Travel medicine resources for Canadian practitioners.

OBJECTIVE: To provide travel medicine practitioners with a comprehensive (though not exhaustive) list of resources. Resources that appear to be most frequently used by health professionals currently practising this specialty have been included. METHODS: Select members of TravelMed, an international e-mail discussion forum for travel medicine practitioners were informally canvassed and presented with a question regarding which travel medicine resources they find to be most useful. Their responses informed the development of this Statement. In addition, the opinions of experts in travel medicine were solicited to identify resources. The scope was international; however, particular attention was given to Canadian sources of information. RESULTS: Travel medicine resources are listed and organized into the following categories: Courses, conferences and local travel medicine groups; Books; Canadian recommendations; Handbooks; periodicals and reports; Journals; Internet medicine forums; Online subscription services; Outbreak reports and travel advisories; Sources of malaria recommendations; More useful websites; Travel medicine clinics in Canada and abroad; and Certification. CONCLUSION: There are many Canadian and international resources available to inform Canadian travel medicine practitioners.

Summary of recommendations on malaria issues in special hosts.

BACKGROUND: On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill. OBJECTIVE: To provide guidelines on malaria issues related to special hosts. METHODS: CATMAT reviewed all major sources of information on malaria prevention, as well as recent research and national and international epidemiological data, to tailor guidelines to the Canadian context. The evidence-based medicine recommendations were developed with associated rating scales for the strength and quality of the evidence. RECOMMENDATIONS: All people visiting malaria endemic regions should use effective personal protective measures (PPM; topical repellants, bed nets, behavioural choices) and the prescribed chemoprophylaxis. Chemoprophylaxis for pregnant and breastfeeding women and for children requires careful consideration in the context of the pregnancy trimester, the age or size of the infant/child as well as their glucose-6-phosphate dehydrogenase (G6PD) status. Recommendations for long-term travellers, expatriates and people visiting friends and relatives (VFRs) do not differ markedly from those for short-term travellers. Some underlying medical conditions may make individuals more vulnerable to malaria. In addition, some conditions or their treatment may preclude the use of one or more antimalarial medications.

Summary of recommendations for the prevention of malaria by the Committee to Advise on Tropical Medicine and Travel (CATMAT).

BACKGROUND: On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill. OBJECTIVE: To provide guidelines on risk assessment and prevention of malaria. METHODS: CATMAT reviewed all major sources of information on malaria prevention, as well as recent research and national and international epidemiological data, to tailor guidelines to the Canadian context. The evidence-based medicine recommendations were developed with associated rating scales for the strength and quality of the evidence. RECOMMENDATIONS: Used together and correctly, personal protective measures (PPM) and chemoprophylaxis very effectively protect against malaria infection. PPM include protecting accommodation areas from mosquitoes, wearing appropriate clothing, using bed nets pre-treated with insecticide and applying topical insect repellant (containing 20%-30% DEET or 20% icaridin) to exposed skin. Selecting the most appropriate chemoprophylaxis involves assessment of the traveller's itinerary to establish his/her malaria risk profile as well as potential drug resistance issues. Antimalarials available on prescription in Canada include chloroquine (or hydroxychloroquine), atovaquone-proguanil, doxycycline, mefloquine and primaquine.

Summary of recommendations for the diagnosis and treatment of malaria by the Committee to Advise on Tropical Medicine and Travel (CATMAT).

BACKGROUND: On behalf of the Public Health Agency of Canada, the Committee to Advise on Tropical Medicine and Travel (CATMAT) developed the Canadian Recommendations for the Prevention and Treatment of Malaria Among International Travellers for Canadian health care providers who are preparing patients for travel to malaria-endemic areas and treating travellers who have returned ill. These recommendations aim to achieve appropriate diagnosis and management of malaria, a disease that is still uncommon in Canada. OBJECTIVE: To provide recommendations on the appropriate diagnosis and treatment of malaria. METHODS: CATMAT reviewed all major sources of information on malaria diagnosis and treatment, as well as recent research and national and international epidemiological data, to tailor guidelines to the Canadian context. The evidence-based medicine recommendations were developed with associated rating scales for the strength and quality of the evidence. RECOMMENDATIONS: Malarial management depends on rapid identification of the disease, as well as identification of the malaria species and level of parasitemia. Microscopic identification of blood samples is both rapid and accurate but can be done only by trained laboratory technicians. Rapid diagnostic tests are widely available, are simple to use and do not require specialized laboratory equipment or training; however, they do not provide the level of parasitemia and do require verification. Polymerase chain reaction (PCR), although still limited in availability, is emerging as the gold standard for high sensitivity and specificity in identifying the species.

