Application of design space and quality by design methodologies combined with ultra high-performance liquid chromatography for the optimization of the sample preparation of complex pharmaceutical dosage forms.

Accurate and precise analytical measurements play a significant role in assessments and decisions that are made throughout the drug development process. Developing a robust and reliable sample preparation is essential for drug product formulations to generate consistent results guaranteeing the product quality. However, due to the complex nature of the different pharmaceutical formulations with diverse excipients, developing robust sample preparation methods can be challenging and time consuming. Ensuring sample extraction robustness of pharmaceutical dosage forms becomes increasingly important with the potential impact to patient safety, product efficacy, and business efficiency. In this work we demonstrate and evaluate potential application of Quality by Design (QbD) principles to develop and optimize a robust sample preparation method in combination with the chromatographic analytical technique for a solid pharmaceutical dosage form. Practicability and utility of a QbD approach in optimization of sample preparation of this drug product are demonstrated as the active pharmaceutical ingredient (API) used in the drug product is proven to be highly sensitive for hydrolysis during analysis. Finally, the ultra-high-performance liquid chromatography method with UV detection that was applied during the design of experiments (DoE) was validated as per regulatory requirements. This systematic approach in analytics could provide guidance for the pharmaceutical industry in the development of robust sample preparation methods for different pharmaceutical dosage forms thus significantly reduce risks associated with the method transfers at clinical and commercial manufacturing sites.

Foodborne zoonotic trematode infections in Yen Bai, Vietnam: a situational analysis on knowledge, attitude, and practice (KAP) and risk behaviors.

Introduction: Foodborne Zoonotic Trematode Infections (FZTi) are neglected tropical diseases of public health concern in Vietnam. The transmission of FZTi is linked to human behavior patterns. The aims to investigate the knowledge, attitude, and practices regarding FZTi among local people. Methods: A cross-sectional study was conducted using a mixed method, which included a baseline survey and in-depth interviews. 375 participants were interviewed face-to-face in the survey, and 27 participants had the in-depth interviews. Results: The results showed that 36.3% passed the knowledge assessment, 86.7% passed the attitude assessment, and 24% passed the practical assessment. There were differences in average knowledge scores among gender (men higher than women, p = 0.006), ethnicities (Kinh higher than Dao and Tay, p < 0.001), and educational level (higher education, higher knowledge score, p < 0.001). There were differences in the frequency of eating raw fish between men and women (men higher than women, p < 0.001), and in the average practice score between men and women (women higher than men, p = 0.028). Eating raw fish and/or undercooked fish, raw vegetables, and drinking untreated water from Thac Ba lake in Yen Bai province were identified as FZTi risk behaviors. The occurrence of these risky habits can be explained by the lack of knowledge on FZTi, poor economic conditions and typical social features of local people. Conclusion: The current knowledge of local people in regard to safe eating practices is poor. They keep performing unsafe practices, which lead to infection with FZTi; therefore, an integrated control of FZTi is essential.

OnabotulinumtoxinA in Migraine and Other Headaches: Review and Update.

PURPOSE OF THE REVIEW: The role of onabotulinumtoxinA in headache management was serendipitously found over a decade ago and approved for chronic migraine in 2010 based on pivotal studies. The purpose of this review is to highlight the impact on headache and other health parameters which is critically reviewed, as well as the putative mechanisms of action. RECENT FINDINGS: OnabotulinumtoxinA is effective in migraine, not only headache frequency and pain intensity but also other health parameters including quality of life. Tolerability is high and benefit/cost analysis is favorable. It should be considered off-label in refractory trigeminal neuralgia and post-herpetic neuralgia but further research in these areas. Ongoing investigation of onabotulinumtoxinA in cluster headache is too preliminary for recommendation of use but promising. Recent and future developments in other headache disorders are discussed. OnabotulinumtoxinA has been approved for migraine almost a decade ago and been proven beneficial not only on headache parameters but other health outcomes. Its role as adjuvant is being studied and emerging in other headache syndromes.

Neck-Tongue syndrome: A systematic review.

