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They discussed the dendrimer–drug interactions and mechanisms discount promethazine 25 mg with visa, encapsulation purchase 25mg promethazine fast delivery, electrostatic Recent Developments in Nanoparticulate Drug Delivery Systems 11 interactions buy promethazine 25 mg, and covalent conjugation of drug and dendrimer molecules. The appli- cation of nanotechnology to drug delivery is widely expected to create novel ther- apeutics, capable of changing the landscape of pharmaceutical and biotechnol- ogy industries. Various nanotechnology platforms are being investigated, either in development or in clinical stages, and many areas of interest where there will be effective and safer targeted therapeutics for a myriad of clinical applications. Multifunctional nanocarriers for mammo- graphic quantification of tumor dosing and prognosis of breast cancer therapy. Dendrimer-modified magnetic nanoparticles enhance effi- ciency of gene delivery system. Immunogenecity of bioactive magnetic nanoparticles: Nat- ural and acquired antibodies. Synthesis and characterization of chitosan- g-ploy(ethylene glycol)-folate as anon viral carrier for tumor targeted gene delivery. Amine containing core shell nanoparticles as potential drug carriers for intracellular delivery. Developments on drug delivery systems for the treatment of mycobacterial infections. Facile biosynthesis, separation and conjugation of gold nanoparticles to doxorubicin. Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications. A nanoparticulate drug delivery system for rivastigmine: Physicochemical and in vitro biological characterization. Recent developments in nanoparticle based drug delivery and tar- geting systems with emphasis on protein based nanoparticles. Characterization of the morphology and thermal properties of Zein Prolamine nanostructures obtained by electrospinning. Formation of silk fibroin nanoparticles in water miscible organic solvent and their characterization. Nanoparticulate drug delivery systems for the non-invasive chemotherapy of brain tumors. Self assembled drug delivery systems; part I: In vitro in vivo studies of the self assembled nanoparticulates of cholesteryl acyl didanosine. Alginate nanoparticles as anti tuberculosis drug carriers: Formulation development, pharmacokinetics and therapeutic potential. Gamma interferon loaded onto albumin nanoparticles: In vitro and in vivo activities against Brucella abortus. Conjugates of poly(D,L-lactide-co-glycolide) on amino cyclodextrins and their nanoparticles as protein delivery system. Studies on the oridonin-loaded poly(D,L-lactic acid) nanoparti- cles in vitro and in vivo. Cisplatin encapsulated in phosphatidylethanolamine liposomes enhances the in vitro cytotoxicity and in vivo intratumor drug accumulation against melanomas. Aclarubicin-loaded cationic albumin-conjugated pegylated nanoparticles for glioma chemotherapy in rats. Cytotoxicity and apoptosis enhancement in brain tumor cells upon coadministration of aclitaxel and ceramide in nanoemulsion formulations. Cisplatin incorporated hyaluronic acid nanoparticles based on ion complex formation. Liposomal coencapsulated fludarabine and mitox- antrone for lymphoproliferative disorder treatment. Polymeric micelles delivery reduces kidney dis- tribution and nephritic effects of cyclosporine A after multiple dosing. Nanoparticulate biopolymers deliver insulin orally eliciting pharmacological response. Preparation and evaluation of poly-butylcyanoacrylate nanoparticles for oral delivery of thymopentin. Amorphous cyclosporine nanodisper- sions for enhanced pulmonary deposition and dissolution. Characterization of prototype self- nanoemulsifying formulations of lipophilic compounds. Poly(N-vinyl-pyrrolidone)-block-poly(D,L- lactide) as polymeric emulsifier for the preparation of biodegradable nanoparticles. The targeted delivery of cancer drugs across the blood brain barrier: Chemical modifications of drugs or drug nanoparticles. The transport of nanoparticles in blood vessels: The effect of vessel permeability and blood rheology. An antisense oligonucleotide carrier based on amino silica nanoparticles for antisense inhibition of cancer cells. Trastuzumab-modified nanoparticles: Optimization of preparation and uptake in cancer cells. Nanotechnology approaches for drug and small molecule delivery across the blood brain barrier. Biodistribution and pharmacokinetic analysis of long- circulating thiolated gelatin nanoparticles following systemic administration in breast cancer-bearing mice.

