Determination of the physical state of drug in microcapsule and microsphere formulations

Tolnaftate microcapsules and microspheres were prepared by gelatin-acacia coacervation and emulsion-solvent evaporation methods respectively. The physical state of the drug in these formulations was determined by using scanning electron microscopy (SEM), X-ray powder diffractometry, and differential scanning calorimetry (DSC). High pressure liquid chromatographic (HPLC) method was used for stability determination and polymer-drug interactions were evaluated using FTIR. The pros and cons of each method, in the assessment of the physical state of drug in these formulations, were investigated. SEM was found to be useful in obtaining a direct visual evidence of the presence of crystalline drug in the microspheres, but not for the microcapsule formulation. The DSC method was used to determine the physical state of the drug qualitatively in both these formulations. In the case of the microcapsules, accurate quantitation of the crystalline drug content by DSC was not possible because of the interference of thermal events. Powder X-ray diffractometric method was able to demonstrate the presence of crystalline drug and polymorphic changes, if any, in both these formulations. HPLC data revealed that the drug was stable in these formulations for at least 6 months. The FTIR studies indicated the absence of any drug interaction with the polymeric matrix materials, during preparation of these dosage forms.     

壳聚糖/明胶复合微球的制备

采用乳化-凝聚法,在油包水(W/O)体系中制备壳聚糖/明胶(Cs/Gel)复合微球,研究乳化剂用量、搅拌速率和水油比等因素对微球粒径以及脱水过程中的丙酮浓度对Cs/Gel复合微球形貌的影响.研究结果表明:乳化剂浓度较低时,微球的粒径随乳化剂浓度的增加呈降低趋势,当乳化剂浓度高于0.012 g·mL-1时微球粒径不再发生...     

Tissue distribution of methotrexate following administration as a solution and as a magnetic microsphere conjugate in rats bearing brain tumors

A novel magnetic microsphere-methotrexate (MM-MTX) drug delivery system was synthesized and evaluated in rats bearing rat glioma-2 (RG-2) tumors. Methotrexate was linked to the surface of the magnetic particle via an aminohexanol linker that would release free drug following hydrolysis. Male Fischer 344 rats bearing RG-2 tumors were administered 3 mg/kg of methotrexate (MTX) either as MM-MTX or as a solution (MTX-S) over 5 min. A 6000 gauss magnetic field was applied for 15 min from the end of MM-MTX administrations. Serial sacrifices were conducted at 15 min, 30 min and 45 min after drug administrations, organs collected, and analyzed for total MTX by a radioassay. At all times, MTX right brain (ipsilateral), brain tumor, and left brain concentrations were approximately 3.5 to 5-fold greater in the MM-MTX group compared to the MTX-S group. MTX concentrations in all other organs were less following administration of MM-MTX than MTX-S except in lung at 30 and 45 min. The targeting efficacy, an index for site-specificity, for both MM-MTX and MTX-S were similar and indicated some enhancement in MTX localization in brain tumor. Confocal and conventional light microscopic analyses demonstrated a diffuse distribution of MM-MTX in tumor consistent with extravascular uptake, whereas a predominant capillary distribution of MM-MTX was observed in normal brain. Following 45 min, the animals treated with MM-MTX died possibly due to redistribution of particles to the lung. This toxicity was dose-dependent. High brain MTX concentrations coupled with extravascular uptake of MM-MTX provide a basis for further investigations with this novel drug delivery system.     

Evaluation of drug formulations using LD50 testing in mice

The LD50 values were utilized to assess the relative rate of absorption of two very poorly soluble drugs. Formulations of these drugs were studied by micronization; addition of surfactant, alkaline or buffering agents, and/or bile salts; coprecipitation; melt or fusion techniques; or granulation with hydrophilic agents. Differences in toxicities were demonstrated from formulations compared to pure drugs by the LD50 method. This study shows that the LD50 is a practical, rapid method of achieving comparative evaluations of drug formulations.     

