Intrathecal drug delivery for pain management: recent advances and future developments

ABSTRACT

Introduction: Chronic pain conditions of malignant and non-malignant etiology afflict a large group of the population and pose a vast economic burden on society. Intrathecal drug therapy is a viable treatment option in such patients who have failed conservative medical measures and less invasive pain management procedures. However, the clinical growth of intrathecal therapy in managing intractable chronic pain conditions continues to face many challenges and is likely underutilized secondary to its high-complexity and lack of understanding.

Areas covered: This review will briefly discuss the history of intrathecal drug delivery systems (IDDS), cerebrospinal fluid (CSF) flow dynamics, types of IDDS, indications and patient profile suitable for this therapy, and risks and complications related to IDDS. We will also discuss challenges faced by physicians utilizing this therapy and the future changes that are needed for making this treatment modality more efficacious.

Expert opinion: IDDS offer an effective therapy for pain control in patients suffering from chronic intractable pain conditions. These devices provide a safer alternative to oral opioid medications with reduced systemic side effects. Adherence to best practices and continued clinical and basic science research is important to ensure continuing success of this therapy.     

Phytoestrogens: recent developments

Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. Based on their chemical structure, phytoestrogens can be classified into four main groups, i. e., isoflavonoids, flavonoids, stilbenes, and lignans. For each group, the chemistry, dietary sources and biotransformation of the most interesting compounds will be discussed. Since phytoestrogens are structurally very similar to the estrogen 17beta-estradiol, they may exhibit selective estrogen receptor modulating activities. Therefore, special attention will be given to the hormonal effects of various isoflavonoids, including genistein, daidzein, coumestrol and equol, several prenylated flavonoids, especially 8-prenylnaringenin, and the stilbene resveratrol. Furthermore, their non-hormonal effects will be discussed briefly. Finally, the latest developments on the potential protective properties of phytoestrogens and phytoestrogen-containing foods against hormone-dependent breast and prostate cancers and cardiovascular diseases, and as estrogen replacement therapy for postmenopausal women will be discussed.     

Cellular and molecular mechanisms driving neuropathic pain: recent advancements and challenges

Introduction: Current pharmacotherapeutics for neuropathic pain offer only symptomatic relief without treating the underlying pathophysiology. Additionally, they are associated with various dose-limiting side effects. Pain research in the past few decades has revolved around the role of oxidative-nitrosative stress, protein kinases, glial cell activation, and inflammatory signaling cascades but has failed to produce specific and effective therapies.

Areas covered: This review focuses on recent advances in cellular and molecular mechanisms of neuropathic pain that may be translated into future therapies. We discuss emerging targets such as WNT signaling mechanisms, the tetrahydrobiopterin pathway, Mrg receptors, endogenous lipid mediators, micro-RNAs and their roles in pain regulation. Recent evidence is also presented regarding genetic and epigenetic mechanisms of pain modulation.

Expert opinion: During chronic neuropathic pain, maladaptation occurs in the peripheral and central nervous systems, including a shift in microglial phenotype from a surveillance state to an activated state. Microglial activation leads to an altered expression of cell surface proteins, growth factors, and intracellular signaling molecules that contribute to development of a neuroinflammatory cascade and chronic pain sensitization. Specific targeting of these cellular and molecular mechanisms may provide the key to development of effective neuropathic pain therapies that have minimal side effects.     

Naturally-occurring xanthones: recent developments

A literature survey covering the report of naturally occurring xanthones from January 2000 to December 2004, with 219 references, is presented in this review. Among 515 xanthones reported in this period, 278 were new natural xanthones. These xanthones have been identified from 20 families of higher plants (122 species in 44 genera), fungi (19 species) and lichens (3 species). The structural formulas of 368 identified xanthones, their distribution and a brief mention of their biological properties are also included.     

Chloramphenicol: recent developments and clinical indications

Recent developments (including more accurate assays) that have led to revised recommendations for route of administration, dosage, and indications for chloramphenicol are reviewed. Chloramphenicol is most bioavailable by the oral route; doses of 75 mg/kg/day provide adequate therapeutic concentrations for most clinical indications. Serum concentrations of the drug should be monitored to ensure adequate therapeutic concentrations and to avoid toxicity. This is particularly important in newborns, in patients with liver dysfunction, and in those receiving concomitant drugs that may influence free chloramphenicol concentrations. The indications for chloramphenicol therapy evaluated are: Haemophilus influenzae infections, anaerobic infections, salmonellosis, Rocky Mountain spotted fever, and eye infections. Chloramphenicol is useful in the treatment of invasive Haemophilus influenzae infections resistant to ampicillin, in selected anaerobic and ocular infections, and for rickettsioses in patients under the age of eight years. Because the rare but life-threatening complication of chloramphenicol (aplastic anemia) persists, indications for the drug's clinical use are narrowing once again with the advent of third-generation cephalosporins highly active against gram-negative bacilli including ampicillin-resistant H. influenzae. Similarly, metronidazole or clindamycin may be preferred for some anaerobic infections.     

