Cialis Super Active

By L. Gunock. University of Scranton.

Structure–activity relation- ship study of bis(substituted aminoalkylamino)anthraquinones generic 20 mg cialis super active with mastercard. Amsacrine is formu- lated as two sterile liquids in separate ampoules order cialis super active cheap, one containing 75 mg of the drug in 1 buy cialis super active 20 mg line. Amsacrine is typically used in combination with other antileukaemic agents generic cialis super active 20mg on line, including cytarabine, thioguanine, 5-azacytidine, vincristine and prednisone (Gennaro, 1995; Editions du Vidal, 1998; Rote Liste Sekretariat, 1998; Thomas, 1998). With the latter method of detection, the limit of sensitivity was approximately 50 ng/mL; with the former, it was 125 ng/mL (Emonds et al. The plasma samples were extracted with hexane at pH 3–4 and re-extracted with diethyl ether at pH 9 in the presence of borate present at a high concentration. After drying, the residue was dissolved in methanol before injection into the chromatograph. Absorbance was detected at 254 nm for plasma and simultaneously at 254 nm and 405 nm for urine samples (Paxton, 1984). Its anti- tumour activity was first described in 1974 (Cain & Atwell, 1974), and the drug entered clinical trials in 1976 (Hornedo & Van Echo, 1985; Louie & Issell, 1985). The use of amsacrine is limited almost exclusively to the treatment of leukaemia in adults and children, in which it has been included in a number of combination chemo- therapy regimens at cumulative doses of 450–600 mg/m2 (Arlin et al. Amsacrine is formulated as two sterile liquids that are combined before intravenous administration, diluted in 500 mL dextrose and typically infused over 30–90 min (Editions du Vidal, 1998; Thomas, 1998). Information from an industry representative indicated that amsacrine is approved for use in at least 18 countries (Parke-Davis Canada, 1999). Positive controls received a single intraperitoneal injection of 500 or 1000 mg/kg bw urethane. In the groups treated with amsacrine, no significant increase in the number of mice with lung adenomas was observed [tumour incidence and multiplicity not reported] (de la Iglesia et al. The animals were then maintained without dosing for the remainder of the 104-week study. The mortality rates were 44% of male controls, 48% at the low dose, 66% at the intermediate dose and 100% at the high dose; and 36% of female controls, 54% at the low dose, 46% at the intermediate dose and 96% at the high dose. The incidences of small intestinal ade- nomas were 0/50, 0/50, 1/50 and 7/50 (p < 0. The incidences of small intestinal adeno- carcinomas were 0/50, 1/50, 7/50 and 10/50 (p < 0. Two adenocarcinomas and one adenoma of the large intestine were observed in males at the high dose and none in the other groups of males; two adenocarcinomas of the large intestine were observed in females at the high dose and none in the other groups. Squamous-cell carcinomas of the skin were observed in 1/50, 0/50, 4/50 and 10/50 (p < 0. Squamous-cell papillomas were observed at increased incidence in male rats (3/50 controls, 20/50 at the high dose; p < 0. The incidences of keratocanthoma of the skin were significantly higher in male rats (3/50, 2/50, 7/50 and 12/50 in controls and at the low, intermediate and high doses, respectively; p < 0. Fibromas of the skin occurred at significantly higher incidences in male rats (0/50, 8/50, 15/10 and 11/50; p < 0. The total plasma clearance rate is 200–300 mL/min per m2, and the apparent distribution volume is 70–110 L/m2, suggesting concentration in tissues (Jurlina et al. During a 1-h infusion of amsacrine at 90–200 mg/m2, the peak plasma concentration was 10–15 μmol/L (Van Echo et al. Although not fully reported, early trials in which amsacrine was given orally failed to reach the maximum tolerated dose, as shown by lack of toxicity even at doses as high as 500 mg/m2 per day, suggesting incomplete or erratic absorption. In sub- sequent studies, the intravenous route was used, with which the maximum tolerated dose in patients with solid tumours is 100–150 mg/m2 when administered over 1–3 h (described by Louie & Issell, 1985). The elimination half-time was increased to 17 h in patients with impaired liver function, but it was not altered significantly in patients with renal impairment. Urinary excretion of amsacrine over 72 h, typically around 12% of the dose, decreased to only 2% in patients with renal impairment and increased to 20% in patients with hepatic impairment (Hall et al. After administration of [14C]amsacrine, the total amount