Effect of cyclosporine on fertility in male rats

The effect of cyclosporine (CsA) on fertility has assumed greater importance with the increasing numbers of pediatric transplantations being performed all over the world. Conflicting reports on the effects of CsA on sex hormones are available. This experimental animal study was designed to examine the effect of CsA on testicular weight, sperm counts, seminiferous tubular diameter (STD), testicular morphology, DNA flowcytometry, sex hormone levels, and fertility in male rats. Those rats who received CsA (20 mg/kg per day) showed significant reductions in testicular weight (P < 0.05), sperm count (P < 0.01), Johnsen score (P < 0.05), STD (P < 0.01), serum testosterone levels (P < 0.05), haploid cell population (P < 0. 001) in the testis, and fertility (P < 0.001) compared to those receiving CsA 10 mg/kg per day and control rats. These findings will have an important bearing for children receiving cyclosporine for long periods to guide the physician in optimally adjusting long-term treatment.     

Intravitreal sustained-release cyclosporine in the treatment of experimental uveitis

Nine building projects are briefly described, including four new libraries, two renovations, and three combined renovations and additions. The libraries range in size from 657 square feet to 136,832 square feet, with seating varying from 14 to 635. Three hospital libraries and four academic health sciences libraries are described in more detail. In each case an important consideration was the provision for computer access. Two of the libraries expanded their space for historical collections. Three of the libraries added mobile shelving as a way of storing print materials while providing space for other activities.     

Sustained decrease in brain regional blood flow after microsphere embolism in rats

BACKGROUND AND PURPOSE: An experimental model that induces sustained ischemia and infarction may provide useful information relevant to prevention of the development of ischemic brain disease. The purpose of the present study was to elucidate the pathophysiological consequences of cerebral blood flow under sustained cerebral ischemia or oligemia and infarction in rats after microsphere embolism. METHODS: We injected 900 microspheres (48 microns in diameter) into the right internal carotid artery of 146 rats and determined the time course of changes in blood flow of the cerebral cortex, striatum, and hippocampus of both hemispheres by the hydrogen clearance method for a period of 28 days after the operation. Infarct area was determined by triphenyltetrazolium chloride staining and hematoxylin and eosin staining methods. RESULTS: Cortical and striatal blood flow of the right hemisphere of microsphere-injected rats was significantly decreased after the embolism, and this was sustained throughout the experiment. Hippocampal blood flow of the microsphere-injected hemisphere was also decreased on days 1 and 3 but tended to return toward control levels thereafter. In the left hemisphere, reduction in regional blood flow was detected in the cortex and hippocampus on day 1 and the striatum on day 3. A triphenyltetrazolium chloride-unstained area had developed by day 3 after the embolism. The extent of the area was similar to that on days 7 and 28. Microscopic examination revealed degenerative areas scattered mainly in the parietotemporal cortex, corpus callosum, hippocampus, thalamus, and lenticular nucleus of the embolized hemisphere, demonstrating the induction of widespread necrosis after embolism. CONCLUSIONS: Microsphere embolism resulted in a sustained decrease in regional blood flow and production of cerebral infarction in the brain regions of the microsphere-injected hemisphere.     

Local joint treatment in chronic polyarthritis: intra-articular corticosteroids and radioactive isotopes

Intrasynovial injection of corticosteroids is currently one of the routine measures in the treatment of patients with rheumatoid arthritis. Crystalline corticosteroid suspensions have proved their value and are effective for approximately one to three weeks. One or two injections can control synovitis for prolonged periods of time. Special attention has to be given to impeccable technique of instillation. However, it must be kept in mind that, within the overall management of rheumatoid arthritis, the intra-articular injection of corticosteroids is a local, palliative and temporary measure. The intrasynovial instillation of radionuclides is used only in selected cases. Therapy of the knee joint is mainly performed with Yttrium-90, less frequently, the interphalangeal joints are treated with Erbium-169. Costs and radiation exposure are low, but a favourable result is only achieved in slightly more than 50 per cent of cases. This review provides a synopsis of the basic concepts and practical applications of intrasynovial corticosteroid and radioisotope injection therapy.     

