Pharmacogenetics of antipsychotic adverse effects: Case studies and a literature review for clinicians

There is a growing body of literature supporting the contribution of genetic variability to the mechanisms responsible for the adverse effects of antipsychotic medications particularly movement disorders and weight gain. Despite the current gap between research studies and the practical tools available to the clinician to identify such risks, it is hoped that in the foreseeable future, pharmacogenetics will become a critical aid to guide the development of personalized therapeutic regimes with fewer adverse effects. We provide a summary of two cases that are examples of using cytochrome P450 pharmacogenetics in an attempt to guide treatment in the context of recent literature concerning the role of pharmacogenetics in the manifestation of adverse effects of antipsychotic therapies. These examples and the review of recent literature on pharmacogenetics of antipsychotic adverse effects illustrate the potential for applying the principles of predictive, preventive, and personalized medicine to the therapy of psychotic disorders.     

Anticipatory control of head posture.

OBJECTIVE: We tested a hypothesis on two patterns of anticipatory postural adjustments (APAs) in neck muscles, reciprocal and co-activation, that may be used in a task-specific way. We also explored possible relation of APAs in leg and trunk muscles to head stabilization. METHODS: Load perturbations (loading and unloading) were applied to the head, trunk, and head and trunk simultaneously using similar hand actions by standing persons. Electromyographic signals (EMGs) from 10 muscles were recorded. Shifts of the center of pressure and EMG indices were computed over typical time intervals for APA. RESULTS: Time-shifted (reciprocal) activation of neck flexor and extensor muscles during APAs was seen when perturbations were applied directly to the head. Simultaneous activation dominated when the perturbations were applied to the trunk. Minimal APAs were seen in the leg/trunk muscles during head perturbation tests. APAs during trunk perturbation were not different from those during trunk and head perturbation. CONCLUSIONS: The results confirm the existence of two different patterns of APAs in neck muscles. A time-shifted (reciprocal) pattern is more likely to be used in anticipation of a perturbation acting directly on the head. A simultaneous activation (co-activation) pattern is used when direction of head perturbation cannot be predicted with certainty. Leg/trunk APAs are unlikely to help stabilize head posture. SIGNIFICANCE: These results are important for better understanding of feed-forward mechanisms of the control of head posture with possible implications for neurological patients who suffer from impaired feed-forward postural control.     

Freeze-drying polymeric colloidal suspensions: nanocapsules, nanospheres and nanodispersion. A comparative study.

Different polymeric nanoparticles were freeze-dried and the powders compared to determine the influence of the lipophilic core (Miglyol 810) or benzyl benzoate) and polymeric material (poly(epsilon-caprolactone) or Eudragit S90) on their drug content and morphology. Diclofenac, a non-steroidal anti-inflammatory drug, was used as a model. To characterize the products, a biological experiment based on the evaluation of the mucosal toxicity of diclofenac was conducted. Nanocapsule and nanosphere suspensions were prepared by nanoprecipitation and freeze-dried after the addition of colloidal silicon dioxide. The powders were examined under scanning electron microscopy (SEM) and gastrointestinal tolerance of products was evaluated in rats. Powders presented drug contents between 90.2+/-5.5 and 101.1+/-1.9% (HPLC). SEM analyzes showed non-spherical microparticles and, at higher magnifications, the micro-powder surface presented a homogeneous nanocovering. Regarding the gastrointestinal tolerance, with the exception of benzyl benzoate-loaded formulations, powders presented lesional indexes lower than the diclofenac salt solution. In contrast to the literature, nanocapsules can be dried by freeze-drying without leakage of drug or breaking the capsule wall.     

The synthesis and antibacterial activities of quinolones containing five- and six-membered heterocyclic substituents at the 7-position

A series of 6-fluoro-7-substituted-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids were prepared. The substituents at the 7-position included five- and six-membered heterocyclic rings such as oxazoline and oxazine as well as five-membered heteroaromatic rings such as oxazoles and imidazoles. The structure--activity relationships (SAR) of these compounds indicated that oxazole substituents containing a 2-methyl group had the greatest in vitro potency. The compounds showed greater in vitro antibacterial activity against Gram-positive organisms than against Gram-negative organisms.     