Objective Neck-Tongue syndrome (NTS) is characterized by brief attacks of neck or occipital pain, or both, brought out by abrupt head turning and accompanied by ipsilateral tongue symptoms. As the disorder is rare, we undertook a systematic review of the literature to identify all reported cases in order to phenotype clinically the disorder and subsequently inform clinical diagnostic criteria. Methods Two electronic databases were searched using the search term "neck tongue syndrome". All English language references were reviewed in full. Cases were abstracted using a standardized abstraction form and the references of the retrieved articles were reviewed by hand to identify additional references and cases. Conference proceedings from recent headache meetings were searched. We also report six new cases from our centers. Results There were 39 primary cases, 56% of which were female. Mean age (SD) at onset was 16 (12) years. Twenty (53%) experienced neck pain, seven (18%) occipital pain, and 11 (29%) both. Pain was most often sharp or stabbing and severe, lasting several seconds to several minutes. Eleven experienced numbness and/or tingling in the neck/occiput following the pain. Thirty-six had an accompanying tongue sensory disturbance and three a motor/posture disturbance; five had both. Thirteen had other headaches, and four a family history of Neck-Tongue syndrome. Conclusions Neck-Tongue syndrome typically has pediatric or adolescent onset, suggesting that ligamentous laxity during growth and development may facilitate transient subluxation of the lateral atlantoaxial joint with sudden head turning. Familial cases suggest a genetic predisposition in some individuals. Neck-Tongue syndrome should be re-instated in the International Classification of Headache Disorders.

Treatment of headache following triptan failure after successful triptan therapy.

OPINION STATEMENT: Triptans should remain the first choice in migraine abortive treatment. They are not always effective or adequate for specific patients. Before declaring a triptan in appropriate for a given patient, the provider ought to be analytical about the rationale and especially the use of objective efficacy outcome measures and ensure that treatment is prescribed and used appropriately. Other ergot derivatives, especially dihydroergotamine, may on one hand share common contraindications of triptans but on the other hand can be quite effective where triptans failed. Non-steroids are simple, readily available, and overall safe, and evidence for their efficacy in migraine is plentiful. Opioid analgesics are blatantly overprescribed especially in non-complicated migraine patients. These should be used with great care and restraint and closely monitored. Frequent opioid usage often leads to tolerance, dependence, and medication overuse headache. Neurostimulation is gaining momentum in the armamentarium of migraine management but at the present time remains primarily focused on prophylaxis, yet abortive use is expected to grow.

Pharmacotherapy of tension-type headache (TTH).

BACKGROUND: Tension-type headache (TTH) is a highly prevalent condition, yet it requires less medical attention than migraine, mostly because the pain and disability burden are milder. METHODS: Proper diagnosis is a paramount step in therapeutic adequacy. It comes from careful history, thorough physical examination and use of ancillary investigations when appropriate to rule out underlying causes of secondary headaches that could mimic TTH, as there is no biological marker for the condition. RESULTS: Research in TTH is insufficient. Thus, pathophysiologic understanding and therapeutic innovations are lagging. In that context, the clinicians should not be surprised by the paucity of pharmacotherapeutic options. CONCLUSION: In this article, we review the existing literature on medications and make practical recommendations based on the evidence of their efficacy. We review both abortive and prophylactic medications (such as tricyclic antidepressants and non-steroidal anti-inflammatory drugs, respectively). Both are used for chronic TTH and abortive medications only for infrequent episodic TTH (ETTH). As far as frequent ETTH, abortive medications are used and prophylactic medications often but not systematically. We comment and advise on general therapeutic principles of TTH management.

Update on the therapy of the trigeminal autonomic cephalalgias.

The treatment of trigeminal autonomic cephalalgias requires very careful attention to clinical aspects. It is important to spend enough time assessing the patient to arrive at an accurate diagnosis. Identifying trigger factors (eg, alcohol), when applicable, is part of the therapy, as behavior modifications may be necessary. Cluster headache treatment should never be delayed; patients should be able to visit the clinic within 48 hours to expedite medication initiation. Abortive therapy typically is best achieved with nasal oxygen, sumatriptan injections, or both. Typically, a steroid taper is begun and will be continued for a few days. A prophylactic agent such as verapamil or topiramate also is initiated immediately and will be taken for a period slightly beyond the expected duration of the last cluster period before an attempt is made to taper it off. For chronic cluster headache, lithium carbonate is recommended after a few weeks if these other treatments have failed. If more than three regimens of medical therapy fail, patients should be considered for neurostimulation procedures. Paroxysmal hemicrania most often responds to indomethacin. Failure may be due to a dosage that is too low. Gastric protection should always be given, because this medication has a high rate of gastric complications. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) remain very difficult to treat. Lamotrigine is the first recommendation. Overall, one of the most crucial aspects of the management of patients with these disabling headache syndromes is patient education regarding what their disorder is and the reasoning behind the therapeutic options offered.

