By B. Yussuf. California Institute of Technology.

The method of principal components is well suited for market research purchase 30 mg actos overnight delivery diabetes 3 month test, it allows you to create a new space of explanatory variables with zero multicollinearity generic actos 30 mg without a prescription test yourself diabetes symptoms quiz, reducing the dimension of this space facilitates visualization of data. The pharmaceutical sector is an important part of the primary health system its condition depends on the overall level of the industry and the economy as a whole. However guarantee level free medical care to the patients is a problem carried out the most difficult and hardest. The availability of drugs is determined by their presence in the pharmaceutical market and economic accessibility that is to sayprice regulation and compensation of spending on medicines through compulsory health insurance. To analyze the current state of pharmaceutical care in Poland and establish a mechanism reimbursement cost of medicines. Some drugs are used to remove symptoms that are easy to identify, such as: painkillers, antipyretics, vitamins, homeopathic medicines can be bought without a prescription. Each patient is insured in Poland has the right to discount the price of the drugs. There are 4 levels of reimbursement of drugs:  100% free (bezpłatny (B) dispensed medicines used to treat severe, chronic diseases such as cancer, tuberculosis, infectious diseases, mental disorders, seizures, etc. Where the retail price is higher than the set limit for financing, the patient must pay the difference between the retail price and size limit funding. For discounted prescriptions mainly released generic drugs because their price is much lower than the original. In the case of the introduction of the first generic drug to limit the group, its price will be not more than 75% of the original drug price. At the end of patent protection, the manufacturer of the original drug should reduce the price by at least 25%, even if his group does not include any generic drag. Draws attention to the fact that the purchase of drugs can use and prescription prescribed in another country. If some medicines that prescribed in the recipe are absent, pharmacist can represcribe them for a patient, and leave the old prescription at the pharmacy. One prescription forms are allowed to issue up to 5 drugs on; the prescription valid 30 days usually. The doctor prescribes medicines in an amount such that enough for 3 months of treatment. According to statistics, the price of drugs in Poland for the last 20 years steadily increased, but still they are three times lower than in other European countries. Established, the average trade margin on drugs Poland is only 17%, and in most European countries – almost 30%. The provision of medical and pharmaceutical care for the population of Poland is in the form of compulsory social health insurance was determined. There are four compensation levels can be carried out on: the full amount (100% – chronic and prolonged) or partially (50% – treatment of the disease for 30 days, and 30% – other by defined list). Today the pharmaceutical market is undergoing significant changes occurring managerial and organizational transformation. This makes it necessary to improve the activities of retail pharmaceutical enterprises on the basis of modern management techniques with the use of marketing tools. Marketing strategy to promote the company acquire particular relevance in terms of competition for the market. The object of research is the process of formation and development of marketing activities of pharmaceutical companies in the current economic conditions. Theoretical generalization method, the method of analysis and synthesis, comparison method, statistical methods, methods of market research are used in the research process. There are one, two or multiple market segments that may be chosen by marketers of pharmaceutical company, and the options are between three broad approaches to the market: concentrated marketing, differentiated marketing and undifferentiated marketing. Products have not set the position, although market segmentations have been chosen. From this we can conclude that the decisive role in the choice of the drug plays its price.