High-throughput cytochrome P450 (CYP) inhibition screening via a cassette probe-dosing strategy. VI. Simultaneous evaluation of inhibition potential of drugs on human hepatic isozymes CYP2A6, 3A4, 2C9, 2D6 and 2E1.

The inhibition potential of drugs towards five major human hepatic cytochrome P450 (CYP) isozymes (CYP2A6, 3A4, 2C9, 2D6, and 2E1) was investigated via cassette dosing of the five probe substrates (coumarin, midazolam, tolbutamide, dextromethorphan, and chlorzoxazone) in human liver microsomes using a 96-well plate format. After microsomal incubations had been terminated with formic acid, the five marker metabolites (7-hydroxycoumarin, 1'-hydroxymidazolam, 4-hydroxytolbutamide, dextrorphan, and 6-hydroxychlorzoxazone) were simultaneously quantified using direct injection/online guard cartridge extraction/tandem mass spectrometry (DI-GCE/MS/MS). Several advantages resulted from the use of a short C(18) guard cartridge (4 mm in length) for DI-GCE/MS/MS, including minimal sample preparation, fast online extraction, short analysis time (2.5 min), and minimal source contamination. In addition, this method demonstrated an inter-day accuracy range from -8.7 - 7.4% with a precision less than 8.3% for the quantification of all the marker metabolites. The inhibition assay for the five CYP isozymes was evaluated using their known selective inhibitors via individual and cassette dosing of the probe substrates. The IC(50) values measured via cassette dosing were consistent with those observed via individual dosing, which were all in agreement with the reported values. In addition, the validated assay was used to evaluate the inhibitory potential of 23 generic drugs (randomly selected) towards the five CYP isozymes. The results suggest the integration of the cassette dosing strategy and the DI-GCE/MS/MS method can provide a reliable in vitro approach to screening the inhibitory potential of new chemical entities, with maximal throughput and cost-effectiveness, in support of drug discovery and development.

High-throughput cytochrome P450 (CYP) inhibition screening via cassette probe-dosing strategy. II. Validation of a direct injection/on-line guard cartridge extraction-tandem mass spectrometry method for CYP2D6 inhibition assessment.

A highly efficient direct injection/on-line guard cartridge extraction-tandem mass spectrometry (DI/GCE-MS-MS) method has been validated for high-throughput evaluation of cytochrome P450 (CYP) 2D6 inhibition potential using human hepatic microsomes and 96-well microtiter plates. Microsomal incubations were terminated with formic acid, centrifuged, and the resulting supernatants were injected for DI/GCE-MS-MS analysis. Due to the novel use of an extremely short C18 guard cartridge, this method exhibits several advantages, such as no sample preparation, excellent on-line extraction, short run time (2.5 min), and minimized source contamination and performance deterioration. The DI/GCE-MS-MS method demonstrates acceptable accuracy and precision for the quantification of dextrorphan, a marker metabolite of dextromethorphan mediated by CYP2D6, in microsomal incubations. The CYP2D6 inhibition assay has been validated using quinidine as a known selective inhibitor of the isoform. The IC50 value (0.20 microM) measured by the new method is in good agreement with the literature value (0.22 microM).

High-throughput cytochrome P450 (CYP) inhibition screening via cassette probe-dosing strategy: III. Validation of a direct injection/on-line guard cartridge extraction-tandem mass spectrometry method for CYP2C19 inhibition evaluation.

A new direct injection/on-line guard cartridge extraction-tandem mass spectrometry (DI/GCE-MS-MS) method has been validated for high-throughput evaluation of cytochrome P450 (CYP) 2C19 inhibition potential using human hepatic microsomes and 96-well microtiter plates. Microsomal incubations were quenched with formic acid, centrifuged, and the resulting supernatants were injected for DI/GCE-MS-MS analysis. Due to the use of a C(18) guard cartridge (4x2.0 mm I.D.), this method exhibits several advantages such as little sample preparation, rapid on-line extraction, short analysis time (2.5 min), and minimal source contamination and performance deterioration. The DI/GCE-MS-MS method demonstrates an inter-day accuracy ranged from 0.3 to 2.4% with precision ranging from 2.0 to 3.0% for the quantification of 4-hydroxymephenytoin, a marker metabolite of S-mephenytoin mediated by CYP2C19, in microsomal incubations. The CYP2C19 inhibition assay has been validated using tranylcypromine as a known inhibitor of the isoform. The IC(50) value (43.5 microM) measured by the new method is in agreement with a reported literature value (approximately 30 microM).

