In vitro and in vivo evaluation of three metronidazole topical products.

Two 1% and one 0.75% metronidazole cream products were approved as bioequivalent products. These products were evaluated for their in vivo cutaneous penetration characteristics by dermatopharmacokinetic (DPK) and dermal microdialysis (DMD) sampling methodologies. The same three products were also evaluated for their rheological and in vitro drug release (IVR) properties. Structural differences were observed in the resulting flow curves. However, similar IVR profiles were obtained for the two topical semisolid dosage forms containing 1% metronidazole. For the lower strength product, a higher IVR rate was associated with the lower DPK profile. All three products exhibited similar values of area under the curve when investigated by DMD. This in vitro evaluation corroborated the divergent penetration characteristics found using in vivo methodologies.

Pharmacokinetics and pharmacodynamics of some oximes and associated therapeutic consequences: a critical review.

Undoubtedly, the use of oximes represents real progress in counteracting intoxications with organophosphates (OP), through potentiating antidotal effects of atropine. The penetration extent of these compounds through the blood-brain barrier (BBB) to significantly reactivate phosphorylated or phosphonylated acetylcholinesterase (AChE) in the brain still remains a debatable issue. Penetration of biological barriers by oximes was investigated mainly through determination of several quantitative parameters characterizing digestive absorption and BBB penetration. A weak penetration of biological barriers could be concluded from the available experimental data. The functional parameters/therapeutic effects following the penetration of oximes through BBB, more precisely the antagonism of OP-induced seizures and hypothermia, prevention of brain damage and respiratory center protection, leading to the final end-point, the survival of intoxicated organisms, are of high interest. It seems obvious that oximes are weakly penetrating the BBB, with minimal brain AChE reactivation (<5%) in important functional areas, such as the ponto-medullar. The cerebral protection achieved through administration of oximes is only partial, without major impact on the antagonism of OP-induced seizures, hypothermia and respiratory center inhibition. The antidotal effects probably result from synergic effects of other PD properties, different from the brain AChE reactivation process. Oxime structures especially designed for enhanced BBB penetration, through potentiating the hydrophobic characteristics, more often produce neurotoxic effects. Certainly, obtaining oximes with broad action spectrum (active against all OP types) would make a sense, but certainly, such a target is not achievable only through the increase in their penetrability in the brain.

Commonality between BCS and TCS.

Both biopharmaceutics classification system (BCS) and topical drug classification system (TCS) are based on sound scientific principles with the aim of providing biowaiver and reducing regulatory burden without lowering the quality requirements and standards of approval for the drug products. BCS is based on the solubility and permeability properties of the active pharmaceutical ingredient (API, or drug substance) whereas the TCS is based on the qualitative and quantitative composition of the dosage form and the in vitro release rate of the active ingredient as key decision tools. Both BCS and TCS take drug release and dissolution as their guiding principle for providing biowaiver, increasing the availability and affordability of safe and effective medicines to the consumers and at the same time maintaining the drug product quality.

Relationships between the antidotal efficacy and structure, PK/PD parameters and bio-relevant molecular descriptors of AChE reactivating oximes: inclusion and integration to biopharmaceutical classification systems.

INTRODUCTION: The therapeutic outcome of oximes used as reactivators of phosphorylated human acetylcholinesterase (AChE) is influenced, among other factors, by their biological distribution, their in vivo ability to achieve the nucleophilic attack and their affinity for the anionic center of the intact/inhibited AChE. AREAS COVERED: An in silico evaluation of the molecular descriptors and biopharmaceutical properties of 454 set of oximes has been achieved. The available pharmacokinetic (PK) data was analyzed, in an attempt to illustrate their common characteristics and particularities. Based on the observed high water solubility and low permeability across biological barriers, we applied the officially adopted classification systems based on biopharmaceutical properties to identify the existing biopharmaceutical differences between the various oxime entities and to predict their in vivo fate. EXPERT OPINION: The structural differences of the organophosphorus compounds (OP) and the available oximes reactivators of OP-inhibited AChE generate distinct toxicokinetic or PK profiles. The tissue compartment specific distribution is one of the key elements for assessment of reactivating efficiency. The distribution through highly specialized barriers, such as blood-brain barrier remains a considerable challenge. The high solubility - low permeability biopharmaceutical profile of oximes can be used to suggest the possible involvement of active transport systems.

A science based approach to topical drug classification system (TCS).

The Biopharmaceutics Classification System (BCS) for oral immediate release solid drug products has been very successful; its implementation in drug industry and regulatory approval has shown significant progress. This has been the case primarily because BCS was developed using sound scientific judgment. Following the success of BCS, we have considered the topical drug products for similar classification system based on sound scientific principles. In USA, most of the generic topical drug products have qualitatively (Q1) and quantitatively (Q2) same excipients as the reference listed drug (RLD). The applications of in vitro release (IVR) and in vitro characterization are considered for a range of dosage forms (suspensions, creams, ointments and gels) of differing strengths. We advance a Topical Drug Classification System (TCS) based on a consideration of Q1, Q2 as well as the arrangement of matter and microstructure of topical formulations (Q3). Four distinct classes are presented for the various scenarios that may arise and depending on whether biowaiver can be granted or not.

Toxicological considerations of acetylcholinesterase reactivators.