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However buy 45 mg actos with mastercard diabetes type 2 cure 2015, many factors can affect distribution buy actos 30 mg with mastercard blood glucose high in morning, including: • differing characteristics of body tissues, • disease states that alter physiology, • lipid solubility of the drug, • regional differences in physiologic pH (e. Certain organs, such as the heart, lungs, and kidneys, are highly perfused with blood; fat tissue and bone (not the marrow) are much less perfused. The importance of these differences in perfusion is that for most drugs the rate of delivery from the circulation to a particular tissue depends greatly on the blood flow to that tissue. Perfusion rate limitations occur when the membranes present no barrier to distribution. If the blood flow rate increases, the distribution of the drug to the tissue increases. Therefore, drugs apparently distribute more rapidly to areas with higher blood flow. Highly perfused organs rapidly attain drug concentrations approaching those in the plasma; less well-perfused tissues take more time to attain such concentrations. Furthermore, certain anatomic barriers inhibit distribution, a concept referred to as permeability-limited distribution. This situation occurs for polar drugs diffusing across tightly knit lipoidal membranes. It is also influenced by the oil/water partition coefficient and degree of ionization of a drug. For example, the blood-brain barrier limits the amount of drug entering the central nervous system from the bloodstream. This limitation is especially great for highly ionized drugs and for those with large molecular weights. After a drug begins to distribute to tissue, the concentration in tissue increases until it reaches an equilibrium at which the amounts of drug entering and leaving the tissue are the same. The drug concentration in a tissue at equilibrium depends on the plasma drug concentration and the rate at which drug distributes into that tissue. In highly perfused organs, such as the liver, the distribution rate is relatively high; for most agents, the drug in that tissue rapidly equilibrates with the drug in plasma. In several disease states, such as liver, heart, and renal failure, the cardiac output and/or perfusion of blood to various tissues are altered. A decrease in perfusion to the tissues results in a lower rate of distribution and, therefore, a lower drug concentration in the affected tissues relative to the plasma drug concentration. When the tissue that receives poor perfusion is the primary eliminating organ, a lower rate of drug elimination results, which then may cause drug accumulation in the body. A drug that is highly lipid soluble easily penetrates most membrane barriers, which are mainly lipid based, and distributes extensively to fat tissues. This difference becomes important when determining loading dosage requirements of drugs in overweight patients. If total body weight is used to estimate dosage requirements and the drug does not distribute to adipose tissue, the dose can be overestimated. Clinical Correlate In general, volume of distribution is based on ideal body weight for drugs that do not distribute well into adipose tissue and on total body weight for drugs that do. Once in breast tissue, the alkaline drugs ionize because breast tissue has an acidic pH; therefore, the drugs become trapped in this tissue. Due to the nature of biologic membranes, drugs that are un-ionized (uncharged) and have lipophilic (fat-soluble) properties are more likely to cross most membrane barriers. Many of these factors can be incorporated into a relatively simple physiologic model. The equation below represents this physiologic model and provides a conceptual perspective of the volume of distribution: V = Vp + Vt(Fp/Ft) where: V = volume of distribution, Vp = plasma volume, Vt = tissue volume, Fp = fraction of unbound drug in the plasma, and Ft = fraction of unbound drug in the tissue. From this model, it is evident that the volume of distribution is dependent on the volume of the plasma (3-5 L), the volume of the tissue, the fraction of unbound drug in the plasma, and the fraction of unbound drug in the tissue. In contrast to plasma protein binding, tissue protein binding cannot be measured directly. We use this equation to help us understand why the volume of distribution of a drug may have changed as a consequence of drug interactions or disease states.

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Given the broad array of challenges and heterogeneity of barriers across settings actos 45mg cheap diabetes symptoms dark urine, no single approach is likely to work for everyone in all settings order actos 15 mg without prescription signs juvenile diabetes babies. Improving the understanding of barriers and innovative strategies to address them are important priorities in implementation research and public health. Related transport costs and loss of income while seeking care serve as disincentives when health facilities are located far from the person’s home. Reorganizing services, such as systems for appointment, triage, separating clinical consultation visits from visits to pick up medicine, integrating and linking services and family-focused care may reduce waiting times at the health facility (59,60). Interventions harnessing social support have emerged as a promising approach to counteract the structural, economic, service delivery and psychosocial constraints that affect retention in care. Use fxed-dose combinations to simplify forecasting and supply management systems Lack of a system for Implement systems for patient monitoring across the continuum of monitoring retention in care care, including cohort analysis and patient tracking systems 184 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection Table 9. Once people are diagnosed and enrolled in chronic care, follow-up visits should be scheduled and planned. Waiting until people present with symptoms or preventable complications is costly and ineffcient. Compared with the acute care model, planned chronic care models provide opportunities for prevention, early identifcation of issues and timely intervention. A system to keep information on the people receiving care at health facilities is critical for ensuring the continuity of chronic care. Health care teams can use it to identify people’s needs, to follow-up and plan care, to monitor responses to treatment and to assess outcomes for both individuals and for the overall treatment cohort. Information systems can be paper-based or based on an electronic registry, depending on local context. Programmes should develop a systematic strategy for collecting and aggregating key information that supports better management of the patient and ensures high-quality care. A robust patient information system is also critical for high-quality monitoring and evaluation of programmes and for supply management systems. When effective operational solutions such as successful service delivery models and processes of care are identifed in existing systems, programmes need to consider scaling up such models of care. Issues to be considered include mobilizing and allocating resources; training, mentoring and supervising health workers; procuring and managing drugs and other medical supplies; and monitoring and evaluation. In most generalized epidemic settings, maternal and child health services are provided at the primary care level, where pregnant women and children predominantly access health services. The quality of some of these studies was downgraded because of relatively few events (65–70). All these factors increased the satisfaction of the people receiving care and may have contributed to improving the quality of care (66,71). Guidance on operations and service delivery 189 and another showed comparable mortality rates. The quality of evidence was weighed along with programmatic risks and benefits; acceptability; values; preferences; cost implications; feasibility; critical contextual constraints; and contextual relevance. Plans for provider-initiated testing and counselling in such settings should emphasize supportive social, policy and legal frameworks (64). Rationale and supporting evidence In many countries, people who inject drugs are a marginalized population with limited access to and utilization of health care services. Randomized trials found that opioid substitution therapy decreases illicit drug use and increases retention in care relative to placebo (98). Observational studies found that opioid substitution therapy decreases mortality relative to not being in care (100). Some studies observed trends for improved viral suppression and reduced mortality, whereas others found comparable rates of viral suppression and mortality (101–103). In several settings, transport cost is a significant barrier to access and retention in care. Attrition declined after 12 months, resulting largely from significantly reduced losses to follow-up.