Larger reciprocal spacings and interfringe angles can be measured inherently more accurately and precisely than smaller reciprocal spacings and interfringe angles trusted promethazine 25mg. The location of the respectively more precise and accurate data points will be in the upper right-hand corners of lattice-fringe fingerprint plots cheap promethazine 25 mg with visa. These three data point position parameters are a minimalistic characteristic of a certain zone axis of a crystalline material buy 25 mg promethazine otc. Such search strategies are in the process of being imple- mented under the name “reduced lattice-fringe fingerprint plots” in both the kine- matic and (two-beam) dynamic diffraction limits at our Web site (20) on the basis Structural Fingerprinting of Nanocrystals in the Transmission Electron Microscope 299 of data of the mainly inorganic subset (15) of the Crystallography Open Database (16–18). One must, however, be aware that symmetry is to some extent “in the eye of the beholder,” as it refers strictly only to mathematical entities. The former are sometimes referred to as the “wallpaper groups,” because any wall- paper can be classified as belonging to one of these groups. While there are 230 space groups in total, their projections in two dimensions in any direction results in just one of the 17 plane groups. There is also a “teach- ing edition” that gives a comprehensive description of the 17 plane groups (88) and the rules on how to obtain plane groups from space groups. Since the symmetry element projection rules are somewhat cumbersome to apply, we are in the process of developing a universal space group projector pro- gram that will be later on interfaced to the mainly inorganic subset (15) of the Crys- tallography Open Database (16–18) and accessible openly at our Web server (20). In short, the projected 2D coordinates (r, s) of the 3D fractional atomic coor- dinates (x, y, z) (also representing 3D direct space vectors from the 3D origin to 300 Moeck and Rouvimov the respective atoms) along any axis [uvw] are obtained by multiplication with the projection matrix Pij ⎡ ⎤ x r P11 P12 P13 ⎣ ⎦ = · y (18) s P21 P22 P23 z The projection of [uvw] is [0, 0] = origin of 2D mesh and the projections of (the direct space 3D lattice) vectors p and q will be the new (2D) unit mesh vectors = (1, 0) and (0, 1) so that one has six equations to solve for the six components of Pij ⎡ ⎤ 1 q1 010 P11 P12 P13 ⎣ ⎦ = · v p2 q2 (19) 001 P21 P22 P23 w p3 q3 with vectors p = p1a + p2b + p3c and q = q1a + q2b + q3c. The simplest matrices Pij are obtained in cases when p and q are both chosen to be unit cell vectors (a, b,orc) of the respective 3D lattice. These matrices are as follows: − u/ a,b w Pij p = a = (100), q = b = (010) (20a) 0 − v/ w 1 − u/ 0 a,c v Pij p = a = (100), q = c = (001) (20b) 0 − w/ 1 v − v/ b,c u Pij p = b = (010), q = c = (001) (20c) − w/ u For the determination of the projected 2D symmetry (plane group) for any space group, one needs to take all symmetry equivalent positions (x, y, z), (x , y , z ),... Since the multiplicity of the general position of a space group is generally higher (i. Finally, one needs to identify the correct plane group by the fulfillment of the condition that all of its symmetry relations for the general position are obeyed. Note that for projections of 3D symmetry elements, the 2D projection mesh axes do not need to be perpendicular to [uvw]. As a consequence, only those six 2D diffraction symmetry groups that contain a twofold rotation axis can be distinguished on the basis of the reflections of the zero-order Structural Fingerprinting of Nanocrystals in the Transmission Electron Microscope 301 Laue zone. For each of these “search-match entities,” we suggest the usage of a crystallographic R value, as it is standard practice for structure factor moduli and reflection intensities in structural electron and X-ray crystallography. The lowest weighted sum of all R values shall then indicate a quite unambiguous structural identification. Obviously, all experimental search-match entities possess random and sys- tematic errors that will determine their respective relative weight. The accuracy and precision of the extracted structure factor moduli will depend on how accurately and precisely the integrated intensities of the reflections can be measured, how well they are integrated by the precession movement of the primary electron beam, and how well they are described by the kinematic or quasi-kinematic scattering approx- imations. If it is expected that some of the experimentally obtainable pieces of structural information possess particularly large random and/or systematic errors, they may simply be excluded from the respective R value in order not to bias the overall fit unduly. A comparatively minor problem is that the theoretical values of the search- match entities are not precisely known either. The accuracy of theoretical structure factors depends on the (not precisely known) accuracy of the atomic scattering fac- tors, which might be for heavier atoms up to 10% (66). The atomic scattering fac- tors for larger scattering angles are known to be more accurate than their counter- parts for smaller scattering angles (3). The theoretical structure factors for larger 302 Moeck and Rouvimov scattering angles will, therefore, be more accurate than their counterparts for smaller