High-throughput cytochrome P450 (CYP) inhibition screening via a cassette probe-dosing strategy. V. Validation of a direct injection/on-line guard cartridge extraction--tandem mass spectrometry method for CYP1A2 inhibition assessment.

An efficient direct injection/on-line guard cartridge extraction-tandem mass spectrometry (DI/GCE--MS--MS) method has been validated for high-throughput evaluation of cytochrome P450 (CYP) 1A2 inhibition potential using human hepatic microsomes and 96-well microtiter plates. Microsomal incubations were terminated with formic acid, centrifuged, and the resulting supernatants were injected for DI/GCE--MS--MS analysis. Due to the use of an extremely short C(18) guard cartridge, this method offers several advantages such as no sample preparation, excellent on-line extraction, short run time and minimal source contamination and performance deterioration. The DI/GCE--MS--MS method demonstrates acceptable accuracy and precision for the quantification of resorufin, a marker metabolite of ethoxyresorufin mediated by CYP1A2, in microsomal incubations. The inhibition potential of CYP1A2 has been evaluated using its selective inhibitors, alpha-naphthoflavone and furafylline. The IC(50) values (120 nM for alpha-naphthoflavone and 5.1 microM for furafylline) measured by the new method are in agreement with the literature values.

High-throughput cytochrome P450 inhibition screening via cassette probe-dosing strategy. IV. Validation of a direct injection on-line guard cartridge extraction/tandem mass spectrometry method for simultaneous CYP3A4, 2D6 and 2E1 inhibition assessment.

A highly efficient direct injection on-line guard cartridge extraction/tandem mass spectrometry (DI-GCE/MS/MS) method has been validated for high-throughput evaluation of cytochrome P450 (CYP) 3A4, 2D6 and 2E1 inhibition potential via cassette dosing of midazolam, dextromethorphan and chlorzoxazone using human hepatic microsomes and 96-well microtiter plates. Microsomal incubations were terminated with formic acid, centrifuged, and the resulting supernatants were injected for analysis by DI-GCE/MS/MS. Due to the novel use of an extremely short C(18) guard cartridge (4 mm in length), this method exhibits several advantages such as no sample preparation, excellent on-line extraction, short run time (2.5 min), and minimized source contamination and performance deterioration. The DI-GCE/MS/MS method demonstrates acceptable accuracy and precision for the simultaneous quantification of 1'-hydroxymidazolam, dextrorphan and 6-hydroxychlorzoxazone in microsomal incubations. The inhibition potential of CYP3A4, 2D6 and 2E1 has been evaluated using their known selective inhibitors. The IC(50) values measured by the cassette dosing approach (high-throughput) are consistent with those observed by an individual dosing regimen (conventional) and are all in good agreement with the literature values. The results suggest that the cassette probe-dosing strategy may provide an in vitro approach to minimize cost while maximizing throughput of CYP inhibition evaluation of new chemical entities in support of drug discovery and development.

High-throughput cytochrome P450 (CYP) inhibition screening via cassette probe-dosing strategy. I. Development of direct injection/on-line guard cartridge extraction/tandem mass spectrometry for the simultaneous detection of CYP probe substrates and their metabolites.

A highly efficient direct injection/on-line guard cartridge extraction/tandem mass spectrometry (DI-GCE/MS/MS) method utilizing electrospray polarity switching was developed for the simultaneous detection of probe substrates and marker metabolites of seven human hepatic cytochrome P450 (CYP) isozymes: CYP1A2, 2A6, 3A4, 2C9, 2C19, 2D6 and 2E1. Microsomal incubations were terminated with formic acid, centrifuged, and the resulting supernatants were injected for analysis by DI-GCE/MS/MS. This method employed an extremely short C(18) cartridge (4 mm in length) which allowed rapid cleanup of sample matrices while retaining the analytes an appropriate time (2. 0-2.2 min). From 1.5 to 2.7 min the effluent was directed to the mass spectrometer for detection otherwise diverted to waste. As a result of the efficient on-line extraction, matrix (e.g., salts and proteins) suppression was minimized. In addition, no visible source contamination was observed and system performance (chromatographic and mass spectrometric) did not significantly deteriorate after 500 consecutive injections. Electrospray polarity switching was strategically executed on a Micromass Quattro II mass spectrometer by establishing dummy ion transitions to protect the analytes from the interference of the overwhelming noise which was unavoidable for the first transition scanned following each polarity switch. This unique strategy led to the simultaneous detection of seven CYP probe substrates and seven corresponding marker metabolites (12 by positive mode and 2 by negative mode).

The pharmacokinetics and safety profile of oral ganciclovir combined with zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients.