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In recent years discount 15mg actos free shipping diabetes insipidus cats, a considerable amount of research literature has documented associations between drug use and dependence buy actos 15mg with amex diabetes test chart, and a range of psychiatric disorders. This is because of the difficulty in separating out true underlying disorders from behaviours that develop as part of drug use. Available clinical, neurobiological and epidemiological evidence is yet to identify a unified explanation as to why there is such a high concordance between drug use and mental illness. It is assumed that the presence of an initial psychiatric illness may, either directly or indirectly, increase the risk of drug use. One of the most widely cited explanations of this causal relationship between psychiatric illness and drug use is that drugs are used to self-medicate the negative pervasive symptoms of psychiatric illness. This is both because the evidence from these investigations is considered relatively weak in determining causality, and because they are limited in number. Drugs alter the normal functioning of brain mechanisms that exist to regulate the functions of mood, thoughts and motivations. A component of why individuals may wish to use drugs is to elicit an alteration in normal brain function. This may include the desire to experience pleasure or to avoid pain (the desired effects of commonly used illicit drugs are explored in greater detail in Appendix 2). Thus, at a biological level, both the immediate and long-term reasons for why people may use a drug can be rationalised by understanding how that drug affects the brain at the pharmacological level. The repeated use of drugs may contribute to their continued re-administration through the development of physical symptoms. These include: • tolerance: which can be defined as a given drug producing a decreasing effect with repeated dosing. Tolerance influences repeated drug use, and as a result larger drug doses must be administered to produce a similar effect • withdrawal: which is the body’s reaction to absolute or relative withdrawal of a drug. Withdrawal is associated with a range of significant negative physical and psychological outcomes, and in certain cases can be fatal. Withdrawal can be alleviated by readministering the drug, which contributes to its repeated use. Among those with sensation seeking as a personality trait, under-responsiveness to natural rewards and the need for greater stimulation has been suggested as motivation for drug taking. Personality traits have been documented to have a substantial heritable component. These models seek to explain addictive behaviour as pairings between a drug, drug-associated stimuli,e and the effect of taking a drug. Enduring changes to behaviour result from, or are influenced by, these interactions. Learning theory may be useful to understand how drug use becomes a facet of identity, and the implications this may have on treatment. In these instances, specific maladaptive traits may become reinforced over time, through the acquisition of drugs or perceived protection against negative experiences (see Chapter 8 for further information on the ‘addict identity’). The rewarding properties of drugs can include sensations of pleasure or relief of pain, tension or fatigue, as well as the ability to enable the user to escape negative feelings or emotions. Thus, the drug is used, it has rewarding effects, and this reinforces repeating this behaviour (ie it influences the continued use of the drugs). The use of psychoactive drugs causes activation to areas of the brain that are normally involved in motivation, such as the mesolimbic dopamine system (see Section 1. This causes the release of dopamine, the neurotransmitter released in response to any positive event or reward. Theories based on classical conditioning are often used to explain complex behaviours, such as drug craving. Research has demonstrated that after repeated drug administration, cues that precede drug ingestion, such as the sight of a needle and syringe, elicit craving for drugs. The drug is the unconditioned stimulus, and the drug-related high is the unconditioned response. The unconditioned response occurs in response to the unconditioned stimulus • the unconditioned response (heroin) is repeatedly paired with the neutral stimulus (syringe) • eventually, the neutral stimulus (syringe) alone is able to elicit a conditioned response, which is to crave using heroin. Operant conditioning The theory of operant conditioning (also known as instrumental learning/conditioning) has also been used to describe why people use drugs. If classical conditioning can be seen as learning through association, then operant conditioning can be seen as learning through reinforcement.