scattering angles. Finally, there is also the possibility that a certain structure may not be in the respective database. With so much experimentally extractable structural fin- gerprinting information that can be combined in different ways for searches and matches with low individual R values, it seems highly impractical to try to predict what the more and most successful identification strategies might be. We, therefore, propose to simply test a range of strategies on different sets of candidate structure data in order to see pragmatically what works well. Reliable spatial information down to the sub-A˚ length scale can nowadays be obtained in both the parallel illumination and the scanning probe (scanning transmission electron microscopic) mode [when there is an effective correction for scan distortions (93) in the latter mode]. Objective lens aberration–corrected transmission electron microscopes and condenser lens aberration–corrected scanning transmission electron microscopes in the bright-field mode allow for sufficiently thin crystals the retrieval of Fourier coef- ficients of the projected electrostatic potential down to the sub-A length scale and,˚ thus, represent a novel type of crystallographic instrument. The higher the directly interpretableb resolution in an aberration-corrected transmission electron microscope is, the lower will, in principle, be the lateral over- lap of the electrostatic potentials from adjacent atomic columns and the more zone axes will be revealed by crossed lattice fringes in structurealb images. Note that the relationship between directly interpretable image resolution and visibility of zone axes is strongly superlinear. This is, for example, demonstrated in Table 1 for a densely packed model crystal with a very small unit cell. This hypothetical material is very densely packed, as 8 atoms occupy one unit cell. It is assumed that both hypothetical atoms have similar atomic scattering factors. A com- plementary integrated diffraction spot–based technique that utilizes a large-angle defocused incident beam and a spherical aberration corrector (and which will be especially useful for beam-sensitive crystals) has recently been developed (95). For noncubic nanocrystals, these lat- tice constant changes may result in changes of the angles between net planes (and, therefore, affect the position of data points in lattice-fringe fingerprint plots) on the order of a tenth of a degree to a few degrees for some combinations of reciprocal lattice vectors while other combinations may be negligibly affected. There are also “crystallographically challenged materials” and “intercalated mesoporous materials,” that is, tens of nanometer-sized entities with a well-defined atomic structure over small length scales that can be described by a relatively large crystallographic unit cell with a low symmetry (99,100). Significant structural dis- tortions that might be considered as classical defects or nanocrystal-specific defects to the average structure may be present to such an extent that it may make little sense to consider the disorder as a defect away from an ideal structure. In short, the deviations from the perfect atomic structure might be rather severe in these mate- rials but remnants of the crystallinity might still be present. For those structures that are really new to science, there will be no entries in the existing databases.

The typical dose is the equivalent of 12–14 mg/m2 mitoxantrone once every three weeks in patients with lymphomas and tumours of solid tissues discount promethazine 25 mg otc, and 12 mg/m2 per day for five days in patients with leukaemia generic promethazine 25mg with mastercard. When mitoxantrone is used in combination with other cytotoxic drugs buy promethazine 25 mg on line, these doses are often lower (Dunn & Goa, 1996; Royal Pharmaceutical Society of Great Britain, 1999). In recent years, mitoxantrone has been used to a limited extent in the treatment of multiple sclerosis, typically at doses lower than those used in malignant disease and on a monthly schedule (Gonsettte, 1996; Millefiorini et al. Studies of Cancer in Humans The Working Group considered only studies in which mitoxantrone was given to patients who did not receive treatments with alkylating agents, with the exception of low doses of cyclophosphamide. A woman, 51 years old, with a primary breast tumour had received a combination of mitoxantrone, vincristine, 5-fluorouracil, cyclophosphamide and radiotherapy (chest and axillary); she developed acute promyelocytic leukaemia nine months later. The first case was that of a woman (aged 56 years) who received eight cycles of mitoxantrone (7 mg/m2), metho- trexate and mitomycin, local radiotherapy to the breast and axilla and tamoxifen. The second patient (aged 39 years) was also treated with eight cycles of mitoxantrone (7 mg/m2), methotrexate and mitomycin and in addition received radiotherapy to the breast. They had previously received radical mastectomy and either cyclophosphamide, metho- trexate and 5-fluorouracil or radiotherapy or both. Treatment with methotrexate, mito- xantrone and mitomycin was followed by tamoxifen, medroxyprogesterone acetate or medroxyprogesterone acetate and radiation therapy. Acute myeloid leukaemia (one case of acute monoblastic leukaemia, one of acute promyelocytic leukaemia and one of acute undifferentiated leukaemia) occurred 