. Lipid peroxidation (LPO) was also evaluated as a marker of cell damage. The results indicated that the copper ion was the most potent metal against this snail, followed by zinc and lead, for which the corresponding LD(50) values were 37.88, 261.72, and 652.55 microg/snail, respectively. The no-observed effect concentration (NOEC) values for Cu, Zn, and Pb were 10, 50, and 500 microg/snail, respectively, and the corresponding lowest-observed effect concentration (LOEC) values were 50, 100, and 1000 microg/snail. All trace metals resulted in a significant increase in the level of LPO, whereas a significant decline in the content of GSH was observed when compared with untreated controls. Treatment with both sublethal doses of the metals caused significant increase in CAT activity, except in the case of 40% LD(50) Zn and 80% LD(50) Cu, which exhibited no alteration in CAT when compared to control animals. GPx was significantly increased in snails exposed to 40% LD(50) Cu and Pb as well as 80% LD(50) Cu. However, an opposite effect was observed in snails exposed to 80% LD(50) Pb and in either 40 or 80% LD(50) of Zn-intoxicated animals. Treatment with Pb at two sublethal doses significantly increased GST activity, whereas treatment the animal with Cu caused significant inhibition in this enzyme. Snails exposed to 40% LD(50) Zn showed significant enhancement of GST, whereas snails exposed to 80% LD(50) showed significantly reduced GST activity. Biphasic responses were observed for CAT, GPx, and GST activities in snails exposed to Cu, Pb, and Zn, respectively. This study suggests that upregulation of the antioxidant enzyme activities, elevation of LPO, and the reduction in GSH content is related to oxidative stress in this species that could be useful as biomarkers for the evaluation of contaminated terrestrial ecosystems.

In vivo evaluation of oxidative stress biomarkers in the land snail, Theba pisana exposed to copper-based pesticides.

The in vivo evaluation of oxidative stress biomarkers in the digestive gland of Theba pisana exposed to sublethal doses (40% and 80% of LD(50) after 48 h) of copper-based pesticides; copper oxychloride, copper hydroxide and copper sulphate was examined. Oxidative individual perturbations were assessed by measuring non-enzymatic (glutathione; GSH) and enzymatic (catalase; CAT, glutathione peroxidase; GPx and glutathione S-transferase; GST) antioxidants in digestive gland of the snails. Lipid peroxidation (LPO) was also evaluated as marker of cell damage. The results indicated that copper sulphate was the most potent compound against this snail followed by copper hydroxide and copper oxychloride where their corresponding LD(50) values were 26.54, 334.54 and 582.18 microg snail(-1), respectively. Copper-based compounds resulted in a significant increase in the level of LPO whereas a significant decline of GSH content in the digestive gland of snails was observed when compared with untreated controls. The CAT, GPx and GST activities of treated snails were significantly higher than those of untreated controls. In general, the activation power of these compounds was in the following order: copper sulphate > copper hydroxide > copper oxychloride. This study suggests that up-regulation of the antioxidant enzyme activities, elevation of LPO and the reduction of GSH content is related to oxidative stress in this species that they could be used as potential biomarkers of copper-based pesticides exposure.

Potential of some monoterpenoids and their new N-methyl carbamate derivatives against Schistosomiasis snail vector, Biomphalaria alexandrina.

Some monoterpenoids and their corresponding new N-methyl carbamate derivatives were used to study their molluscicidal effect on Biomphalaria alexandrina, the snail-vector of Schistosoma mansoni in Egypt. Improving the efficacy of the tested monoterpenoids and/or their corresponding carbamates by either piperonyl butoxide (PBO) or triton X-100 (TX) was also performed. Thymol, ß-citronellol, carvacrol, and geraniol exhibited high molluscicidal activity against the snails. Geraniol, ß-citronellol, and carvacrol were strongly synergized by PBO but, an opposite trend was found with TX. The molluscicidal activity of geraniol or ß-citronellol when mixed with PBO was as potent as copper sulfate. Another attempt to improve the bioactivity of monoterpenoids was through their structure modifications. Thus, conversion of the tested monoterpenoids into their corresponding carbamates led to enhancement in the activity of aliphatic monoterpenoids and reduction in the aromatics.