Diagnosis of rheumatoid polyarthritis at onset. Manifestations, enigmas, hopes or solution

Quantitative nutrient requirements for unrestricted autotrophic growth of Alcaligenes eutrophus were determined. Minimum saturating concentrations of Mg2+, SO42-, PO43-, Fe3+, and Na2+ for an optical density increase of 2 were 10(-4) M 8 X10(-5) M, 5 X 10(-4) to 6 X 10(-4) M, 10(-5) M, and 10(-7) to 2 X 10(-7) M, respectively. Trace metal requirements for cobalt, chromium, and copper were also demonstrated, but minimum concentrations could not be determined because other reagents contributed a high background of these metals. Under certain conditions an apparent response to zinc was observed, although other experiments suggest the zinc salt contained another metal that was required for growth. Poly-beta-hydroxybutyrate biosynthesis was shown to be initiated by a magnesium or sulfate deficiency as well as by a nitrogen or phosphate deficiency.     

Ultrastructural study on cytotoxic effects of cyclosporine A in spermiogenesis in rats

Cyclosporine A (CsA) is known to have testicular toxicity, leading to male infertility. The occurrence of numerous anomalous spermatids and residual bodies in the epididymal ducts of rats treated with CsA was observed in our previous studies. To examine the fine structural changes of impaired spermiogenesis induced by CsA, rats were treated s.c. with 40 mg/kg/day CsA for 2 weeks. Desquamation of round spermatids still surrounded by a slender Sertoli cell cytoplasm was occasionally observed. A prominent change in the seminiferous tubules was an occurrence of numerous residual bodies containing one or more flagella. They were not phagocytosed by the Sertoli cell, and accumulated in the epididymal ducts. Cellular components in the epididymal lumen included degenerating round spermatids and abnormal spermatozoa and residual bodies. Although separation of the head from the tail of the spermatozoa was rarely seen, various kinds of abnormalities of flagella were frequently encountered; compact aggregation of numerous flagella in a single spermatozoon or residual body, disarrangement of mitochondrial or fibrous sheath with outer dense fibers, and fusion of flagella with a single intervening mitochondrial layer. These findings indicate that CsA gives rise to toxic effects on the spermiogenesis by impairing directly the spermiogenic cell development and by impeding Sertoli cell function including a reduction of its phagocytic activity.     

Pharmacokinetics of an oral solution of the microemulsion formulation of cyclosporine in maintenance pediatric liver transplant recipients

BACKGROUND: A comparison of the oral bioavailability of cyclosporine from the original formulation (CsA) and from the new formulation, cyclosporine for microemulsion (CsA-ME), was made in pediatric maintenance liver transplant patients within two age groups (group 1, ages 1-5 years; group 2, ages 6-17 years) in an open-label, multicenter, randomized crossover trial. All patients were at least 6 months past transplantation and were receiving CsA maintenance therapy. METHODS: In study period 1 (days 1 through 14), patients were administered either CsA or CsA-ME at the same b.i.d. dosage as their maintenance therapy. Upon entry into period 2 (days 15 through 28), patients were converted to the alternate formulation at a 1:1 mg dose ratio. On day 29, all patients returned to the CsA treatment administered at study entry, with follow-up on day 35. Dosage adjustments were not allowed with either CsA or CsA-ME. Twelve-hour pharmacokinetic profiling was performed at the end of periods 1 and 2. RESULTS: Both the mean area under the concentration-versus-time curve and the mean maximum blood concentration of cyclosporine-both normalized for dose-were significantly increased: by 66% and 109%, respectively, in patients receiving CsA-ME compared with those receiving CsA in group 1 and by 39% and 75%, respectively, in group 2. During this study, liver function remained stable, and serum creatinine and blood pressure did not differ significantly between treatment groups. CONCLUSIONS: This study shows increased bioavailability in all patients converted to CsA-ME, with the greatest increase seen in patients with the lowest initial cyclosporine bioavailability. The tolerability was similar between the two formulations during this study.     