INTRODUCTION: The more or less systematic studies on the specific activity of oximes as reactivators of acetylcholinesterase (AChE) inhibited by organophosphorus (OP) compounds provide a panoramic image of their pharmacological and toxicological profiles. Established structure-activity relationships are still unable to adequately predict their antidotal efficacy. However, the in vivo behavior of oximes is a direct consequence of their physico-chemical properties, considerably limiting the passive transport across the biological barriers. AREAS COVERED: This paper discusses the efficacy of oximes from a biokinetic perspective. The non-homogenous distribution of oximes versus OP in tissues was considered and correlated with the highly variable AChE reactivation at both peripheral and central levels. The acute toxicity and formation of highly toxic phosphylated oximes are presented as possible sources for reduced therapeutic efficacy. EXPERT OPINION: Biokinetic of oximes is 'structure dependent', with variable, tissue-specific distribution and activity. The existing knowledge does not allow to state true limits for a minimum extent of AChE reactivation in different tissues granting the survival of intoxicated organisms. An increased penetration of biological barriers is not automatically equivalent to a high extent of reactivation or antidotal efficacy and most probably, induces significant risks because of the intrinsic toxicity of the oxime.

Drug-induced hypo- and hyperprolactinemia: mechanisms, clinical and therapeutic consequences.

INTRODUCTION: The altered profiles of prolactin secretion in the anterior hypophysis, generated by pathological, pharmacological or toxicological causes, have special consequences on multiple functions in both genders. AREAS COVERED: This selective review presents the main mechanisms controlling prolactin secretion, focusing on the interplay of various neurotransmitters or xenobiotics, but also on the role of psychic or posttraumatic stress. A detailed analysis of several pharmacotherapeutic groups with hyperprolactinemic effects emphasize on the relevance of the pharmacokinetic/pharmacodynamic mechanisms and the clinical significance of the long term administration. EXPERT OPINION: Accurate monitoring and evaluation of the hyperprolactinemia induced by xenobiotics is strongly recommended. The typical antipsychotics and some of the atypical agents (amisulpride, risperidone, paliperidone), as well as some antidepressants, antihypertensives and prokinetics, are the most important groups inducing hyperprolactinemia. The hyperprolactinemic effects are correlated with their affinity for dopamine D2 receptors, their blood-brain barrier penetration and, implicitly, the requested dose for adequate occupancy of cerebral D2 receptors. Consequently, integration of available pharmacokinetic and pharmacodynamic data supports the idea of therapeutic switch to non-hyperprolactinemic agents (especially aripiprazole) or their association, for an optimal management of antipsychotic-induced hyperprolactinemia. Possible alternative strategies for counteracting the xenobiotics-induced hyperprolactinemia are also mentioned.

New insights on the consequences of biotransformation processes on the distribution and pharmacodynamic profiles of some neuropsychotropic drugs.

The metabolic processes frequently trigger highly complex pharmacokinetic (PK) and pharmacodynamic (PD) characteristics for the coexisting entities, parent drug and its active or inactive metabolites. The interpretation of both individual and cumulative profiles, frequently used in the therapeutic drug monitoring procedures, must take into consideration the biological coherence of the changes of the molecular descriptors characterizing the metabolites versus the parent drugs, and further qualitative and quantitative consequences on permeability processes across highly specialized biological barriers (e.g. blood-brain barrier [BBB]). This paper analyzes the correlation of molecular descriptor differences and the PK/PD consequences for three representative psychotropic drugs (risperidone, clozapine and tramadol) and their active metabolites, underlying the safety and efficacy concerns of using the products of metabolic processes as potential new drugs. The minimal structural changes are correlated with the predicted or experimental penetrability across the biological membranes, with a special emphasis on BBB penetration, as the limiting phase for the effect at central nervous system level. The PD characteristics related to the active metabolites are compared to the ones reported for the parent drugs, concerning mainly the affinity for cerebral receptors and the type of activity at a specific level. For the neuropsychotropic substances, with BBB penetrability as a sine qua non condition, the comparative analysis of PK/PD properties for the parent drug and its metabolites generates a complete and highly complex image of the consequences of their coexistence, since these entities must be conceived and analyzed not separately, but by inclusion of usually complementary properties generating a unique therapeutic profile.

The toxicokinetics and toxicodynamics of organophosphonates versus the pharmacokinetics and pharmacodynamics of oxime antidotes: biological consequences.

This paper presents basic data on organophosphonate (OP) mechanisms of action, especially by toxicokinetic/toxicodynamic (TK/TD) process correlations. It is generally accepted that at least during onset of OP biological systems interaction, blood and tissue cholinesterase's inhibition represents OP exposure marker and initiating mechanisms for toxicodynamic effects, characteristic for cholinergic crisis. OP penetrability of various biological barriers conditioning TK characteristics are determined by a series of physico-chemical properties. Non-cholinergic effects, direct interactions with cellular structures and subsequent effects (excitotoxicity) triggered by cholinergic crisis are also briefly presented. Opposed to these OP TK/TD characteristics, the authors analysed the pharmacokinetic/pharmacodynamic (PK/PD) characteristics and their correlations for oximes, as basic OP antidotes, besides atropine and anticonvulsants. Phosphorilated cholinesterasis reactivators are mono or bispyridinium derivatives with quaternary ammonium atoms, high water solubility, ionized at physiological pH, distribution in extra-cellular space, very low digestive absorption and blood-brain barrier (BBB) penetrability. OP nerve gas acute toxicity is correlated with anti-acetylcholinesterase (AChE) activity and partition coefficient. The toxicity rank seems to be determined by lipophilicity, besides their specific AChE inhibitory property. It has the effect that acute toxicity is the resultant of a TD process closely linked and dependent in vivo upon molecular descriptors determinant for the TK process. For cholinesterasis reactivators, molecular and PK characteristics limit their effects, especially to the peripheral level. The absent or much reduced BBB penetrability allowed some researchers to suggest that reactivators' penetration and presence at central level are not necessary. The study of PK/PD correlations, molecular descriptors and biological membrane permeability of oximes can better define their antidotal effects mechanisms and, maybe, open a new perspective for field development.