Future therapeutic perspectives for tension-type headache.

The therapy for tension-type headache remains insufficient, and recent advances have been scarce. Although tricyclic antidepressants are at the forefront of treatment advances, upcoming agents tentatively modifying central sensitization are promising. Botulinum toxin failed to meet expectations. This article reviews current treatments, emphasizing newer approaches. Much remains to be achieved.

Substances, relationships and the omnipresence of the body: an overview of Ashéninka ethnomedicine (Western Amazonia).

Indigenous Amazonian ethnomedicine usually relies on numerous forms of healing, exercised by both specialists and non-specialists. Such is the case among the "Asheninka del Ucayali" (Arawak from the Peru-Brazil border). This paper attempts to elicit the underlying consistencies of their manifold, often contradictory practices and statements.It draws on ethnographic data gathered between 1997 and 2000, and is essentially based on my own interviews and participant observation. Concerning some specific points these data are also compared with ethnobotanical findings, to highlight significant peculiarities of the Asheninka approach.The first question is about the nature of a "good medicine". When the Asheninka borrow botanical knowledge from another ethnic group and comment the fact, the contrast between indigenous self-assessments and objective ethnobotanical measurements points out a crucial difference: While the Western approach focuses essentially on chemical effectiveness of the plants themselves, Asheninka people pay much more attention to relational aspects.The relational dimension also involves the plants themselves, as a sort of person. The point has implications in Asheninka shamanism and herbalism. A shaman does not necessarily need to be a good botanist. His main concern is managing a network of personal relationships involving all kinds of living beings. This network is supposed to be the mainspring of illness - a belief shared by both shamans and ordinary people.However, most ordinary people have detailed herbal knowledge. In fact, this everyday herbalism amounts to an alternative explanatory model. Such a coexistence of two contrasting explanatory systems is frequent in Amazonia. Among the Asheninka, nevertheless, the underlying hierarchy is clear: the herbal, apparently more materialistic, approach is embedded in the shamanic, plainly relational, model.

Burden of tension-type headache.

Epidemiology of headache has been the subject of increased attention recently. It appears that the overall human and financial cost of headache is considerable. Moreover, when the comorbidity and indirect implications of headache are taken into account, the result can be staggering. Most of the literature has concentrated on migraine rather than other headache types such as tension-type headache. This article gathers emerging data that give an estimate of some of the aspects of the burden imparted by tension-type headache on society. It also briefly considers some of the factors that could positively influence this challenge of modern medicine.

At the crossroads between tension-type headache and fibromyalgia.

Fibromyalgia syndrome and tension-type headache have multiple clinical features in common, and pathogenic mechanisms partly overlap. Significant differences need to be recognized as well. Studying the correlations of these often comorbid conditions represents a unique opportunity to gain insight into their pathophysiology and that of other chronic pain syndromes, to increase the accuracy of their diagnosis, and to improve the therapeutic armamentarium.

Are the headache guidelines useful in therapeutic decisions for primary care physicians, general neurologists, and headache specialists?

The International Headache Society Classification of Headache Disorders has been widely accepted as the gold standard for classification of headache. Initially a research tool, this classification is now increasingly used in the daily practice of headache medicine. Accurate diagnosis is a prerequisite to planning a therapeutic approach. The three commentaries here discuss the use of this tool in the setting of primary care, general neurology, and subspecialty headache medicine. As the Section Editor, I hope these perspectives are helpful to the reader.

Pharmacoprophylaxis of tension-type headache.

Although tension-type headache typically is not as disabling as migraine, its chronic form may significantly impair patients' functional ability. The pathogenesis of tension-type headache remains largely unknown. Compared with migraine, tension-type headache is the object of much less research. For a number of years, research on headache therapy has vastly emphasized migraine. Even cluster headache, which is far less frequent than tension-type headache, has been subject to more therapeutic trials than tension-type headache. Therefore, it is not surprising that since the advent of studies (as early as 1964) on amitriptyline, which remains a pivotal treatment choice, the number of emerging treatments for this condition remains scarce, even in 2005. This emphasizes the need for renewed interest in this field. However, alternate treatment approaches, such as botulinum toxin injections, albeit controversial, have renewed hopes lately. In addition, recent progress in the understanding of tension-type headache pathophysiology, such as the role of peripheral and central sensitization, has revived interest in the field. This is a review of available, proven, or suspected prophylactic therapies for tension-type headache.

Posttraumatic Headache.

