Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from the pharmaceutical industry and regulatory agencies as a means to provide a consistent supply of medicines. Crystallisation is a key operation in the isolation of the majority of pharmaceuticals and has been demonstrated in a continuous manner on a number of compounds using a range of processing technologies and scales. Whilst basic design principles for crystallisations and continuous processes are known, applying these in the context of rapid pharmaceutical process development with the associated constraints of speed to market and limited material availability is challenging. A systematic approach for continuous crystallisation process design is required to avoid the risk that decisions made on one aspect of the process conspire to make a later development step or steps, either for crystallisation or another unit operation, more difficult. In response to this industry challenge, an innovative system-wide approach to decision making has been developed to support rapid, systematic, and efficient continuous seeded cooling crystallisation process design. For continuous crystallisation, the goal is to develop and operate a robust, consistent process with tight control of particle attributes. Here, an innovative system-based workflow is presented that addresses this challenge. The aim, methodology, key decisions and output at each at stage are defined and a case study is presented demonstrating the successful application of the workflow for the rapid design of processes to produce kilo quantities of product with distinct, specified attributes suited to the pharmaceutical development environment. This work concludes with a vision for future applications of workflows in continuous manufacturing development to achieve rapid performance based design of pharmaceuticals

Motor neuron disease and its association with non-Hodgkin's lymphoma

[No abstract available

Reflex epilepsy

Reflex seizures refer to epileptic seizures evoked by a specific external stimulus or internal mental process or by activity of the patient. Approximately 5% of all seizures are reflex epilepsy. The most common precipitants are visual. A variety of somatosensory phenomena including thinking, reading, listening to music, and eating may also induce reflex seizures. In this review, the most common reflex epilepsies are discussed. © 2011 - IOS Press and the authors

Paraneoplastic muscle and neuromuscular junction diseases [Paraneoplastik kas ve nöromusküler kavşak hastaliklari]

Weakness, sensory loss, and paresthesias are common nonspecific symptoms, but can be important indicators of neurologic disorders associated with malignancy, referred to as paraneoplastic disorders. Paraneoplastic syndromes are defined as clinical syndromes involving nonmetastatic systemic effects that accompany malignant disease. In a broad sense, these syndromes are collections of symptoms that result from substances produced by the tumor, and they occur remotely from the tumor itself. Loosely defined, these may include nonspecific systemic effects such as fever, infections, metabolic abnormalities, and so forth. Additionally, several specific neurological disorders are recognized as the remote effects of a neoplasm. Recognition of these conditions is important because they may be the presenting feature of an occult malignancy. Currently, the mechanisms of how cancers affect distant sites are not understood precisely. Neurologic paraneoplastic syndromes are believed to occur when cancer-fighting antibodies or white blood cells known as T cells mistakenly attack normâl cells in the nervous system. When a tumor arises, the body may produce antibodies to fight it by binding to and destroying tumor cells. Unfortunately, in some cases, these antibodies cross-react with normâl tissues and destroy them, which may stimulate the onset of paraneoplastic disorders. However, not all paraneoplastic syndromes are associated with these antibodies. These disorders typically affect middle-aged to older persons and are most common in persons with lung, ovarian, lymphatic, or breast cancer. Neurologic symptoms generally develop over a period of days to weeks and usually occur prior to tumor detection, which can complicate diagnosis. These symptoms may include difficulty in walking and/or swallowing, loss of muscle tone, loss of fine motor coordination, slurred speech, memory loss, vision problems, sleep disturbances, dementia, seizures, sensory loss in the limbs, and vertigo. In this review, it is aimed to draw attention of the reader to the rarely seen paraneoplastic muscle and neuromuscular junction diseases

Metformin-induced paroxysmal dystonia

[No abstract available

The effects of valproic acid and carbamazepine on strength-duration properties of peripheral nerve