The effects of induced diabetes and cutaneous Leishmania infection on the pharmacokinetics of antimony in hamsters.

Patients with certain diseases appear to be at greater risk of developing adverse drug interactions, either because of the disease state itself or the drugs used to treat it. The effects of streptozotocin-induced diabetes and/or cutaneous Leishmania major infection on the pharmacokinetics of antimony (SbV) have now been investigated, in hamsters treated with sodium stibogluconate (Pentostam). The animals were randomly divided into five groups, each of 20 hamsters, known as D (for diabetes without leishmaniasis), DL (diabetes induced prior to the leishmaniasis), L (leishmaniasis without diabetes), LD (diabetes induced after leishmanial infection) and C (the control group, of animals with neither diabetes nor leishmaniasis). After its diabetes and/or leishmaniasis (if any) was established, each animal was given an intramuscular dose of sodium stibogluconate (80 mg/kg) each day for 3 weeks. Blood samples were collected after the first or last doses, to allow the pharmacokinetic parameters of SbV after single and multiple dosing to be compared. Although the between-dose interval (24 h) was more than 10 times longer than the terminal elimination rate constant (t1/2) at steady state, there was a significant increase in the mean peak SbV concentration (Cmax), as the result of multiple dosing, in all five groups (P<0.001 for each). The hamsters with diabetes showed the least accumulation of SbV in their blood, whether or not they were infected with L. major. In the non-diabetic animals of groups L and C, the apparent total clearance of SbV (CL/F) was decreased by multiple dosing, being, respectively, 34.5% and 23.0% lower after the 21st dose than after the first. An increase in urine volume was the reason for the significant increase in CL/F in group D (P<0.001), and this offset the decrease in CL/F seen in the L group, resulting in no change in CL/F in the animals of the DL group. Three weeks of antileishmanial treatment produced no significant reductions in the leishmanial lesions on the parasite-inoculated foot-pads of the hamsters in the L or DL groups but such reductions were detected in the animals of the LD group (P<0.001). In conclusion, it appears that the administration of SbV over a few weeks may cause renal toxicity and, in clinical use, should therefore be accompanied by the regular monitoring of renal function. A cautious increase in SbV dosing may be necessary for the effective treatment of L. major (and perhaps other species of Leishmania) in diabetic patients.

Soil amendment with dried weed leaves as non-chemical approach for the management of Meloidogyne incognita infecting tomato.

In pot trial, dried ground weed leaves of Cynodon dactylon, Datura stramonium, Eichhomia crassipes, Emex spinosus, Ricinus communis and Sisymbrium irio were mixed with soil at the rate of 1, 3, 5 and 10 g/kg soil and compared their nematicidal potential with carbofuran as a standard against the root-knot nematode, M. incognita infecting tomato. In addition, their effects on growth rate of tomato plants were also investigated. The results showed that M. incognita populations in the soil and root galling were significantly suppressed when the dried leaves of the tested weeds at all rates were allowed to decompose in the soil. All amendments exhibited varying degree of reduction compared to control. The highest reduction was noticeable with the plants grown in Sisymbrium irio amended soil followed by Datura stramonium and Emex spinosus. In addition, employing high rate of the tested weeds gave higher activity in suppressing the nematode both in the soil and in tomato roots than using low rate. The data also indicated that all amendments at low rates significantly increased growth indices of tomato over control treatment, except Cynodon dactylon and Emex spinosus which decreased it, particularly in the shoot system. On the other hand, their high rates showed phytotoxic effects. These weed species may offer considerable promise as soil amendments for control of root-knot nematode, M. incognita.

Residual behaviour of profenofos on some field-grown vegetables and its removal using various washing solutions and household processing.