Myelin formation by mouse glia in myelin-deficient rats treated with cyclosporine

Previous attempts to generate myelin in the myelin-deficient rat spinal cord by transplanting mouse glia were not successful. In order to determine whether this result was due to graft rejection or to interspecies mismatch of cellular or molecular components at the axoglial junction, we have repeated the experiment in cyclosporine-treated rats. Our results show that in the immunosuppressed hosts, foetal glial xenografts form an abundance of myelin within the dorsal columns at or near the injection site about two weeks after the operation. In some cases, myelination extends virtually across the entire width of the dorsal columns. Ultrastructurally, the myelin sheaths are normal in all respects, including the presence of the 'radial component'. The lateral edges of the myelin lamellae form typical paranodal axoglial junctions, some displaying periodic 'transverse bands'. We infer that previous mouse to rat xenograft failures reflect host immune response rather than mismatch of heterologous junctional components. We also compared foetal, early post-natal and adult xenografts. Foetal donor cells, containing an abundance of precursors but virtually no mature oligodendrocytes, are more effective than neonatal donor cells in forming myelin, and after adult grafts, we found no myelin formation. Thus, in xenografts, as in allografts, foetal precursor cells are far more suitable than glia from mature donors in generating significant amounts of myelin.     

Evaluation of fluvastatin in the treatment of hypercholesterolemia in renal transplant recipients taking cyclosporine

Occlusive atherosclerosis is a major cause of morbidity and mortality in renal transplant recipients. Hyperlipidemia associated with the transplanted state may be at least partially responsible for this complication and is therefore an important target of therapy. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are powerful cholesterol-lowering drugs, but their broad use in transplant recipients has been hindered by concerns about interactions with cyclosporine. Cyclosporine interferes with the elimination of these agents, increasing their plasma and tissue levels and predisposing the patient to rhabdomyolysis. Fluvastatin, the first entirely synthetic HMG-CoA reductase inhibitor, possesses a distinct pharmacologic profile, including a shorter half-life and virtually no active circulating metabolites. Therefore, it may interact differently with cyclosporine. The pharmacokinetics and safety of fluvastatin, 20 mg/day, were evaluated in 20 hypercholesterolemic renal transplant recipients also receiving cyclosporine, usually in combination with azathioprine and methylprednisolone, during the 14-week study. Fluvastatin area under the curve, maximum plasma concentration, and time to maximum plasma concentration were minimally increased in these patients, unlike findings reported for lovastatin, pravastatin, and simvastatin. This suggests that metabolism of fluvastatin may be less affected by cyclosporine than that of other reductase inhibitors. Fluvastatin was well tolerated, with no evidence of myopathy, rhabdomyolysis, or ophthalmologic abnormalities. These findings and the significant reductions in total cholesterol and low-density lipoprotein cholesterol levels and the ratio of low-density to high-density lipoproteins achieved in these patients support the broader use of fluvastatin to treat hypercholesterolemia in renal transplant recipients.     

Craniofacial and TMJ effects after glutamate and TRH microsphere implantation in proximity to trigeminal motoneurons of growing rats

The sequelae of sustained, in vivo delivery of two important neurotransmitter substances, glutamate and thyrotropin-releasing hormone (TRH), upon craniofacial growth and development have previously not been investigated. Our purpose was to document and compare the relative effects of glutamate and TRH microspheres stereotactically placed in proximity to trigeminal motoneurons within the trigeminal motor nucleus. The following null hypotheses were tested: (1) TRH microspheres in proximity to trigeminal motoneurons have no significant effect upon the craniofacial skeleton, and (2) there are no significant differences between the relative effects of chronic, long-term delivery of glutamate and TRH upon the neuromusculoskeletal system of growing rats. Forty male Sprague-Dawley rats were divided into 4 experimental groups (glutamate microspheres, TRH microspheres, blank microspheres, sham surgeries) and underwent stereotactic neurosurgery at 35 days; 5 rats of each group were killed at 14 and 21 days for data collection. Histology revealed that implants were clustered in the pontine reticular formation, close to the ventrolateral tegmental nucleus. Both glutamate and TRH rats had implant-side deviation of their facial skeleton and snout regions; 4 x 2 ANOVA and post hoc t-tests revealed significant (P < or = 0.05, 0.01) differences between groups and sides for motoneuron count, muscle weight, and osteometric data. TRH rats also demonstrated larger implant-side TMJ discs and mandibular fossae in comparison with the other groups. The stated null hypotheses were therefore rejected.     