Posttraumatic headache (PTH) is divided into acute and chronic groups whose management and prognosis are clearly different. Although IHS criteria stipulate that PTH should have an onset within 2 weeks of the trauma, it has been observed that a headache linked to the trauma can start later. PTH can be clinically divided into the following groups: migraine-like headache, tension-type-like headache, cluster-like headache, cervicogenic-like headache, and others. Based on these clinical distinctions, therapy can be administered accordingly. However, the distinction is relative and numerous clinical features may be common to all. There seems to be a weak inverse relationship between the severity of the head trauma and the occurrence of a PTH, especially chronic. A holistic approach is not only useful but it is necessary for a therapeutic success. Early and aggressive treatment and empathy are essential to the patient's improvement. Prompt recognition and treatment of laceration, peripheral nociceptive sources such as cervical joint displacement, vascular factors, may diminish chronicity. Neuromodulation of pain with prophylactic agents is recommended early. Although it is less necessary for the acute PTH, it will be crucial for the chronic form and should be initiated no later than 2 months cut-off time between acute and chronic PTH. Recognition and treatment of psychiatric factors such as depression and anxiety will lessen the risk of chronicity. Analgesic rebound-withdrawal headache commonly is seen in chronic PTH. This must be corrected rapidly because it can protract the headache and render other inappropriate therapeutic measures inefficient.

Alternative therapies for tension-type headache.

Treatment of tension-type headache remains very challenging. In addition to conventional therapies, alternative methods such as physical therapy, acupuncture, and botulinum toxin have been studied. In this article, recent literature is reviewed and discussed and challenges for the evaluation of these approaches are considered. Although the clinical evidence is still incomplete, certain treatments are promising and the active ongoing research hopefully will soon yield more answers. Of note, the specific issue of psychologic therapy is dealt with elsewhere in this issue.

Cluster Headache and Cluster Variants.

Patients must be cognizant of the time course of the cluster headache periods to optimally tailor their therapy. Steroids provide the fastest onset of prophylactic effect. Once steroids are initiated, it remains difficult to wean patients off of them, and that is why it is always recommended to associate another prophylactic agent from the onset with the steroids. All triptans can be considered; however, only injectable sumatriptan and zolmitriptan have been the subject of controlled studies, and the former remains the gold standard because of its speed of action. Lithium, although not a first-line therapy, remains mainly efficacious for the chronic form of cluster headache. There does not seem a significant tendency for analgesic rebound-withdrawal headache with cluster headache compared with migraine. Scientific studies of the treatment of cluster headache are inherently difficult because of the rarity of the syndrome, the short duration of attacks, and the relatively short duration of the cluster period, along with the presence of spontaneous remissions. Moreover, still a significant proportion of the available evidence on this subject is uncontrolled. Active, rather than placebo, control individuals are recommended. As far as surgical procedures are concerned, although only recently introduced and less documented, gamma-knife radiosurgery should be preferred to the procedures associated with craniotomy, which are inherently associated with a higher complication potential risk.

Regeneration of rat sciatic nerve across a LactoSorb bioresorbable conduit with interposed short-segment nerve grafts.

OBJECT: This study was conducted to evaluate peripheral nerve regeneration through a conduit composed of a bioresorbable material (LactoSorb). METHODS: Sprague-Dawley rats weighing approximately 250 g were randomized into five groups. A 20-mm-long sciatic nerve gap was created, then it was bridged by a reverse nerve autograft (Group I), an empty silicone tube (Group II), a silicone tube containing a short (2-mm) interposed nerve segment (Group III), an empty LactoSorb conduit (Group IV), or a LactoSorb conduit containing a 2-mm interposed nerve segment (Group V). The intact sciatic nerve served as the control in each animal. At 16 weeks postoperatively, no nerve regeneration was observed through either the empty silicone tube or the empty LactoSorb conduit. There was regeneration in all animals receiving the reverse autograft as well as in all animals receiving the silicone or LactoSorb conduit containing the 2-mm interposed nerve segment. Effective regeneration was assessed based on histological, electrophysiological, and morphometric criteria. CONCLUSIONS: The results indicate that a conduit made of resorbable material will support sciatic nerve regeneration over a critical gap defect.

Magnetic resonance angiogram evidence of vasospasm in familial hemiplegic migraine.

We report a case of familial hemiplegic migraine in an 11-year-old girl who presented with coma and left hemiparesis. Magnetic resonance imaging showed reversible vasospasm and evidence of oligemia, bringing new information regarding neurovascular changes in familial hemiplegic migraine.