of radiolabel excreted in urine was 35% in patients with normal organ function, 49% in patients with liver impairment and 2–16% in patients with renal impairment. In two patients from whom biliary outflow was collected, 8% and 36% of the administered radiolabel was recovered within 72 h, < 2% being unchanged amsacrine (Hall et al. Amsacrine is taken up rapidly by nucleated blood cells in vivo, peak concentrations occurring shortly after the end of a 3-h infusion; the concentration was about five times greater than the peak plasma concentration. The kinetics of elimination from peripheral blast cells was similar to that from plasma (Linssen et al. High tissue concentrations of amsacrine were still present two weeks after treatment (Stewart et al. The concentrations in cerebrospinal fluid were < 2% of the corresponding plasma concentration in one study (Hall et al. About 97% of a dose of amsacrine is bound to protein bound in plasma in both cancer patients and healthy volunteers. Studies of human plasma in vitro showed no change in protein binding across a concentration range of 1–100 μmol/L. This typically includes biphasic elimination, with a rapid distribution phase and a more prolonged terminal elimination phase with a half-time of about 0. The pharmacokinetics was typically predictable in all species, including humans (Paxton et al. The bioavailability of orally administered amsacrine in mice (10 mg/kg bw) and rats (100 mg/kg bw) was incomplete and variable (Cysyk et al. After intravenous administration of [14C]amsacrine to mice and rats, > 50% of the radiolabel was excreted in bile within the first 2 h, and the bile:plasma ratio was > 400:1 (Cysyk et al. In mouse bile, 5′- and 6′-glutathione conjugates were present in roughly equal amounts and accounted for 70% of the excreted biliary radiolabel after administration of radio- labelled amsacrine (Robertson et al. In rats, the principal biliary metabolite was the 5′-glutathione conjugate, which accounted for 80% of the excreted radiolabel within the first 90 min and > 50% of the administered dose over 3 h (Shoemaker et al. In rat liver microsomes and human neutrophils, intermediate oxidation products have been identified as N1′-methanesulfonyl-N4′-(9-acridinyl)-3′-methoxy-2′,5′-cyclohexa- diene-1′,4′-diimine and 3′-methoxy-4′-(9-acridinylamino-2′,5′-cyclohexadien-1′-one (Shoemaker et al. The same conjugation products were reported after exposure of Chinese hamster fibroblasts to amsacrine or its methanesulfonyl oxidation product in culture. The rate of glutathione conjugate formation during exposure to the oxidation product in cultured cells was rapid, whereas formation after exposure to amsacrine was slow, suggesting a low rate of oxidation of amsacrine to its oxidation products, with subsequent conju- gation formation in this system (Robbie et al. In all of the phase I studies, the dose-limiting toxic effect was myelosuppression, resulting mainly in leuko- penia. Other effects included nausea, vomiting, fever, injection-site reaction, skin rash and discolouration (due to the yellow colour of the drug), mucositis and alopecia. Paraesthesia and hepatoxicity were seen in a few patients, but cardiac toxicity was not observed in one study (Louie & Issell, 1985). At these doses, the leukopenia is mild to moderate in most patients but more severe in around 30% of patients (Hornedo & Van Echo, 1985). Myelo- suppression is usually more severe in previously treated patients, and is much more severe with high doses of amsacrine (600–1000 mg/m2). Stomatitis and mucositis become more frequent with higher doses (> 120 mg/m2) (Slevin et al. Hepatoxicity has been reported, typically manifest as transient increases in serum bilirubin concentration and/or hepatic enzyme activity, but lethal hepatotoxicity has also been reported (Appelbaum & Shulman, 1982). Phlebitis occurred in up to 17% of patients in early studies with amsacrine (Legha et al. The more common effects were alterations in the electro- cardiogram and arrhythmia, but cardiomyopathy and congestive heart failure also occurred (Weiss et al. Amsacrine has been used safely in patients with pre- existing arrhythmia when a serum potassium concentration of > 4 mmol/L was main- tained (Arlin et al. Toxic effects on the gastrointestinal and central nervous system were observed at lethal doses in dogs (6. In subsequent studies, evidence of cardiotoxicity was not seen in rats (Kim et al. Intravenous dosing of rats at 1 or 3 mg/kg bw per day for five days resulted in hair loss, diarrhoea and leukopenia; these effects were reversible (Pegg et al.