12–30 months after the start of treatment with the mitoxantrone-containing regimen. The patient had been treated with high doses of corticosteroids during exacerbation of the multiple sclerosis. Five years before the diagnosis of acute promyelocytic leukaemia, the patient had received an intravenous dose of mitoxantrone (10 mg/m2) once a month for five months (total dose, 87. The patient was reported to have no history of exposure to known leukaemogenic risk factors or a personal or family history of malignancy. Partridge and Lowdell (1999) reported the development of myelodysplastic syndrome in a 62-year-old woman treated for advanced breast cancer with five courses of mitoxantrone (7 mg/m2), methotrexate and mitomycin. In addition, she had received radiotherapy to the breast and axilla and tamoxifen. The planned doses for the intravenous regimen that included mitomycin (n = 30) were: mitoxantrone, 8 mg/m2 every three weeks (total dose, 64 mg); mito- mycin, 8 mg/m2 every six weeks (total dose, 32 mg) and methothrexate, 30 mg/m2 every three weeks (total dose, 240 mg). The planned doses for the intravenous regimen that did not include mitomycin (n = 29) were: mitoxantrone, 12 mg/m2 every three weeks (total dose, 96 mg) and methothrexate, 35 mg/m2 every three weeks (total dose, 280 mg). During follow-up for a median of 72 months, two cases of acute myeloid leukaemia (one of acute myelomonocytic leukaemia and one of acute myeloblastic leukaemia) and one case of myelodysplastic syndrome occurred. All three patients had received treatment without mitomycin in combination with tamoxifen (three cases), radiotherapy (one case) or other cytostatic drugs (one case). The interval between treatment and diagnosis was 17 and 18 months for the cases of acute myeloid leukaemia and 36 months for the case of myelodysplastic syndrome. The frequency of acute myeloid leukaemia and myelodysplastic syndrome was 3/59 (5%) in the two treatment groups combined and 3/29 in the group given treatment without mitomycin, who had received a higher dose of mitoxantrone and a slightly higher dose of methotrexate than the group treated with mitomycin. The dose of mitoxantrone associated with leukaemia was higher than that usually given in the treatment of advanced breast cancer. These were not considered further because the follow-up was rarely longer than one year and the patients would previously have been treated with leukaemogenic agents and/or radiation. Studies of Cancer in Experimental Animals No data were available to the Working Group. There are no published data on the bio- availability of orally administered mitoxantrone in humans, but a number of studies have reported the pharmacokinetics of mitoxantrone given as an intravenous infusion over 3–60 min at doses of 1–80 mg/m2. All showed an initial rapid phase representing distri- bution of the drug into blood cells, with a half-time of about 5 min (range, 2–16 min) and a long terminal half-time of about 30 h (range, 19–72 h) (Savaraj et al. Many early studies reported much shorter terminal half-times, but suitably sensitive assays may not have been used or adequate numbers of late samples collected. Tri-exponential elimination has been reported, the second distribution phase having a half-time of about 1 h (Alberts et al. The extent of the distribution into blood cells is illustrated by the observation that at the end of a 1-h infusion, the concentrations of mito- xantrone in leukocytes were 10 times higher than those in plasma (Sundman-Engberg et al. The typical peak plasma concentration after a 30–60-min infusion of 12 mg/m2 was about 500 ng/mL (Smyth et al. The rapid disappearance from plasma results in a total plasma clearance rate of about 500 mL/min, while the large volume of distribution of 500–4000 L/m2 indicates tissue sequestration of the drug (Savaraj et al. Studies of patients given mitoxantrone at doses up to 80 mg/m2 (standard dose, 12 mg/m2) suggest that the kinetics is linear up to this dose (Alberts et al. Studies of the urinary excretion of mitoxantrone concur that little of the admin- istered dose is cleared renally. In one study, urinary recovery of radiolabel after intravenous administration of [14C]mito- xantrone accounted for 6. The elimination half-time of mitoxantrone in two patients with impaired liver function was 63 h, whereas that in patients with normal liver function was 23 h (Smyth et al. Faecal recovery of radiolabel after a single 12 mg/m2 dose was 18% (range, 14–25%) over five days (Alberts et al. These results suggest that the liver is important in the elimination of mito- xantrone and that patients with impaired liver function or an abnormal fluid compart- ment may be at increased risk for toxic effects. The sequestration of mitoxantrone by body tissues results in retention of the drug for long periods. The characteristic blue–green colour of mitoxantrone has been observed on the surface of the peritoneum more than one month after intraperitoneal administration, and the concentrations in peritoneal tissue 6–22 weeks after intra- peritoneal dosing ranged from < 0. Mito- xantrone was readily detectable in post-mortem tissue samples from all 11 patients who had received mitoxantrone intravenously between 10 and 272 days before death. The highest concentrations were found in the thyroid, liver and heart and the lowest in brain tissue (Stewart et al.