Two open-label, randomized, multiple-dose, three-way crossover studies were performed to assess the pharmacokinetics and safety of oral ganciclovir 1000 mg q8h in asymptomatic patients seropositive for human immunodeficiency virus and cytomegalovirus. Ganciclovir was administered alone and in combination with zalcitabine 0.75 mg q8h (study 1) or stavudine 40 mg q12h (study 2). In the presence of zalcitabine, the only statistically significant change in the pharmacokinetic parameters of ganciclovir was a 22.2% mean increase in AUC0-8. However, there was no significant change in the renal clearance of ganciclovir when coadministered with zalcitabine, suggesting that the increase in serum ganciclovir concentration cannot be attributed to competition for active renal tubular secretion. No change in zalcitabine pharmacokinetics was observed in combination with ganciclovir. There were no significant changes in the pharmacokinetics of ganciclovir or stavudine when coadministered. Ganciclovir was well tolerated when given alone and in combination with either zalcitabine or stavudine.

The pharmacokinetics and safety profile of oral ganciclovir in combination with trimethoprim in HIV- and CMV-seropositive patients.

AIMS: We investigated the pharmacokinetics and safety profile of oral ganciclovir coadministered with trimethoprim in HIV-and CMV-seropositive patients. METHODS: In an open-label, randomized, 3-way crossover study, 12 adult males received oral ganciclovir 1000 mg every 8h, oral trimethoprim 200 mg once daily, or both drugs concomitantly in a sequence of three 7-day treatment periods. Pharmacokinetic parameters were determined and adverse events recorded for each treatment. RESULTS: The presence of trimethoprim significantly decreased CLr (12.9%, P=0.0068) and increased t1/2 (18.1%, P=0.0378) of ganciclovir. However, these changes are unlikely to be clinically meaningful. There were no statistically significant changes in trimethoprim pharmacokinetic parameters in the presence of ganciclovir, with the exception of a 12.7% increase in Cmin. Ganciclovir was well tolerated when administered alone or in combination with trimethoprin. CONCLUSIONS: There was no clinically significant pharmacokinetic interaction between oral ganciclovir and trimethoprim when coadministered.

Movement analysis in infancy may be useful for early diagnosis of autism.

All of the 17 autistic children studied in the present paper showed disturbances of movement that with our methods could be detected clearly at the age of 4-6 months, and sometimes even at birth. We used the Eshkol-Wachman Movement Analysis System in combination with still-frame videodisc analysis to study videos obtained from parents of children who had been diagnosed as autistic by conventional methods, usually around 3 years old. The videos showed their behaviors when they were infants, long before they had been diagnosed as autistic. The movement disorders varied from child to child. Disturbances were revealed in the shape of the mouth and in some or all of the milestones of development, including, lying, righting, sitting, crawling, and walking. Our findings support the view that movement disturbances play an intrinsic part in the phenomenon of autism, that they are present at birth, and that they can be used to diagnose the presence of autism in the first few months of life. They indicate the need for the development of methods of therapy to be applied from the first few months of life in autism.

Verbal instructional sets to normalise the temporal and spatial gait variables in Parkinson's disease.

Gait in Parkinson's disease is characterised by slowed velocity; shuffling, small steps; and absent arm swing. Drug therapy intervention is beneficial in improving mobility, though with prolonged use its effects may diminish. The purpose of this study was to examine whether Parkinsonian patients could improve their gait patterns in response to five instructional sets: natural walking; walking while deliberately swinging the arms; walking with large steps; fast walking; and walking while counting aloud. Eight subjects with idiopathic Parkinson's disease and eight age matched control subjects were tested using motion analysis. The findings indicated that parkinsonian patients followed the instructions which immediately altered a series of single walking variables. Simultaneously, automatically activated changes occurred in other gait variables producing more normal gait. The instructional set is a strategy which can aid normalisation of Parkinsonian gait although its benefits may depend on the stage of disease progression and the degree of attention to the instructions.

Keeping the Body Straight in the Unconstrained Locomotion of Normal and Dopamine-Stimulant-Treated Rats.

During unconstrained locomotor behavior, rats move in and out of a straight posture of the body (including the head). In the present study, the stability of maintaining a straight body was examined in untreated rats and in rats treated with saline (SAL) or with 1 of 3 dopamine stimulants (n = 4 rats per group). The stability of maintaining a straight body can range from very high (with 0.5 mg/kg quinpirole [QUIN]), to high (first half-session with 5 mg/kg (+)-amphetamine [AMPH]), to very low (second half-session with 5 mg/kg AMPH), or can be maintained at a level similar to that observed in untreated rats (with 1.25mg/kg apomorphine [APO]). Stability was assessed by videotaping the rats and, then, by using frame-by-frame analysis, scoring the cumulative proportion of time spent in a straight posture, the frequency of transitions from one hemisphere to the other without being trapped in the midline plane, and the degree of lateral bending during turning and during walking on a curved path. The present study is one in a series identifying key variables that constrain as many degrees of freedom as possible in rat locomotor behavior. The uncovering of such variables is an indispensible step that precedes dynamic systems stability analysis and provides candidates for key variables for the modeling of motor coordination.