Usually purchase cialis super active pills in toronto, the assay is performed on one portion of the sample and the drying on a separate portion altogether cialis super active 20mg fast delivery. The underlying principle of the method is based upon the precipitation of amodiaquine base that is generated as a precipitate when the salt is decomposed in aqueous medium with dilute ammonia generic cialis super active 20 mg online. Cognate Assays A few other pharmaceutical substances are also determined after conversion to free bases as recorded in Table : 10 discount cialis super active 20mg on-line. Substances Assayed After Conversion to Free Compound In certain specific cases either the pure pharmaceutical substance or dosage forms are quantitatively converted to free compound. This conversion to free compound is quantitative and hence forms the basis of gravimetric analysis. A few typical examples belonging to this category are, namely : progesterone suspension sterile, progesterone tablets, sodium lauryl sulphate, mephobarbital tablets and sorbitan monooleate. Mephobarbital Tablets Materials Required : Mephobarbital : 300 mg ; hexane : 100 ml ; chloroform : 150 ml ; alcohol (95% v/v) : l0 ml. Transfer an accurately weighed portion of the powder equivalent to about 300 mg of mephobarbital to an extraction thimble. Extract with 15 ml of solvent hexane, allow the thimble to drain, transfer to a continuous extraction apparatus pro- vided with a tared flask, and extract the mephobarbital with chloroform for 2 hours. Evaporate the chloroform on a steam bath with the aid of a current of air, cool, dissolve the residue in about 10 ml of alcohol, evaporate, dry the residue at 105°C for 1 hour, cool and weigh. The weight of the residue represents the weight Cl3H14N2O3 in the portion of the tablets taken. Substances Assayed after Conversion to Derivatives or Substitution Products In pharmaceutical drug analysis a host of organic pharmaceutical substances are invariably converted quantitatively to their corresponding derivatives by virtue of interactions with certain functional entities, namely : aldehyde, ketone, amino, carboxyl, phenolic, hydroxyl etc. However, in some cases it may be feasible to obtain uniform substitution products of organic pharmaceutical substances quantitatively, for instance : tetraido derivative of phenolphthalein is obtained from the phenolphthalein tablets. It is important to mention here that the number of organic pharmaceutical substances which may be analysed by this method is limited because of two vital reasons, they are : (a) the reversible nature of reactions, and (b) the formation of products of side reactions simultaneously. Benzylpenicillin(Syn : Benzylpenicillin Sodium or Potassium Salt) Materials Required : Benzylpenicillin sodium (say) : 0. Theory : Benzylpenicillin (sodium or potassium salt) may be assayed gravimetrically by quantitative conversion to the 1-ethylpiperidinium benzylpenicillin derivative. The ultimate precipitation is caused by l- ethyl piperidine after the respective sodium or potassium salt of benzylpencillin has been duly converted with phosphoric acid to the corresponding penicillanic acid (i. The reactions may be expressed as follows : Therefore, we have : C16H17N2NaO4S ≡ C23H31N3O3S or 356. Now, centrifuge for 1 minute, break the surface with the help of a pointed glass rod, so that all crystalline particles are covered by liquid, and again centrifuge for 1 minute. Decant off the supernatant liquid, wash the precipitate with 2 ml of ice-cold dry acetone in amyl acetate (1 : 1) and again centrifuge for 1. Theory : The assay of cholesterol is solely based on the fact that practically all 3 β-hydroxysterols e. The complex thus obtained is crystalline in nature, fairly stable and possesses very low solubilities. Insert the stopper and allow to stand at room temperature (25 ± 2°C) for 12 hours, filter through a Gooch crucible, and wash with 5. Filter the precipitate of the resulting complex through a prepared Gooch crucible, previously dried to constant weight at 105°C. Wash the precipitate with ethanol followed by acetone and carbon tetrachloride, allow to drain as completely as possible, and dry to a constant weight at 105°C. Theory : The gravimetric assay of thiamine hydrochloride is based upon the precipitation of it as thiamine silicotungstate with silicotungstic acid in a slightly acidic medium. For a reasonably precise and accurate determination the precipitating reagent must contain <| 1. Interestingly, the thiamine silicotungstate complex possesses more or less a constant composition. Transfer the precipitate quantitatively