Effect of cyclosporine on immune responses in submaxillary lymph nodes of pituitary-grafted rats

This work was undertaken to analyze the interrelationships between prolactin and cyclosporine in affecting immune responsiveness in submaxillary lymph nodes. Male rats received an anterior pituitary graft within breast muscles on day 5, or under the kidney capsule, on day 30 or 60 of life. On day 70 (rats operated on day 5 or 30) or on day 100 (rats operated on day 60) animals were injected with Freund's complete adjuvant and cyclosporine (5 mg/kg for 5 days), and were killed 2 days after immunization. Natural killer (NK) activity in submaxillary lymph node decreased in neonatally pituitary-grafted rats and increased in rats grafted on day 30 or 60, as did lymph node cellularity. Lipopolysaccharide (LPS)- and concanavalin A (ConA)-induced proliferation diminished in lymph nodes of rats grafted on day 30 or 60, respectively. Cyclosporine treatment diminished lymph node cell number and NK activity and increased the proliferative response to ConA. Cyclosporine depressive effect on lymph node cellularity was counteracted by the presence of a pituitary graft, as were the inhibition of NK activity and the stimulatory effect on ConA-induced cell proliferation. In pituitary-grafted rats, cyclosporine decreased submaxillary lymph node LPS-induced proliferation. Cyclosporine decreased the high circulating prolactin levels found in pituitary-grafted rats. The results are compatible with age-dependent, inhibitory and promoting activities of hyperprolactinemia on immune responses in lymph nodes, affected in a complex antagonistic and synergistic way by cyclosporine immunosuppression.     

Renal biopsy in connection with long-term treatment of psoriasis with cyclosporine

Renal biopsies were performed in 30 psoriatics during long-term low-dose cyclosporin (CSA) therapy (range 2.5-6 mg/kg/day) of from six months to eight years. The study included pretreatment biopsies in 25 of the patients. After two years all biopsies shared features consistent with CSA nephropathy despite completely normal pretreatment morphology in 18 of the 25 patients. The severity of the findings, which consisted of arteriolar hyalinosis, focal interstitial fibrosis and sclerotic glomeruli, increased with length of therapy. Mild renal lesions were seen during the first two years. After four years all but one had arteriolar hyalinosis, with interstitial fibrosis pronounced in five and moderate in six of 11 patients. At the same time glomerular sclerosis had become significant. A decrease in glomerular filtration rate (GFR) correlated with the severity of the fibrosis. GFR studied in 14 patients six months to seven years after discontinuation of CSA was still significantly decreased in relation to baseline prior to therapy. The data from our study together with experiences from cardiac-transplanted patients indicate that patients with psoriasis, after two years therapy with CSA, should be rotated to other treatments or be followed carefully by GFR and sequential renal biopsies.     

Lesions of the cranio-vertebral region in rheumatoid polyarthritis

During 9 experimental and 93 clinical operations on the open heart under circulatory bypass the authors studied microclots of multicomponent perfusion mixtures. They observed an increased number of microclots after infusion of high-molecular plasma-substituting solutions and long-term intraapparatus recirculation. During the bypass there was an increased number of microclots in the "machine-patient" system. The complex of measures suggested by the authors contributes to a delay in additional formation of microclots during the perfusion and also reduces the number of posttransfusion complications.     

Conditioned cyclosporine effects but not conditioned taste aversion in immunized rats.

In 2 experiments, the development of adjuvant arthritis (an experimental autoimmune disease) was inhibited by exposing rats to a flavored solution that had previously been paired with injections of cyclosporine (an immunodepressive drug) compared with rats with the same history but exposed to a flavored solution that had previously not been paired with drug injections. In contrast to earlier experiments on conditioned cyclophosphamide effects, rats did not avoid the taste that had previously been paired with drug administration. Thus, conditioned immunopharmacologic effects were not confounded with taste aversion. These observations are interpreted as reflecting an associative learning process that affected the development of an autoimmmune disease. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Trunk strength testing in patient evaluation and treatment

A wide variety of trunk strength testing devices has been developed, the goal being to quantify back strength, patient effort, and spinal function or dysfunction. Although the idea of applying quantitative values to spine function is appealing, controversy exists regarding the reliability and validity of these testing systems. In this issue, two experienced investigators give their opinions as to the values and pitfalls of lumbar trunk strength testing, and provide insight into the most appropriate applications of these often costly systems.