CC-1065 and the duocarmycins: recent developments

It is accepted that neoplastic diseases are related to gene alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA based moieties. In this field, analogues of naturally occurring antitumour agents, such as CC-1065 and/or the duocarmycins, represent a new class of highly potent antineoplastic compounds, currently under investigation. CC-1065 and duocarmycins represent a class of exceptionally potent antitumour antibiotics that derive their biological effects from the reversible, stereo-electronically-controlled sequence selective alkylation of DNA. All natural compounds showed a cytotoxicity against leukaemia L1210 cell lines in the range 10 - 220pM but while CC-1065 showed a good antitumour activity in an in vivo model (optimal dose from 10 - 100 μg/g), duocarmycins showed weak antitumour activity. Despite its potency, CC-1065 cannot be used in humans due to eventual fatality. For this reason many scientists have focused their attention on this class of compounds, in order to obtain new derivatives with equal in vitro potency but a better profile in in vivo models. This effect is accompanied by dramatic changes in the morphology of hepatic mitochondria. On this basis, the recent developments on SARs for this class of compounds and their possible use as therapeutic agents are reviewed, with particular emphasis on recent patent literature and, finally, a conclusive opinion will be given on this topic.     

Behavioral pharmacology: recent developments and new trends

Pharmacology has traditionally focused on and found order in the study of drug effects on relatively isolated pieces of tissue or organ systems. Research in behavioral pharmacology has demonstrated that comparable order also exists when drugs are examined at the level of integrated behavior. Substantial progress has been made in delineating specific behavioral and environmental determinants of drug action that are objective, quantifiable and reproducible. These findings, together with those from related areas of research, promise to yield significant information about environmental and neurochemical determinants of behavior and the behavioral effects of drugs.     

Antipsychotic drugs: recent developments and novel agents

A sizeable number of new chemical entities designed to effectively treat acute and chronic schizophrenic behaviour have been disclosed in the patent literature during 1995 and 1996 and are discussed in this update. While the majority of these cases involve compounds which display high affinity for CNS dopamine receptors (particularly D2 and D4 subtypes), many others claim the ability to produce efficacy through indirect regulation of dopaminergic activity, e.g., via serotonin selective mechanisms. Still others offer the possibility of relief through interactions with less obvious receptors including neurokinin, glutamate and nicotinic systems. Many of these inventions also claim the potential for clozapine-like ‘atypical’ profiles, but with the advantage of being free from the potential for inducing blood disorders, like agranulocytosis, which could limit market exposure of a commercial product. The gradual emergence and success of new antipsychotic drugs, including risperidone, which combine potent dopamine and serotonin receptor selectivities in a single compound, demonstrate the advances possible in the pharmacotherapy of schizophrenia, but equally highlights the shortcomings (e.g., extrapyramidal side-effects [EPS] liability, ineffective treatment of refractory/non-responsive population) still to be adequately addressed.     

Aspirin and prostaglandins: some recent developments.

The results of experiments designed to test the validity of the hypothesis that the anti-inflammatory and anti-rheumatic actions of aspirin are due to the inhibition of prostaglandin synthetase activity are reviewed.     

New fecal markers: recent developments and perspectives

Fecal occult blood testing is the most widely prescribed screening test for colorectal cancer. Recent development of immunological tests has increased specificity. Fecal DNA analysis opens up a new field for early detection of this widespread neoplasia. Inflammatory bowel disease is another important area where the development of fecal markers provides an interesting alternative to the gold standard but costly and invasive endoscopic investigations with histological analysis of biopsy specimens. Fecal TNFalpha and calprotectin can now be proposed to distinguish organic from non-organic intestinal disease, so select candidates for further investigations, and to assess disease activity. Measurement of fecal elastase provides real progress in screening for exocrine pancreatic insufficiency in patients with malabsorption syndrome. The development of non-invasive fecal markers is thus of increasing interest, providing data about the entire gastrointestinal tract useful for screening and individual patient management.     

Pharmacokinetic studies of antimalarials: recent developments

Pharmacokinetic studies are essential for the development of safe and effective antimalarial treatment regimens, but there are clinical situations in which there are limited data on drug disposition. These include very young children, pregnant women, and where drug interactions may alter treatment response. New approaches such as sampling methods involving low volumes and minimal preparation such as dried blood spots, highly sensitive and specific multidrug assays, and population PK analyses which can evaluate the influence of covariates such as age, pregnancy and coadministered therapies, can generate robust data that inform treatment in the most challenging situations in the tropics.