Transcytotic mechanisms occur in type-I cells for albumin and pulmonary delivered macromolecules may be transported by similar routes purchase promethazine 25mg visa. The role of these mechanisms in the absorption of drugs into the bloodstream has not been quantified and for some drugs purchase promethazine 25mg otc, more than one route of absorption exists discount promethazine 25mg without prescription. Absorption from the gastrointestinal tract may also occur, either because of direct swallowing of a portion of the inhaled dose, or because of secondary swallowing following mucociliary clearance. Many isozymes of the cytochrome P-450 family have been identified in the respiratory tract with the highest concentrations of these occurring in the nasal and smaller airways with lower levels in the trachea and main bronchi. Their distribution tends to be more widespread and their activities much higher than is seen with the P-450 systems. Locally-acting inhaled drugs may be inactivated by these enzyme systems, for example isoprenaline and rimiterol are metabolized by catechol-O-methyl transferase. The inhaled steroid beclomethasone dipropionate is hydrolysed by esterases, firstly to an active metabolite, beclomethasone monopropionate, and then to an inactive metabolite, beclomethasone. Inhaled drugs intended for systemic action are likely to be subjected to some first-pass metabolism during their absorption from the lung. The extent of this pre-systemic first-pass metabolism in the lung has not been fully quantified for many drugs but is estimated to be far less than that seen in the gastrointestinal tract and liver after oral dosing (see Section 6. A brief overview of both the advantages and disadvantages of pulmonary drug delivery is given below. Local administration is also associated with some disadvantages for these drugs: • oropharyngeal deposition may give local side-effects; • patients may have difficulty using the delivery devices correctly. The disadvantages of the lungs for delivery of systemically-acting drugs include: • The lungs are not readily accessible surfaces for drug delivery. Complex delivery devices are required to target drugs to the airways and these devices may be inefficient. Dexterity is also required, which may be lacking in the very young and elderly populations. For the systemic delivery of drugs with a narrow therapeutic index, such variations may be unacceptable. Efficient drug delivery of slowly absorbed drugs must overcome the ability of the lung to remove drug particles by mucociliary transport. In order to deliver drugs to the lung, a therapeutic aerosol must be generated for inhalation. An aerosol can be considered as a colloidal, relatively stable two- phase system, consisting of finely divided condensed matter in a gaseous continuum. Atomization is the process by which an aerosol is produced and can be electrically, pneumatically or mechanically powered. The mechanism, advantages, disadvantages and the potential strategies for improvement of the devices used for aerosol generation are summarized in Table 10. Selection of appropriate salts and pH adjustment will usually permit the desired concentration to be achieved. If this is 263 not feasible, then the use of co-solvents such as ethanol and/or propylene glycol can be considered. However, such solvents change both the surface tension and viscosity of the solvent system which in turn influence aerosol output and droplet size. Water insoluble drugs can be formulated either by micellar solubilization, or by forming a micronized suspension. Nebulizer solutions are often presented as concentrated solutions from which aliquots are withdrawn for dilution before administration. Both excipient types have been implicated with paradoxical bronchospasm and hence the current tendency to use small unit-dose solutions that are isotonic and free from preservatives and antioxidants. Atomization is the process by which sprays are produced by converting a liquid into aerosolized liquid particles. The large increase in the liquid-air interface, together with the transportation of the drops, requires energy input. The forces governing the process of converting a liquid into aerosolized liquid particles are: • surface tension—serves to resist the increase in the liquid-air interface; • viscosity—resists change in shape of the drops as they are produced; • aerodynamic forces—cause disruption of the interface by acting on the bulk liquid. The primary drops may be further dispersed into even smaller drops or coalescence may occur. They have in-built baffles to ensure that large primary drops are returned to the reservoir and thus the aerosol emitted from the device has a size distribution which will aid airway penetration. Nebulizers generate aerosols by one of two principal mechanisms: • high velocity airstream dispersion (air-jet or Venturi nebulizers); • ultrasonic energy dispersion (ultrasonic nebulizers). Drug solution is drawn from the reservoir up the capillary as a result of the region of negative pressure created by the compressed air passing over the open end of the capillary (Venturi effect). The larger drops are removed by the various baffles and internal surfaces and return to the reservoir. The smaller respirable drops are carried on the airstream out of the nebulizer and via either a mouthpiece or face mask into the airways of the patient. However, generally less than 1% of entrained liquid is released from the nebulizer. There are many commercially available nebulizers with differing mass output rates and aerosol size distributions which will be a function of operating conditions, such as compressed air flow rate. As described above, for maximum efficacy, the drug-loaded droplets need to be less than 5 μm.