and wash it thoroughly with four quantities each of 5. Simultaneously, determine the loss in weight on drying a separate portion of the sample at 105°C. Theory : Gravimetric analysis of proguanil hydrochloride involves the precipitation of the proguanil- cupric complex that results on the addition of ammoniacal cupric chloride solution to a solution of proguanil hydrochloride. Chill the solution below 10°C in an ice-bath and then add ammoniacal-cupric-chloride solution with continuous stirring till the resulting solution attains a permanent deep-colour. Allow the solution to stand for 90 minutes to complete the complexation and then filter through a No. Simultaneously, find out the loss in weight on drying with a separate portion of the sample at 105°C and incorporate this in the calculation. Benzethonium Chloride Theory : In general, quaternary nitrogen containing compounds like—choline chloride, acetylpyridinium chloride, benzethonium chloride, and bethanechol chloride readily form insoluble salts quantitatively with tetraphenyl boron and this puts forward the basis for the gravimetric assay of the above cited pharmaceutical substances. Allow to cool and dilute to 100 ml with ethanol 96%] : 50 ml ; sodium tetraphenyl borate solution (1% w/v in chloroform) : 50 ml ; sintered-glass crucible No : 4. Cool to ambient temperature and add suffcient bromophenol blue solution gradually till the solution yields a blue Chloroform-soluble complex. Now, add sodium tetraphenyl borate solution in small lots at intervals with constant stirring until the complete precipitation of insoluble benzethonium tetraphenyl borate complex takes place. Allow the solution to stand for 60 minutes to complete the complexation and subsequently filter through a No. Transfer the precipitate quantitatively into the crucible and wash the precipitate with cold chloroform. Cognate Assays Quite a few official pharmaceutical substances and their respective dosage forms can be assayed gravimetrically after conversion to their corresponding derivatives or substitution products. How does the ‘Law of Mass Action and Reversible Reactions’ help in accomplishing the gravimetric analysis? How would you assay the following ‘drugs’ gravimetrically : (i) Sodium chloride (ii) Potassium alum (iii) Barium sulphate (iv) Piperazine phosphate. Gravimetric analysis may be accomplished by one of the following means and ways : (a) Substances assayed after conversion to Free Acid, (b) Substances assayed after conversion to Free Base, (c) Substances assayed after conversion to Free Compound, and (d) Substances assayed after conversion to Derivatives. In usual practice, data are generated as a result of continuously re- corded curves that may be considered as ‘thermal spectra’. These thermal spectra also termed as‘thermograms, often characterize a single or multicomponent system in terms of : (a) temperature dependencies of its thermodynamic properties, and (b) physicochemical reaction kinetics. All the above mentioned techniques shall be discussed briefly with specific reference to their theory, instrumentation, methodology and applications wherever necessary. Static Thermogravimetric Analysis In this particular instance the sample under analysis is maintained at a constant temperature for a period of time during which any changes in weight are observed carefully. Dynamic Thermogravimetric Analysis In dynamic thermogravimetric analysis a sample is subjected to conditions of predetermined, carefully controlled continuous increase in temperature that is invariably found to be linear with time. Balance Automatic gas switching Furnace First gas Sample Second gas Flow meter Cooling fan Needle Pure gas valve outlet Stopper Figure 11. Balances They are usually of two types : (a) Null-point Type : It makes use of an appropriate sensing-element which aptly detects any slightest deviation of the balance beam and provides the application of a restoring force, directly propor- tional to the change in weight, thereby returning the beam to its original null-point. The restoring- force is subsequently recorded either directly or with the aid of a transducer. Furnace The furnace must be designed in such a fashion so as to incorporate an appropriate smooth input thereby maintaining either a fixed temperature or a predetermined linear-heating programme (e. The temperature control of the furnace is satisfactorily achieved via a thermocouple mounted very close to the furnace-winding. The maximum operational temperature may be obtained by using different thermocouples as indicated below : S. Graphite-Tube Furnace* > 1500 *Control and measurement of temperatures are critical and problematic. Recorder The recording device must be such so as to : (i) record both temperature and weight continuously, and (ii) make a definite periodic record of the time. The successive plateaus correspond to the anhydrous oxalate (100-250°C), calcium carbonate (400-500°C), and finally calcium oxide (700-850°C). In other words, these plateaus on the decomposition curve designate two vital aspects, namely : (a) clear indication of constant weight, and (b) stable phases within a specified temperature interval. The chemical reactions involved may be summarized as follows : 100-250°C 400-500°C 700-850°C CaC2O4.