Stimulation of nerve growth factor and substance P expression in the iris–trigeminal axis of diabetic rats—involvement of oxidative stress and effects of aldose reductase inhibition

In rats with streptozotocin-induced diabetes, we measured increased (by 61%; P<0.05) mRNA for nerve growth factor (NGF) in the iris together with increased (by 82%; P<0.05) mRNA for preprotachykinin (the substance P precursor) in the trigeminal ganglion, suggesting that increased NGF was driving increased substance P gene expression. In other diabetic rats, these changes were prevented by treatment with either an antioxidant (butylated hydroxytoluene; 1% by diet) or an aldose reductase inhibitor (ARI) (sorbinil; 25 mg/kg/day p.o.) and the sorbinil treatment was associated with significant inhibition of polyol pathway intermediates in both lens and sciatic nerve. This suggests that polyol pathway activity in the lens may translate to oxidative stress-driving stimulation of NGF gene expression in the iris. The change is selective for NGF, because expression of the analogous neurotrophin, neurotrophin-3 (NT-3), was unaltered in the same irises. These changes suggest that oxidative stress and/or inflammation can drive up NGF expression in diabetes—a mechanism that might participate in iritis.     

Cardiovascular and respiratory changes during acute pulmonary edema produced by nephrotoxic serum in the rat

The intravenous injection of rabbit anti-rat kidney serum in rats produces, with a latency of 30 to 60 seconds, the triad sinus bradycardia (or S-A blockade), systemic hypotension and apnea. Recordings of the intracardiac pressures showed a rise in the right and a simultaneous fall in the left ventricular pressure, 30 to 60 seconds after the serum injection. These initial effects were followed by pulmonary edema and death. Bilateral vagotomy prevented the bradycardia and apnea, but not the intracardiac changes, edema and death. Atropine also prevented the bradycardia, but not the apnea, edema and death. Experiments using alpha and beta adrenergic blocking agents seem to indicate that the edema is not caused by the release of catecholamines. It is suggested that the edema could be explained by a rise in the pulmonary capillary pressure, due to the antigen-antibody reaction. The triad bradycardia, systemic hypotension and apnea seems to be the first sign of the pulmonary edema, is reflex in nature, and is assumed to be due to stimulation of J receptors in the lungs, by a mechanical effect (edema). Phenylbutazone and acetylsalicylic acid give a partial protection against the pulmonary edema. Ultramorphological observations of lungs with edema were described.     

A Decline in C6 Antibody Titer Occurs in Successfully Treated Patients with Culture-Confirmed Early Localized or Early Disseminated Lyme Borreliosis

C₆, a Borrelia burgdorferi-derived peptide, is used as the antigen in the C₆-Lyme disease diagnostic test. We assessed retrospectively whether a fourfold decrease or a decrease to a negative value in anti-C₆ antibody titer is positively correlated with a positive response to treatment in a sample of culture-confirmed patients with either early localized (single erythema migrans [EM]; n = 93) or early disseminated (multiple EM; n = 27) disease. All of these patients had been treated with antibiotics and were free of disease within 6 to 12 months of follow-up. Results show that a serum specimen taken at this time was either C₆ negative or had a ≥4-fold decrease in C₆ antibody titer with respect to a specimen taken at baseline (or during the early convalescent period if the baseline specimen was C₆ negative) for all of the multiple-EM patients (P < 0.0001) and in 89% of the single-EM patients (P < 0.0001). These results indicate that a decline in anti-C₆ antibody titer coincides with effective antimicrobial therapy in patients with early localized or early disseminated Lyme borreliosis.     

Granulocyte precursors are the principal cells in bone marrow that stimulate allospecific cytolytic T-lymphocyte responses.

Mouse bone marrow cells were fractionated and enriched for functional activity as stimulators of allospecific cytolytic T-lymphocyte (CTL) responses in vitro. The relevant stimulator cells were enriched sequentially in the low-density fraction of bone marrow, its 2-hr adherent and 18-hr non-adherent fractions and in the FcR-negative fraction of 18-hr non-adherent cells. The functionally enriched cell population contained over 90% granulocyte precursors by ultrastructural analysis. The results indicate that granulocyte precursors are the principal cells in bone marrow that stimulate alloreactive T-cell responses.     

The 4p- syndrome—An autopsy study

The autopsy of an infant with the 4p- or Wolf-Hirschhorn syndrome revealed visceral abnormalities not previously described, i.e., agenesis of the gallbladder and spleen. The parent's chromosomes were normal.