Profenofos (Selecron 72% EC), was sprayed on field-grown pepper and eggplant at the recommended rate of 1.28 kg a,i/ha. Fruit samples were collected at 1 h to 14 days after application and analysed to determine the content and dissipation rate of profenofos. The effect of different washing solutions and some household processing on the removal of such residues from treated vegetables were also investigated. Profenofos residues were quantified by using gas chromatography. The results showed that the consumable safety time were found to be 10 days on sweet pepper and 14 days on hot pepper and eggplant fruits. The initial disappearance of profenofos appeared to follow first order kinetics with different rates of reaction of 0.38, 0.40 and 0.35 day(-1) for hot pepper, sweet pepper and eggplant, respectively. The corresponding half-lives (t1/2) were 1.84, 1.74 and 1.96 days. Also, the results indicated that tap water, potassium permenganate and acetic acid solution gave high percent removal of profenofos residues from hot and sweet pepper fruits, while no detectable residues was found in eggplant fruit after washing with soap and acetic acid solutions. In general, all tested washing solutions gave higher percent removal of profenofos residues from eggplant fruit than the two other pepper fruits. Blanching and frying of pepper and eggplant fruits resulted in great reduction to almost completely removed (approximately 100%) of the deposited profenofos. In addition, pickling process removed 92.58 and 95.61% from hot pepper fruit after one week and after two weeks, respectively.

Synthesis and molluscicidal structure-activity relationships of some novel 1,2,4-triazole N-methyl carbamates.

A new series of 1,2,4-triazole derivatives and their corresponding carbamates have been synthesized and screened for their molluscicidal activity against two types of terrestrial snail, Helix aspersa and Theba pisana, by two methods of application, either as contact or as bran baits. Several of the tested compounds exhibited good molluscicidal activity, and T pisana was more sensitive than H aspersa. Substitution at the o- and/or p-positions of the phenyl ring with chlorine or bromine gave higher molluscicidal activity than the unsubstituted compound, with o,p-dichloro substitution being optimum. In addition, compounds containing two triazole moieties showed higher molluscicidal activity, particularly as stomach poisons, than the contact toxic effect of the corresponding compound with one triazole ring. In general, carbamate derivatives were more active than their corresponding 1,2,4-triazole derivatives.

Preparation and in vivo evaluation of parenteral metoclopramide-loaded poly(alkylcyanoacrylate) nanospheres in rats.

Metoclopramide-loaded poly(alkylcyanoacrylate) (PACA) nanospheres were prepared by emulsifier-free polymerization in aqueous media at ambient conditions. The optimum polymerization conditions for metoclopramide sorption on PACA nanospheres in the presence of dextran (DEX) or hydroxypropyl-beta-cyclodextran (HPCD) in the polymerization medium were studied and the feasibility of either poly(isobutylcyanoacrylate) (PIBCA) or poly(ethylcyanoacrylate) (PECA) nanospheres as parenteral prolonged release drug delivery system of metaclopramide in rats was also investigated. The optimum time for the addition of metaclopramide after initiating the polymerization was 1 h, which results in 14.8 +/- 0.4 and 9.2 +/- 0.5% of drug loading for PIBCA and PECA, respectively. The HPCD in the polymerization medium of PECA nanospheres improved the drug adsorption compared to DEX at all times, but the difference was only significant (p < 0.05) when metoclopramide was added at 0 and 30 min. Wistar rats were given subcutaneous (s.c.) injections of metoclopramide solution (5 mg/kg) and three different metoclopramide nanospheres suspensions (10 mg/kg) on two phases. The drug solution is rapidly absorbed, distributed, and eliminated. The maximum drug concentration was observed after 30 min of s.c. administration of all the tested nanosphere formulations. PECA-HPCD showed the highest concentration (3.16 +/- 0.66 mg/L) followed by PIBCA-DEX (1.95 +/- 0.37 mg/L) and PECA-DEX (1.68 +/- 0.28 mg/L). The AUCs of PECA-DEX, PECA-HPCD and PIBCA-DEX were 4.8, 1.88 and 2.43 times higher than that of the solution form, respectively. Following PECA-DEX the maximum drug concentration, 1.68 +/- 0.28 mg/L, rapidly decreased to 0.54 +/- 0.05 mg/L. The drug was successfully maintained around this serum drug concentration up to 12 h in rats and the mean drug concentration was reduced to 0.2 +/- 0.02 mg/L, 63% reduction, after 24 h of nanosphere administration. The developed aqueous parenteral prolonged release preparation (PECA-DEX) could be used as a promising intermittent formula for metoclopramide or other drugs when the oral route is not accessible, especially during managing chronic nausea in patients with advanced cancer.