PubMedID: 24419444Objective: To study strength-duration properties of motor and sensory axons to evaluate whether there is a change in current through the persistent sodium (Na+) channels of sensory and motor axons in peripheral nerves of epileptic patients before and after valproic acid (VPA) and carbamazepine (CBZ) treatment due to the presence of similar channels in the CNS and peripheral nervous system (PNS). Methods: This study, conducted in Baskent University Faculty of Medicine, Adana, Turkey from January 2011 to February 2012, involved 10 patients with partial epilepsy, 10 patients with primary generalized epilepsy who were not currently prescribed anticonvulsant therapy, and 10 control subjects. Using an electromyography machine, stimulus intensity was performed to produce the target (40% of maximum) compound muscle action potentials and compound sensory action potentials. The currents required for different stimulus durations, 0.05, 0.1, 0.2, 0.3, 0.5, and 1 ms, were produced. Stimulus-response curves were then constructed, and the strength-duration time constants were estimated using Weiss's formula. Results: The rheobase of motor and sensory fibres was lower in the control group than the values of patients before and after CBZ and VPA therapy. Conclusions: In the PNS of epileptic patients, CBZ and VPA therapy results in decreased axonal excitability. This method may be used in investigating the underlying pathology of peripheral nerve diseases in vivo

Vascular compression of multiple cranial nerves: The clinical syndromes

Abnormal changes such as loops, tortuosity, and ectasia in vascular structures that form vertebrobasilar system can cause mechanical vascular-compression syndromes. Neurologic symptoms might be encountered by compression of one or more of these cranial nerves. The compression of 3 nerves together has not been reported in the literature. Here, we present a patient with facial pain, vertigo, and tinnitus associated with the vascular compression of 5, 7, and 8 cranial nerves. A 52-year-old man was admitted to the clinic with complaints of pain located in the left upper part of face, with tinnitus being prominent on the left, and positional vertigo developing occasionally. The physical and neurologic examinations were normal. Cerebral magnetic resonance imaging and magnetic resonance angiography showed tortuosity in both the vertebral arteries and in the basilar artery, as well as the external compression of trigeminal 5, 7, and 8 nerve complexes by the intradural segment of the left vertebral artery. Internal acoustic channel magnetic resonance imaging revealed the compression of the 7 and 8 nerve complexes by the left basilar artery. © 2008 Lippincott Williams & Wilkins, Inc

Restless leg syndrome in the differential diagnosis of entrapment and peripheral neuropathies

Restless leg syndrome (RLS) is an abnormal sensation disorder. Defining the syndrome is difficult. It is transmitted autosomal dominant genetically, is especially prevalent in the lower limbs, and is seen in both genders. In the differential diagnosis of RLS, nocturnal leg cramps, akathisia, peripheral neuropathy, entrapment neuropathy, and vascular disease (for example, deep vein thrombosis) should be considered. A 52-year-old woman was admitted to our clinic with signs of paresthesia, she had abnormal sensation disorder in both legs and the right arm, which she had difficulty defining. She had applied to another center with the same complaints and had been evaluated as entrapment neuropathy, carpal tunnel syndrome, and/or peripheral neuropathy. Her electromyographic examination carried out by us was normal. The history, neurological examination findings, and results of standard laboratory analyses provided a diagnosis of idiopathic RLS. After the diagnosis of RLS in the proband, we questioned other family members. Her large family had 63 members, 35 males, and 28 females. Of 63 members, 17 also had an RLS diagnosis

Myasthenia gravis and psoriasis vulgaris

Myasthenia gravis is a rare autoimmune disorder in which antibodies form against acetylcholine nicotinic postsynaptic receptors at the myoneural junction. Psoriasis vulgaris is a chronic, recurring, and an inflammatory skin disease. Myasthenia gravis and psoriasis are both autoimmune diseases and correlated with specific human histocompatibility antigens. In this report, a 53-year-old woman who has myasthenia gravis accompanied with psoriasis vulgaris is presented. To conclude, this association is extremely rare and the pathogenetic etiology was thought to depend on a generalized immunological disturbance