An injection of amphetamine following an intravenous barbiturate is said to provoke a striking onrush of talking and activity from psychiatric patients cheap 20mg cialis super active overnight delivery. Without adequately controlling his study cialis super active 20mg low cost, one author claims that methamphetamine produces such a strong urge to talk that the criminal who feigns amnesia or withholds vital information cannot control himself and thus gives himself away effective 20mg cialis super active. Iproniazid buy 20mg cialis super active visa, an antidepressive drug which is relatively slow and sometimes dramatic in its thera- -131- peutic effect, should be considered for experimentation. This drug, and similar, less toxic analogs which are being developed, might be considered for use in special instances. For example, informants suffering from chronic depression, whether due primarily to emotional factors, situational stress, or physical debilitation, might become very responsive after using a medication of this type. As a class, the stimulants probably present the most obvious exploitative potential for an interrogator. The use of such drugs by an interrogator would tend to produce a state of anxiety or terror in most subjects, and promote perceptual distortions and psychotic disorientation. Their use could constitute a definite threat to most medically unsophisticated subjects, i. When the subject is not under the influence of such drugs, vital information might be extracted as a price for ceasing further medication. An enlightened informant would not have to feel threatened, for the effect of these hallucinogenic agents is transient in normal individuals. The information given during the psychotic drug state would be difficult to assess, for it may be unrealistic and bizarre. The introduction of new drugs like tranquilizers that sedate but do not impair intellectual functioning in moderate dosage (e. There is a possibility that these tranquilizers might be of use with selected informants who are highly agitated and disturbed, and who might give information they prefer to withhold in return for the tranquility they experience with such a sedative. Under the influence of this drug, the less emotionally upset informant might find that he can better master his anxieties and keep his resolve to remain silent. The ability of the subject to give information is not notably affected by a mainte- -132- nance dosage. The motivational effects of obtaining drug supplies, while extreme, are not of a different order for most subjects than those which the interrogator could produce by other more rapid means. The exploitation of addiction probably constitutes a threat to persons previously addicted, or to those who become addicted in the captivity situation as a sequel to other aspects of their treatment, rather than through the deliberate creation of addiction for exploitative purposes. Another use to which interrogators might put drugs and placebos would involve their ability to absolve the subject of responsibility for his acts. The popular meaning of being "drugged" or "doped" implies that an individual in this state has lost control over his actions and that society will not hold him responsible for them. When the transmittal of information is likely to induce guilt in the source, the interviewer can forestall some of this reaction by the administration of a placebo or drug. In some cases, this will be all that is require4l to remove the barrier to information transmittal. What are the over-all conclusions that can be drawn from this review and critical analysis of the use of pharmacologic agents in obtaining information? Are pharmacologic agents of any value to the interrogator in eliciting vital information? The answer is that drugs can operate as positive catalysts to productive interrogation. Combined with the many other stresses in captivity that an individual may be obliged to undergo, drugs can add to the factors aimed at weakening the