The sheer largeness of peptide drugs also means that they are more biologically and chemically diverse discount actos 45mg amex diabetes prevention india. In actual practice purchase 45mg actos amex diabetes diet nhs, however, peptide drugs are often used to derive small nonpep- tide drug molecules. Doing so offers the benefts from both classes and the fne line that differentiates between a peptide drug and small drug molecule becomes faded. Indeed, after a lengthy process of rational drug design where residues are changed from natural amino acids to nonnatural amino acids then to nonamino acids, it becomes rather challenging at times to classify if a drug is peptide or nonpeptide. Although we would like to classify a nonpeptide drug as a compound that does not possess any amino acid, out of respect for the developers of the drugs, in this chapter, we will keep the nonpeptide or peptide assignments that the drug developers have chosen, and will thus avoid any debate over semantics. We will focus on success- ful stories of peptide-derived drugs that are processed by enzymes. We will try to be as up-to-date as possible in the information that we provide at the time that this chapter is being written. It should be noted that, in this chapter, most comparisons done between differ- ent drugs are restricted to our own personal viewpoint; because of legal reasons and personal pride, the drug developers would claim originality to their own discoveries. Hence, we would like the readers to read with an open mind and come up with their own interpretations of the information that we provide. During the process of changing a peptide drug to a peptide-like drug and eventually to a nonpeptide drug, the naming of each residue becomes confusing because two or more residues may be merged into one functional structure. We will be using the Schechter and Berger [1] nomen- clature that assumes that the substrate binds to the active site of an enzyme in an extended backbone conformation. Within the active site, subsites, also referred to as pockets, ′ are denoted as Sn and Sn, where n represents the number of subsite away from the catalytic S1 subsite, with the prime symbol denoting the opposite direction. Often, N-terminal residues are referred as Pn, whereas C-terminal ′ residues are referred as Pn. The naming of peptide drugs follows the same rules as ′ ′ that of peptide substrates. For example, P2–P1–P1–P2 is a tetrapeptide drug with a ′ scissile bond between the P1 and P residues. For peptide inhibitors, the inhibitory 1 unit, which is the unit that prevents enzyme cleavage, is assigned to the P1 residue. One should keep in mind that because the numbering is based on the subsites of the active site rather than the sequential order of the residues of the peptide drug, and that the chemical structures of the enzyme and peptide drug are three-dimensional by nature, that in some cases, the numbering of the residues of the peptide drug may not follow a sequential order. In simpler words, there are cases where the peptide drug does not bind to the active site in an extended backbone conformation. An example of an irregular order numbering is argatroban, a direct thrombin inhibitor, which has aP3–P1–P2 sequence (Section 5. Hence, it is often easier to commercialize natural enzymes or activators of enzymes found in nature, and to develop inhibitors of enzymes, than to create more potent enzyme activators. A philosophical reasoning for this observation could be that nature has selected the best enzymes and their activators, whereas man can only copy or destroy nature’s refnements. Despite the previous statement, researchers have designed a few enzyme activators, such as α-methyldopa and droxidopa (Section 5. Here, we are loosely equating the term enzyme activator to substrate, because as far as we are aware, there is no allosteric activator in the pharmaceutical market. Most activators of enzymes, or the enzymes themselves, are developed via either extraction of pharmacologically active natural substances from a crude inexpensive natural source or by replicating the natural substances by synthetic means. On the contrary, most potent inhibitors of enzymes are derived from natural lead compounds, or from natural substrates that have been corrupted to become enzyme inhibitors. From our own experience, the frst step in substrate-based drug design of modula- tors is to establish an assaying system for enzyme activity. A modulator is either an activator or inhibitor, which in our case, applies to a substrate or its peptide inhibitor. As the initial step, a reproducible enzyme activity assay system must be developed from a substrate and enzyme that both must be stable and pure. It is noteworthy that the enzyme often can process several different substrates and the choice of substrate, especially in substrate-based design of enzyme inhibitors, will determine the structural outcome of the derived modulators. In order to improve the processing effciency of the substrate by the enzyme, the substrate and enzyme may be structurally altered by synthetic means to improve purity and stability, so as to reduce variations between experiment results. Often, the fnal substrate used in the assay is a shortened yet active version of a natural substrate, and the enzyme is modifed from its natural form to prevent self-digestion.