Compound complementarities in the study of motivated behavior.

In his classic article, Stellar (1954) proposed that diverse motivated behaviors reflected the activity of excitatory and inhibitory centers in the hypothalamus. His specific and testable ideas provided the theoretical focus for a great deal of fruitful research on the biological bases of behavior for 2 decades. Subsequently, new findings and technical developments again changed the perspective and experimental approaches in behavioral neuroscience. The authors suggest that the modern emphasis on the anatomy and chemical function of neuronal systems has come at the expense of understanding the subcomponents of behavior and the hierarchical levels of integration involved in transforming reflexes into operant acts. Increased attention in the future to the infrastructure of the behaviors being elucidated, when combined with reductionistic studies of neurons, will fulfill the potential contribution to behavioral neuroscience that is implicit in Stellar's article.

Haloperidol exaggerates proprioceptive-tactile support reflexes and diminishes vestibular dominance over them.

Rats made immobile and cataleptic by haloperidol, a dopamine receptor blocker, maintain their static stable equilibrium by employing a variety of allied postural support reflexes. Under some test conditions, competition between such reflexes occurs, and in haloperidol-treated rats, unlike undrugged controls, proprioceptive-tactile stimuli appear to be dominant over vestibular stimuli. We investigated this relationship in rats by testing their air-righting with and without simultaneous contact of the tail on a wooden platform. The rats were lightly held in a supine position by the shoulders and pelvis, with or without tail contact on a small wooden platform 47 cm above the ground. Undrugged rats showed the normal pattern of righting which involves axial rotation with cephalocaudal recruitment whether the tail is contacting the platform or not. Upon release, the haloperidol-treated rats (2.5 mg/kg) gripped the platform with their tail, which interfered with the air-righting reflex. This demonstrates that in haloperidol-treated rats, the dominance of tactile-proprioceptive postural support reflexes over those triggered vestibularly.

Single and multiple dose pharmacokinetics of ticlopidine in young and elderly subjects.

The pharmacokinetics of orally administered ticlopidine hydrochloride, a novel inhibitor of platelet aggregation, were determined both after a single dose and after 21 days of twice daily dosing in 12 young (mean 28.6 years) and 13 elderly (mean 69.5 years) subjects. Concentrations of unchanged ticlopidine in plasma were measured by g.l.c. After a single 250 mg dose of ticlopidine, the mean area under the curve, AUC (0-12 h) was 1.11 micrograms ml-1 h in young subjects and 2.04 micrograms ml-1 h in old subjects (P = 0.002). Mean values of t1/2,z in young and elderly subjects were 7.9 h and 12.6 h, respectively (P = 0.01). Steady state plasma drug concentrations were attained after 14 days of dosing with ticlopidine. After the final dose on day 21, AUC values in elderly subjects were 2-3 times those in young subjects (P less than 0.001). The plasma t1/2,z averaged 4.0 days for young subjects and 3.8 days for elderly subjects (P = 0.7). The longer t1/2,z and higher AUC values after multiple dosing probably reflect an increase in bioavailability of ticlopidine after repeated dosing, saturation of metabolism or insufficient analytical sensitivity to characterize the terminal elimination phase after single dose.

Labyrinthine and other supraspinal inhibitory controls over head-and-body ventroflexion.

The vestibular head righting reflex can be demonstrated by holding an adult rat vertically downward, so that the snout points downward. In this situation, the animal dorsiflexes its head and neck, bringing the head towards its normal orientation in space. Bilateral labyrinthectomy not only blocks this response, but releases an actively maintained ventroflexion of the head and neck. Bilateral electrolytic lesions of the lateral hypothalamus (LH) exaggerate such ventroflexion in labyrinthectomized rats. By themselves, LH lesions had no such effect. Therefore, it is argued that there are vestibular and supraspinal inhibitory mechanisms which, in the intact adult animal, keep this ventroflexion response in check. In addition, when the rats were held with their heads down, and with gentle paw contact with the ground, they did not ventroflex. However, they ventroflexed immediately upon releasing this paw contact. These observations suggest that there are tactile mechanisms which can also inhibit this exaggerated ventroflexion released by labyrinthectomy.