The effect of absorption enhancers on the initial degradation kinetics of insulin by alpha-chymotrypsin.

The goal of this investigation was to establish a fast method to screen various insulin absorption enhancers by following their effect on the initial kinetics of insulin incubated with alpha-chymotrypsin at 37 degrees C. A simple, sensitive and reproducible reversed phase high performance liquid chromatography (HPLC) method has been developed to carry out this goal. Linear responses (r > 0.999) were observed over the range of 0.4-4 U/ml for insulin. There was no significant difference (P < 0.05) between inter- and intra-day studies for insulin. The mean relative standard deviations (RSD%) of the results of within-day precision and accuracy of insulin were 12%. The assay was sensitive to detect the existence of any metabolite due to the addition of any absorption enhancers, even if it was not seen with insulin alone. Three metabolites (A-C) were detected only when insulin was incubated with alpha-chymotrypsin at 37 degrees C. Metabolite D was observed when either glycocholic acid (0.5, 1%) or taurochenodeoxycholate (0.5, 1%) was incubated with insulin in the absence of alpha-chymotrypsin at 37 degrees C. The compounds that significantly increased insulin T50% were glycyrrhizic acid (0.5%) > deoxycholic acid (1%) > deoxycholic acid (0.5%) > glycyrrhizic acid (1%) > cholic acid (0.5, 1%). Capric acid (0.5%), hydroxypropyl-alpha-cyclodextrin (0.5, 1%) and dimethyl-alpha-cyclodextrin (0.5, 1, 5%) did not significantly affect insulin T50%. The bile salts increased insulin T50% in this order: deoxycholate > cholate > glycocholate > taurocholate > taurodeoxycholate > taurochenodeoxycholate > glycodeoxycholate. The results obtained would support the feasibility of utilizing such method for screening any compound incorporated in insulin formulation. These compounds should be used in the minimum possible concentration to avoid or minimize insulin degradation.

Enhancement of absorption of insulin-loaded polyisobutylcyanoacrylate nanospheres by sodium cholate after oral and subcutaneous administration in diabetic rats.

Polyisobutylcyanoacrylate (PIBCA) nanospheres were employed as biodegradable polymeric carriers for oral (p.o.) and subcutaneous (s.c.) delivery of insulin. The polymerization technique used was able to hold 65%-95% of insulin added 30 min after initiation of polymerization. The percentage drug loading was monomer concentration dependent. Insulin adsorption to the nanospheres was measured by radioimmunoassay. Although Pluronic F68 (0.5%) did not significantly alter the in vitro insulin degradation half-life T50%, sodium cholate (0.5%) increased the degradation T50% of insulin by 56% (from 13.6 +/- 1.6 to 22.1 +/- 2 min). This study also investigated the in vivo performance of insulin-loaded PIBCA in aqueous suspension with or without sodium cholate (0.5%) and Pluronic F68 (0.5%) surfactants after oral and subcutaneous administration to alloxan-induced diabetic rats. Insulin absorption was evaluated by its hypoglycemic effect. Insulin associated with PIBCA nanospheres retains its biological activity up to 15 h and 24 h after oral and subcutaneous administrations, respectively. Administered orally insulin-loaded (75 U/kg) nanospheres, in the presence of surfactants, significantly reduced the mean blood glucose level from 392 +/- 32 to 80 +/- 13 mg/dl within 2 h and maintained it at 100 mg/dl or less for more than 8 h. On the other hand, the subcutaneous administration of insulin-loaded (25 U/kg) nanospheres significantly decreased the blood glucose level from 406 +/- 33 to 88.5 +/- 12.8 mg/dl within 1 h, and the lowered glucose level was maintained at 100 mg/dl or less for more than 12 h; it returned to its initial value 24 h after administration. Insulin-loaded nanospheres with surfactants showed significant (P < .05) pharmacological availability (PA%) of 37.6% +/- 3.7% and 65.2% +/- 2.7% after oral and subcutaneous dosages, respectively. The existence of surfactants with PIBCA nanospheres improved the oral PA% by 49.2%. These findings suggest that the developed PIBCA, in the presence of surfactants, would be useful not only in improving insulin gastrointestinal absorption, but also in sustaining its systemic action by lowering the blood glucose to an acceptable level.