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CdSe Qdots can be used to build on–off switches by utilizing Forster resonance energy transfer between the¨ Qdot donor and an organic acceptor 30 mg actos visa diabetes symptoms youth. In such this optical sensing scheme discount 30 mg actos with mastercard diabetes definition guidelines, Qdots could act both as donor and as acceptor. This on–off switch has the potential to be used as a sensor in many important applications, including healthcare, environmental monitoring, and biodefense systems. All of these experiments confirmed that water-soluble Qdots have potential applications in biosensor or bioimaging. This approach is general and the concept of an antibody fragment bound to a Qdot sur- face through noncovalent self-assembly should find wider use for other analytes of interest. In this case, population-average data are determined and one can get robust data from complex milieu or whole blood circulation. From Figure 10(A), it was determined that the X-ray absorption of Qdots was less than that of Omnipaque. In this respect, Qdot may not provide sufficient contrast for current radiographic practice. A typical room temperature hysteresis curve for paramagnetic CdS:Mn is shown in Figure 10(B). Protons are excited with short pulses of radio frequency radiation, and the free induction decay as they relax is measured and deconvoluted by a Fourier transform, which provides an image of the tissue. Areas of bone or tendon, which have a low proton density, have a weak signal and appear dark. Regions having air pockets and fecal matter, such as the bowel, are hard to image because 1. Therefore, various contrast agents such as perfluo- rochemicals, oils, fats, and nanomaterials, are studied to circumvent these imaging problems. Unlike organic molecules, nanomaterials-based contrast agents are mis- cible in aqueous systems that allow them to be used intravenously. Therefore, they are well suited for in vivo applications such as tracking blood flow in the brain. The advantage of Qdots over other nanoparticles is that they offer multimodal imaging capabilities (37). For example, paramagnetic contrast agents change the rate at which pro- tons decay from their excited state to the ground state, allowing more rapid decay through energy transfer to a neighboring nucleus (78). When paramagnetic Qdots are delivered to the liver, the uptake rate of Qdots by healthy liver cells is much higher than that by diseased cells. In these reports, the Qdots are often coated with a water-soluble paramagnetic coating to enhance contrast. Longitudinal (T1) and traverse (T2) proton relaxation times were measured with a single slice, spin– echo image sequence at 4. The efficacy of a contrast agent is generally expressed by its relaxivity (R ), that is defined by 1/T = 1/T0 + R [Gd] i i i (84), where Ti is the relaxation time for a contrast agent solution concentration of [Gd], and T0 is the relaxation time in the absence of a contrast agent. Compared 1 2 to commercially available contrast agents, Gd-Qdots exhibited higher R1 and R2 values under the same magnetic field strength of 4. High relaxivities were attributed to a reduced tumbling rate of the Gd3+-based contrast agents by grafting the contrast agent to rigid macromolecules and avoiding free rotation of the chelate (86,87). Although the Gd-Qdots can serve as either a T1 or T2 contrast agent, the R2/R1 ratio of ∼7. Linear plots of Gd concentration versus 1/T1 (C) and 1/T2 (D) to obtain ionic relaxivities of R1 and R2 of Gd-Qdots (81). These studies support the promise of a quantum leap in the extensive use of Qdots in future biological applications. It is predicted that Qdots will provide unprecedented sensitivity and selectivity over the traditional practices on molecular imaging. The use of Qdots emitting in near-infrared region will provide greater sensitivity and the longer lifetime of their excited states as compared to organic fluorophores and proteins for improved bioimaging. Despite the advantages for Qdots-based bioimaging, few issues related to Qdots need to be addressed before in vivo use, especially their toxicity. Some of the Qdots properties are limiting, such as the fact that their typical size is a few times larger than that of the traditional organic marker dyes. As research on nanoparticles with novel properties continues, it should be Semiconducting Quantum Dots for Bioimaging 363 possible to overcome these drawbacks and to develop multifunctional, multimodal Qdot-based systems for better biological imaging within a few years.