resistance of the potential informant. However, for many reasons, the use of drugs by an interrogator is not certain to produce valid results. The effects of drugs depend to a large extent on the personality make-up and physical status of the informant and the kind of rapport that the interrogator is able to establish with him. Even under the most favorable circumstances, the information obtained could be contaminated by fantasy, distortion, and untruth, especially when hallucinogenic or sedative drugs are employed. Are there ways in which the informant can resist revealing vital information under interrogation with drugs? The informant should know that a drug of itself cannot force him to tell the truth, although it may make him talkative, overemotional, mentally confused, or sleepy. He should also know that the effects of drugs are quite variable from individual to individual, and that those who may use drugs against him cannot predict with certainty what effects will occur in his particular case. To a victim of such attempts the imperfect predictability of many of the direct effects and side effects of any drug offers many opportunities for simulation. It is likely that most nonfatal drugs will have a transient, time-limited action rather than a permanent one. There is no need for the informant to become panicky at any bizarre or uncomfortable reactions he may experience, for these reactions will probably disappear. Finally, since the interrogator wants accurate and factual information, the informant can confound the interrogator as to what is fact and fiction by a number of means. He can simulate drowsiness, confusion, and disorientation early during the administration of the drug. As a final suggestion, this reviewer is inclined to agree with West (130) that the basic training of military personnel can be helpful in developing techniques of resistance to interrogation. A brief course on the limitations of the use of drugs in interrogation and on the kinds of pharmacologic effects to be expected from the different types of drugs would be helpful. Such training could decrease the fear, hypersuggestibility, and other deleterious reactions that evolve from the uncertain, the unpredictable, and the unknown. A comparative behavior and psychodynamic study of reserpine and equally potent doses of raudixin in schizophrenics. Zur Pharmakologie des Reserpin, eines neuen Alkaloids aus Rauwolfia serpentina Benth. Drugs that produce deviations in mood, including anxiety presumably without impairing capacities for orientation or at least secondarily to changes in mood. Sodium amytal as an aid in state hospital practice: Single interviews with 100 patients. Pharmacologic explorations of the personality: Narcoanalysis and "methedrine" shock. Clinical studies on alpha (2-piperidyl) benzhydrol hydrochloride, a new antidepressant drug. Experimental investigation into the validity of confessions obtained under sodium amytal narcosis. The relationship of gender and intelligence to choice of words: A normative study of verbal behavior. The speech patterns of schizophrenic patients: A method of assessing relative degree of personal disorganization and social alienation. Motivational determinants in the modification of behavior by morphine and pentobarbital. In Group for the Advancement of Psychiatry, Methods of forceful indoctrination: Observations and interviews. A preliminary investigation into abreaction comparing methedrine and sodium amytal with other methods. Relationship between effects of a number of centrally acting drugs and personality. A controlled investigation into the value of chlorpromazine in the management of anxiety states. The effects of methedrine and of lysergic acid diethylamide on mental processes and on the blood adrenaline level. Mental effects of reduction of ordinary levels of physical stimuli on intact healthy persons. Psychological changes in normal and abnormal individuals under the influence of sodium amytal. Modifications in ego structure and personality reactions under the influence of the effects of drugs. Intravenous barbiturates: An aid in the diagnoses and treatment of conversion hysteria and malingering. Studies in psychopharmacologic psychotherapy: Effective psychotherapy during drug- induced states. Electroencephalogram and psychopathological manifestations in schizophrenia as influenced by drugs. The transference and non-specific drug effects in the use of the tranquilizer drugs, and their influence on affect. Clinical study of the mescaline psychosis with special reference to the mechanism of the genesis of schizophrenia and other psychotic states.