Reproduced with permission from: Biodistribution and gene expression of plasmid/lipid complexes after systemic administeration actos 30 mg free shipping diabetes test how long, Mahato R cheap 15mg actos free shipping diabetes type 2 disease process. Southern-blot analysis of blood showed the rapid degradation of plasmid, with a half-life of less than 5 min for intact plasmid, and was no longer detectable at 1 hr postinjection. By Southern-blot analysis, there was no detectable plasmid in the brain, large intestine, small intestine, or gonads at the 1-hr timepoint. Southern blot analysis also demonstrated that plasmid remained in the liver, spleen, lung, marrow, and muscle, although at diminished levels, up to 24 hr postinjection. The plasma membrane is the next obstacle to be overcome in delivering genes into a cell. Gene delivery systems rely on binding to cell surface molecules, either specific, non- specific or both, prior to cellular internalization. The surface bound material usually gains entry into the cell either by endocytosis or membrane fusion. The schematic representation of the process of gene delivery and expression is shown in Figure 14. Gene delivery systems can distribute plasmids to the desired target cells, after which the plasmid is internalized into the cell by a number of mechanisms, such as adsorptive endocytosis, receptor-mediated endocytosis, micropinocytosis, caveolae-mediated endocytosis and phagocytosis (see Section 1. The intracellular fate of plasmids depends on the means by which they are internalized and translocated to the cytoplasms and then to the nucleus. Extacellular environment → tissue targetability → cellular uptake → intracellular trafficking → nuclear entry → gene expression The transition from coated vesicle to early endosome is accompanied by acidification of the vesicular lumen that continues into the late endosomal and lysosomal compartments, reaching a final pH in the perinuclear lysosome of approximately 4. Such acidification associated with endosome maturation provides the means by which certain viruses gain access to the cytosol. Acid-induced conformational changes in the viral proteins trigger translocation across the endosomal membrane via a fusion process. By taking advantage of the endosomal acidification, pH-sensitive liposomes, adenovirus and endosomolytic peptides have been used to facilitate the release of plasmids into the cytoplasm prior to lysosomal degradation. Non-clathrin-coated pit internalization can occur through smooth imagination of 150–300 nm vesicles or via potocytosis. This pathway has been shown to be involved in the transport of folate and other small molecules into the cytoplasm. Plasmids are taken up by muscles through the T-tubules system and caveolae via potocytosis. Muscle cells appear to take up plasmids through the T-tubule system and caveolae via potocytosis. Apart from coated or uncoated pit pathways, cells may also take up plasmid/cationic carrier complexes via plasma membrane destabilization. Particles greater than 200 nm in diameter are not 350 efficiently taken up by endocytosis, but cells may also take up some larger plasmid/cationic carrier complexes via phagocytosis. Plasmid/cationic carrier complexes have been proposed to internalize into the endosome and initiate the destabilization of endosomal membranes. This destabilization would induce diffusion of anionic lipids from the external layer of the endosomal membrane into the complexes and form charge neutralized ion pairs with the cationic lipids. Destabilization and/or fusion of the complex with the plasma membrane would permit the same anionic lipids to diffuse to the surface, as would fusion with the endosomal membrane. Transfection efficiency is dependent on mitotic activity, as cells prevented from going into mitosis after transfection express transgenes much less efficiently than proliferating cells. In search for an explanation, the transport of plasmids across the nuclear membranes has been studied. Plasmids injected into the cytoplasm of quiescent human fibroblasts are not expressed, in contrast to plasmid injected into the nucleus. This has been found to be true for the cationic lipid-based systems; as plasmid injected into the cytoplasm of Xenopus oocytes is not expressed, unlike that injected into the nucleus, it must be concluded that the plasmid must dissociate from the cationic lipids before entering into the nucleus. A fundamental limitation to gene expression using most of the gene delivery systems is the inability of plasmid in the cytoplasm to migrate into the nucleus. Microtubules and actin filaments have been proposed to be involved in intracellular trafficking of macromolecules, including plasmids. These cytoskeletal components maintain intracellular distribution of organelles and facilitate trafficking between organelles. Motor proteins, motor protein receptors, or the relevant peptide sequences may be conjugated to or complexed with plasmid. This may result in association of plasmids with myotubules or actin filaments for more efficient transport through the cytoplasm to regions bordering the nucleus.