Adenoviral vectors infect both dividing and non-dividing cells in many different tissues including airway epithelial cells order cheap cialis super active on-line, endothelial cells buy 20mg cialis super active with visa, hepatocytes and various tumors generic cialis super active 20mg without prescription. The adenovirus genome is much larger (about 35 kb) and its organization is much more complex than retroviruses purchase cialis super active 20 mg with amex. Genes introduced into cells using adenoviral vectors are maintained in the nucleus episomally and provide transsient expression of transgenes. Compared to viral vectors, gene medicines present several potential advantages, including: • low cost; • non-infectivity; • absence of immunogenicity; • good compliance; 337 • well-defined characteristics; • possibility of repeated clinical administration. Plasmids encode bacterial origin of replication, usually derived from a high copy plasmid and a selectable marker, usually a gene that confers resistance to an antibiotic, such as kanamycin or neomycin. These “prokaryotic” plasmid segments permit the production of large quantities of a given plasmid in bacteria. The minimal transcription unit required for the expression of a therapeutic protein consists of 5′ enhancer/promoter upstream of the gene encoding for the therapeutic protein and a poly(A) signal downstream of the gene. Tissue- specific promoters are designed to interact with transcription factors or other nuclear proteins present in the desired target cells. The chicken skeletal a-actin promoter contains positive as-acting elements required for efficient transcriptional activity in myogenic cells. Therefore, an a-actin promoter could direct high expression of recombinant protein in skeletal muscle. The efficiency of polyadenylation is important for gene expression, as transcripts that fail to be cleaved and polyadenylated are rapidly degraded in the nuclear compartment. Therefore, in vivo pulsatile production of certain therapeutic proteins may be beneficial for their clinical applications. This can be achieved by including gene switches in a gene expression system to turn on or off the transcription of an administered gene. A gene switch is designed to be part of a gene expression system that contains both the gene switch and a therapeutic gene. In the positive system, the target gene will be inactive until the administration of an exogenous compound or ligand. Such inducing agents or drugs include progesterone antagonists, tetracycline, ecdysone and rapamycin. This section describes the development of several lipid, peptide and polymer-based gene delivery systems. However, the encapsulation efficiency of plasmids is very low, because of the large dimension of plasmids compared to the internal diameter of the vesicles. The pH-sensitive immunoliposomes have been shown to mediate 6~8 times higher levels of transgene expression into mouse lymphoma cells, compared to non-pH-sensitive immunoliposomes. A negatively charged phospholipid such as phosphatidylserine, phosphatidic acid or phosphatidyl glycerol, in the absence or presence of cholesterol, are utilized to produce a suspension of multilamellar vesicles containing plasmids, which are then converted to small unilamellar vesicles by sonication. Cochleates have been shown to encapsulate plasmid and enhance plasmid stability and transfection efficiency. A cationic lipid consists of: • a hydrophobic lipid anchor group • a linker group • a positively charged headgroup. Lipid anchors help in forming liposomes (or micellar structures) and determine the physical properties of a lipid bilayer, such as membrane rigidity and rate of lipid exchange between lipid 341 membranes. The linker group is an important component, which determines the chemical stability and biodegradability of a cationic lipid. The head groups of cationic lipid appear to be critical for transfection and cytotoxicity of corresponding liposome formulations. The cationic amphiphiles differ markedly in structure and may be single or multiple charged as primary, secondary, tertiary and/or quaternary amines. Examples are lipospermine, cationic cholesterol, cationic detergent or lipopolysine. The relative proportions of each component and the structure of the head group influence the physicochemical properties of plasmid/lipid complexes. Many effective cationic lipids contain protonatable polyamines linked to dialkyl or cholesterol anchors. To increase the biodegradability of cationic lipids, a series of cationic lipids have been synthesized in which the ether bonds were replaced with ester bonds. Cationic lipid-based gene delivery systems lack target specificity, which results in low transfection efficiency in certain tissues due to the interference from cationic lipid-binding macromolecules either in the circulation or in the extracellular matrix. To circumvent this problem, neutral plasmid/lipospermine complexes containing a trigalactolipid have been prepared and shown to efficiently transfect hepatoma HepG2 cells bearing asialoglycoprotein receptor. Addition of 25% (mol mol−1) of the triantennary galactolipid increased the transfection efficiency by a thousand fold, compared to the lipid-based system with no targeting ligand. An efficient transfection of β-galactosidase into HeLa cells has been shown with the combination of transferrin and cationic liposome Lipofectin, whereas Lipofectin alone had low transfection efficiency. Asialofetuin is an asialoglycoprotein containing terminal galactosyl residues that have been used to target liposomes to the liver. The resulting complexes retain their ability to interact specifically with target cell receptors, leading to receptor-mediated internalization of the complex into the cells. It is known that the active sites of enzymes, receptor ligands and antibodies usually involve about 5 to 20 amino acids. One example of such a gene delivery system comprises: 343 • a galactosylated peptide that both condenses the plasmid into monodisperse nanoparticles of about 100 nm in diameter and enables specific recognition and binding to asialoglycoprotein receptors; • an amphipathic, pH-selective peptide that enables the plasmid to leave the endosomes prior to their fusion with lysosomes and entry into the cytoplasm. Two general classes of lipopeptide analogs of Tyr-Lys-Ala-Lys -n Trp-Lys peptides have been prepared by including a hydrophobic anchor. The general structures are N, N- dialkyl-Gly-Tyr-Lys-Ala-Lys -Trp-Lys and N ,N -diacyl-Lys-Lys -Trp-Lys. These peptides differ from theα n n parent structures in that they self-associate to form micelles in aqueous solutions. The lytic characteristics are revealed as the carboxyl groups of the aspartyl and glutamyl side chains are protonated, which allows the peptides to assume a a-helical conformation that can be inserted into the membrane bilayer. The hydrophobic face contains only strongly apolar amino acids, while negatively charged glutamic acid residues dominate the hydrophilic face at physiological pH. At a given charge ratio of condensing peptide to plasmid, the transfection efficiency has been shown to be proportional to the concentration of the endosomolytic peptide added to the complex. The increased hydrophobicity of the complex may enhance interaction with cell membranes and facilitate cell uptake. However, these polymers cannot be used for in vivo application due to their poor transfection efficiency and high cytotoxicity. The effect of colloidal and surface characteristics of plasmid/ dendrimer complexes on gene transfer has been examined. These complexes were monodisperse, with a mean hydrodynamic diameter of about 200 nm. The particle size, surface charge and gene transfer efficiency of plasmid/dendrimer complexes prepared with the 5th generation of dendrimers has been shown to be influenced by dendrimer concentration in the complexes. The colloidal and surface properties of plasmid/chitosan complexes have been shown to depend on the molecular weight of chitosan, the ratio of plasmid to chitosan and the preparation medium. Smaller nanoparticles have been observed with low molecular weight chitosan (2 kDa) as compared to high molecular weight chitosan (540 kDa). Interestingly, the transfection efficiency of the complexes was not affected by the presence of serum proteins, even though the presence of serum is known to adversely affect the transfection efficiency. The blood capillary walls are comprised of four layers, namely plasma-endothelial interface, endothelium, basal lamina, and adventia. Macromolecules can cross the endothelial barrier: • through the cytoplasm of endothelial cells themselves; • across the endothelial cell membrane vesicles; • through inter-endothelial cell junctions; • through endothelial cell fenestrae. Based on the morphology and continuity of the endothelial layer, capillary endothelium can be divided into three categories: continuous, fenestrated, and discontinuous endothelium (see Section 5. The continuous capillaries are found in skeletal, cardiac, and smooth muscles, as well as in lung, skin, subcutaneous and mucous membranes. The endothelial layer of brain microvasculature is the tightest endothelium, with no fenestrations. Capillaries with fenestrated endothelia and a continuous basement membrane are generally found in the kidney, small intestine and salivary glands.